The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing beta-Cell Function and Hepatic Insulin Sensitivity

Objective Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional. Design and methods We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers. Results Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin. Conclusions Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function.

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Ameliorative Effects of Probiotic Lactobacillus paracasei NL41 on Insulin Sensitivity, Oxidative Stress, and Beta‐Cell Function in a Type 2 Diabetes Mellitus Rat Model

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201900457 ◽

2019 ◽

Vol 63 (22) ◽

pp. 1900457 ◽

Cited By ~ 6

Author(s):

Zhu Zeng ◽

Qipeng Yuan ◽

Rui Yu ◽

Jinlan Zhang ◽

Huiqin Ma ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Insulin Sensitivity ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Probiotic Lactobacillus

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Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa863 ◽

2020 ◽

Author(s):

Melissa K Thomas ◽

Amir Nikooienejad ◽

Ross Bray ◽

Xuewei Cui ◽

Jonathan Wilson ◽

...

Keyword(s):

Type 2 Diabetes ◽

Regression Analysis ◽

Insulin Sensitivity ◽

Beta Cell ◽

Beta Cell Function ◽

Receptor Agonist ◽

Cell Function ◽

Linear Regression Analysis ◽

Multiple Linear Regression Analysis

Abstract Context Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide. Objective Explore mechanisms of glucose control by tirzepatide. Design Post hoc analyses of fasting biomarkers and multiple linear regression analysis. Setting Forty-seven sites in 4 countries. Patients or other Participants Three hundred and sixteen subjects with type 2 diabetes. Interventions Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo. Main Outcome Measures Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks. Results Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively. Conclusions Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.

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Estimating insulin sensitivity and beta cell function: perspectives from the modern pandemics of obesity and type 2 diabetes

Diabetologia ◽

10.1007/s00125-012-2684-0 ◽

2012 ◽

Vol 55 (11) ◽

pp. 2863-2867 ◽

Cited By ~ 16

Author(s):

J. J. Nolan ◽

K. Færch

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function

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Role of exercise on insulin sensitivity and beta-cell function: is exercise sufficient for the prevention of youth-onset type 2 diabetes?

Annals of Pediatric Endocrinology & Metabolism ◽

10.6065/apem.2040140.070 ◽

2020 ◽

Vol 25 (4) ◽

pp. 208-216

Author(s):

Joon Young Kim ◽

Justin Y. Jeon

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Onset Type

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Obstructive Sleep Apnea, Glucose Tolerance, and β-Cell Function in Adults With Prediabetes or Untreated Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study

10.2337/figshare.13607591.v1 ◽

2021 ◽

Author(s):

Babak Mokhlesi ◽

Ashley H. Tjaden ◽

Karla A. Temple ◽

Sharon L. Edelstein ◽

Susan Sam ◽

...

Keyword(s):

Type 2 Diabetes ◽

Obstructive Sleep Apnea ◽

Insulin Sensitivity ◽

Beta Cell ◽

Sleep Duration ◽

Beta Cell Function ◽

Cell Function ◽

Cell Responses ◽

Obstructive Sleep

Objective: Obstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet beta-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with beta-cell function in overweight/obese adults with prediabetes or recently-diagnosed, treatment-naïve type 2 diabetes. Research Design and Methods: 221 adults (57.5% men, age 54.5±8.7 years, BMI 35.1±5.5 kg/m2) completed one week of wrist actigraphy and one night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA1c, OGTT-derived and clamp-derived outcomes were evaluated with adjusted regression models. Results: Mean±SD objective sleep duration by actigraphy was 6.6±1.0 hours/night. OSA defined as an apnea-hypopnea index (AHI) ≥5 events per hour was present in 89% of the participants; 20% mild, 28% moderate and 41% severe. Higher AHI was associated with higher HbA1c (p =0.007). However, OSA severity, measured by either AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or <6 h vs. ≥6 h) were not associated with fasting glucose, 2-h glucose, insulin sensitivity or beta-cell responses. Conclusion: In this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently-diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or beta-cell responses.

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Increased Risk for Type 2 Diabetes in Relation to Adiposity in Middle-Aged Black South African Men compared to Women

10.1101/2021.10.19.21265228 ◽

2021 ◽

Author(s):

Clement Kufe ◽

Lisa Micklesfield ◽

maphoko Masemola ◽

Tinashe Chikowore ◽

Andre-Pascal Kengne ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Beta Cell ◽

South African ◽

Beta Cell Function ◽

Cell Function ◽

C Peptide ◽

Black South African ◽

Regional Adiposity

Aims: Despite a higher prevalence of overweight and obesity in black South African women compared to men, the prevalence of type 2 diabetes does not differ. We explored if this could be due to sex differences in insulin sensitivity, clearance and or beta cell function, and also sex-specific associations with total and regional adiposity. Methods: This cross-sectional study included 804 black South African men (n=388) and women (n=416). Dual-energy x ray absorptiometry was used to measure total and regional adiposity. Insulin sensitivity (Matsuda index), secretion (C peptide index) and clearance (C peptide/insulin ratio) were estimated from an oral glucose tolerance test. Results: After adjusting for sex differences in fat mass index, men were less insulin sensitive and had lower beta cell function than women (p<0.001), with the strength of the associations with measures of total and central adiposity being greater in men than women (p<0.001 for interactions). Further, the association between total adiposity and type 2 diabetes risk was also greater in men than women (relative risk ratio (95% confidence interval): 2.05 (1.42 to 2.96), p<0.001 vs. 1.38 (1.03 to 1.85), p=0.031). Conclusion: With increasing adiposity, particularly increased centralisation of body fat linked to decreased insulin sensitivity and beta cell function, Black African men are at greater risk for type 2 diabetes than their female counterparts.

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