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Effects of Treatment of Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes With Metformin Alone or in Combination With Insulin Glargine on ?-Cell Function: Comparison of Responses In Youth And Adults.

ABSTRACT: ?-Cell dysfunction is central to the pathogenesis of impaired glucose tolerance (IGT) and type 2 diabetes. Compared with adults, youth have hyperresponsive ?-cells and their decline in ?-cell function appears to be more rapid. However, there are no direct comparisons of ?-cell responses to pharmacological intervention between the two age-groups. The Restoring Insulin Secretion (RISE) Adult Medication Study and the RISE Pediatric Medication Study compared interventions to improve or preserve ?-cell function. Obese youth (n = 91) and adults (n = 132) with IGT or recently diagnosed type 2 diabetes were randomized to 3 months of insulin glargine followed by 9 months of metformin, or 12 months of metformin. Hyperglycemic clamps conducted at baseline, after 12 months of medication, and 3 months after medication withdrawal assessed ?-cell function as steady-state and maximal C-peptide responses adjusted for insulin sensitivity. Temporal changes in ?-cell function were distinctly different. In youth, ?-cell function deteriorated during treatment and after treatment withdrawal, with no differences between treatment groups. In adults, ?-cell function improved during treatment, but this was not sustained after treatment withdrawal. The difference in ?-cell function outcomes in response to medications in youth versus adults supports a more adverse trajectory of ?-cell deterioration in youth.

SUBMITTER: RISE Consortium

PROVIDER: S-EPMC6692818 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Effects of Treatment of Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes With Metformin Alone or in Combination With Insulin Glargine on β-Cell Function: Comparison of Responses In Youth And Adults.

Diabetes 20190609 8

β-Cell dysfunction is central to the pathogenesis of impaired glucose tolerance (IGT) and type 2 diabetes. Compared with adults, youth have hyperresponsive β-cells and their decline in β-cell function appears to be more rapid. However, there are no direct comparisons of β-cell responses to pharmacological intervention between the two age-groups. The Restoring Insulin Secretion (RISE) Adult Medication Study and the RISE Pediatric Medication Study compared interventions to improve or preserve β-ce ...[more]

PMID: 31178433

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Project description:The presence of islet autoantibodies and islet reactive T cells (T+) in adults with established type 2 diabetes (T2D) have been shown to identify those patients with more severe β-cell dysfunction. However, at what stage in the progression toward clinical T2D does islet autoimmunity emerge as an important component influencing β-cell dysfunction? In this ancillary study to the Restoring Insulin SEcretion (RISE) Study, we investigated the prevalence of and association with β-cell dysfunction of T+ and autoantibodies to the 65 kDa glutamic acid decarboxylase antigen (GADA) in obese pre-diabetes adults with impaired glucose tolerance (IGT) and recently diagnosed treatment naïve (Ndx) T2D. We further investigated the effect of 12 months of RISE interventions (metformin or liraglutide plus metformin, or with 3 months of insulin glargine followed by 9 months of metformin or placebo) on islet autoimmune reactivity. We observed GADA(+) in 1.6% of NdxT2D and 4.6% of IGT at baseline, and in 1.6% of NdxT2D and 5.3% of IGT at 12 months, but no significant associations between GADA(+) and β-cell function. T(+) was observed in 50% of NdxT2D and 60.4% of IGT at baseline, and in 68.4% of NdxT2D and 83.9% of IGT at 12 months. T(+) NdxT2D were observed to have significantly higher fasting glucose (p = 0.004), and 2 h glucose (p = 0.0032), but significantly lower steady state C-peptide (sscpep, p = 0.007) compared to T(-) NdxT2D. T(+) IGT participants demonstrated lower but not significant (p = 0.025) acute (first phase) C-peptide response to glucose (ACPRg) compared to T(-) IGT. With metformin treatment, T(+) participants were observed to have a significantly lower Hemoglobin A1c (HbA1c, p = 0.002) and fasting C-peptide (p = 0.002) compared to T(-), whereas T(+) treated with liraglutide + metformin had significantly lower sscpep (p = 0.010) compared to T(-) participants. In the placebo group, T(+) participants demonstrated significantly lower ACPRg (p = 0.001) compared to T(-) participants. In summary, T(+) were found in a large percentage of obese pre-diabetes adults with IGT and in recently diagnosed T2D. Moreover, T(+) were significantly correlated with treatment effects and β-cell dysfunction. Our results demonstrate that T(+) are an important component in T2D.

Dataset Information

Effects of Treatment of Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes With Metformin Alone or in Combination With Insulin Glargine on ?-Cell Function: Comparison of Responses In Youth And Adults.

Publications

Effects of Treatment of Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes With Metformin Alone or in Combination With Insulin Glargine on β-Cell Function: Comparison of Responses In Youth And Adults.

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