Shape of the OGTT glucose response curve: relationship with ß-cell function and differences by sex, race, and BMI in adults with early type 2 diabetes treated with metformin.

INTRODUCTION: The shape of the glucose curve during an oral glucose tolerance test (OGTT) reflects ß-cell function in populations without diabetes but has not been as well studied in those with diabetes. A monophasic shape has been associated with higher risk of diabetes, while a biphasic pattern has been associated with lower risk. We sought to determine if phenotypic or metabolic characteristics were associated with glucose response curve shape in adults with type 2 diabetes treated with metformin alone. RESEARCH DESIGN AND METHODS: This is a cross-sectional analysis of 3108 metformin-treated adults with type 2 diabetes diagnosed <10 years who underwent 2-hour 75 g OGTT at baseline as part of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Insulin sensitivity (homeostasis model of insulin sensitivity, HOMA2-S) and ß-cell function (early, late, and total incremental insulin and C peptide responses adjusted for HOMA2-S) were calculated. Glucose curve shape was classified as monophasic, biphasic, or continuous rise. RESULTS: The monophasic profile was the most common (67.8% monophasic, 5.5% biphasic, 26.7% continuous rise). The monophasic subgroup was younger, more likely male and white, and had higher body mass index (BMI), while the continuous rise subgroup was more likely female and African American/black. HOMA2-S and fasting glucose did not differ among the subgroups. The biphasic subgroup had the highest early, late, and total insulin and C peptide responses (all p<0.05 vs monophasic and continuous rise). Compared with the monophasic subgroup, the continuous rise subgroup had similar early insulin (p=0.3) and C peptide (p=0.6) responses but lower late insulin (p<0.001) and total insulin (p=0.008) and C peptide (p<0.001) responses. CONCLUSIONS: Based on the large multiethnic GRADE cohort, sex, race, age, and BMI were found to be important determinants of the shape of the glucose response curve. A pattern of a continuously rising glucose at 2 hours reflected reduced ß-cell function and may portend increased glycemic failure rates. TRIAL REGISTRATION NUMBER: NCT01794143.

Association of glycemia with insulin sensitivity and ß-cell function in adults with early type 2 diabetes on metformin alone.

AIMS: Evaluate the relationship between measures of glycemia with ß-cell function and insulin sensitivity in adults with early type 2 diabetes mellitus (T2DM). METHODS: This cross-sectional analysis evaluated baseline data from 3108 adults with T2DM <10 years treated with metformin alone enrolled in the Glycemia Reduction Approaches in Diabetes. A Comparative Effectiveness (GRADE) Study. Insulin and C-peptide responses and insulin sensitivity were calculated from 2-h oral glucose tolerance tests. Regression models evaluated the relationships between glycemic measures (HbA1c, fasting and 2-h glucose), measures of ß-cell function and insulin sensitivity. RESULTS: Insulin and C-peptide responses were inversely associated with insulin sensitivity. Glycemic measures were inversely associated with insulin and C-peptide responses adjusted for insulin sensitivity. HbA1c demonstrated modest associations with ß-cell function (range: r - 0.22 to -0.35). Fasting and 2-h glucose were associated with early insulin and C-peptide responses (range: r - 0.37 to -0.40) as well as late insulin and total insulin and C-peptide responses (range: r - 0.50 to -0.60). CONCLUSION: Glycemia is strongly associated with ß-cell dysfunction in adults with early T2DM treated with metformin alone. Efforts to improve glycemia should focus on interventions aimed at improving ß-cell function. This Trial is registered in Clinicaltrials.gov as NCT01794143.

Factors associated with early relapse to insulin dependence in unprovoked A-ß+ ketosis-prone diabetes.

OBJECTIVE: Unprovoked "A-ß+" Ketosis-Prone Diabetes (KPD), a unique diabetic syndrome of adult-onset, obesity and proneness to ketoacidosis, is associated with rapid recovery of ß cell function and insulin-independence. Whereas most patients experience prolonged remission, a subset relapses early to insulin dependence. We sought to define factors associated with early relapse. METHODS: We utilized a prospective, longitudinal database to analyze 50 unprovoked A-ß+ KPD patients with >2 measurements of ß cell function and glycemia following baseline assessment. RESULTS: 19 patients (38%) relapsed to insulin dependence <1 year after the index DKA episode, while 31 (62%) remained insulin-independent for >1 year (median 4.2 years). Younger age at baseline (OR=0.947, P=0.033), and lower HOMA2-%ß (OR=0.982, P=0.001), lower HOMA2-IR (OR=0.582, P=0.046) and higher HbA1c at 1 year (OR=1.71, P=0.002) were associated with early relapse. A multivariate model with these variables and the interaction of HOMA2-%ß and HbA1c at 1 year provided a good fit (P<0.05). CONCLUSIONS: Relapse to insulin dependence in unprovoked A-ß+ KPD patients is associated with younger age and, after 1 year, lack of robust increase in ß cell functional reserve, and suboptimal glycemic control. Measurements of these parameters 1 year after the index DKA episode can be used to assess the need for insulin therapy.

Impaired mitochondrial fatty acid oxidation and insulin resistance in aging: novel protective role of glutathione.

Aging is associated with impaired fasted oxidation of nonesterified fatty acids (NEFA) suggesting a mitochondrial defect. Aging is also associated with deficiency of glutathione (GSH), an important mitochondrial antioxidant, and with insulin resistance. This study tested whether GSH deficiency in aging contributes to impaired mitochondrial NEFA oxidation and insulin resistance, and whether GSH restoration reverses these defects. Three studies were conducted: (i) in 82-week-old C57BL/6 mice, the effect of naturally occurring GSH deficiency and its restoration on mitochondrial (13) C1 -palmitate oxidation and glucose metabolism was compared with 22-week-old C57BL/6 mice; (ii) in 20-week C57BL/6 mice, the effect of GSH depletion on mitochondrial oxidation of (13) C1 -palmitate and glucose metabolism was studied; (iii) the effect of GSH deficiency and its restoration on fasted NEFA oxidation and insulin resistance was studied in GSH-deficient elderly humans, and compared with GSH-replete young humans. Chronic GSH deficiency in old mice and elderly humans was associated with decreased fasted mitochondrial NEFA oxidation and insulin resistance, and these defects were reversed with GSH restoration. Acute depletion of GSH in young mice resulted in lower mitochondrial NEFA oxidation, but did not alter glucose metabolism. These data suggest that GSH is a novel regulator of mitochondrial NEFA oxidation and insulin resistance in aging. Chronic GSH deficiency promotes impaired NEFA oxidation and insulin resistance, and GSH restoration reverses these defects. Supplementing diets of elderly humans with cysteine and glycine to correct GSH deficiency could provide significant metabolic benefits.

Gene therapy for diabetes: metabolic effects of helper-dependent adenoviral exendin 4 expression in a diet-induced obesity mouse model.

Exendin 4 (Ex4) is a glucagon-like peptide-1 receptor (GLP- 1R) agonist which is available as a short-acting injectable treatment for type 2 diabetes. Our aim was to characterize the long-term effects of elevated steady-state levels of Ex4 provided by in vivo gene therapy. We constructed a helper-dependent adenoviral (HDAd) vector for long-term expression of Ex4 in vivo. A high-fat diet (HFD)-induced obesity (DIO) mouse model was chosen to approximate the metabolic derangements seen in obese patients. Mice were treated with a single injection of HDAd-Ex4 and were monitored for 15 weeks. Both hepatic Ex4 RNA and plasma Ex4 were detectable at the end of the study. HDAd-Ex4 treatment improved glucose homeostasis without increasing insulin levels. However, there was evidence of enhanced insulin action and decreased gluconeogenic enzyme expression. HDAd-Ex4 caused decreased weight gain without detectable changes in food intake, in part, due to increases in energy expenditure (EE). HDAd-Ex4 DIO mice also had reduced hepatic fat and an improved adipokine profile. In the liver, there was decreased expression of genes that were involved in de novo fatty acid synthesis. These observations are important in considering the development of longer acting GLP-1R agonists for the treatment of type 2 diabetes.