Biochemistry, Genetics and Molecular Biology › Genetics

Diabetes and associated disorders

Description

This cluster of papers focuses on the genetics, pathogenesis, and treatment strategies for type 1 diabetes. It covers topics such as the role of HLA genes, environmental triggers, autoimmune responses, insulin production, and the use of immunotherapy. The cluster also delves into the epidemiology and C-peptide levels associated with type 1 diabetes.

Keywords

Type 1 Diabetes; Genetics; Autoimmunity; HLA Genes; Insulin Production; Environmental Triggers; C-Peptide Levels; Immunotherapy; Islet Autoimmunity; Epidemiology

Abstract A human B lymphocyte-specific antigen (B1) was identified and characterized by the use of a monoclonal antibody. By indirect immunofluorescence, cytotoxicity, and quantitative absorption, B1 was present on approximately … Abstract A human B lymphocyte-specific antigen (B1) was identified and characterized by the use of a monoclonal antibody. By indirect immunofluorescence, cytotoxicity, and quantitative absorption, B1 was present on approximately 9% of the peripheral blood mononuclear cell fraction and >95% of B cells from blood and lymphoid organs in all individuals tested. Monocytes, resting and activated T cells, null cells, and tumors of T cell and myeloid origin were B1 negative. B1 was distinct from standard B cell phenotypic markers, including Ig and Ia antigen. Removal of the B1 positive population in peripheral blood eliminated all B cells capable or responding to pokeweed mitogen by maturation to Ig-producing cells.
Abstract The scid mutation was backcrossed ten generations onto the NOD/Lt strain background, resulting in an immunodeficient stock (NOD/LtSz-scid/scid) with multiple defects in adaptive as well as nonadaptive immunologic function. … Abstract The scid mutation was backcrossed ten generations onto the NOD/Lt strain background, resulting in an immunodeficient stock (NOD/LtSz-scid/scid) with multiple defects in adaptive as well as nonadaptive immunologic function. NOD/LtSz-scid/scid mice lack functional lymphoid cells and show little or no serum Ig with age. Although NOD/(Lt-)+/+ mice develop T cell-mediated autoimmune, insulin-dependent diabetes mellitus, NOD/LtSz-scid/scid mice are both insulitis- and diabetes-free throughout life. However, because of a high incidence of thymic lymphomas, the mean lifespan of this congenic stock is only 8.5 mo under specific pathogen-free conditions. After i.v. injection of human CEM T-lymphoblastoid cells, splenic engraftment of these cells was fourfold greater in NOD/LtSz-scid/scid mice than in C.B17/Sz-scid/scid mice. Although C.B-17Sz-scid/scid mice exhibit robust NK cell activity, this activity is markedly reduced in both NOD/(Lt-)+/+ and NOD/LtSz-scid/scid mice. Presence of a functionally less mature macrophage population in NOD/LtSz-scid/scid vs C.B-17Sz-scid/scid mice is indicated by persistence in the former of the NOD/Lt strain-specific defect in LPS-stimulated IL-1 secretion by marrow-derived macrophages. Although C.B-17Sz-scid/scid and C57BL/6Sz-scid/scid mice have elevated serum hemolytic complement activity compared with their respective +/+ controls, both NOD/(LtSz-)+/+ and NOD/LtSz-scid/scid mice lack this activity. Age-dependent increases in serum Ig levels (> 1 micrograms/ml) were observed in only 2 of 30 NOD/LtSz-scid/scid mice vs 21 of 29 C.B-17/Sz-scid/scid animals. The multiple defects in innate and adaptive immunity unique to the NOD/LtSz-scid/scid mouse provide an excellent in vivo environment for reconstitution with human hematopoietic cells.
Microbial exposures and sex hormones exert potent effects on autoimmune diseases, many of which are more prevalent in women. We demonstrate that early-life microbial exposures determine sex hormone levels and … Microbial exposures and sex hormones exert potent effects on autoimmune diseases, many of which are more prevalent in women. We demonstrate that early-life microbial exposures determine sex hormone levels and modify progression to autoimmunity in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D). Colonization by commensal microbes elevated serum testosterone and protected NOD males from T1D. Transfer of gut microbiota from adult males to immature females altered the recipient's microbiota, resulting in elevated testosterone and metabolomic changes, reduced islet inflammation and autoantibody production, and robust T1D protection. These effects were dependent on androgen receptor activity. Thus, the commensal microbial community alters sex hormone levels and regulates autoimmune disease fate in individuals with high genetic risk.
Patients with diabetes mellitus (DM) have infections more often than those without DM. The course of the infections is also more complicated in this patient group. One of the possible … Patients with diabetes mellitus (DM) have infections more often than those without DM. The course of the infections is also more complicated in this patient group. One of the possible causes of this increased prevalence of infections is defects in immunity. Besides some decreased cellular responses in vitro, no disturbances in adaptive immunity in diabetic patients have been described. Different disturbances (low complement factor 4, decreased cytokine response after stimulation) in humoral innate immunity have been described in diabetic patients. However, the clinical relevance of these findings is not clear. Concerning cellular innate immunity most studies show decreased functions (chemotaxis, phagocytosis, killing) of diabetic polymorphonuclear cells and diabetic monocytes/macrophages compared to cells of controls. In general, a better regulation of the DM leads to an improvement of these cellular functions. Furthermore, some microorganisms become more virulent in a high glucose environment. Another mechanism which can lead to the increased prevalence of infections in diabetic patients is an increased adherence of microorganisms to diabetic compared to nondiabetic cells. This has been described for Candida albicans. Possibly the carbohydrate composition of the receptor plays a role in this phenomenon.
Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression … Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression temporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibody against CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease.
Importance-Type 1 diabetes usually has a preclinical phase identified by circulating islet autoantibodies, but the rate of progression to diabetes after seroconversion to islet autoantibodies is uncertain.Objective-To determine the rate … Importance-Type 1 diabetes usually has a preclinical phase identified by circulating islet autoantibodies, but the rate of progression to diabetes after seroconversion to islet autoantibodies is uncertain.Objective-To determine the rate of progression to diabetes after islet autoantibody seroconversion.Design, Setting, and Participants-Data were pooled from prospective cohort studies performed in Colorado (recruitment, 1993-2006), Finland (recruitment, 1994-2009), and Germany (recruitment, 1989-2006) examining children genetically at risk for type 1 diabetes for the development of insulin autoantibodies, glutamic acid decarboxylase 65 (GAD65) autoantibodies, insulinoma antigen 2 (IA2) autoantibodies, and diabetes.Participants were all children recruited and followed up in the 3 studies (Colorado, 1962; Finland, 8597; Germany, 2818).Follow-up assessment in each study was concluded by July 2012.Main Outcomes and Measures-The primary analysis was the diagnosis of type 1 diabetes in children with 2 or more autoantibodies.The secondary analysis was the diagnosis of type 1 diabetes in children with 1 autoantibody or no autoantibodies.Results-Progression to type 1 diabetes at 10-year follow-up after islet autoantibody seroconversion in 585 children with multiple islet autoantibodies was 69.7% (95% CI, 65.1%-74.3%),and in 474 children with a single islet autoantibody was 14.5% (95% CI, 10.3%-18.7%).Risk of diabetes in children who had no islet autoantibodies was 0.4% (95% CI, 0.2%-0.6%)by the age of 15 years.Progression to type 1 diabetes in the children with multiple islet autoantibodies was faster for children who had islet autoantibody seroconversion younger than age 3 years (hazard ratio [HR], 1.65 [95% CI, 1.30-2.09;P < .001];10-year risk, 74.9% [95% CI, 69.7%-80.1%])vs children 3 years or older (60.9% [95% CI, 51.5%-70.3%]);for children with the human leukocyte antigen (HLA) genotype DR3/DR4-DQ8 (HR, 1.35 [95% CI, 1.09-1.68;P=. 007]; 10-year risk, 76.6% [95% CI, 69.2%-84%]) vs other HLA genotypes (66.2% [95% CI, 60.2%-72.2%]);and for girls (HR, 1.28 [95% CI, 1.04-1.58;P=.02];10-year risk, 74.8% [95% CI, 68.0%-81.6%])vs boys (65.7% [95% CI, 59.3%-72.1%]).Conclusions and Relevance-The majority of children at risk of type 1 diabetes who had multiple islet autoantibody seroconversion progressed to diabetes over the next 15 years.Future prevention studies should focus on this high-risk population.
Concept of Diabetes Mellitus: Diabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its … Concept of Diabetes Mellitus: Diabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its pathogenesis involves both genetic and environmental factors. The long-term persistence of metabolic disorders can cause susceptibility to specific complications and also foster arteriosclerosis. Diabetes mellitus is associated with a broad range of clinical presentations, from being asymptomatic to ketoacidosis or coma, depending on the degree of metabolic disorder. Classification (Tables 1 and 2, and Figure 1): Table 1. Etiological classification of diabetes mellitus and glucose metabolism disorders I. Type 1 (destruction of pancreatic β-cells, usually leading to absolute insulin deficiency) A. Autoimmune B. Idiopathic II. Type 2 (ranging from predominantly insulin secretory defect, to predominantly insulin resistance with varying degrees of insulin secretory defect) III. Due to other specific mechanisms or diseases (see Table 2 for details) A. Those in which specific mutations have been identified as a cause of genetic susceptibility (1) Genetic abnormalities of pancreatic β-cell function (2) Genetic abnormalities of insulin action B. Those associated with other diseases or conditions (1) Diseases of exocrine pancreas (2) Endocrine diseases (3) Liver disease (4) Drug- or chemical-induced (5) Infections (6) Rare forms of immune-mediated diabetes (7) Various genetic syndromes often associated with diabetes IV. Gestational diabetes mellitus Note: Those that cannot at present be classified as any of the above are called unclassifiable. The occurrence of diabetes-specific complications has not been confirmed in some of these conditions. Table 2. Diabetes mellitus and glucose metabolism disorders due to other specific mechanisms and diseases A. Those in which specific mutations have been identified as a cause of genetic susceptibility B. Those associated with other diseases or conditions (1) Genetic abnormalities of pancreatic β-cell functionInsulin gene (abnormal insulinemia, abnormal proinsulinemia, neonatal diabetes mellitus) HNF 4α gene (MODY1) Glucokinase gene (MODY2) HNF 1α gene (MODY3) IPF-1 gene (MODY4) HNF 1β gene (MODY5) Mitochondria DNA (MIDD) NeuroD1 gene (MODY6) Kir6.2 gene (neonatal diabetes mellitus) SUR1 gene (neonatal diabetes mellitus) AmylinOthers(2) Genetic abnormalities of insulin actionInsulin receptor gene (type A insulin resistance, leprechaunism, Rabson–Mendenhall syndrome etc.) Others (1) Diseases of exocrine pancreasPancreatitisTrauma/pancreatectomyNeoplasmHemochromatosisOthers(2) Endocrine diseasesCushing’s syndromeAcromegalyPheochromocytomaGlucagonomaAldosteronismHyperthyroidismSomatostatinomaOthers(3) Liver diseaseChronic hepatitisLiver cirrhosis Others(4) Drug- or chemical-inducedGlucocorticoidsInterferonOthers(5) InfectionsCongenital rubellaCytomegalovirusOthers(6) Rare forms of immune-mediated diabetesAnti-insulin receptor antibodiesStiffman syndromeInsulin autoimmune syndromeOthers(7) Various genetic syndromes often associated with diabetesDown syndromePrader-Willi syndromeTurner syndromeKlinefelter syndromeWerner syndromeWolfram syndromeCeruloplasmin deficiencyLipoatrophic diabetes mellitusMyotonic dystrophyFriedreich ataxiaLaurence-Moon-Biedl syndromeOthers The occurrence of diabetes-specific complications has not been confirmed in some of these conditions. Figure 1Open in figure viewerPowerPoint A scheme of the relationship between etiology (mechanism) and patho-physiological stages (states) of diabetes mellitus. Arrows pointing right represent worsening of glucose metabolism disorders (including onset of diabetes mellitus). Among the arrow lines, indicates the condition classified as ā€˜diabetes mellitus’. Arrows pointing left represent improvement in the glucose metabolism disorder. The broken lines indicate events of low frequency. For example, in type 2 diabetes mellitus, infection can lead to ketoacidosis and require temporary insulin treatment for survival. Also, once diabetes mellitus has developed, it is treated as diabetes mellitus regardless of improvement in glucose metabolism, therefore, the arrow lines pointing left are filled in black. In such cases, a broken line is used, because complete normalization of glucose metabolism is rare. The classification of glucose metabolism disorders is principally derived from etiology, and includes staging of pathophysiology based on the degree of deficiency of insulin action. These disorders are classified into four groups: (i) type 1 diabetes mellitus; (ii) type 2 diabetes mellitus; (iii) diabetes mellitus due to other specific mechanisms or diseases; and (iv) gestational diabetes mellitus. Type 1 diabetes is characterized by destruction of pancreatic β-cells. Type 2 diabetes is characterized by combinations of decreased insulin secretion and decreased insulin sensitivity (insulin resistance). Glucose metabolism disorders in category (iii) are divided into two subgroups; subgroup A is diabetes in which a genetic abnormality has been identified, and subgroup B is diabetes associated with other pathologic disorders or clinical conditions. The staging of glucose metabolism includes normal, borderline and diabetic stages depending on the degree of hyperglycemia occurring as a result of the lack of insulin action or clinical condition. The diabetic stage is then subdivided into three substages: non-insulin- requiring, insulin-requiring for glycemic control, and insulin-dependent for survival. The two former conditions are called non-insulin-dependent diabetes and the latter is known as insulin-dependent diabetes. In each individual, these stages may vary according to the deterioration or the improvement of the metabolic state, either spontaneously or by treatment. Diagnosis (Tables 3–7 and Figure 2): Table 3. Criteria of fasting plasma glucose levels and 75 g oral glucose tolerance test 2-h value Normal range Diabetic range Fasting value <110 mg/dL (6.1 mmol/L) ≄126 mg/dL (7.0 mmol/L) 75 g OGTT 2-h value <140 mg/dL (7.8 mmol/L) ≄200 mg/dL (11.1 mmol/L) Evaluation of OGTT Normal type: If both values belong to normal range *Diabetic type: If any of the two values falls into diabetic range Borderline typeNeither normal nor diabetic types *Casual plasma glucose ≄200 mg/dL (≄11.1 mmol/L) and HbA1c≄6.5% are also regarded as to indicate diabetic type. Even for normal type, if 1-h value is 180 mg/dL (10.0 mmol/L), the risk of progression to diabetes mellitus is greater than for <180 mg/dL (10.0 mmol/L) and should be treated as with borderline type (follow-up observation, etc.). Fasting plasma glucose level of 100–109 mg/dL (5.5–6.0 mmol/L) is called ā€˜high-normal’: within the range of normal fasting plasma glucose. Plasma glucose level after glucose load in oral glucose tolerance test (OGTT) is not included in casual plasma glucose levels. The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). Table 4. Procedures for diagnosing diabetes mellitus Clinical diagnosis (1) At initial examination, a ā€˜diabetic type’ is diagnosed if any of the following criteria are met: (i) fasting plasma glucose level ≄126 mg/dL (7.0 mmol/L), (ii) 75 g OGTT 2-h value ≄200 mg/dL (11.1 mmol/L), (iii) casual plasma glucose level ≄200 mg/dL (11.1 mmol/L) or (iv) *HbA1c≄6.5%. Re-examination is carried out at another date and diabetes mellitus is diagnosed if ā€˜diabetic type’ is confirmed again**. However, diagnosis cannot be made on the basis of a repeated HbA1c test alone. If the same blood sample is confirmed to be diabetic type by both plasma glucose and HbA1c levels (any of [i] to [iii] plus [iv]), then diabetes mellitus can be diagnosed from the initial test (2) If plasma glucose level shows diabetic type (any of [i] to [iii]) and either of the following conditions exists, diabetes mellitus can be diagnosed immediately at the initial examination• The presence of typical symptoms of diabetes mellitus (thirst, polydipsia, polyuria, weight loss)• The presence of definite diabetic retinopathy (3) If it can be confirmed that either of the above conditions 1 or 2 existed in the past, diabetes mellitus must be diagnosed or suspected even if present test values do not meet the above conditions (4) If diabetes mellitus is suspected but the diagnosis cannot be made by the above (1) to (3), the patient should be followed-up (5) The following points should be kept in mind when selecting the method of determination in initial examination and re-examination• If HbA1c is used at initial examination, another method of determination is required for diagnosis at re-examination. As a rule, both plasma glucose level and HbA1c should be measured• If casual plasma glucose level is ≄200 mg/dL (11.1 mmol/L) at the initial test, a different test method is desirable for re-examination• In the case of disorders and conditions in which HbA1c may be inappropriately low, plasma glucose level should be used for diagnosis (Table 5) Epidemiological study For the purpose of estimating the frequency of diabetes mellitus, determination of ā€˜diabetic type’ from a single test can be considered to represent ā€˜diabetes mellitus’. Whenever possible, the criteria to be used are HbA1c≄6.5% or OGTT 2-h value ≄200 mg/dL (11.1 mmol/L) Health screening It is important to detect diabetes mellitus and identify high risk groups without overlooking anyone. Therefore, besides measuring plasma glucose and HbA1c, clinical information such as family history and obesity should be referred *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). **Hyperglycemia must be confirmed in a non-stressful condition. OGTT, oral glucose tolerance test. Table 5. Disorders and conditions associated with low HbA1c values Anemia Liver disease Dialysis Major hemorrhage Blood transfusion Chronic malaria Hemoglobinopathy Others Table 6. Situations where a 75-g oral glucose tolerance test is recommended Strongly recommended (suspicion of present diabetes mellitus cannot be ruled out) Fasting plasma glucose level is 110–125 mg/dL (6.1–6.9 mmol/L) Casual plasma glucose level is 140–199 mg/dL (7.8–11.0 mmol/L) *HbA1c is 6.0–6.4% (excluding those having overt symptoms of diabetes mellitus) Testing is desirable (high risk of developing diabetes mellitus in the future;Testing is especially advisable for patients with risk factors for arteriosclerosis such as hypertension, dyslipidemia and obesity.) Fasting plasma glucose level is 100–109 mg/dL (5.5–6.0 mmol/L) *HbA1c is 5.6–5.9% Strong family history of diabetes mellitus or present obesity regardless of above criteria *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). Table 7. Definition and diagnostic criteria of gestational diabetes mellitus Definition of gestational diabetes mellitus Glucose metabolism disorder with first recognition or onset during pregnancy, but that has not developed into diabetes mellitus Diagnostic criteria of gestational diabetes mellitus Diagnosed if one or more of the following criteria is met in a 75 g OGTT Fasting plasma glucose ≄92 mg/dL (5.1 mmol/L) 1-h value ≄180 mg/dL (10.0 mmol/L) 2-h value ≄153 mg/dL (8.5 mmol/L) However, diabetes mellitus that is diagnosed according to ā€˜Clinical diagnosis’ outlined in Table 4 is excluded from gestational diabetes mellitus (IADPSG Consensus Panel, Reference 42, partly modified with permission of Diabetes Care). Figure 2Open in figure viewerPowerPoint Flow chart outlining steps in the clinical diagnosis of diabetes mellitus. *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). Categories of the State of Glycemia: Confirmation of chronic hyperglycemia is essential for the diagnosis of diabetes mellitus. When plasma glucose levels are used to determine the categories of glycemia, patients are classified as having a diabetic type if they meet one of the following criteria: (i) fasting plasma glucose level of ≄126 mg/dL (≄7.0 mmol/L); (ii) 2-h value of ≄200 mg/dL (≄11.1 mmol/L) in 75 g oral glucose tolerance test (OGTT); or (iii) casual plasma glucose level of ≄200 mg/dL (≄11.1 mmol/L). Normal type is defined as fasting plasma glucose level of <110 mg/dL (<6.1 mmol/L) and 2-h value of <140 mg/dL (<7.8 mmol/L) in OGTT. Borderline type (neither diabetic nor normal type) is defined as falling between the diabetic and normal values. According to the current revision, in addition to the earlier listed plasma glucose values, hemoglobin A1c (HbA1c) has been given a more prominent position as one of the diagnostic criteria. That is, (iv) HbA1c≄6.5% is now also considered to indicate diabetic type. The value of HbA1c, which is equivalent to the internationally used HbA1c (%) (HbA1c [NGSP]) defined by the NGSP (National Glycohemoglobin Standardization Program), is expressed by adding 0.4% to the HbA1c (JDS) (%) defined by the Japan Diabetes Society (JDS). Subjects with borderline type have a high rate of developing diabetes mellitus, and correspond to the combination of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) noted by the American Diabetes Association (ADA) and WHO. Although borderline cases show few of the specific complications of diabetes mellitus, the risk of arteriosclerosis is higher than those of normal type. When HbA1c is 6.0–6.4%, suspected diabetes mellitus cannot be excluded, and when HbA1c of 5.6–5.9% is included, it forms a group with a high risk for developing diabetes mellitus in the future, even if they do not have it currently. Clinical Diagnosis: 1 If any of the criteria for diabetic type (i) through to (iv) is observed at the initial examination, the patient is judged to be ā€˜diabetic type’. Re-examination is conducted on another day, and if ā€˜diabetic type’ is reconfirmed, diabetes mellitus is diagnosed. However, a diagnosis cannot be made only by the re-examination of HbA1c alone. Moreover, if the plasma glucose values (any of criteria [i], [ii], or [iii]) and the HbA1c (criterion [iv]) in the same blood sample both indicate diabetic type, diabetes mellitus is diagnosed based on the initial examination alone. If HbA1c is used, it is essential that the plasma glucose level (criteria [i], [ii] or [iii]) also indicates diabetic type for a diagnosis of diabetes mellitus. When diabetes mellitus is suspected, HbA1c should be measured at the same time as examination for plasma glucose. 2 If the plasma glucose level indicates diabetic type (any of [i], [ii], or [iii]) and either of the following conditions exists, diabetes mellitus can be diagnosed immediately at the initial examination. • The presence of typical symptoms of diabetes mellitus (thirst, polydipsia, polyuria, weight loss) • The presence of definite diabetic retinopathy 3 If it can be confirmed that the above conditions 1 or 2 existed in the past, diabetes mellitus can be diagnosed or suspected regardless of the current test results. 4 If the diagnosis of diabetes cannot be established by these procedures, the patient is followed up and re-examined after an appropriate interval. 5 The physician should assess not only the presence or absence of diabetes, but also its etiology and glycemic stage, and the presence and absence of diabetic complications or associated conditions. Epidemiological Study: For the purpose of estimating the frequency of diabetes mellitus, ā€˜diabetes mellitus’ can be substituted for the determination of ā€˜diabetic type’ from a single examination. In this case, HbA1c≄6.5% alone can be defined as ā€˜diabetes mellitus’. Health Screening: It is important not to misdiagnose diabetes mellitus, and thus clinical information such as family history and obesity should be referred to at the time of screening in addition to an index for plasma glucose level. Gestational Diabetes Mellitus: There are two hyperglycemic disorders in pregnancy: (i) gestational diabetes mellitus (GDM); and (ii) diabetes mellitus. GDM is diagnosed if one or more of the following criteria is met in a 75 g OGTT during pregnancy: 1 Fasting plasma glucose level of ≄92 mg/dL (5.1 mmol/L) 2 1-h value of ≄180 mg/dL (10.0 mmol/L) 3 2-h value of ≄153 mg/dL (8.5 mmol/L) However, diabetes mellitus that is diagnosed by the clinical diagnosis of diabetes mellitus defined earlier is excluded from GDM. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00074.x, 2010)
Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-alpha, … Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-alpha, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione.Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-alpha, and IL-18 levels rose (P<0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher (P<0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-alpha levels higher (P<0.05) than those of control subjects. The increase in plasma cytokine levels during the clamping lasted longer (4 hours versus 2 hours, P<0.01) in the IGT subjects than in the control subjects, and the cytokine peaks of IGT subjects after the first glucose pulse were higher (P<0.05) than those of control subjects. On another occasion, 10 control and 8 IGT subjects received the same glucose pulses as above during an infusion of glutathione; plasma cytokine levels did not show any significant change from baseline after the 3 glucose pulses.Hyperglycemia acutely increases circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with IGT. This suggests a causal role for hyperglycemia in the immune activation of diabetes.
Programmed death 1 (PD-1), an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. PD-1 has two ligands: PD-1 ligand 1 (PD-L1), which is expressed broadly on hematopoietic and … Programmed death 1 (PD-1), an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. PD-1 has two ligands: PD-1 ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells; and PD-L2, which is restricted to macrophages and dendritic cells. To investigate whether PD-L1 and PD-L2 have synergistic or unique roles in regulating T cell activation and tolerance, we generated mice lacking PD-L1 and PD-L2 (PD-L1/PD-L2(-/-) mice) and compared them to mice lacking either PD-L. PD-L1 and PD-L2 have overlapping functions in inhibiting interleukin-2 and interferon-gamma production during T cell activation. However, PD-L1 has a unique and critical role in controlling self-reactive T cells in the pancreas. Our studies with bone marrow chimeras demonstrate that PD-L1/PD-L2 expression only on antigen-presenting cells is insufficient to prevent the early onset diabetes that develops in PD-L1/PD-L2(-/-) non-obese diabetic mice. PD-L1 expression in islets protects against immunopathology after transplantation of syngeneic islets into diabetic recipients. PD-L1 inhibits pathogenic self-reactive CD4+ T cell-mediated tissue destruction and effector cytokine production. These data provide evidence that PD-L1 expression on parenchymal cells rather than hematopoietic cells protects against autoimmune diabetes and point to a novel role for PD-1-PD-L1 interactions in mediating tissue tolerance.
Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially.An expert … Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially.An expert committee drafted evidence-based recommendations for the use of laboratory analysis in patients with diabetes. An external panel of experts reviewed a draft of the guidelines, which were modified in response to the reviewers' suggestions. A revised draft was posted on the Internet and was presented at the AACC Annual Meeting in July, 2000. The recommendations were modified again in response to oral and written comments. The guidelines were reviewed by the Professional Practice Committee of the American Diabetes Association.Measurement of plasma glucose remains the sole diagnostic criterion for diabetes. Monitoring of glycemic control is performed by the patients, who measure their own plasma or blood glucose with meters, and by laboratory analysis of glycated hemoglobin. The potential roles of noninvasive glucose monitoring, genetic testing, autoantibodies, microalbumin, proinsulin, C-peptide, and other analytes are addressed.The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are of minimal clinical value at the present time, and measurement of them is not recommended.
1. Quantitative study of insular tissue has revealed that the number of B cells is greatly diminished in Patients with acute juvenile diabetes from the time of clinical onset of … 1. Quantitative study of insular tissue has revealed that the number of B cells is greatly diminished in Patients with acute juvenile diabetes from the time of clinical onset of the disease. The number of these cells is as a rule less than 10 per cent of normal. Such B cells as are still present show the cytological signs of marked activity. 2. The normal or supranormal insular activity that is usually found in juvenile diabetics in this stage of the disease cannot therefore be due to the presence of a normal insular tissue, but is produced by a small number of hyperactive B cells. 3. On the basis of histological findings (presence of islets of large size, signs of new islet formation), it may be assumed that during the preclinical phase of juvenile diabetes, an extrapancreatic factor has exerted a strong stimulant action on the insular tissue. In the long run this must lead to exhaustion of the islet-forming capacity on the pancreatic parenchyma and to a decrease in the number of the B cells. By the time the disease becomes clinically manifest only the latter stage of this process can be observed and the majority of islets consist of A cells or of atrophic tissue devoid of B cells. 4. Peri- and intra-insular inflaminatory infiltrates have been found in 68 per cent of those patients with juvenile diabetes who died soon after the clinical onset of their disease. In other words, and contrary to the generally held view, this lesion is not uncommon. It is specific for diabetes and has never been observed in the chronic cases 5. In patients with chronic juvenile diabetes, the B cells are completely absent, except in occasional cases. The islets consist of small, atrophic cells. 6. A valid assessment of the functional capacity of insular tissue can only be achieved if as much use as pos sible is made of quantitative technics and of cytological examination
PRECIPITATING FACTORS -The most common precipitating factor in the development of DKA and HHS is infection (1,4,10).Other precipitating factors include discontinuation of or inadequate insulin therapy, pancreatitis, myocardial infarction, cerebrovascular … PRECIPITATING FACTORS -The most common precipitating factor in the development of DKA and HHS is infection (1,4,10).Other precipitating factors include discontinuation of or inadequate insulin therapy, pancreatitis, myocardial infarction, cerebrovascular accident, and
This article reviews the development of the immune response through neonatal, infant and adult life, including pregnancy, ending with the decline in old age. A picture emerges of a child … This article reviews the development of the immune response through neonatal, infant and adult life, including pregnancy, ending with the decline in old age. A picture emerges of a child born with an immature, innate and adaptive immune system, which matures and acquires memory as he or she grows. It then goes into decline in old age. These changes are considered alongside the risks of different types of infection, autoimmune disease and malignancy.
DURING the past decade a wealth of information concerning the pathogenesis of Type I diabetes has become available. Two spontaneous animal models of the disease have been discovered and characterized … DURING the past decade a wealth of information concerning the pathogenesis of Type I diabetes has become available. Two spontaneous animal models of the disease have been discovered and characterized (the Biobreeding rat and the non-obese diabetic mouse); the importance of a gene or genes in the major histocompatibility complex in Type I diabetes of human beings, of mice, and of rats has been appreciated; and the prognostic importance of selected assays for islet-cell antibodies has been defined. T-cell abnormalities that precede diabetes have been discovered. Evidence has suggested that progressive loss of first-phase insulin secretion precedes diabetes, and immunologic . . .
Diagnoses of type 1 and type 2 diabetes in youths present a substantial clinical and public health burden. The prevalence of these diseases increased in the 2001-2009 period, but data … Diagnoses of type 1 and type 2 diabetes in youths present a substantial clinical and public health burden. The prevalence of these diseases increased in the 2001-2009 period, but data on recent incidence trends are lacking.
We appreciate the comment by Kilpatrick et al. (1) regarding the International Expert Committee report on the diagnosis of diabetes with the A1C assay (2). The Committee considered all of … We appreciate the comment by Kilpatrick et al. (1) regarding the International Expert Committee report on the diagnosis of diabetes with the A1C assay (2). The Committee considered all of the limitations of the A1C assay for populations in which it is not available or is currently too expensive, as well as for individuals in whom the assay may be misleading. On the basis of these recognized limitations, the Committee emphasized the use of the currently recommended glucose tests and criteria in such populations or individuals. We did not ā€œbreeze overā€ any of the relative advantages or disadvantages of the A1C assay as a means of diagnosis; rather, the …
Abstract Background: Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies … Abstract Background: Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. Approach: An expert committee drafted evidence-based recommendations for the use of laboratory analysis in patients with diabetes. An external panel of experts reviewed a draft of the guidelines, which were modified in response to the reviewers’ suggestions. A revised draft was posted on the Internet and was presented at the AACC Annual Meeting in July, 2000. The recommendations were modified again in response to oral and written comments. The guidelines were reviewed by the Professional Practice Committee of the American Diabetes Association. Content: Measurement of plasma glucose remains the sole diagnostic criterion for diabetes. Monitoring of glycemic control is performed by the patients, who measure their own plasma or blood glucose with meters, and by laboratory analysis of glycated hemoglobin. The potential roles of noninvasive glucose monitoring, genetic testing, autoantibodies, microalbumin, proinsulin, C-peptide, and other analytes are addressed. Summary: The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are of minimal clinical value at the present time, and measurement of them is not recommended.
A classification of diabetes and other categories of glucose intolerance, based on contemporary knowledge of this heterogeneous syndrome, was developed by an international workgroup sponsored by the National Diabetes Data … A classification of diabetes and other categories of glucose intolerance, based on contemporary knowledge of this heterogeneous syndrome, was developed by an international workgroup sponsored by the National Diabetes Data Group of the NIH. This classification, and revised criteria for the diagnosis of diabetes, were reviewed by the professional members of the American Diabetes Association, and similar versions were circulated by the British Diabetic Association, the Australian Diabetes Society, and the European Association for the Study of Diabetes. The ADA has endorsed the proposals of the international workgroup, and the Expert Committee on Diabetes of the World Health Organization has accepted its substantive recommendations. It is proposed that this classification be used as a uniform framework in which to conduct clinical and epidemiologie research so that more meaningful and comparative data will be obtained on the scope and impact of the various forms of diabetes and other classes of glucose intolerance. Medical treatment of diabetes is not considered in this paper, and the classification is not an attempt to define guidelines for therapy of patients. The salient changes proposed in the classification are that 1. The insulin-dependent, ketosis-prone type of diabetes, which is associated with increased or decreased frequency of certain histocompatibility antigens (HLA) on chromosome 6 and with islet cell antibodies, be considered a distinct subclass of diabetes [insulin-dependent diabetes mellitus (IDDM)]. This type of diabetes has been inappropriately termed juvenile diabetes. Since it can occur at any age, it is recommended that diagnosis based on age of onset be eliminated. 2. The noninsulin-dependent, nonketosis-prone types of diabetes, which are not secondary to other diseases or conditions, be considered a second distinct subclass of diabetes [noninsulin-dependent diabetes mellitus (NIDDM)]. This subclass has been divided-according to whether or not obesity is present (obese NIDDM and nonobese NIDDM, respectively), and patients in this subclass can be further characterized by the type of treatment they receive (insulin, oral hypoglycemie agents, diet) or by other characteristics of interest to the researcher. It is believed that heterogeneity within this subclass, and also within IDDM, will be demonstrated by further research. 3. The types of diabetes caused by other conditions or found in increased frequency with other conditions (implying an etiologie relationship) be considered a third subclass of diabetes mellitus—diabetes associated with certain conditions and syndromes. This subclass has been divided according to the known or suspected etiologie relationships. 4. The class gestational diabetes be restricted to women in whom glucose intolerance develops or is discovered during pregnancy. 5. Individuals with plasma glucose (PG) levels intermediate between those considered normal and those considered diabetic [see (8)] be termed to have impaired glucose tolerance. It is proposed that the terms chemical, latent, borderline, subclinical, and asymptomatic diabetes, which have been applied to persons in this class, be abandoned, since use of the term diabetes invokes social, psychologic, and economic sanctions that are unjustified in light of the lack of severity of their glucose intolerance.
The American Diabetes Association (ADA) ā€œStandards of Care in Diabetesā€ includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals … The American Diabetes Association (ADA) ā€œStandards of Care in Diabetesā€ includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
The epidemic nature of diabetes mellitus in different regions is reviewed.The Middle East and North Africa region has the highest prevalence of diabetes in adults (10.9%) whereas, the Western Pacific … The epidemic nature of diabetes mellitus in different regions is reviewed.The Middle East and North Africa region has the highest prevalence of diabetes in adults (10.9%) whereas, the Western Pacific region has the highest number of adults diagnosed with diabetes and has countries with the highest prevalence of diabetes (37.5%).Different classes of diabetes mellitus, type 1, type 2, gestational diabetes and other types of diabetes mellitus are compared in terms of diagnostic criteria, etiology and genetics.The molecular genetics of diabetes received extensive attention in recent years by many prominent investigators and research groups in the biomedical field.A large array of mutations and single nucleotide polymorphisms in genes that play a role in the various steps and pathways involved in glucose metabolism and the development, control and function of pancreatic cells at various levels are reviewed.The major advances in the molecular understanding of diabetes in relation to the different types of diabetes in comparison to the previous understanding in this field are briefly reviewed here.Despite the accumulation of extensive data at the molecular and cellular levels, the mechanism of diabetes development and complications are still not fully understood.Definitely, more extensive research is needed in this field that will eventually reflect on the ultimate objective to improve diagnoses, therapy and minimize the chance of chronic complications development.
Abstract Aims Assessment of islet autoimmunity and presymptomatic type 1 diabetes (T1D) among children from the general population of North‐Eastern Poland. Materials and Methods Venous blood samples have been collected … Abstract Aims Assessment of islet autoimmunity and presymptomatic type 1 diabetes (T1D) among children from the general population of North‐Eastern Poland. Materials and Methods Venous blood samples have been collected from 3575 children aged 1–9 years and analysed in a stepwise procedure starting with 3 Screen Islet Cell Autoantibody ELISA and IAA ELISA. Next, samples found positive in either test were verified for individual autoantibodies. Children with confirmed islet cell autoimmunity were invited for the follow‐up consisting of laboratory testing, metabolic staging and education. Results Among tested children detailed antibody testing confirmed islet cell autoimmunity in 7.78% participants and 1.17% of the total number presented multiple positive islet autoantibodies (IAb). IAAs were the most frequently reported (50.75%), while IA‐2As were the least frequent (8.4%). IAAs were observed more frequently in individuals with T1D family history ( p = 0.04), and in children aged 1–3 years ( p = 0.02). The frequency of IA2‐As and ZnT8As increased with age ( p = 0.035 and p = 0.02) and ZnT8As were observed more frequently in females ( p = 0.024). The prevalence of multiple positive IAbs was almost 2.5‐times higher in children with T1D family history than in other peers. One hundred and thirteen children participated in follow‐up. Within individuals with dysglycaemia almost 67% presented a single autoantibody and two participants (1.77%) presented Stage 3 diabetes – both diagnosed before DKA occurred. Conclusions Results confirm the importance of screening for IAbs in general paediatric population as a method of prediction of T1D development. The study also shows that patients with a single positive islet autoantibody may have already developed dysglycaemia and therefore need monitoring.
Abstract Health economics of screening for early type 1 diabetes (T1D) is an emerging area of research. Historically, screening for early T1D has been limited to prospective cohort studies of … Abstract Health economics of screening for early type 1 diabetes (T1D) is an emerging area of research. Historically, screening for early T1D has been limited to prospective cohort studies of the aetiology and natural history of the disease as well as trials of secondary prevention. In the past few years, successful large‐scale studies have expanded the screening to the general population, providing data needed to estimate the cost‐effectiveness of such programs and their economic viability as they become part of public health preventive services. This review covers available results of health economics analyses from early estimates through state transition cohort simulation models relying on birth cohort studies to real‐world experience from general population screening and, finally, predictions to a national scale. The cost‐effectiveness analyses of screening for early T1D to date suggest that the financial investment in such programs is justified by the health benefits and savings achieved. Screening can be cost‐effective if it reduces the incidence of diabetic ketoacidosis at diagnosis and decreases healthcare costs associated with long‐term complications. However, the cost‐effectiveness varies based on population prevalence of T1D, frequency of diabetic ketoacidosis at clinical diagnosis, screening test accuracy and cost as well as healthcare system efficiency. All these factors influence the HbA1c at diagnosis and glycaemic control as well as insulin requirements later in the course of the disease. Earlier interventions aiming at delaying insulin dependency may further improve the cost‐effectiveness. Plain Language Summary Type 1 diabetes (T1D) is one of the most frequent severe chronic diseases of childhood, increasing in numbers with age, affecting in lifetime 1 in 100 people. It is caused by the immune system attacking insulin‐producing cells in the pancreas. Stage 1 of T1D is diagnosed when multiple markers of the attack (islet autoantibodies) are detected. The disease progresses to stage 2 when most of the insulin is lost and blood sugar levels become abnormal. Stage 3 is defined by very high blood sugars leading often to diabetic ketoacidosis (DKA) and need of insulin treatment to safe life. This progression happens over a period of months or years, providing an opportunity for screening to detect the disease early and slow the progression with drug therapy as well as to provide education that prevents DKA. Early diagnosis and start of insulin therapy when HbA1c is just above 6.5% helps to avoid multiorgan complications that increase with age and account for most of the direct medical cost and lost workforce participation and productivity associated with T1D. Studies following high‐risk youth for decades provided early estimates of the cost‐effectiveness of screening for stage 1 and stage 2 T1D. Screening cannot be limited to relatives of people with T1D because they represent only 10‐15% of new T1D diagnoses. In recent years, successful programs such as Fr1da in Germany or Autoimmunity Screening for Kids (ASK) in USA expanded the screening to the general population, providing data needed to estimate cost‐effectiveness as they become part of public health preventive services. Testing for islet autoantibodies dramatically reduced the incidence of DKA at diagnosis and may decrease healthcare costs associated with long‐term complications; however, an extended follow‐up of screening participants is necessary. Screening for early T1D can be combined with screening for celiac disease, high cholesterol levels, or other conditions detectable by blood test, further improving cost‐effectiveness. The widely accepted routine newborn screening for about 30 rare diseases, affecting 1 in 600 infants, costs $125‐150 per child. In contrast, 1 in 30 children has early T1D or celiac disease that could be detected for less than $50 per child screened. Results of the programs in Germany and USA indicate that the cost‐effectiveness of screening depends on population prevalence of T1D, frequency of DKA, screening test accuracy and cost as well as healthcare system efficiency. These analyses allow national‐scale predictions of the number of high‐risk youths and the resources necessary to successfully monitor them during stage 1 and 2. Screening at age 2 and 6 years in Germany would annually yield a similar number of children at early stage T1D to those currently diagnosed at stage 3 and reduce DKA at diagnosis by 61%. If all USA children were screened today, it is estimated that 350,000 would be diagnosed with stage 1 and 70,000 with stage 2 T1D. The cost‐effectiveness of analyses of screening for early T1D suggest that financial investment in such programs is justified by the observed health benefits and savings.
Current practice guidelines recommend considering a diagnosis of maturity-onset diabetes of the young (MODY) in patients with diabetes with an affected parent but without typical features of type 1 diabetes … Current practice guidelines recommend considering a diagnosis of maturity-onset diabetes of the young (MODY) in patients with diabetes with an affected parent but without typical features of type 1 diabetes (T1D) or type 2 diabetes (T2D). To test if these criteria apply to a real-world cohort of racially/ethnically diverse children with diabetes. We performed a retrospective case review of electronic medical records (EMR) of youth diagnosed with MODY in a large academic pediatric hospital in Southwestern U.S. Cases were ascertained based on the identification of a molecular diagnosis of MODY. We studied 50 genetically confirmed cases of MODY: 60% GCK-MODY (MODY2, n=30), 16% HNF1A-MODY (MODY3, n=8), 18% HNF1B-MODY (MODY5, n=9), 4% HNF4A-MODY (MODY1, n=2), and 2% with a dual molecular diagnosis resulting from variants in more than one MODY gene (n=1). Race/ethnicity other than non-Hispanic White, lack of parental diabetes history, obesity/overweight at diagnosis, dyslipidemia and/or hypertension and acanthosis nigricans documented on physical exam were observed, respectively, in 52% (n=26), 24% (n=12), 22.2% (n =11), 30% (n=15), and 12% (n=6) of MODY cases. Furthermore, islet antibody positivity was observed in 8% of the cases GCK-MODY (n=4). The mean hemoglobin A1c at diabetes diagnosis was higher in patients with HNF4A-MODY (7.0%), HNF1A-MODY (6.7%), and HNF1B-MODY (6.7%), than in those with GCK-MODY (6.1%, p=0.005). Four (13.3%) GCK-MODY patients had persistent proteinuria of undetermined cause. The current guidelines to consider a diagnosis of MODY may not apply to a racially/ethnically diverse U.S. population of children with diabetes.
This review synthesizes current knowledge on islet autoantibodies (IAs) as predictive biomarkers for type 1 diabetes (T1D), focusing on their role in disease staging, autoantibody patterns, advancements in screening methodologies, … This review synthesizes current knowledge on islet autoantibodies (IAs) as predictive biomarkers for type 1 diabetes (T1D), focusing on their role in disease staging, autoantibody patterns, advancements in screening methodologies, and the implications of implementing population-wide screening initiatives. Autoantibody profiling has refined T1D risk stratification, with progression rates influenced by IA characteristics including number, type, order of appearance, and affinity. While screening efforts initially targeted genetically at-risk groups, approximately 90% of new TID diagnoses occur in individuals without a family history, underscoring the need for broader population-based screening. The approval of teplizumab, a therapy shown to delay clinical T1D onset, represents a paradigm shift by providing an intervention following early identification through screening. Technological advancements have further optimized IA detection and therapeutic strategies. However, challenges such as cost-effectiveness, implementation logistics, and assay standardization remain. T1D is a chronic autoimmune disorder characterized by progressive pancreatic beta-cell destruction, leading to insulin deficiency. The natural history of T1D is typically marked by the appearance of IAs long before clinical symptoms emerge, providing a window for early detection and intervention. Identifying at-risk individuals during this asymptomatic phase can reduce disease severity at clinical onset and facilitate timely application of disease-modifying therapies like teplizumab. Emerging evidence emphasizes that IA characteristics collectively shape disease risk and progression. Advancements in screening technologies and therapies continue to support the integration of IA screening into clinical care, marking a significant step toward effective T1D prevention and management.
Abstract The autoimmune response directed against pancreatic β cells is the most essential pathogenic process in type 1 diabetes (T1D) in humans. Spontaneous animal models of T1D greatly contribute to … Abstract The autoimmune response directed against pancreatic β cells is the most essential pathogenic process in type 1 diabetes (T1D) in humans. Spontaneous animal models of T1D greatly contribute to our understanding of the disease pathogenesis and therapeutic options. Amongst many disease models, a significant proportion of T1D research is performed on multiple low dose streptozotocin induced diabetes in experimental animals, in parallel. Here, we discuss advantages of this model for contemporary T1D research. Additionally, challenges and perspectives for further improvement of the model are presented.
It is well established that no disease had developed due to lack of expression of ABO blood group antigens, but the susceptibility to some diseases has been linked with an … It is well established that no disease had developed due to lack of expression of ABO blood group antigens, but the susceptibility to some diseases has been linked with an individual's ABO phenotype. This study is aimed at determining the relation of ABO blood groups to the lipid profile in hypertensive subjects. Lipid profile and blood group was determined in sixty-eight (68) hypertensive subjects aged 35-70 years and thirty (30) non-hypertensive apparently healthy individuals. Blood group, blood pressure and lipid profile such as Total cholesterol (TC), Triglyceride (TG), High density lipoprotein (HDL), very low-density lipoprotein (VLDL) and Low-density lipoprotein (LDL) were evaluated from the blood collected from the patients using standard methods. The ABO and rhesus blood group of subjects was carried out by standard tile technique. Data were analyzed for statistical significance using t-test and Pearson correlation. The results obtained show that the level of triglycerides (1.369 ± 0.570 mmol/L) was higher in blood group A subjects with hypertension compared to blood group A control subjects (0.861 ± 0.259 mmol/L) (p=0.016). The level of LDL (4.133 ± 1.363 mmol/L) was higher in blood group B subjects with hypertension compared to blood group B control subjects (2.150 ± 1.015 mmol/L) (p=0.006). There was a significant correlation between total cholesterol, and systolic blood pressure in blood group A subjects (p = 0.012, r = 0.672). Again, there was a significant positive correlation between LDL and systolic blood pressure in blood group A subjects (p = 0.010, r = 0.685). The correlation between systolic and diastolic blood pressure with the other variables in blood group O and rhesus D positive subjects were not statistically significant. Triglycerides and low-density lipoprotein were higher in blood group A and Blood group B with hypertension. There was a significant positive correlation between total cholesterol, LDL and systolic blood pressure in blood group ā€œAā€ individuals.
A cetoacidose diabĆ©tica (CAD) Ć© uma emergĆŖncia mĆ©dica comum em pacientes caninos com diabetes mellitus (DM) descompensada. Este relato descreve o caso de uma cadela da raƧa Yorkshire Terrier, 11 … A cetoacidose diabĆ©tica (CAD) Ć© uma emergĆŖncia mĆ©dica comum em pacientes caninos com diabetes mellitus (DM) descompensada. Este relato descreve o caso de uma cadela da raƧa Yorkshire Terrier, 11 anos, castrada, com histórico de uso prolongado de glicocorticoides e suspeita de hipercortisolismo, que apresentou quadro de anorexia, vĆ“mitos, prostração e perda de peso progressiva. O tratamento envolveu fluidoterapia intensiva, insulinoterapia regular, correção de distĆŗrbios eletrolĆ­ticos e acidobĆ”sicos. A paciente respondeu favoravelmente ao tratamento, apresentando melhora clĆ­nica progressiva e estabilidade metabólica, culminando em alta hospitalar após 122 horas. O presente relato ressalta a importĆ¢ncia do manejo intensivo e monitoramento rigoroso em casos de CAD.
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Introduction and Objective: Autoimmune type 1 diabetes (T1D) often goes undiagnosed until a major clinical event triggers disease recognition. Identifying individuals in early T1D stages remains a clinical challenge given … Introduction and Objective: Autoimmune type 1 diabetes (T1D) often goes undiagnosed until a major clinical event triggers disease recognition. Identifying individuals in early T1D stages remains a clinical challenge given inefficient screening thus limiting opportunities for early intervention. This study aimed to develop a predictive machine learning model that identified individuals before the onset of stage 3 T1D. Methods: This was a retrospective cohort study that utilized medical claims data and lab test results from the US Managed Markets Insight &amp; Technology (MMIT) dataset to develop two age specific AI/ML Models (0-24 years and 25+ years) for identifying individuals with presumed early stage T1D at least one year from first observed T1D diagnosis. Confirmed stage 3 T1D cases, used to train and validate the model, were required to have ≄2 claims for T1D, a ratio of T1D : type 2 diabetes claims of ≄0.5, ≄1 claim for insulin or continuous glucose monitoring, and claims activity of at least 1 medical and 1 pharmacy claim in each year for two years before first observed T1D diagnosis or treatment (index). The model was trained on patient data &amp;gt;12 months prior to index to identify patients at least one year before the appearance of a T1D diagnosis or treatment. Variables included T1D and non-T1D associated clinical variables, autoimmune markers, comorbidities, demographic factors, and sequential medical events. Results: Both models were able to detect diagnosed T1D patients (~80% sensitivity in the 0-24 model; ~92% in the 25+model) at ~8% precision in the 0-24 model (~14k true positives in ~167k predicted positives) and ~10% in the 25+ model (~16k in ~169k). Conclusion: The study demonstrates the potential clinical utility of machine learning models for the early detection of type 1 diabetes. This may enable earlier diagnosis through increased screening efficiency and yield, allowing for timely intervention and better management of T1D, ultimately improving patient outcomes. Disclosure F. Lam: Consultant; Sanofi. V. Tiwari: Consultant; Sanofi. G. Mion: Consultant; Sanofi. D. Khedekar: Consultant; Sanofi. P. Mukherjee: Consultant; Sanofi. S. Pandey: Consultant; Sanofi. D. Desai: Consultant; Sanofi. L. Wilson: Employee; Sanofi-Aventis U.S. Stock/Shareholder; Sanofi-Aventis U.S. J. Dunne: Employee; Sanofi, Novo Nordisk. L. Hao: Employee; Sanofi. M. Wieloch: Employee; Sanofi. Stock/Shareholder; Sanofi. J.H. Zaccai: Employee; Sanofi. R.B. McQueen: Speaker's Bureau; Sanofi. Other Relationship; Sanofi. K.M. Simmons: Consultant; Sanofi. Research Support; Sanofi. Advisory Panel; Sanofi, Shoreline Biosciences. E.K. Sims: Consultant; Sanofi. Speaker's Bureau; Med Learning Group. Other Relationship; American Diabetes Association. Funding This study was funded by Sanofi.
Abstract Aims This study evaluates the contribution of common variants in Maturity-Onset Diabetes of the Young (MODY) genes on type 1 diabetes (T1D), using a polygenic score (PGS) approach. Methods … Abstract Aims This study evaluates the contribution of common variants in Maturity-Onset Diabetes of the Young (MODY) genes on type 1 diabetes (T1D), using a polygenic score (PGS) approach. Methods 485 children and youth diagnosed with T1D from at least 1 year and 271 healthy controls (HC) were recruited. Personal information (i.e. age, sex, height, weight) were collected for each participant, and clinical information (i.e. age at diagnosis, disease duration, presence of autoantibodies and ketoacidosis at onset (DKA)) were also obtained for T1D subjects. Participants were genotyped using Illumina Infinium Global Screening Array. PGS based on Single Nucleotide Polymorphisms (SNPs) in 16 MODY genes were developed. The association of this PGS with T1D susceptibility and clinical disease characteristics was assessed by regression analysis. Results A PGS including 335 SNPs in MODY genes discriminates T1D from HC (AUC = 60.1%, AIC = 787.6). This PGS was significantly higher in T1D compared to HC (p-value = 0.0004, pseudo-R2 = 2.85%). Moreover, regression analysis between PGS and T1D clinical characteristics showed higher PGS values in T1D subjects with zinc transporter 8 autoantibodies (ZnT8A) compared with T1D subjects without ZnT8A (p-value = 0.04). A similar trend was also observed for antibodies directed against glutamic acid decarboxylase (GADA), although the association did not reach statistical significance (p-value = 0.06). Conclusions Our study suggests that a polygenic approach based on MODY genes may discriminate T1D from HC and may contribute to patient stratification, helping to better understand T1D heterogeneity.
Early diagnosis and treatment of type 1 diabetes mellitus. Issues of clinical feasibility, organization, and accessibility of medical care. Resolution on the results of the Expert Council held on December … Early diagnosis and treatment of type 1 diabetes mellitus. Issues of clinical feasibility, organization, and accessibility of medical care. Resolution on the results of the Expert Council held on December 17, 2024, Moscow.
Introduction The effect of aerobic exercise on glucose concentration has been reported in healthy normal and over-conditioned dogs and in experimental dog models. However, the effect of aerobic exercise on … Introduction The effect of aerobic exercise on glucose concentration has been reported in healthy normal and over-conditioned dogs and in experimental dog models. However, the effect of aerobic exercise on interstitial glucose concentration (IG) has not been reported in dogs with insulin-treated naturally-occurring diabetes mellitus. Objective Determine if aerobic exercise decreases IG in outpatient diabetic dogs. Methods Five NPH insulin-treated client-owned diabetic dogs were prospectively enrolled into this interventional longitudinal cohort study. Dogs with a flash glucose monitoring system performed once daily aerobic exercise over 30 min for 7 consecutive days, if IG was <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mo>≄</mml:mo></mml:math> 60 mg/dL during the preceding 12 h of observation. Dogs weighing &amp;lt;10 kg exercised (walked or jogged) for 1.5–2 miles, dogs 10–20 kg exercised for 2–2.5 miles, and dogs &amp;gt;20 kg exercised for 2.5–3 miles. Multivariable mixed-effects linear regression models followed by post-hoc analyses were used to estimate the marginal mean differences between IG 0.5, 1, 1.5, 2, and 4 h after exercise compared with marginal mean baseline IG measured twice over 30 min just before each daily exercise period, which served as the control. Results Marginal means (95% confidence intervals) of IG were significantly lower 1.5 h after exercise [188 mg/dL (96-281 mg/dL)] and 2 h after exercise [185 mg/dL (82–287 mg/dL)] compared with marginal mean IG measured just before exercise [223 mg/dL (129–317 mg/dL, p = 0.03, p = 0.008, respectively)]. Marginal means of IG were not significantly different 4 h after exercise compared with marginal mean IG measured just before exercise. Conclusion Our preliminary data suggest that aerobic exercise may reduce IG levels up to two hours following exercise. These findings indicate that exercise could potentially serve as an adjunct approach to managing insulin-treated diabetic dogs in a home setting.
Abstract The prevalence of type 1 diabetes is increasing, with significant implications for public health systems worldwide. This review provides a global overview of the current epidemiology of type 1 … Abstract The prevalence of type 1 diabetes is increasing, with significant implications for public health systems worldwide. This review provides a global overview of the current epidemiology of type 1 diabetes, examining the trends, risk factors, and regional variations in incidence. We explore the influence of genetic, environmental, and socio‐economic factors on the rising incidence of type 1 diabetes. The review also highlights temporal trends in the management of type 1 diabetes and the risk of mortality and morbidity from acute and long‐term complications, including hypoglycaemia, diabetic ketoacidosis, and retinopathy. By synthesizing global and regional data, we aim to provide valuable insights for local health service planning, disease prediction, and tailored interventions. This article underscores the importance of continued research into the epidemiology of type 1 diabetes to better inform prevention, treatment, and management strategies of this growing global health challenge. Plain Language Summary Type 1 diabetes (T1D) is an autoimmune condition that begins silently, with the body attacking insulin‐producing cells in the pancreas. This process occurs in two early, silent stages, detectable through blood tests for antibodies, before symptoms appear. It eventually progresses to stage 3, when symptoms develop and insulin treatment becomes necessary. Prevalence T1D affects about 9 million people globally, including over 1.5 million children. In addition to those with symptoms, many children and adults may unknowingly have early stage T1D. These can be detected through screening and are estimated to affect around 0.3% of the population. Incidence In 2024, there were over 500,000 new diagnoses of T1D worldwide, with cases increasing each year. Rates vary by region, age, and sex. Most diagnoses occur in childhood or early adulthood, with a peak around puberty, though it can develop later in life. Rates are highest in high‐income countries such as Finland and Australia. Lower rates in other regions may reflect limited surveillance. Some countries have reported fluctuating trends, possibly linked to infections. Improved awareness and diagnostics explain and changing risk factors may also play a role. Risk Factors The risk of T1D is impacted by genetic, demographic, and environmental factors. Family history increases risk, though the majority of people diagnosed don’t have a family history. Genetic risk scores can also help identify children at higher risk. Risk changes with age, early signs often appear before age 3, and younger children tend to progress more quickly. Two childhood diagnosis peaks occur at ages 4–7 years and 10–14 years. Researchers are exploring possible subtypes of T1D based on age and disease behaviour. White European populations have the highest rates, but increases are also seen in other groups. Environmental factors like viral infections, caesarean birth, and early diet are being studied. Complications Managing T1D is complex, however poor control can lead to short‐term emergencies like hypoglycaemia or diabetic ketoacidosis (DKA), and long‐term complications affecting the eyes, kidneys, and nerves. In recent decades, treatment has improved with better insulin regimens and technologies such as insulin pumps, continuous glucose monitors, and hybrid closed‐loop systems. These reduce complications and improve quality of life. Yet challenges remain, including high DKA rates at diagnosis—especially in young children and ethnic minorities, and high diabetic retinopathy rates that can impact vision. Early, tight glucose control reduces long‐term risks, but people with T1D still face a higher risk of early death. Future Research Directions Major research gaps remain, especially in low‐ and middle‐income countries. Data on early‐stage and adult‐onset T1D is limited but improving. As new therapies emerge, like teplizumab which is used to delay progression to stage 3, disease patterns may shift. Long‐term data from modern technologies is still developing, with linked administrative data offering a promising solution. Conclusion T1D is rising globally and still carries serious health risks. Understanding who is affected, when, and how the disease progresses is essential to improving prevention, care, and outcomes.
Abstract Aims To examine if SARS‐CoV‐2 infection is associated with new‐onset type 1 diabetes in the post‐acute period in children and young people (CYP). Methods In this population cohort, we … Abstract Aims To examine if SARS‐CoV‐2 infection is associated with new‐onset type 1 diabetes in the post‐acute period in children and young people (CYP). Methods In this population cohort, we used data on all hospital activity in England to estimate type 1 diabetes incidence among CYP aged 0–17 exposed to SARS‐CoV‐2 between May 2020 and August 2022, from day 28 after a positive test for the following 6 months. We compared this with unexposed CYP who were hospitalized for elective procedures or following trauma during the pandemic, and in the 2 years prior to the pandemic (historic cohorts). We excluded CYP with prior chronic illnesses. We undertook Cox regression analyses adjusted for age, sex, ethnicity, deprivation and season of index date, and stratified by periods when different SARS‐CoV‐2 variants were dominant. Results There were 1,087,604 CYP in the exposed cohort, 143,748 in the trauma cohort, 253,368 in the elective cohort, 160,925 in the historic trauma cohort and 388,673 in the historic elective cohort. Hazard of developing type 1 diabetes was significantly higher among those exposed than unexposed CYP: 2.4 [1.58–3.64] relative to the trauma cohort, 2.9 [2.00–4.13] relative to the elective cohort, 4.2 [2.56–7.04] relative to the historic trauma cohort and 2.4 [1.81–3.10] relative to the historic elective cohort. Associations may be strongest during the Delta period. Conclusions SARS‐CoV‐2 infection is associated with subsequent incident type 1 diabetes in the 1–7 months after an acute infection in previously healthy CYP.
A total of 250 males and females were recruited to participate in this cross-sectional and case-control study that aimed at measuring several biomarkers [fasting blood glucose (FBG), glycated hemoglobin (HbA1c), … A total of 250 males and females were recruited to participate in this cross-sectional and case-control study that aimed at measuring several biomarkers [fasting blood glucose (FBG), glycated hemoglobin (HbA1c), thyroid hormonal profile, and antithyroglobulin antibody (ATG)] in diabetic and non-diabetic patients and comparing circulating markers of diabetes mellitus with elevated serum ATG levels in type II diabetes patients who used various analyzers. The assays were performed on Roche COBAS C311, COBAS e 411/601, and Beckman Coulter (DXC 700 AU) analyzers. The mean and standard deviation were calculated, and the independent t-test and one-way analysis of variance were used for comparison. Linear regression was conducted to assess correlations. A p-value of &lt;0.05 was considered statistically significant. This study included 125 diabetic patients compared with 125 healthy males and females, with ages ranging from 20 to 81 years and a duration of diabetes mellitus between 4 to 15 years. The results demonstrated a significant difference in FBG, HbA1c, thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and ATG levels between the diabetic patients and the healthy individuals, compared to age, gender, and duration of the disease. A moderate positive correlation was observed between FBG and HbA1c, as well as between FT3 and FT4; a negative correlation was found between FBG and HbA1c levels and TSH levels. A significant positive correlation between ATG and serum TSH levels observed in patients with type 2 diabetes mellitus indicated a strong relationship between thyroid dysfunction and diabetes, compared to the age and duration of the disease.
<title>Abstract</title> <bold>Purpose:</bold> Herein, animal cases of insulin-induced hypoglycemia are presented in nondiabetic patients. We report an outbreak of iatrogenic insulin poisoning in dogs. <bold>Methods:</bold> Twenty dogs presented peracute clinical signs, … <title>Abstract</title> <bold>Purpose:</bold> Herein, animal cases of insulin-induced hypoglycemia are presented in nondiabetic patients. We report an outbreak of iatrogenic insulin poisoning in dogs. <bold>Methods:</bold> Twenty dogs presented peracute clinical signs, and seven were submitted for <italic>postmortem</italic> and histological examination in the <italic>Setor de Anatomia Patológica</italic> (SAP) at the Federal Rural University of Rio de Janeiro, Brazil. Blood serum samples from the cardiac clot of the right ventricle of the dogs were sent for radioimmunoassay examination for insulin dosage. Vitreous humor samples were submitted for flame atomic emission photometry for potassium level determination. <bold>Results:</bold> All dogs had previously attended an anti-rabies vaccination campaign on the same day and time and showed peracute clinical signs after the application. The respondents reported suspicions about accidental parenteral administration of insulin in the dogs. Tremors, inability to stand still, tachypnea, and intense vocalization were evident in 2 to 13 hours of clinical evolution. Histologically, there was neuronal necrosis in the temporal and frontal cortex. Radioimmunoassay identified insulin in three of the submitted samples. Flame atomic emission photometry revealed high levels of potassium in all samples. The epidemiological, clinical, and histopathological findings associated with identifying insulin in the blood serum and atomic emission spectroscopy for potassium recovery endorsed the suspicion of insulin poisoning. <bold>Conclusion:</bold> For the first time in veterinary medicine, accidental insulin-induced hypoglycemia is reported in nondiabetic dogs. Flame atomic emission photometry was a promising tool for indicating high circulating insulin levels in forensic veterinary medicine.
Diabetic Ketoacidosis (DKA) is a serious acute complication of diabetes mellitus characterized by hyperglycemia, metabolic acidosis and ketonemia. Although more frequent in patients with type 1 diabetes, it can also … Diabetic Ketoacidosis (DKA) is a serious acute complication of diabetes mellitus characterized by hyperglycemia, metabolic acidosis and ketonemia. Although more frequent in patients with type 1 diabetes, it can also occur in individuals with type 2 diabetes under metabolic stress conditions. Main triggers include inadequate insulin use, infections and events that increase insulin demand or counterregulatory hormone production. Management requires a multidisciplinary approach, encompassing fluid replacement, electrolyte correction, insulin administration and treatment of the precipitating factor. Restoration of intravascular volume, inhibition of lipolysis and reversal of ketogenesis are fundamental for clinical stabilization. In this context, continuous monitoring of blood glucose and electrolytes particularly potassium is essential to avoid serious complications such as fatal hypokalemia. The most common iatrogenic complications are hypoglycemia and electrolyte disturbances (hypokalemia and hypophosphatemia), as well as cerebral edema, more prevalent in pediatric patients. Early identification and control of severity signs, together with effective management of the precipitating factor, are crucial to reduce DKA associated morbidity and mortality.
ABSTRACT Hypobaric hypoxia, a defining feature of high‐altitude environments, induces significant physiological and pathological changes in the human body. Under the disrupted homeostasis and altered disease microenvironment caused by high‐altitude … ABSTRACT Hypobaric hypoxia, a defining feature of high‐altitude environments, induces significant physiological and pathological changes in the human body. Under the disrupted homeostasis and altered disease microenvironment caused by high‐altitude conditions, the immune system exhibits distinct responses compared to those observed in low‐altitude settings. Our study investigates the impact of hypobaric hypoxia on autoimmune and autoinflammatory diseases and explores the underlying molecular mechanisms. Using an environmental simulation chamber, we subjected mouse models of experimental autoimmune encephalomyelitis (EAE) and psoriasis to hypobaric hypoxia, simulating conditions at an altitude of 6000 m. Pathological analysis and flow cytometry demonstrated exacerbated disease severity and elevated Th17 cell levels. Given the established role of Th17 cells as key effector cells in autoimmune and autoinflammatory diseases, we further investigated their response through transcriptomic comparisons under normoxic and hypoxic conditions, which identified Activin A as a central regulator of hypoxia‐induced Th17 cell differentiation. In mice exposed to hypobaric hypoxia, pharmacological inhibition of Activin A significantly alleviated the severity of psoriasis. Western blotting, flow cytometry, and immunofluorescence analyses confirmed that under normoxic conditions, Activin A stimulation amplified the pathogenic Th17 cell molecular program, whereas blockade of p‐PKM2 or ERK signaling suppressed this effect. Collectively, our findings uncover a molecular mechanism whereby hypoxia‐triggered Activin A release drives pathogenic Th17 differentiation via the ERK pathway, promoting p‐PKM2 nuclear translocation and subsequent transcriptional activation of Th17 master regulators and effector cytokines. This study provides a theoretical foundation for understanding immune dysregulation at high altitudes and offers potential therapeutic strategies for mitigating high‐altitude‐associated immune disorders.
New research published in JAMA Internal Health has found significant declines in self‐reported mental health among mothers in the United States, with smaller declines in self‐reported physical health. New research published in JAMA Internal Health has found significant declines in self‐reported mental health among mothers in the United States, with smaller declines in self‐reported physical health.
An article recently published in the World Journal of Diabetes , provides valuable insights into using immune biomarkers to identify renal damage in pediatric patients with newly diagnosed type 1 … An article recently published in the World Journal of Diabetes , provides valuable insights into using immune biomarkers to identify renal damage in pediatric patients with newly diagnosed type 1 diabetes (T1D). Although these findings are promising, clinical translation of these immune markers into routine diagnostics and preventive care remains challenging. In this letter, we propose building on the authors’ work by exploring the integration of immune biomarkers into a more comprehensive dynamic risk stratification model for early renal injury. Combining immune system indicators with metabolic and genetic factors could enhance the predictive accuracy and support more personalized interventions. Longitudinal studies are needed to evaluate temporal changes in immune biomarkers and their association with long-term renal outcomes in children with T1Ds. Immunomodulatory therapies targeting early immune dysfunction can prevent or slow the progression of diabetic nephropathy. By incorporating these aspects, we hope to translate immune biomarkers from research into practical clinical tools, ultimately improving patient outcomes and reducing the burden of kidney-related complications in pediatric diabetes.
Insulin resistance is a condition wherein cells fail to adequately respond to insulin. It is a prevalent medical condition associated with several diseases, such as type 2 diabetes mellitus, metabolic … Insulin resistance is a condition wherein cells fail to adequately respond to insulin. It is a prevalent medical condition associated with several diseases, such as type 2 diabetes mellitus, metabolic syndrome, hypertension, obesity, and polycystic ovary syndrome. Insulin resistance may be involved in metabolic disturbances, such as hyperglycemia, hyperinsulinemia, dyslipidemia, hyperuricemia, endothelial dysfunction, elevated inflammatory markers, and a prothrombotic state. Severe insulin resistance syndromes are a heterogeneous group of rare disorders. These disorders are characterized by profound insulin resistance, substantial metabolic abnormalities, and different clinical manifestations and complications. They may be hereditary or acquired, caused by defects in insulin action and cellular responsiveness to insulin. Severe insulin resistance syndromes may also be due to aberrations in adipose tissue function and development. The majority of these disorders are associated with an increased risk of severe complications and mortality. This review aims to summarize the current knowledge on the epidemiology, pathophysiology, complications and prognosis of severe insulin resistance syndromes, as well as to categorize these syndromes by disease process, including defects in insulin receptor, intracellular insulin signaling defects, lipodystrophies, etc.
Introduction and Objective: Unprovoked ketosis-prone type 2 diabetes (KPD) is characterized by sudden onset of diabetic ketosis/ketoacidosis (DK/DKA) without precipitating factors, negative anti-islet autoantibodies, and preservation of β-cell function after … Introduction and Objective: Unprovoked ketosis-prone type 2 diabetes (KPD) is characterized by sudden onset of diabetic ketosis/ketoacidosis (DK/DKA) without precipitating factors, negative anti-islet autoantibodies, and preservation of β-cell function after recovery from DKA using intensive insulin therapy. Although the involvement of glucagon in the pathology of various types of diabetes has attracted attention, there have been few reports on the significance of glucagon in KPD. Methods: We aimed to clarify the significance of glucagon in the pathogenesis of KPD by measuring blood glucagon levels using ELISA method in 35 KPD persons (mean age 42.9 years, 32 males, mean disease duration 0.63 years). Results: Fasting blood glucagon and serum C-peptide levels were positively correlated in the KPD group (p&amp;lt;0.01), suggesting the involvement of α-cell dysfunction. A similar positive correlation was observed in acute-onset type 1 diabetes (AT1D) group (p&amp;lt;0.05). We previously reported the involvement of autoimmune response similar to that in AT1D could be shown in KPD, speculating that islet-related autoimmune responses may be involved in the α-cell dysfunction in KPD. Meanwhile, the relationship between glucagon secretion and amino acid metabolism in α-cell has recently attracted attention. Although blood branched-chain amino acid (BCAA) level is generally increased in a state of DKA, BCAA metabolism in α-cells is reportedly impaired in the presence of α-cell dysfunction, resulting in excessive secretion of glucagon. Thus, we investigated the relationship between blood glucagon and BCAA levels in 20 KPD persons (mean age 41.8 years, 17 males, mean disease duration 0.84 years), revealing a significant positive correlation between the two levels (p&amp;lt;0.05). Conclusion: Even if blood BCAA level is high at the onset of DKA, excessive glucagon secretion from α-cells may occur in KPD persons, suggesting the presence of α-cell dysfunction, and presumably leading to the development of ketosis in KPD easily. Disclosure A. Satomura: None. Y. Oikawa: None. S. Nakanishi: None. S. Suzuki: None. A. Shimada: Speaker's Bureau; Sanofi.
Introduction and Objective: Randomized Phase I-III human clinical trials of the bacillus Calmette-GuĆ©rin (BCG) vaccine, originally developed &amp;gt;100 yrs ago to prevent tuberculosis infection, suggest that BCG may protect humans … Introduction and Objective: Randomized Phase I-III human clinical trials of the bacillus Calmette-GuĆ©rin (BCG) vaccine, originally developed &amp;gt;100 yrs ago to prevent tuberculosis infection, suggest that BCG may protect humans from immune diseases such as type 1 diabetes (T1D) and from some infectious diseases. Immune and metabolic mechanisms account for BCG’s ability to regulate glucose control in T1D, including through correction of underlying aerobic glycolysis defects in white blood cells and gradual induction of regulatory T cells to suppress autoimmunity. Here we provide an update on our institution’s BCG programs. Methods: Over 600 patients with early onset T1D (&amp;lt; 21 yrs of age) have been enrolled in clinical protocols to test BCG’s ability to lower HbA1c, reduce insulin requirements and stabilize blood sugars; 364 have been treated. An additional study in T1D evaluates BCG’s ability to protect from infectious disease. Current pediatric studies use 2 BCG doses; adult trials use 6 doses. Results: Long-term follow-up of a completed, randomized, placebo-controlled Phase I clinical trial in adults with longstanding early onset T1D (no pancreas C-peptide) continues to show that HbA1c values are lowered for 8+ yrs after multi-dose BCG treatment. In two open-label clinical trials in adults with early onset T1D, HbA1c reduction of 10-15% was observed after multi-dose BCG treatment. A randomized, double-blind, placebo-controlled Phase II trial in adults with longstanding early or late onset T1D (n=150) has followed all patients for 5 yrs; read-out is pending. Phase II, double-blind, randomized, placebo-controlled pediatric trials are evaluating BCG in longstanding and new-onset T1D. Conclusion: BCG can work decades after T1D onset by changing glucose metabolism within lymphocytes, independently of the pancreas. Pediatric trials have the advantage of early age of onset and remaining pancreas function in some cases. BCG vaccine therapy may provide a safe and affordable medical intervention in longstanding T1D. Disclosure W. Kuhtreiber: None. J.L. Dorsey: None. N.G. Kartsounis: None. S.E. Bradley: None. E. Jones: None. A.J. Roberts: None. D.A. Mounier: None. H. Hayashi: None. K. Le: None. L. Adams: None. J. Braley: None. D.L. Faustman: None. Funding Iacocca Foundation
Introduction and Objective: Type 1 diabetes (T1D) is a classical autoimmune disorder. Intra-islet endothelial cells constitute the key barrier that separates Langerhans β cells from immune system, forming the so-called … Introduction and Objective: Type 1 diabetes (T1D) is a classical autoimmune disorder. Intra-islet endothelial cells constitute the key barrier that separates Langerhans β cells from immune system, forming the so-called islet endothelial immune interface (IEII). Though epigenetic remodeling related to environmental perturbation modifies T1D progression, its potential effect on IEII and the underlying mechanisms remain elusive. In our study, we attempt to elucidate the role of MBD2, the DNA methylation reader, in regulating IEII function and to explore the IEII-targeted T1D intervention strategy. Methods: Endothelial specific Mbd2-knockout mice and MS-1 cell line were used for the in vivo and in vitro studies. Then, CUT&amp;Tag sequencing, deep RNA sequencing, multi-color flow cytometry and immunofluorescent staining were carried out for mechanistic dissection. Results: Bioinformatic analysis of human islet single cell sequencing data revealed that the IEII of T1D patients exhibits lower Mbd2 expression along with enhanced ā€œTNFā€ and ā€œcell adhesionā€ pathways. Additionally, among the three major inflammatory cytokines (TNF-α, IL-1β, and IFN-γ), only TNF-α markedly changes the DNA methylation level of IEII. CUT&amp;Tag combined with deep RNA sequencing in TNF-α treated endothelial cells demonstrated that MBD2 ablation derepresses Ncoa1, which then serves as the transcription coactivator of NF-kB to enhance ICAM1 expression. In consistent, MBD2 knockout mice showed more severe pancreatic islet damage and immune cell infiltration, leading to higher diabetes incidence. Application of the Ncoa1 inhibitor bufalin reduces ICAM1 expression and strengthens the barrier function of IEII, thereby delaying the progression of T1D. Conclusion: To summarize, loss of MBD2 exacerbates TNF-α induced IEII adhesion through the upregulation of Ncoa1-NF-kB-ICAM1 pathway to accelerate T1D progression. IEII-targeted drugs, such as bufalin, hold great promise for clinic T1D management. Disclosure X. Li: None. R. Yang: None. F. Sun: None. R. Duan: None. Y. Zhao: None. L. Gao: None. C. Zhang: None. J. Li: None. C. Wang: None. S. Liu: None. Funding Department of Science and Technology of Shanxi Province (202404010920011, 202304021301066, 202204051002029); Shanxi Bethune Hospital (2024AOXIANG03)
Introduction and Objective: This study analyzes trends in Type 1 diabetes mellitus (T1DM) incidence, prevalence, mortality, and disability-adjusted life years (DALYs) in China from 1990 to 2021, with projections through … Introduction and Objective: This study analyzes trends in Type 1 diabetes mellitus (T1DM) incidence, prevalence, mortality, and disability-adjusted life years (DALYs) in China from 1990 to 2021, with projections through 2036. Methods: Data from the GBD 2021 study were used to calculate annual changes in age-standardized rates (ASRs) for T1DM via joinpoint regression. Age-period-cohort analysis assessed age, period, and cohort effects, while decomposition analysis examined demographic and epidemiological factors. Bayesian modeling projected trends to 2036. Results: From 1990 to 2021, new T1DM cases in China rose from 22,722 to 32,058, with age-standardized incidence increasing by 1.16% annually. Prevalence doubled to 1,442,775, with a 1.15% annual rise. Mortality fell from 5,732 to 3,960, and DALYs dropped from 328,727 to 248,596. The highest incidence was in children aged 5-9, while prevalence peaked in older adults. Males had a higher disease burden, with a narrowing gender gap in mortality and DALYs. Decomposition analysis showed that epidemiological factors were key drivers. Projections indicate continued increases in incidence and prevalence, especially among males, through 2036. Conclusion: T1DM burden has increased over the past three decades, especially among older adults and males, emphasizing the need for targeted interventions and improved healthcare infrastructure. Disclosure Z. Li: None. R. Duan: None. X. Chen: None. J. Li: None. W. Ren: None. X. Li: None. X. Fan: None. P. Yang: None. D. Yan: None. C. Wang: None. S. Liu: None. Funding Key Laboratory Construction Plan Project of Shanxi Province (202404010920011); Fundamental Research Program of Shanxi Province (202303021212330); Science and Technology Achievements Transformation and Guidance Special Program Project of Shanxi Province (202304021301066); Scientific Research Funding Project for Returned Overseas Scholars of Shanxi Province (2024-143); Special Program for Science and Technology Innovation Talent Teams of Shanxi Province (202204251002029); Metabolic Disease (Type 1 Diabetes) Clinical Medical Research Center Construction Project of Shanxi Province (20240410501001); National Key Technology Research and Development Program on Prevention and Treatment of Cancer, Cardiovascular and Cerebrovascular Diseases, Respiratory Diseases, and Metabolic Diseases (2023ZD0507302); Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital (2024AOXIANG03)
Introduction and Objective: People living with type 1 diabetes (pwT1D) are at risk for micro and macrovascular complications, mental health issues, as well as higher risk for additional autoimmune diseases … Introduction and Objective: People living with type 1 diabetes (pwT1D) are at risk for micro and macrovascular complications, mental health issues, as well as higher risk for additional autoimmune diseases (AD+). We aimed to understand the association between additional ADs and T1D related physical and mental burdens in Canadian adults. Methods: This was a cross-sectional study using data from the BEhaviors, Therapies, TEchnologies, and hypoglycemic Risk in T1D (BETTER) registry of adults (≄18 years) living with T1D. We compared reported prevalence of micro and macrovascular complications, hypoglycemia, and mental health questionnaire (PHQ-9 and DDS) scores between those with T1D alone and T1D with AD+. Results: Our study included 3222 participants (66.2% female, age 42.7 +/-15.0 years); 36.3% of respondents reported ≄1 additional AD and this AD+ group was older (+4.4 years) with a higher percentage of females (77.5%). pwT1D from AD+ group had similar HbA1c (p=0.20) but were more likely to report hypoglycemia: level 2 in the past month (OR: 1.27 [95%Cl 1.06-1.52]) and level 3 hypoglycemia (1.22 [1.05-1.42]) since diagnosis. The presence of additional ADs was associated with more chronic complications (cardiovascular disease, retinopathy, neuropathy, nephropathy, gastroparesis) (1.38-1.49), higher depression scores (p=0.015) and anxiety/depression medication use (1.31 [1.10-1.56]). However, there was no effect on diabetes distress score (DDS) (p=0.14). Higher number of ADs was associated with higher depression scores (p=0.03) and higher number of chronic complications (p&amp;lt;0.0001). Conclusion: Having additional ADs with T1D is associated with higher levels of both physical and mental complications of T1D. Disclosure C.A.A. Locatelli: None. M.K. Talbo: Other Relationship; Dexcom, Inc. V. Messier: None. R.P.R. Rabasa-Lhoret: Advisory Panel; Abbott, Eli Lilly and Company, Novo Nordisk, Sanofi, Insulet Corporation. Other Relationship; Medtronic. Advisory Panel; Bayer Pharmaceuticals, Inc. Funding The BETTER registry is supported by grants from the Canadian Institutes of Health Research (grant number JT1- 157204); Breakthrough T1D Canada (grant number 3- SRA-2024-1523-M-N); and DiabĆØte QuĆ©bec as well as through non-restrictive grants from Eli Lilly Canada Inc., Novo Nordisk Canada and Sanofi-Aventis Canada and a donation from Dexcom Canada.
Introduction and Objective: Prevalence of type 2 diabetes (T2D) in children is increasing, and this condition can have a substantial impact on children’s lives. Existing patient reported outcome (PRO) measures … Introduction and Objective: Prevalence of type 2 diabetes (T2D) in children is increasing, and this condition can have a substantial impact on children’s lives. Existing patient reported outcome (PRO) measures may not be sensitive to differences among the newer treatments for pediatric diabetes. This qualitative study was designed to explore the impact of T2D among pediatric patients and to support the development of a questionnaire to assess the impact of T2D in this population. Methods: Qualitative concept elicitation interviews were conducted with children and adolescents with T2D and their caregivers to identify the impact of T2D and its treatment. Results were used to inform the development of a child-report questionnaire assessing the impact of pediatric T2D. This questionnaire was then evaluated in interviews with pediatric patients with T2D. Results: The concept elicitation interviews included 13 pediatric patients with T2D (mean age = 14.2 years; 61.5% male) and their caregivers (mean age = 44.5 years; 76.9% female). Respondents reported broad areas of impact including eating, emotional functioning, school, family relationships, activities, social life, and overall health. Patients also reported opinions on their treatment including ease of use, blood glucose control, and weight control. A new PRO measure, the Pediatric Type 2 Diabetes Impact Measure (P-TIM), was developed based on these findings. The questionnaire was refined based on interviews with 10 participants with pediatric T2D (mean age = 15.0 years; 50% female). Results suggest that the final instrument is clear, comprehensive, and relevant to patients. Conclusion: Results support the content validity of the P-TIM, which was designed to assess the impact of T2D and its treatment, including concepts that are relevant to newer medications (e.g., weight control). The P-TIM may be useful for evaluating the impact of treatment for children and adolescents with T2D. Disclosure K. Boye: None. L.S. Matza: Other Relationship; Evidera. K. Stewart: Other Relationship; Evidera. M. Stefan: Other Relationship; Evidera. L. Hetherington: Other Relationship; Evidera. Funding This study was funded by Eli Lilly and Company. Evidera received funds from Eli Lilly and Company to conduct this study.
Introduction and Objective: We asked whether insulin (Ins) and C-peptide (C-P) kinetics (β-cell residence times [RT}} measured from islets vs plasma correlate closely Methods: 2H2 O was given for 3 … Introduction and Objective: We asked whether insulin (Ins) and C-peptide (C-P) kinetics (β-cell residence times [RT}} measured from islets vs plasma correlate closely Methods: 2H2 O was given for 3 - 18 hr to 32 female ZDF rats fed high fat diet (to induce T2D) or chow. RT of Ins and C-P were measured by high-resolution mass spectrometry Results: Ins labeling in islets vs plasma correlate closely (r2 0.91 - 0.96, p&amp;lt;0.0001, Fig 1). RT of islet Ins is significantly shorter in T2D (3.4 hr) vs. non-T2D (8.6 hr, p &amp;lt;0.0001). New plasma Ins is 10-20% higher than islets (Fig. 2). C-P gave similar results Fig 1. New Ins in islets vs. plasma (n=16/ group) Fig.2. Difference between new Ins in plasma and islets (n= 4 - 6/time point) Conclusion: Ins and C-P kinetics in plasma accurately reflect kinetics and RT in islets. A higher fraction new insulin in plasma than islets indicates some direct secretion without mixing into islet storage pools Disclosure E.J. Zanley: None. J. Willency: Employee; Eli Lilly and Company. J.V. Ficorilli: Employee; Eli Lilly and Company. K.L. Duffin: None. V. Pirro: Employee; Eli Lilly and Company. J. Perfield: Employee; Eli Lilly and Company. O. Cabrera: Employee; Eli Lilly and Company. M.K. Hellerstein: Research Support; Lilly USA LLC. Consultant; Lilly USA LLC. Funding Lilly LRAP
Introduction and Objective: DKA at the time of first presentation of T1DM is preventable. The aim of this study was to determine the proportion of individuals with a new onset … Introduction and Objective: DKA at the time of first presentation of T1DM is preventable. The aim of this study was to determine the proportion of individuals with a new onset T1DM, by race and ethnicity, presenting with DKA in a large integrated healthcare system based in Northern California (Sutter Health). Methods: ICD-9 and ICD-10 codes were used to identify adults and children with DKA one month either side of a new diagnosis of T1DM, between January 2016 and September 2024. T1DM cases were identified using prescription for insulin and relevant codes in the electronic health record problem list, or billing data. Testing for the difference in proportion of T1DM patients with DKA were made using the Pearson Chi-Square test. Results: Of 10,956 new T1DM patients, 699 (6.4%) had a co-diagnosis of DKA within one month of a first diagnosis of T1DM. Rates of T1DM presenting with DKA were different by race/ethnicity (p&amp;lt;0.0001) comparing White (5.9%) vs Hispanic (7.8%), Black (10.2%), and Asian (6.6%) patients. Across age groups, the rate of DKA within one month of a first diagnosis of T1DM was highest among those aged 18-25 years (p&amp;lt;0.0001). Conclusion: The risk of DKA at the first presentation of T1DM varies by race and ethnicity. As DKA is preventable, greater efforts are required to reduce this disproportionate risk especially for communities of color. Disclosure S. Mudiganti: None. P. Kenkare: None. D. Kerr: None.
Introduction and Objective: EVs are membrane-bound nanoparticles that contribute to cell:cell communication. β cell EV PD-L1 protein is increased by interferon (IFN) exposure and is able to bind and inactivate … Introduction and Objective: EVs are membrane-bound nanoparticles that contribute to cell:cell communication. β cell EV PD-L1 protein is increased by interferon (IFN) exposure and is able to bind and inactivate CD8+ T cells, suggesting a role in the interplay between β cell destruction and survival in T1D. However, mechanisms underlying β cell PD-L1 incorporation into EVs and its physiological effects are not completely understood. Methods: NIT-1 β cells were transfected with siRNA for STAT1+2 (vs. scramble control), then treated with 24h 2000 U/mL IFN-α (vs. vehicle). Murine NIT-1 β cells were transfected with PD-L1 to make PD-L1 overexpressing (PD-L1 OE) EVs. Anti-CD3 and CD28-activated nonobese diabetic mouse (NOD) splenocytes were treated with PD-L1 OE EVs. Flow cytometry-based assays tested functional impacts on CD4+ T cells. To test translational relevance, EV PD-L1 was quantified in pancreas slice perifusate from human organ donors with (n=11) or without (n=12) T1D using the ExoView-R200 imaging platform. Results: IFN-α treatment doubled β cell EV PD-L1 cargo without increasing EV numbers; this increase was abrogated by genetic STAT1/STAT2 inhibition. Compared to wild-type EVs, PD-L1 OE EVs suppressed CD4+ T cell proliferation (0.4-fold reduction in CTV dye dilution) and decreased CD69 and CD25 activation marker expression. Anti-PD-L1 antibody pre-treatment reversed these effects, confirming a specific role for EV PD-L1 in CD4+ T cell suppression. Pancreas slice EVs exhibited significant heterogeneity in EV PD-L1 content, but overall EV PD-L1 was increased in donors with T1D vs. nondiabetic controls. Conclusion: β cell EV PD-L1 is increased in pancreas slice perifusate from donors with T1D. STAT pathway activation is required for IFN-induced β cell EV PD-L1 shuttling. Increased β cell EV PD-L1 modulates CD8+ and CD4+ T cells, suggesting a key role in the β cell:immune system dialogue surrounding β cell destruction in T1D. Disclosure I. Amalaraj: None. C. Rao: None. S. Roy: None. J. Piganelli: None. E.K. Sims: Consultant; Sanofi. Speaker's Bureau; Med Learning Group. Other Relationship; American Diabetes Association.