Cobelli, Claudio

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.

Background: Several clinical trials have been performed to assess safety and efficacy of closed-loop control. Some included physical activity (PA), with the goal of challenging the control algorithms with a rapid change in insulin sensitivity while reducing the risk of hypoglycemia. However, the question remains as to the necessity to inform the control algorithm on the imminent PA. The aim here is to assess in silico (i) if it is necessary to announce upcoming PA and (ii) if this is the case, what is the safest strategy of basal insulin reduction in the context of the closed-loop control. Methods: We modified the University of Virginia/Padova type 1 diabetes simulator to incorporate the effect of PA based on a study in healthy subjects that demonstrated an almost doubling of insulin sensitivity during PA versus rest. Two in silico experiments, including a PA session, have been simulated on the virtual adult population: One in the absence of and one with different degrees of reductions and durations of basal insulin infusion rates. Results: Most in silico subjects experienced hypoglycemia in the absence of basal insulin adjustment. We show that, in the absence of patient-specific information, a safe and effective strategy is to reduce basal insulin by 50% starting 90 min before exercise and by 30% during exercise. Conclusions: Our results suggest that control algorithms could benefit by knowing an upcoming PA. Ideally, the control algorithm should be informed about the patient-specific basal insulin reduction pattern. An alternative strategy that has been proposed here has been deemed safe and effective in in silico experiments.

Background: Glucose sensors measure glucose concentration in the interstitial fluid (ISF), remote from blood. ISF glucose is well known to be “delayed” with respect to blood glucose (BG). However, ISF glucose is not simply a shifted-in-time version of BG but exhibits a more complex pattern. Methods: To gain insight into this problem, one can use linear systems theory. However, this may lose a more clinical readership, thus we use simulation and two case studies to convey our thinking in an easier way. In particular, we consider BG concentration measured after meal and exercise in 12 healthy volunteers, whereas ISF glucose is simulated using a well-accepted model of blood–ISF glucose kinetics, which permits calculation of the equilibration time, a parameter characterizing the system. Two metrics are defined: blood and ISF glucose difference at each time point and time to reach the same glucose value in blood and ISF. Results: The simulation performed and the two metrics show that the relationship between blood–ISF glucose profiles is more complex than a pure shift in time and that the pattern depends on both equilibration time and BG. Conclusions: In this in silico study, we have illustrated, with simple case studies, the meaning of the of ISF glucose with respect to BG. Understanding that ISF glucose is not just a shifted-in-time version but a distorted mirror of BG is important for a correct use of continuous glucose monitoring for diabetes management.

Fasting hyperglycemia occurs when an excessive rate of endogenous glucose production (EGP) is not accompanied by an adequate compensatory increase in the rate of glucose disappearance (Rd). The situation following food ingestion is more complex as the amount of glucose that reaches the circulation for disposal is a function of the systemic rate of appearance of the ingested glucose (referred to as the rate of meal appearance [Rameal]), the pattern and degree of suppression of EGP, and the rapidity of stimulation of the Rd. In an effort to measure these processes, Steele et al. proposed what has come to be referred to as the dual-tracer method in which the ingested glucose is labeled with one tracer while a second tracer is infused intravenously at a constant rate. Unfortunately, subsequent studies have shown that although this approach is technically simple, the marked changes in plasma specific activity or the tracer-to-tracee ratio, if stable tracers are used, introduce a substantial error in the calculation of Rameal, EGP, and Rd, thereby leading to incorrect and at times misleading results. This Perspective discusses the causes of these so-called “nonsteady-state” errors and how they can be avoided by the use of the triple-tracer approach.

Background: The relationship between daily psychological stress and BG fluctuations in type 1 diabetes (T1DM) is unclear. More research is needed to determine if stress-related BG changes should be considered in glucose control algorithms. This study in the usual free-living environment examined relationships among routine daily stressors and BG profile measures generated from CGM readings. Methods: A total of 33 participants with T1DM on insulin pumps wore a CGM device for 1 week and recorded daily ratings of psychological stress, carbohydrates, and insulin boluses. Results: Within-subjects ANCOVAs found a significant relationship between daily stress and indices of BG variability/instability ( r = .172 to .185, P = .011 to .018, r 2 = 2.97% to 3.43%), increased % time in hypoglycemia ( r = .153, P = .036, r 2 = 2.33%) and decreased carbohydrate consumption ( r = –.157, P = .031, r 2 = 2.47%). Models accounted for more variance for individuals reporting the highest daily stress. There was no relationship between stress and mean daily glucose or low/high glucose risk indices. Conclusions: These preliminary findings suggest that naturally occurring daily stressors can be associated with increased glucose instability and hypoglycemia, as well as decreased food consumption. In addition, findings support the hypothesis that some individuals are more metabolically reactive to stress. More rigorous studies using CGM technology are needed to understand whether the impact of daily stress on BG is clinically meaningful and if it is a behavioral factor that should be considered in glucose control systems for some individuals.

Abstract Context: Early postprandial hyperglycemia and delayed hypoglycemia remain major problems in current management of type 1 diabetes (T1D). Objective: Our objective was to investigate the effects of pramlintide, known to suppress glucagon and delay gastric emptying, on postprandial glucose fluxes in T1D. Design: This was a single-center, inpatient, randomized, crossover study. Patients: Twelve patients with T1D who completed the study were analyzed. Interventions: Subjects were studied on two occasions with or without pramlintide. Triple tracer mixed-meal method and oral minimal model were used to estimate postprandial glucose turnover and insulin sensitivity (SI). Integrated liver insulin sensitivity was calculated based on glucose turnover. Plasma glucagon and insulin were measured. Main Outcome Measure: Glucose turnover and SI were the main outcome measures. Results: With pramlintide, 2-hour postprandial glucose, insulin, glucagon, glucose turnover, and SI indices showed: plasma glucose excursions were reduced (difference in incremental area under the curve [iAUC], 444.0 mMmin, P = .0003); plasma insulin concentrations were lower (difference in iAUC, 7642.0 pMmin; P = .0099); plasma glucagon excursions were lower (difference in iAUC, 1730.6 pg/mlmin; P = .0147); meal rate of glucose appearance was lower (difference in iAUC: 1196.2 μM/kg fat free mass [FFM]; P = .0316), endogenous glucose production was not different (difference in iAUC: −105.5 μM/kg FFM; P = .5842), rate of glucose disappearance was lower (difference in iAUC: 1494.2 μM/kg FFM; P = .0083). SI and liver insulin sensitivity were not different between study visits (P > .05). Conclusions: Inhibition of glucagon and gastric emptying delaying reduced 2-hour prandial glucose excursions in T1D by delaying meal rate of glucose appearance.

Background: Glucagon-like peptide-1 (GLP-1) is a powerful insulin secretagogue that is secreted in response to meal ingestion. The ability to quantify the effect of GLP-1 on insulin secretion could provide insights into the pathogenesis and treatment of diabetes. We used a modification of a model of GLP-1 action on insulin secretion using data from a hyperglycemic clamp with concomitant GLP-1 infusion. We tested this model using data from a mixed meal test (MMT), thereby measuring GLP-1-induced potentiation of insulin secretion in response to a meal. Materials and Methods: The GLP-1 model is based on the oral C-peptide minimal model and assumes that over-basal insulin secretion depends linearly on GLP-1 concentration through the parameter Π, representing the β-cell sensitivity to GLP-1. The model was tested on 62 subjects across the spectrum of glucose tolerance (age, 53 ± 1 years; body mass index, 29.7 ± 0.6 kg/m 2 ) studied with an MMT and provided a precise estimate of both β-cell responsivity and Π indices. By combining Π with a measure of L-cell responsivity to glucose, one obtains a potentiation index (PI) (i.e., a measure of the L-cell's function in relation to prevailing β-cell sensitivity to GLP-1). Results: Model-based measurement of GLP-1-induced insulin secretion demonstrates that the PI is significantly reduced in people with impaired glucose tolerance, compared with those with normal glucose tolerance. Conclusions: We describe a model that can quantitate the GLP-1-based contribution to insulin secretion in response to meal ingestion. This methodology will allow a better understanding of β-cell function at various stages of glucose tolerance.

The diabetes-associated allele in TCF7L2 increases the rate of conversion to diabetes; however, the mechanism by which this occurs remains elusive. We hypothesized that the diabetes-associated allele in this locus (rs7903146) impairs insulin secretion and that this defect would be exacerbated by acute free fatty acid (FFA)–induced insulin resistance. We studied 120 individuals of whom one-half were homozygous for the diabetes-associated allele TT at rs7903146 and one-half were homozygous for the protective allele CC. After a screening examination during which glucose tolerance status was determined, subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, FFA was elevated by infusion of Intralipid plus heparin. On the other study day, subjects received the same amount of glycerol as present in the Intralipid infusion. β-Cell responsivity indices were estimated with the oral C-peptide minimal model. We report that β-cell responsivity was slightly impaired in the TT genotype group. Moreover, the hyperbolic relationship between insulin secretion and β-cell responsivity differed significantly between genotypes. Subjects also exhibited impaired suppression of glucagon after an oral challenge. These data imply that a genetic variant harbored within the TCF7L2 locus impairs glucose tolerance through effects on glucagon as well as on insulin secretion.