Search

Insulin is an essential hormone that regulates glucose homeostasis and metabolism. Insulin resistance (IR) arises when tissues fail to respond to insulin, and it leads to serious health problems including Type 2 Diabetes (T2D). Obesity is a major contributor to the development of IR and T2D. We previously showed that gene expression of alcohol dehydrogenase 1B (ADH1B) was inversely correlated with obesity and IR in subcutaneous adipose tissue of Mexican Americans. In the current study, a meta-analysis of the relationship between ADH1B expression and BMI in Mexican Americans, African Americans, Europeans, and Pima Indians verified that BMI was increased with decreased ADH1B expression. Using established human subcutaneous pre-adipocyte cell lines derived from lean (BMI < 30 kg m -2 ) or obese (BMI ≥ 30 kg m -2 ) donors, we found that ADH1B protein expression increased substantially during differentiation, and overexpression of ADH1B inhibited fatty acid binding protein expression. Mature adipocytes from lean donors expressed ADH1B at higher levels than obese donors. Insulin further induced ADH1B protein expression as well as enzyme activity. Knockdown of ADH1B expression decreased insulin-stimulated glucose uptake. Our findings suggest that ADH1B is involved in the proper development and metabolic activity of adipose tissues and this function is suppressed by obesity.

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2 ., (© 2017 by the American Diabetes Association.)

Aim: The aim of this study was to examine the relationship between whole-body insulin-mediated glucose disposal and the fasting plasma glucose concentration in nondiabetic individuals., Research Design and Methods: Two hundred fifty-three nondiabetic subjects with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance, and combined glucose intolerance received a 75-g oral glucose tolerance test and euglycemic hyperinsulinemic clamp. Total glucose disposal (TGD) during the insulin clamp was compared in IFG and NGT individuals and was related to fasting and 2-hour plasma glucose concentrations in each group., Results: TGD varied considerably between NGT and IFG individuals and displayed a strong inverse relationship with the 2-hour plasma glucose (PG; r = 0.40, P < .0001) but not with the fasting PG. When IFG and NGT individuals were stratified based on their 2-hour PG concentration, the increase in 2-hour PG was associated with a progressive decrease in TGD in both groups, and the TGD was comparable among NGT and IFG individuals., Conclusion: The present results indicate the following: 1) as in NGT, insulin-stimulated TGD varies considerably in IFG individuals; 2) the large variability in TGD in IFG and NGT individuals is related to the 2-hour PG concentration; and 3) after adjustment for the 2-hour proglucagon concentration, IFG subjects have comparable TGD with NGT individuals.

To assess the relationship between the fasting plasma glucose (FPG) concentration and insulin secretion in normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) subjects, 531 nondiabetic subjects with NGT (n = 293) and IGT (n = 238; 310 Japanese and 232 Mexican Americans) received an oral glucose tolerance test (OGTT) with measurement of plasma glucose, insulin, and C-peptide every 30 min. The insulin secretion rate was determined by plasma C-peptide deconvolution. Insulin sensitivity (Matsuda index) was measured from plasma insulin and glucose concentrations. The insulin secretion/insulin resistance (IS/IR) or disposition index was calculated as DeltaISR/DeltaG / IR. As FPG increased in NGT subjects, the IS/IR index declined exponentially over the range of FPG from 70 to 125 mg/dl. The relationship between the IS/IR index and FPG was best fit with the equation: 28.8 exp(-0.036 FPG). For every 28 mg/dl increase in FPG, the IS/IR index declined by 63%. A similar relationship between IS/IR index and FPG was observed in IGT. However, the decay constant was lower than in NGT. The IS/IR index for early-phase insulin secretion (0-30 min) was correlated with the increase in FPG in both NGT and IGT (r = -0.43, P < 0.0001 and r = -0.20, P = 0.001, respectively). However, the correlation between late-phase insulin secretion (60-120 min) and FPG was not significant. In conclusion, small increments in FPG, within the "normal" range, are associated with a marked decline in glucose-stimulated insulin secretion and the decrease in insulin secretion with increasing FPG is greater in subjects with NGT than IGT and primarily is due to a decline in early-phase insulin secretion.

The study aim was to investigate the effect of endogenous insulin release on lipolysis in subcutaneous adipose tissue after adrenergic stimulation in obese subjects diagnosed with type 2 diabetes (T2D). In 14 obese female T2D subjects, or 14 obese non-T2D controls, glycerol concentration was measured in response to the α1,2,ß-agonist norepinephrine, the α1-agonist norfenefrine and the ß2-agonist terbutaline (each 10−4 M), using the microdialysis technique. After 60 minutes of stimulation, an intravenous glucose load (0.5 g/kg lean body mass) was given. Local blood flow was monitored by means of the ethanol technique. Norepinephrine and norfenefrine induced a four and three fold rise in glycerol dialysate concentration (p<0.001, each), with a similar pattern in adipose tissue. Following agonist stimulation and glucose infusion, endogenous insulin release inhibited lipolysis in the presence of norepinephrine, which was more rapid and pronounced in healthy obese controls than in T2D subjects (p = 0.024 obese vs T2D subjects). Insulin-induced inhibition of lipolysis in the presence of norfenefrine was similar in all study participants. In the presence of terbutaline the lipolysis rate increased two fold until the effect of endogenous insulin (p<0.001). A similar insulin-induced decrease in lipolysis was observed for each of the norfenefrine groups and the terbutaline groups, respectively. Adipose tissue blood flow remained unchanged after the iv-glucose load. Both norepinephrine and norfenefrine diminished blood flow slightly, but insulin reversed this response (p<0.001 over the entire time). Terbutaline alone and terbutaline plus increased endogenous insulin augmented local blood flow (p<0.001 over the entire time). In conclusion, a difference in insulin-induced inhibition of lipolysis was observed in obese T2D subjects compared to obese healthy controls following modulation of sympathetic nervous system activity and is assumed to be due to ß1-adrenoceptor mediated stimulation by norepinephrine. [ABSTRACT FROM AUTHOR]

This study was undertaken to test the hypothesis that short-term exposure (4 h) to physiological hyperinsulinemia in normal, healthy subjects without a family history of diabetes would induce a low grade inflammatory response independently of glycemic status. Twelve normal glucose tolerant subjects received a 4-h euglycemic hyperin- sulinemic clamp with biopsies of the vastus lateralis muscle. Microar- ray analysis identified 121 probe sets that were significantly altered in response to physiological hyperinsulinemia while maintaining euglycemia. In normal, healthy human subjects insulin increased the mRNAs of a number of inflammatory genes (CCL2, CXCL2 and THBD) and transcription factors (ATF3, BHLHB2, HES1, KLFIO, JUNB, FOS, and FOSB). A number of other genes were upregulated in response to insulin, including RRAD, MT, and SGK. CITED2, a known coactivator of PPARa, was significantly downregulated. SGK and CITED2 are located at chromosome 6q23, where we previously detected strong linkage to fasting plasma insulin concentrations. We independently validated the mRNA expression changes in an additional five subjects and closely paralleled the results observed in the original 12 subjects. A saline infusion in healthy, normal glucose- tolerant subjects without family history of diabetes demonstrated that the genes altered during the euglycemic hyperinsulinemic clamp were due to hyperinsulinemia and were unrelated to the biopsy procedure per se. The results of the present study demonstrate that insulin acutely regulates the levels of mRNAs involved in inflammation and transcription and identifies several candidate genes, including HES 1 and BHLHB2, for further investigation. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To evaluate ethnic differences in the contribution of decline in insulin secretion and insulin sensitivity in impaired glucose tolerance (IGT). Methods: Seven hundred and eighteen subjects of Arab, Japanese and Mexican American decent received oral glucose tolerance test (OGTT) with plasma glucose and insulin measurement every 30min. The Matsuda index of insulin sensitivity and the relation between incremental increase under plasma insulin to glucose curves during the OGTT (ΔI 0–120/ΔG 0–120) were calculated. Results: NGT Japanese subjects had highest insulin sensitivity index (7.1±4.6) and lowest insulin secretion index ((ΔI 0–120/ΔG 0–120 =1.1±0.9). Mexican Americans and Arabs had lower insulin sensitivity (4.1±2.8 and 3.5±2.3, respectively) and higher insulin secretion indices (2.2±2.0 and 2.5±2.5). IGT subjects in all ethnic groups had reduced insulin sensitivity and insulin secretion compared to NTG subjects. However, the reduction in insulin sensitivity was the largest in Mexican American (30%), the smallest in Arabs (11.5%) and intermediate in Japanese (23%). Conversely, the decrease in insulin secretion was the greatest in Arabs (80%), the smallest in Mexican Americans (41%) and intermediate in Japanese (55%). In a multivariate regression analysis model, the decline in insulin secretion was a stronger determinant of 2-h plasma glucose in Arabs than the reduction in insulin sensitivity while the opposite was observed in Mexican Americans and Japanese. Conclusion: Differences in insulin sensitivity and insulin secretion are present amongst different ethnic groups. The relative contributions of reduced insulin action and impaired insulin secretion are likely to contribute differentially to progression from NGT to IGT (and diabetes) in different ethnic groups. [Copyright &y& Elsevier]

This study was conducted to observe changes in insulin secretion and insulin action in subjects with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). A total of 319 subjects were studied with an oral glucose tolerance test (OGTT). Fasting plasma glucose and insulin concentrations were measured at baseline and every 30 min during the OGTT. Fifty-eight subjects also received a euglycemic-hyperinsulinemic clamp. Insulin sensitivity was calculated as the total glucose disposal (TGD) during the last 30 min of the clamp. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from fasting plasma glucose and insulin concentrations. Subjects with IFG had TGD similar to normal glucose-tolerant subjects, while subjects with IGT and combined IFG/IGT had significantly reduced TGD. HOMA-IR in subjects with IFG was similar to that in subjects with combined IFG/IGT and significantly higher than HOMA-IR in subjects with IGT or NGT. Insulin secretion, measured by the insulinogenic index (ΔI0-30/ΔG0-30) and by the ratio of the incremental area under the curve (AUC) of insulin to the incremental AUC of glucose (0-120 min), was reduced to the same extent in all three glucose-intolerant groups. When both measurements of β-cell function were adjusted for severity of insulin resistance, subjects with IGT and combined IFG/IGT had a significantly greater reduction in insulin secretion than subjects with IFG. Subjects with IGT and IFG have different metabolic characteristics. Differences in insulin sensitivity and insulin secretion may predict different rates of progression to type 2 diabetes and varying susceptibility to cardiovascular disease. Diabetes 55:1430-1435, 2006 [ABSTRACT FROM AUTHOR]