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Objective: To evaluate racial/ethnic differences in pancreatic triglyceride (TG) levels and their relationship to β-cell dysfunction in humans.Research Design and Methods: We studied black, Hispanic, and white adults who completed three research visits: screening and an oral glucose tolerance test; frequently sampled intravenous glucose tolerance tests for evaluation of β-cell function and insulin resistance; and proton magnetic resonance spectroscopy for evaluation of pancreatic and hepatic TG levels.Results: Pancreatic TG levels were higher in Hispanics and whites than in blacks (P = 0.006). Hepatic TG levels were highest in Hispanics (P = 0.004). Compensatory insulin secretion and disposition index were higher in blacks (P = 0.003 and P = 0.024, respectively). Insulin sensitivity was comparable between Hispanics and blacks and was lower than in whites (P = 0.005). In blacks, compensatory insulin secretion increased steeply with small increments in pancreatic TG levels (R(2) = 0.45, slope = 247). In whites, the range of pancreatic TG levels was higher, and the slope was less steep than in blacks (R(2) = 0.27, slope = 27). In Hispanics, pancreatic TG levels were similar to those of whites, but compensatory insulin secretion was described by a combination of pancreatic and hepatic TG levels and visceral fat mass ( R(2) = 0.32).Conclusions: In a multiethnic sample of adults with mild obesity and without diabetes, we found striking ethnic differences in the levels of pancreatic TGs and in the relationship between pancreatic TGs and β-cell dysfunction. Our data implicate pancreatic TG content measured by proton magnetic resonance spectroscopy as a noninvasive novel biomarker for pancreatic β-cell dysfunction, especially in the Hispanic population. [ABSTRACT FROM AUTHOR]

Objective: Disposition index (DI) and glucose effectiveness (S(G)) are risk factors for diabetes. However, the effect of DI and S(G) on future diabetes has not been examined in large epidemiological studies using direct measures.Research Design and Methods: Insulin sensitivity index (S(I)), acute insulin response (AIR), and S(G) were measured in 826 participants (aged 40-69 years) in the Insulin Resistance Atherosclerosis Study (IRAS) by the frequently sampled intravenous glucose tolerance test. DI was expressed as S(I) x AIR. At the 5-year follow-up examination, 128 individuals (15.5%) had developed diabetes.Results: The area under the receiver operating characteristic curve of a model with S(I) and AIR was similar to that of DI (0.767 vs. 0.774, P = 0.543). In a multivariate logistic regression model that included both DI and S(G), conversion to diabetes was predicted by both S(G) (odds ratio x 1 SD, 0.61 [0.47-0.80]) and DI (0.68 [0.54-0.85]) after adjusting for demographic variables, fasting and 2-h glucose concentrations, family history of diabetes, and measures of obesity. Age, sex, race/ethnicity, glucose tolerance status, obesity, and family history of diabetes did not have a significant modifying impact on the relation of S(G) and DI to incident diabetes.Conclusions: The predictive power of DI is comparable to that of its components, S(I) and AIR. S(G) and DI independently predict conversion to diabetes similarly across race/ethnic groups, varying states of glucose tolerance, family history of diabetes, and obesity. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of a 20-week endurance training program in healthy, previously sedentary participants on measures derived from an intravenous glucose tolerance test (i.v.GTT).Research Design and Methods: An i.v.GTT was performed before and after a standardized training program in 316 women and 280 men (173 blacks and 423 whites). Participants exercised on cycle ergometers 3 days per week for 60 sessions. The exercise intensity was progressively increased from 55% VO2max for 30 min per session to 75% VO2max for 50 min per session.Results: Mean insulin sensitivity increased by 10% (P < 0.001) following the intervention, but the variability in the changes was high. Men had larger improvements than women (P = 0.02). Improvements in fasting insulin were transitory, disappearing 72 h after the last bout of exercise. There were also significant mean increases in the glucose disappearance index (3%, P = 0.02) and in glucose effectiveness (11%, P < 0.001), measures of glucose tolerance and of the capacity of glucose to mediate its own disposal, respectively. The acute insulin response to glucose, a measure of insulin secretion, increased by 7% in the quartile with the lowest baseline glucose tolerance and decreased by 14% in the quartile with the highest baseline glucose tolerance (P < 0.001). The glucose area below fasting levels during the i.v.GTT was reduced by 7% (P = 0.02).Conclusions: Although the effects of structured regular exercise were highly variable, there were improvements in virtually all i.v.GTT-derived variables. In the absence of substantial weight loss, regular exercise is required for sustained improvements in glucose homeostasis. [ABSTRACT FROM AUTHOR]

Insulin clearance has recently been highlighted as a fundamental aspect of glucose metabolism, as it has been hypothesized that its impairment could be related to an increased risk of developing type 2 diabetes. This review focuses on methods used to calculate insulin clearance: from the early surrogate indices employing C-peptide:insulin molar ratio, to direct measurement methods used in animal models, to modeling-based techniques to estimate the components of insulin clearance (hepatic versus extrahepatic). The methods are explored and interpreted by critically highlighting advantages and limitations., (© 2020 by the American Diabetes Association.)

Objective: Standardized, reproducible, and feasible quantification of β-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states., Research Design and Methods: Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT)., Results: From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations., Conclusions: Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use., (© 2016 by the American Diabetes Association.)

Objective: We aimed to identify factors that are independently associated with the metabolic clearance rate of insulin (MCRI) and to examine the association of MCRI with incident type 2 diabetes in nondiabetic Hispanics and African Americans., Research Design and Methods: We investigated 1,116 participants in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study with baseline examinations from 2000 to 2002 and follow-up examinations from 2005 to 2006. Insulin sensitivity (S(I)), acute insulin response (AIR), and MCRI were determined at baseline from frequently sampled intravenous glucose tolerance tests. MCRI was calculated as the ratio of the insulin dose over the incremental area under the curve of insulin. Incident diabetes was defined as fasting glucose ≥126 mg/dL or antidiabetic medication use by self-report., Results: We observed that S(I) and HDL cholesterol were independent positive correlates of MCRI, whereas fasting insulin, fasting glucose, subcutaneous adipose tissue, visceral adipose tissue, and AIR were independent negative correlates (all P < 0.05) at baseline. After 5 years of follow-up, 71 (6.4%) participants developed type 2 diabetes. Lower MCRI was associated with a higher risk of incident diabetes after adjusting for demographics, lifestyle factors, HDL cholesterol, indexes of obesity and adiposity, and insulin secretion (odds ratio 2.01 [95% CI 1.30-3.10], P = 0.0064, per one-SD decrease in loge-transformed MCRI)., Conclusions: Our data showed that lower MCRI predicts the incidence of type 2 diabetes.

Objective: Glucokinase (GCK) acts as a component of the "glucose sensor" in pancreatic β-cells and possibly in other tissues, including the brain. However, >99% of GCK in the body is located in the liver, where it serves as a "gatekeeper", determining the rate of hepatic glucose phosphorylation. Mutations in GCK are a cause of maturity-onset diabetes of the young (MODY), and GCKR, the regulator of GCK in the liver, is a diabetes susceptibility locus. In addition, several GCK activators are being studied as potential regulators of blood glucose. The ability to estimate liver GCK activity in vivo for genetic and pharmacologic studies may provide important physiologic insights into the regulation of hepatic glucose metabolism., Research Design and Methods: Here we introduce a simple, linear, two-compartment kinetic model that exploits lactate and glucose kinetics observed during the frequently sampled intravenous glucose tolerance test (FSIGT) to estimate liver GCK activity (K(GK)), glycolysis (K(12)), and whole body fractional lactate clearance (K(01)). RESULTS To test our working model of lactate, we used cross-sectional FSIGT data on 142 nondiabetic individuals chosen at random from the Finland-United States Investigation of NIDDM Genetics study cohort. Parameters K(GK), K(12), and K(01) were precisely estimated. Median model parameter estimates were consistent with previously published values., Conclusions: This novel model of lactate kinetics extends the utility of the FSIGT protocol beyond whole-body glucose homeostasis by providing estimates for indices pertaining to hepatic glucose metabolism, including hepatic GCK activity and glycolysis rate.

Objective: To determine the meaning of S(i) = 0 derived from the frequently sampled intravenous glucose tolerance test., Research Design and Methods: The issue of assessing insulin resistance in large studies is important because the most definitive method ("gold standard"), the hyperinsulinemic-euglycemic clamp, is expensive and invasive. The frequently sampled intravenous glucose tolerance test (FSIGTT) has been widely used, but in insulin-resistant subjects (especially diabetic subjects), it yields considerable numbers of subjects whose S(i) is zero. The interpretation of an S(i) equaling zero is unknown., Results: -To address this issue, we examined 1482 subjects from the Insulin Resistance Atherosclerosis Study (IRAS) using an insulin-modified FSIGTT and minimal model calculation of S(i). The proportion of insulin-resistant subjects (S(i) < 1.61 x 10(-4) [min(-1). microU(-1) x ml(-1)] based on the median of the nondiabetic population) was 38.6% in subjects with normal glucose tolerance (NGT), 74% in subjects with impaired glucose tolerance (IGT), and 92% in subjects with type 2 diabetes. The proportion of subjects with S(i) = 0 was 2.2% in subjects with NGT, 13.2% in subjects with IGT, and 35.7% in subjects with type 2 diabetes. In subjects with IGT, those with S(i) = 0 had significantly lower HDL cholesterol levels and higher BMI, waist circumference, fibrinogen, plasminogen-activator inhibitor 1 (PAI-1), C-reactive protein (CRP), and 2-h insulin levels than insulin-resistant subjects with S(i) > 0. In type 2 diabetes, subjects with S(i) = 0 had significantly greater BMI and waist circumference and higher triglyceride, PAI-1, CRP, fibrinogen, and fasting and 2-h insulin levels than insulin-resistant subjects with S(i) > 0. In addition, diabetic subjects with S(i) = 0 had more metabolic disorders related to the insulin resistance syndrome than diabetic insulin-resistant subjects with S(i) > 0., Conclusions: We found very few subjects with S(i) = 0 among subjects with NGT and few subjects with S(i) = 0 among subjects with IGT. In contrast, S(i) = 0 was common in subjects with diabetes. Subjects with S(i) = 0 tended to have more features of the insulin resistance syndrome than other insulin-resistant subjects with S(i) > 0, as would be expected of subjects with almost no insulin-mediated glucose disposal, thus suggesting that subjects with S(i) = 0 are correctly classified as being very insulin resistant rather than having failed the minimal model program.

Objective: The objective of this study was to compare insulin resistance relative to body fat and the associated compensatory responses in 57 healthy children living in Los Angeles, California (14 Caucasians, 15 African-Americans, and 28 Hispanics)., Research Design and Methods: Insulin sensitivity and acute insulin response were determined by intravenous glucose tolerance test. Insulin secretion, hepatic insulin extraction, and insulin clearance were estimated by C-peptide and insulin modeling., Results: Insulin sensitivity was significantly lower in Hispanics and African-Americans compared with Caucasian children, and acute insulin response was significantly higher in African-American children. No ethnic differences were noted in the first-phase secretion, but second-phase insulin secretion was significantly higher in Hispanic children than in African-American children (200 +/- 53 vs. 289 +/- 41 nmol/min; P = 0.03). The greater acute insulin response in African-Americans, despite lower secretion, was explained by a lower hepatic insulin extraction in African-Americans compared with Hispanics (36.6 +/- 2.9 vs. 47.3 +/- 2.2%; P = 0.0006)., Conclusions: In conclusion, Hispanic and African-American children are more insulin resistant than Caucasian children, but the associated compensatory responses are different across ethnic groups.

Objective: This study aimed to establish whether total fat or central fat was related to measures of insulin in obese Hispanic children with a family history of type 2 diabetes., Research Design and Methods: Subjects were 32 children aged 8-13 years. Visceral fat and subcutaneous abdominal fat were determined by magnetic resonance imaging at the umbilicus and total body fat was determined by dual-energy X-ray absorptiometry. Insulin sensitivity (S(i)) and acute insulin response (AIR) were determined by frequently sampled intravenous tolerance test with minimal modeling., Results: Mean fasting glucose and insulin, S(i), and AIR (+/- SD) were 5.3 +/- 0.3 mmol/l, 206 +/- 105 pmol/l, 11.8 +/- 5.7 [x 10(-4) min(-1)/(pmol/l)], and 17,175 +/- 9,695 (pmol/l x 10 min), respectively. In multivariate regression analysis, total fat mass was independently and positively related to fasting insulin (P < 0.01) and negatively related to S(i) (P < 0.05) but was not related to AIR. Visceral fat was independently and positively related to fasting insulin (P < 0.05) and AIR (P < 0.01) and negatively related to S(i) (P < 0.001)., Conclusions: -These findings support the hypothesis that specific accumulation of visceral fat in addition to overall adiposity in Hispanic children increases the risk of type 2 diabetes.

Objective: To examine the effects of caloric restriction, independent of differences in weight loss, on improvements in glycemic control, fasting insulin, and insulin sensitivity., Research Design and Methods: We randomized 93 obese type II diabetic patients to two different degrees of calorie restriction (1,674 or 4,185 kJ/day; 400 or 1,000 kcal/day) and compared the changes in fasting glucose, fasting insulin, and insulin sensitivity that resulted from a comparable reduction in body weight (11% of initial body weight). Insulin sensitivity was assessed using the minimal model analysis of frequently sampled intravenous glucose tolerance tests., Results: Despite equal weight losses, subjects in the 1,674 kJ/day (400 kcal) condition had lower fasting glucose levels (7.61 vs. 10.13 mM, P = 0.03) and greater insulin sensitivity (1.79 vs. 1.13, P = 0.04) after weight loss than did subjects in the 4,185 kJ/day (1,000 calorie) condition. Subjects were restudied 15 weeks later when both groups were consuming a 4,185 kJ/day (1,000 kcal/day) diet. Subjects who increased from 1,674 to 4,185 kJ (400 to 1,000 calories) had worse fasting glycemic control in spite of continued weight loss, whereas subjects who remained on 4,185 kJ (1,000 calories) throughout had further improvements in both blood glucose and insulin sensitivity with increased weight loss., Conclusions: Both degree of calorie restriction and magnitude of weight loss have independent effects on improvements in glycemic control and insulin sensitivity.

Objective: To determine the bioavailability and bioactivity of subcutaneously injected insulin., Research Design and Methods: A randomized block design with six male mongrel dogs as subjects. In protocol 1, purified pork insulin was infused intravenously to simulate the pattern of appearance in the blood that would have been expected from subcutaneous injection. Three intravenous doses (0.05, 0.10, and 0.15 U/kg) were infused on separate days in a pattern (0-300 min) designed to approximately simulate the absorption rate of subcutaneously injected insulin. In protocol 2, interscapular subcutaneous injections of pork insulin at 0.10 U/kg were made., Results: Integrated insulin, decrement in plasma glucose, and maximal glucose clearance for subcutaneous injection experiments were similar to intravenous infusion of equal dose (P greater than 0.10) but significantly different from low-dose infusions (P less than 0.025). Similar results were observed for hepatic glucose output and glucose uptake. Hypoglycemia elicited counterregulatory responses that appeared to be under a threshold differentiated at a plasma glucose of approximately 3 mM. Integrated insulin was plotted against insulin dose to create dose-response curves for intravenous data. The curve was then used to predict the actual appearance rate of insulin in plasma for subcutaneous injection. The estimated bioavailability of subcutaneous insulin was 103.0 +/- 10.5% of the injected dose., Conclusions: We concluded that, in dogs, insulin delivered subcutaneously in the interscapular area is not significantly degraded before absorption, resulting in metabolic effects equal to intravenous insulin infusion of equivalent dose.