Association of single nucleotide polymorphisms with insulin secretion, insulin sensitivity, and diabetes in women with a history of gestational diabetes mellitus

Background This study investigated whether single nucleotide polymorphisms (SNPs) reported by previous genome-wide association studies (GWAS) to be associated with impaired insulin secretion, insulin resistance, and/or type 2 diabetes are associated with disposition index, the homeostasis model assessment of insulin resistance (HOMA-IR), and/or development of diabetes following a pregnancy complicated by gestational diabetes mellitus (GDM). Methods Seventy-two SNPs were genotyped in 374 women with previous GDM from Southern Sweden. An oral glucose tolerance test was performed 1–2 years postpartum, although data on the diagnosis of diabetes were accessible up to 5 years postpartum. HOMA-IR and disposition index were used to measure insulin resistance and secretion, respectively. Results The risk A-allele in the rs11708067 polymorphism of the adenylate cyclase 5 gene (ADCY5) was associated with decreased disposition index (beta = − 0.90, SE 0.38, p = 0.019). This polymorphism was an expression quantitative trait loci (eQTL) in islets for both ADCY5 and its antisense transcript. The risk C-allele in the rs2943641 polymorphism, near the insulin receptor substrate 1 gene (IRS1), showed a trend towards association with increased HOMA-IR (beta = 0.36, SE 0.18, p = 0.050), and the T-allele of the rs4607103 polymorphism, near the ADAM metallopeptidase with thrombospondin type 1 motif 9 gene (ADAMTS9), was associated with postpartum diabetes (OR = 2.12, SE 0.22, p = 0.00055). The genetic risk score (GRS) of the top four SNPs tested for association with the disposition index using equal weights was associated with the disposition index (beta = − 0.31, SE = 0.29, p = 0.00096). In addition, the GRS of the four SNPs studied for association with HOMA-IR using equal weights showed an association with HOMA-IR (beta = 1.13, SE = 0.48, p = 9.72874e−11). All analyses were adjusted for age, body mass index, and ethnicity. Conclusions This study demonstrated the genetic susceptibility of women with a history of GDM to impaired insulin secretion and sensitivity and, ultimately, to diabetes development.

Relationship Between Insulin Secretion and Insulin Sensitivity and its Role in Development of Type 2 Diabetes Mellitus: Beyond the Disposition Index

We assessed whether the relationship between insulin secretion and sensitivity predicted development of type 2 diabetes in American Indians participating in a longitudinal epidemiologic study. At baseline, when all subjects did not have diabetes, 1566 participants underwent oral tests and 420 had intravenous measures of glucose regulation with estimates of insulin secretion and sensitivity. Standardized major axis regression was used to study the relationship of secretion and sensitivity. Distances away from and along the regression line estimated compensatory insulin secretion and secretory demand, respectively. This relationship differed according to glucose tolerance and BMI categories. The distance away from the line is similar to the disposition index (DI) defined as the product of estimated secretion and sensitivity, but the regression line may differ from a line with constant DI (i.e., it is not necessarily hyperbolic). Subjects with the same DI but different levels of insulin secretion and sensitivity had different incidence rates of diabetes; lower sensitivity with higher secretory demand was associated with greater diabetes risk. Insulin secretion and insulin sensitivity, analyzed together, predict diabetes better than DI alone. Physiologically, this may reflect long-term risk associated with increased allostatic load resulting from the stimulation of insulin hypersecretion by increased glycemia.

Relationship Between Insulin Secretion and Insulin Sensitivity and its Role in Development of Type 2 Diabetes Mellitus: Beyond the Disposition Index

We assessed whether the relationship between insulin secretion and sensitivity predicted development of type 2 diabetes in American Indians participating in a longitudinal epidemiologic study. At baseline, when all subjects did not have diabetes, 1566 participants underwent oral tests and 420 had intravenous measures of glucose regulation with estimates of insulin secretion and sensitivity. Standardized major axis regression was used to study the relationship of secretion and sensitivity. Distances away from and along the regression line estimated compensatory insulin secretion and secretory demand, respectively. This relationship differed according to glucose tolerance and BMI categories. The distance away from the line is similar to the disposition index (DI) defined as the product of estimated secretion and sensitivity, but the regression line may differ from a line with constant DI (i.e., it is not necessarily hyperbolic). Subjects with the same DI but different levels of insulin secretion and sensitivity had different incidence rates of diabetes; lower sensitivity with higher secretory demand was associated with greater diabetes risk. Insulin secretion and insulin sensitivity, analyzed together, predict diabetes better than DI alone. Physiologically, this may reflect long-term risk associated with increased allostatic load resulting from the stimulation of insulin hypersecretion by increased glycemia.

Impact of Lifestyle Behaviors on Postprandial Hyperglycemia during Continuous Glucose Monitoring in Adult Males with Overweight/Obesity but without Diabetes

Data regarding hyperglycemia-related factors were scarce in people without diabetes. Fifty males (age 50–65 years) with overweight/obesity but without diagnosis of diabetes were recruited. After excluding participants with the 2 h plasma glucose value during a 75 g oral glucose tolerance test ≥200 mg/dL, continuous glucose monitoring (CGM) was performed for 6 days. Subjects with ≥1800 CGM readings were included (n = 36). The CGM indices of hyperglycemia were significantly associated with disposition index and snacking frequency. In receiver-operating characteristic analysis for predicting the maximal CGM glucose ≥200 mg/dL, the area under curves of disposition index, snacking frequency, and minimal daily step counts during the study were 0.69, 0.63, and 0.68, whereas the cutoff values were 1.57, once daily, and 2499 steps, respectively. After adjustments, the lower disposition index (≤1.57), higher snacking frequency (≥1 per day), and lower minimal step (≤2499 steps per day) categories conferred 14.5, 14.5, and 6.6-fold increased probabilities for having the maximum level ≥ 200 mg/dL, respectively. In addition, the snacking habits were significantly associated with insulin resistance and compensatory hyperinsulinemia. In conclusion, in middle aged males with overweight/obesity but without diabetes, snacking and physical inactivity serve as the major drivers of postprandial hyperglycemia independently of β-cell function.

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

<p><b>Objective</b>: We aimed to test whether type 2 diabetes (T2D)-associated <i>TCF7L2</i> genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D).</p> <p><b>Research Design and Methods</b>: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (n=1,061; mean age=16.3 years) with <i>TCF7L2</i> 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. </p> <p><b>Results</b>: None, one and two T2D-linked <i>TCF7L2</i> alleles were present, respectively, in 48.1%, 43.9% and 8.0% of the participants. Insulin sensitivity (as reflected by 1/I_F) 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 <i>TCF7L2</i> SNPs. In multivariate analysis models with age, BMI Z-score, ethnicity, sex and <i>TCF7L2 </i>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/I_F) and lower disposition index; there was no significant effect of the <i>TCF7L2</i> SNPs on any of these indices. When restricting the analyses to participants with normal OGTT (n=743, 70%), the results were similar.</p> <p><b>Conclusions</b>: In non-diabetic autoantibody-positive individuals, <i>TCF7L2</i><i> </i>SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI-Z-score, age, sex and ethnicity. </p>

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

<p><b>Objective</b>: We aimed to test whether type 2 diabetes (T2D)-associated <i>TCF7L2</i> genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D).</p> <p><b>Research Design and Methods</b>: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (n=1,061; mean age=16.3 years) with <i>TCF7L2</i> 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. </p> <p><b>Results</b>: None, one and two T2D-linked <i>TCF7L2</i> alleles were present, respectively, in 48.1%, 43.9% and 8.0% of the participants. Insulin sensitivity (as reflected by 1/I_F) 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 <i>TCF7L2</i> SNPs. In multivariate analysis models with age, BMI Z-score, ethnicity, sex and <i>TCF7L2 </i>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/I_F) and lower disposition index; there was no significant effect of the <i>TCF7L2</i> SNPs on any of these indices. When restricting the analyses to participants with normal OGTT (n=743, 70%), the results were similar.</p> <p><b>Conclusions</b>: In non-diabetic autoantibody-positive individuals, <i>TCF7L2</i><i> </i>SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI-Z-score, age, sex and ethnicity. </p>

Defining the Relative Role of Insulin Clearance in Early Dysglycemia in Relation to Insulin Sensitivity and Insulin Secretion: The Microbiome and Insulin Longitudinal Evaluation Study (MILES)

Insulin resistance and insufficient insulin secretion are well-recognized contributors to type 2 diabetes. A potential role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining decreased insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in a cohort of 353 non-Hispanic White and African American individuals recruited in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Regression models examined the individual and joint contributions of these traits to early dysglycemia (prediabetes or newly diagnosed diabetes). In separate models, reduced insulin sensitivity, reduced disposition index, and reduced insulin clearance were associated with dysglycemia. In a joint model, only insulin resistance and reduced insulin secretion were associated with dysglycemia. Models with insulin sensitivity, disposition index, or three insulin traits had the highest discriminative value for dysglycemia (area under the receiver operating characteristics curve of 0.82 to 0.89). These results suggest that in the race groups studied, insulin resistance and compromised insulin secretion are the main independent underlying defects leading to early dysglycemia.