Vella, Adrian

Aims To compare the performance of population‐based kinetics with that of directly measured C‐peptide kinetics when used to calculate β‐cell responsivity indices, and to study people with and without acute insulin resistance to ensure that population‐based kinetics apply to all conditions where β‐cell function is measured. Methods Somatostatin was used to inhibit endogenous insulin secretion in 56 people without diabetes. Subsequently, a C‐peptide bolus was administered and the changing concentrations were used to calculate individual kinetic measures of C‐peptide clearance. In addition, the participants were studied on 2 occasions in random order using an oral glucose tolerance test (OGTT). On one occasion, free fatty acid elevation, to cause insulin resistance, was achieved by infusion of Intralipid + heparin. The Disposition Index (DI) was then estimated by the oral minimal model using either population‐based or individual C‐peptide kinetics. Results There were marked differences in the exchange variables ( k 12 and k 21 ) of the model describing C‐peptide kinetics, but smaller differences in the fractional clearance; that is, the irreversible loss from the accessible compartment ( k 01 ), obtained from population‐based estimates compared with experimental measurement. Because it is predominantly influenced by k 01 , DI estimated using individual kinetics correlated well with DI estimated using population‐based kinetics. Conclusions These data support the use of population‐based measures of C‐peptide kinetics to estimate β‐cell function during an OGTT.

Glucose is the main substrate utilized by the brain and as such multiple regulatory mechanisms exist to maintain glucose concentrations. When these mechanisms fail or are defective, hypoglycemia ensues. Due to these robust mechanisms, hypoglycemia is uncommon and usually occurs in the setting of the treatment of diabetes using glucose-lowering agents such as sulfonylureas or insulin. The symptoms of hypoglycemia are non-specific and as such it is important to confirm hypoglycemia by establishing the presence of Whipple’s triad before embarking on an evaluation for hypoglycemia. When possible, evaluation of hypoglycemia should be carried out at the time of spontaneous occurrence of symptoms. If this is not possible then one would want to create the circumstances under which symptoms occur. In cases where symptoms occur in the post absorptive state, a 72-h fast should be performed. Likewise, if symptoms occur after a meal then a mixed meal study may be the test of choice. The causes of endogenous hyperinsulinemic hypoglycemia include insulinoma, post-bariatric hypoglycemia and noninsulinoma pancreatogenous hypoglycemia syndrome. Autoimmune hypoglycemia syndrome is clinically and biochemically similar to insulinoma but associated with high levels of insulin antibodies and plasma insulin. Other important causes of hypoglycemia include medications, non-islet cell tumors, hormonal deficiencies, critical illness and factitious hypoglycemia. We provide an overview of the pathogenesis and management of hypoglycemia in these situations.

Type 2 diabetes mellitus is a polygenic disease with a variable phenotype. Many genetic associations have been described; however, understanding their underlying pathophysiological role in Type 2 diabetes mellitus is important for development of future therapeutic targets. Here, we review the physiological mechanisms of diabetes-associated variants that affect glycemia.

Context: Prediabetes is a heterogeneous disorder classified on the basis of fasting glucose concentrations and 2-hour glucose tolerance. Objective: We sought to determine the relative contributions of insulin secretion and action to the pathogenesis of isolated impaired glucose tolerance (IGT). Design: The study consisted of an oral glucose tolerance test and a euglycemic clamp performed in two cohorts matched for anthropometric characteristics and fasting glucose but discordant for glucose tolerance. Setting: An inpatient clinical research unit at an academic medical center. Patients or Other Participants: Twenty-five subjects who had normal fasting glucose (NFG) and normal glucose tolerance (NGT) and 19 NFG/IGT subjects participated in this study. Intervention(s): Subjects underwent a seven-sample oral glucose tolerance test and a 4-hour euglycemic, hyperinsulinemic clamp on separate occasions. Glucose turnover during the clamp was measured using tracers, and endogenous hormone secretion was inhibited by somatostatin. Main Outcome Measures: We sought to determine whether hepatic glucose metabolism, specifically the contribution of gluconeogenesis to endogenous glucose production, differed between subjects with NFG/NGT and those with NFG/IGT. Results: Endogenous glucose production did not differ between groups before or during the clamp. Insulin-stimulated glucose disappearance was lower in NFG/IGT (24.6 ± 2.2 vs 35.0 ± 3.6 μmol/kg/min; P = .03). The disposition index was decreased in NFG/IGT (681 ± 102 vs 2231 ± 413 × 10−14 dL/kg/min2 per pmol/L; P < .001). Conclusions: We conclude that innate defects in the regulation of glycogenolysis and gluconeogenesis do not contribute to NFG/IGT. However, insulin-stimulated glucose disposal is impaired, exacerbating defects in β-cell function.

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.

OBJECTIVE We compared 3-year achievement of an American Diabetes Association composite treatment goal (HbA1c <7.0%, LDL cholesterol <100 mg/dL, and systolic blood pressure <130 mmHg) after 2 years of intensive lifestyle-medical management intervention, with and without Roux-en-Y gastric bypass, with one additional year of usual care. RESEARCH DESIGN AND METHODS A total of 120 adult participants, with BMI 30.0–39.9 kg/m2 and HbA1c ≥8.0%, were randomized 1:1 to two treatment arms at three clinical sites in the U.S. and one in Taiwan. All patients received the lifestyle-medical management intervention for 24 months; half were randomized to also receive gastric bypass. RESULTS At 36 months, the triple end point goal was met in 9% of lifestyle-medical management patients and 28% of gastric bypass patients (P = 0.01): 10% and 19% lower than at 12 months. Mean (SD) HbA1c values at 3 years were 8.6% (3.5) and 6.7% (2.0) (P < 0.001). No lifestyle-medical management patient had remission of diabetes at 36 months, whereas 17% of gastric bypass patients had full remission and 19% had partial remission. Lifestyle-medical management patients used more medications than gastric bypass patients: mean (SD) 3.8 (3.3) vs. 1.8 (2.4). Percent weight loss was mean (SD) 6.3% (16.1) in lifestyle-medical management vs. 21.0% (14.5) in gastric bypass (P < 0.001). Over 3 years, 24 serious or clinically significant adverse events were observed in lifestyle-medical management vs. 51 with gastric bypass. CONCLUSIONS Gastric bypass is more effective than lifestyle-medical management intervention in achieving diabetes treatment goals, mainly by improved glycemic control. However, the effect of surgery diminishes with time and is associated with more adverse events.