110-OR: Type 2 Diabetes (T2D)–Associated TCF7L2 Genetic Variants and Indices of Insulin Secretion and Sensitivity in Individuals at Risk for Type 1 Diabetes (T1D)

AbstractDiabetes mellitus is a complex metabolic disorder, caused by defects in insulin action and/or insulin production and is defined as afasting hyperglycaemia of >126 mg/dl, with normoglycaemia being ≥70 and ≤ 110 mg/dl. There are two main types of diabetes. Type 1 diabetes (around 10% of cases) is an autoimmune disease, usually of early onset, in which pancreatic islet beta cells that secrete insulin are destroyed. Type 2 diabetes (around 85% of cases) is characterised principally by insulin resistance and impaired insulin secretion. Heredity and obesity are major risk factors for Type 2 diabetes. Diabetes is associated with potentially life-threatening microvascular and macrovascular complications caused by elevated serum glucose levels. Treatment of diabetes aims at restoring glycaemic control. In Type 1 diabetes, this can be achieved by injecting insulin. Oral hypoglycaemic medications that stimulate insulin secretion and/or modify glucose metabolism can be used as a first-line treatment in Type 2 diabetes mellitus. However, insulin is usually necessary in later phases of the disease. Lifestyle changes, such as diet and exercise, are also important. Glycaemic control can be measured by fasting blood glucose levels and also by glycosylated haemoglobin levels. The latter measure gives an indication of glycaemic control over a period of three months, and a reduction in glycosylated haemoglobin is the most appropriate treatment goal in the management of diabetes.

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TCF7L2 Genetic Variants do not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-positive Individuals at Risk for Type 1 Diabetes

10.2337/figshare.14770083 ◽

2021 ◽

Author(s):

Maria J. Redondo ◽

Megan V. Warnock ◽

Ingrid M. Libman ◽

Laura E. Bocchino ◽

David Cuthbertson ◽

...

Keyword(s):

At Risk ◽

Type 1 Diabetes ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Genetic Variants ◽

Disposition Index ◽

Oral Glucose ◽

Z Score ◽

C Peptide

Objective: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). Research Design and Methods: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (n=1,061; mean age=16.3 years) with TCF7L2 SNP information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, p-values <0.0086 were considered statistically significant. Results: None, one and two T2D-linked TCF7L2 alleles were present, respectively, in 48.1%, 43.9% and 8.0% of the participants. Insulin sensitivity (as reflected by 1/IF) decreased with increasing BMI-Z-score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI-Z-score. Oral disposition index was negatively correlated with age, BMI-Z-score and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariate analysis models with age, BMI Z-score, ethnicity, sex and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI Z-score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/IF) and lower disposition index; there was no significant effect of the TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with normal OGTT (n=743, 70%), the results were similar. Conclusions: In non-diabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI-Z-score, age, sex and ethnicity.

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Minireview: Glucagon in the Pathogenesis of Hypoglycemia and Hyperglycemia in Diabetes

Endocrinology ◽

10.1210/en.2011-1499 ◽

2012 ◽

Vol 153 (3) ◽

pp. 1039-1048 ◽

Cited By ~ 121

Author(s):

Philip E. Cryer

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Insulin Secretion ◽

Pancreatic Islet ◽

Plasma Glucose ◽

Glucose Concentration ◽

Glucagon Secretion ◽

Β Cell

Pancreatic islet α-cell glucagon secretion is critically dependent on pancreatic islet β-cell insulin secretion. Normally, a decrease in the plasma glucose concentration causes a decrease in β-cell insulin secretion that signals an increase in α-cell glucagon secretion during hypoglycemia. In contrast, an increase in the plasma glucose concentration, among other stimuli, causes an increase in β-cell insulin secretion that signals a decrease, or at least no change, in α-cell glucagon secretion after a meal. In absolute endogenous insulin deficiency (i.e. in type 1 diabetes and in advanced type 2 diabetes), however, β-cell failure results in no decrease in β-cell insulin secretion and thus no increase in α-cell glucagon secretion during hypoglycemia and no increase in β-cell insulin secretion and thus an increase in α-cell glucagon secretion after a meal. In type 1 diabetes and advanced type 2 diabetes, the absence of an increment in glucagon secretion, in the setting of an absent decrement in insulin secretion and an attenuated increment in sympathoadrenal activity, in response to falling plasma glucose concentrations plays a key role in the pathogenesis of iatrogenic hypoglycemia. In addition, there is increasing evidence that, in the aggregate, suggests that relative hyperglucagonemia, in the setting of deficient insulin secretion, plays a role in the pathogenesis of hyperglycemia in diabetes. If so, abnormal glucagon secretion is involved in the pathogenesis of both hypoglycemia and hyperglycemia in diabetes.

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TYK2 Promoter Variant Is Associated with Impaired Insulin Secretion and Lower Insulin Resistance in Japanese Type 2 Diabetes Patients

Genes ◽

10.3390/genes12030400 ◽

2021 ◽

Vol 12 (3) ◽

pp. 400

Author(s):

Hitoe Mori ◽

Hirokazu Takahashi ◽

Keiichiro Mine ◽

Ken Higashimoto ◽

Kanako Inoue ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Insulin Secretion ◽

Fasting Insulin ◽

C Peptide ◽

Impaired Insulin ◽

Diabetes Patients

Accumulating evidence has suggested that viral infection causes type 1 diabetes due to direct β-cell damage and the triggering of autoimmune reactivity to β cells. Here, we elucidated that the tyrosine kinase 2 (Tyk2) gene, encoding an interferon receptor signaling molecule, is responsible for virus-induced diabetes in mice, and its promoter variant confers a risk of type 1 diabetes in humans. This study investigated the relationship between a TYK2 promoter variant (TYK2PV) and insulin secretion in type 2 diabetes patients. TYK2PV status was determined using direct DNA sequencing and its associations with fasting insulin, C-peptide, and homeostatic model assessment of insulin resistance (HOMA-IR) were evaluated in type 2 diabetes patients without sulfonylurea or insulin medication. Of the 172 patients assessed, 18 (10.5%) showed TYK2PV-positivity. Their body mass index (BMI) was significantly lower than in those without the variant (23.4 vs. 25.4 kg/m2, p = 0.025). Fasting insulin (3.9 vs. 6.2 μIU/mL, p = 0.007), C-peptide (1.37 vs. 1.76 ng/mL, p = 0.008), and HOMA-IR (1.39 vs. 2.05, p = 0.006) were lower in those with than in those without the variant. Multivariable analysis identified that TYK2PV was associated with fasting insulin ≤ 5 μIU/mL (odds ratio (OR) 3.63, p = 0.025) and C-peptide ≤ 1.0 ng/mL (OR 3.61, p = 0.028), and also lower insulin resistance (HOMA-IR ≤ 2.5; OR 8.60, p = 0.042). TYK2PV is associated with impaired insulin secretion and low insulin resistance in type 2 diabetes. Type 2 diabetes patients with TYK2PV should be carefully followed in order to receive the appropriate treatment including insulin injections.

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TCF7L2 Genetic Variants do not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-positive Individuals at Risk for Type 1 Diabetes

10.2337/figshare.14770083.v2 ◽

2021 ◽

Author(s):

Maria J. Redondo ◽

Megan V. Warnock ◽

Ingrid M. Libman ◽

Laura E. Bocchino ◽

David Cuthbertson ◽

...

Keyword(s):

At Risk ◽

Type 1 Diabetes ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Genetic Variants ◽

Disposition Index ◽

Oral Glucose ◽

Z Score ◽

C Peptide

Objective: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). Research Design and Methods: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (n=1,061; mean age=16.3 years) with TCF7L2 SNP information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, p-values <0.0086 were considered statistically significant. Results: None, one and two T2D-linked TCF7L2 alleles were present, respectively, in 48.1%, 43.9% and 8.0% of the participants. Insulin sensitivity (as reflected by 1/IF) decreased with increasing BMI-Z-score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI-Z-score. Oral disposition index was negatively correlated with age, BMI-Z-score and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariate analysis models with age, BMI Z-score, ethnicity, sex and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI Z-score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/IF) and lower disposition index; there was no significant effect of the TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with normal OGTT (n=743, 70%), the results were similar. Conclusions: In non-diabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI-Z-score, age, sex and ethnicity.

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