No abstract

OBJECTIVE -We sought to determine whether an oral disposition index (DI O ) predicts the development of diabetes over a 10-year period. First, we assessed the validity of the DI O by demonstrating that a hyperbolic relationship exists between oral indexes of insulin sensitivity and ␤-cell function.RESEARCH DESIGN AND METHODS -A total of 613 Japanese-American subjects (322 men and 291 women) underwent a 75-g oral glucose tolerance test (OGTT) at baseline, 5 years, and 10 years. Insulin sensitivity was estimated as 1/fasting insulin or homeostasis model assessment of insulin sensitivity (HOMA-S). Insulin response was estimated as the change in insulin divided by change in glucose from 0 to 30 min (⌬I 0 -30 /⌬G 0 -30 ).RESULTS -⌬I 0 -30 /⌬G 0 -30 demonstrated a curvilinear relationship with 1/fasting insulin and HOMA-S with a left and downward shift as glucose tolerance deteriorated. The confidence limits for the slope of the log e -transformed estimates included Ϫ1 for ⌬I 0 -30 /⌬G 0 -30 versus 1/fasting insulin for all glucose tolerance groups, consistent with a hyperbolic relationship. When HOMA-S was used as the insulin sensitivity measure, the confidence limits for the slope included Ϫ1 only for subjects with normal glucose tolerance (NGT) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) but not diabetes. On the basis of this hyperbolic relationship, the product of ⌬I 0 -30 /⌬G 0 -30 and 1/fasting insulin was calculated (DI O ) and decreased from NGT to IFG/IGT to diabetes (P Ͻ 0.001). Among nondiabetic subjects at baseline, baseline DI O predicted cumulative diabetes at 10 years (P Ͻ 0.001) independent of age, sex, BMI, family history of diabetes, and baseline fasting and 2-h glucose concentrations.CONCLUSIONS -The DI O provides a measure of ␤-cell function adjusted for insulin sensitivity and is predictive of development of diabetes over 10 years.

OBJECTIVEGastric bypass (GB) surgery is associated with postprandial hyperinsulinemia, and this effect is accentuated in postsurgical patients who develop recurrent hypoglycemia. Plasma levels of the incretin glucagon-like peptide 1 (GLP-1) are dramatically increased after GB, suggesting that its action contributes to alteration in postprandial glucose regulation. The aim of this study was to establish the role of GLP-1 on insulin secretion in patients with GB.RESEARCH DESIGN AND METHODSTwelve asymptomatic individuals with previous GB (Asym-GB), 10 matched healthy nonoperated control subjects, and 12 patients with recurrent hypoglycemia after GB (Hypo-GB) had pre- and postprandial hormone levels and insulin secretion rates (ISR) measured during a hyperglycemic clamp with either GLP-1 receptor blockade with exendin-(9–39) or saline.RESULTSBlocking the action of GLP-1 suppressed postprandial ISR to a larger extent in Asym-GB individuals versus control subjects (33 ± 4 vs.16 ± 5%; P = 0.04). In Hypo-GB patients, GLP-1 accounted for 43 ± 4% of postprandial ISR, which was not significantly higher than that in Asym-GB subjects (P = 0.20). Glucagon was suppressed similarly by hyperglycemia in all groups but rose significantly after the meal in surgical individuals but remained suppressed in nonsurgical subjects. GLP-1 receptor blockade increased postprandial glucagon in both surgical groups.CONCLUSIONSIncreased GLP-1–stimulated insulin secretion contributes significantly to hyperinsulinism in GB subjects. However, the exaggerated effect of GLP-1 on postprandial insulin secretion in surgical subjects is not significantly different in those with and without recurrent hypoglycemia.

OBJECTIVEThe orexigenic gut hormone ghrelin and its receptor are present in pancreatic islets. Although ghrelin reduces insulin secretion in rodents, its effect on insulin secretion in humans has not been established. The goal of this study was to test the hypothesis that circulating ghrelin suppresses glucose-stimulated insulin secretion in healthy subjects.RESEARCH DESIGN AND METHODSGhrelin (0.3, 0.9 and 1.5 nmol/kg/h) or saline was infused for more than 65 min in 12 healthy patients (8 male/4 female) on 4 separate occasions in a counterbalanced fashion. An intravenous glucose tolerance test was performed during steady state plasma ghrelin levels. The acute insulin response to intravenous glucose (AIRg) was calculated from plasma insulin concentrations between 2 and 10 min after the glucose bolus. Intravenous glucose tolerance was measured as the glucose disappearance constant (Kg) from 10 to 30 min.RESULTSThe three ghrelin infusions raised plasma total ghrelin concentrations to 4-, 15-, and 23-fold above the fasting level, respectively. Ghrelin infusion did not alter fasting plasma insulin or glucose, but compared with saline, the 0.3, 0.9, and 1.5 nmol/kg/h doses decreased AIRg (2,152 ± 448 vs. 1,478 ± 2,889, 1,419 ± 275, and 1,120 ± 174 pmol/l) and Kg (0.3 and 1.5 nmol/kg/h doses only) significantly (P < 0.05 for all). Ghrelin infusion raised plasma growth hormone and serum cortisol concentrations significantly (P < 0.001 for both), but had no effect on glucagon, epinephrine, or norepinephrine levels (P = 0.44, 0.74, and 0.48, respectively).CONCLUSIONSThis is a robust proof-of-concept study showing that exogenous ghrelin reduces glucose-stimulated insulin secretion and glucose disappearance in healthy humans. Our findings raise the possibility that endogenous ghrelin has a role in physiologic insulin secretion, and that ghrelin antagonists could improve β-cell function.

Insulin transported from plasma into the central nervous system (CNS) is hypothesized to contribute to the negative feedback regulation of body adiposity. Because CNS insulin uptake is likely mediated by insulin receptors, physiological interventions that impair insulin action in the periphery might also reduce the efficiency of CNS insulin uptake and predispose to weight gain. We hypothesized that high-fat feeding, which both reduces insulin sensitivity in peripheral tissues and favors weight gain, reduces the efficiency of insulin uptake from plasma into the CNS. To test this hypothesis, we estimated parameters for cerebrospinal fluid (CSF) insulin uptake and clearance during an intravenous insulin infusion using compartmental modeling in 10 dogs before and after 7 weeks of high-fat feeding. These parameters, together with 24-h plasma insulin levels measured during ad libitum feeding, also permitted estimates of relative CNS insulin concentrations. The percent changes of adiposity, body weight, and food intake after high-fat feeding were each inversely associated with the percent changes of the parameter k 1 k 2 , which reflects the efficiency of CNS insulin uptake from plasma (r = -0.74, -0.69, -0.63; P = 0.015, 0.03, and 0.05, respectively). These findings were supported by a non-model-based calculation of CNS insulin uptake: the CSF-to-plasma insulin ratio during the insulin infusion. This ratio changed in association with changes of k 1 k 2 (r = 0.84, P = 0.002), body weight (r = -0.66, P = 0.04), and relative adiposity (r = -0.72, P = 0.02). By comparison, changes in insulin sensitivity, according to minimal model analysis, were not associated with changes in k 1 k 2 , suggesting that these parameters are not regulated in parallel. During high-fat feeding, there was a 60% reduction of the estimated CNS insulin level (P = 0.04), and this estimate was inversely associated with percent changes in body weight (r = -0.71, P = 0.03). These results demonstrate that increased food intake and weight gain during high-fat feeding are associated with and may be causally related to reduced insulin delivery into the CNS. Diabetes 49:1525-1533, 2000 I nsulin secreted by the endocrine pancreas plays a complex role in the regulation of fuel homeostasis. Even as insulin is recognized for its anabolic effects in the periphery, insulin acts in the central nervous system (CNS) as a catabolic agent by inhibiting food intake (1) and stimulating fat oxidation (2). These CNS properties, together with many convergent observations, implicate insulin as a signal that provides negative feedback to the CNS for the long-term regulation of energy balance (3-5). According to this hypothesis, interventions that chronically lower CNS insulin levels will increase the tendency for storing energy in the form of adipose tissue. Hence, interventions that chronically lower the circulating insulin levels, the efficiency of CNS insulin uptake, or both could stimulate energy intake and promote increased adiposity.In dogs, insulin enters the CNS via...

Studies of metabolic processes have been enhanced by our understanding of the relationships among obesity, body fat distribution, insulin sensitivity and islet beta-cell function. Thus, we have learned that although insulin resistance is usually associated with obesity, even lean subjects can be insulin resistant due to the accumulation of visceral fat. Insulin sensitivity and beta-cell function are also intimately linked. The hyperbolic relationship between these two parameters explains why insulin-resistant individuals have markedly enhanced insulin responses, whereas subjects who are insulin sensitive exhibit very low responses. Failure to take into account this relationship will lead to erroneous conclusions. By accounting for this important interaction, it has been clearly demonstrated that subjects at high risk of developing type 2 diabetes (older individuals, women with a history of gestational diabetes or polycystic ovary syndrome, subjects with impaired glucose tolerance and first-degree relatives of individuals with type 2 diabetes) have impaired beta-cell function. Furthermore, the progression from normal glucose tolerance to impaired glucose tolerance and type 2 diabetes is associated with declining insulin secretion.

. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab 285: E701-E707, 2003. First published May 28, 2003 10.1152/ ajpendo.00024.2003.-Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release. It has been hypothesized that GLP-1 also reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has independent actions on endogenous glucose production, we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on glucose appearance (R a) and glucose disposal (Rd) was measured in eight men during a pancreatic clamp that was performed by infusing octreotide to suppress secretion of islet hormones, while insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. After stabilization of plasma glucose and equilibration of [ 3 H]glucose tracer, GLP-1 was given intravenously for 60 min. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 Ϯ 14 vs. 113 Ϯ 11 pM; 0.153 Ϯ 0.029 vs. 0.156 Ϯ 0.026 nM; and 64.7 Ϯ 11.5 vs. 65.8 Ϯ 13.8 ng/l, respectively). With the initiation of GLP-1, plasma glucose decreased in all eight subjects from steadystate levels of 4.8 Ϯ 0.2 to a nadir of 4.1 Ϯ 0.2 mM. This decrease in plasma glucose was accounted for by a significant 17% decrease in R a, from 22.6 Ϯ 2.8 to 19.1 Ϯ 2.8 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 (P Ͻ 0.04), with no significant change in Rd. These findings indicate that, under fasting conditions, GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion.incretin; glucose production; pancreatic clamp; gastrointestinal hormone; glucose tolerance GLUCAGON-LIKE PEPTIDE-1 (GLP-1; 7-36 amide) is an intestinal hormone that plays an important role in glucose homeostasis. GLP-1 is a potent insulinotropin that is secreted after meal ingestion, thereby contributing to the incretin effect (the greater insulin release occurring after oral compared with intravenous glucose administration; see Refs. 9, 28, and 35). GLP-1 also decreases glucagon release, either through direct interaction with the ␣-cell or indirectly via stimulation of insulin and somatostatin secretion (10, 47). Thus the overall effect of GLP-1 on pancreatic islet secretion is to decrease circulating glucose concentrations. In addition to the regulation of islet hormones, GLP-1 slows gastric emptying (49), another action that attenuates the rise in plasma glucose after meal ingestion. This broad range of acute effects on processes governing circulating levels of glucose has stimulated interest in using GLP-1 or GLP-1 analogs for the treatment of diabetes.Many investigators have also suggested that GLP-1 has effects on glucose metabolism beyond the regulation of pancreatic islet hormone secretion, e.g., extrapancreatic effects. The first report was from Gutniak and colleagues (20)...

Glucagon-like peptide 1 (GLP-1) is an insulin secretagogue synthesized in the intestine and released in response to meal ingestion. It is secreted primarily in two forms, GLP-1-(7-37) and GLP-1-(7-36)NH(2), both of which bind to a specific GLP-1 receptor (GLP-1r) on the pancreatic beta-cell and augment glucose-stimulated insulin secretion. Once secreted, GLP-1-(7-36)NH(2) is rapidly metabolized to GLP-1-(9-36)NH(2), which is the predominant form of GLP-1 in postprandial plasma because of its relatively slower clearance. Although no clear biological role for GLP-1-(9-36)NH(2) in humans has been identified, recent studies in animals suggest two potential effects: to antagonize the effects of intact GLP-1 and to promote glucose disappearance in peripheral tissues. In the studies reported here we compared the independent effects of GLP-1-(7-36)NH(2), GLP-1-(7-37), and GLP-1-(9-36)NH(2) on parameters of iv glucose tolerance and determined whether GLP-1-(9-36)NH(2) inhibits the insulinotropic actions of GLP-1. Ten healthy subjects underwent 4 separate frequently sampled iv glucose tolerance tests during infusions of GLP-1-(7-37), GLP-1-(7-36)NH(2), GLP-1-(9-36)NH(2), or saline. Results from the iv glucose tolerance test were used to obtain indexes of beta-cell function (acute insulin response to glucose) and iv glucose tolerance (glucose disappearance constant), and the minimal model of glucose kinetics was used to obtain indexes of glucose effectiveness and insulin sensitivity. Compared with control studies, both GLP-1-(7-36)NH(2) and GLP-1-(7-37) significantly increased acute insulin response to glucose, glucose disappearance constant, glucose effectiveness, and glucose effectiveness at zero insulin, but did not change the insulin sensitivity index. In contrast, none of the parameters of glucose tolerance was measurably affected by GLP-1-(9-36) amide. In a second set of experiments, 10 healthy subjects had glucose-stimulated insulin secretion measured during an infusion of GLP-1-(7-36)NH(2) alone or with a simultaneous infusion of GLP-1-(9-36)NH(2) that increased plasma levels approximately 10-fold over those produced by unmetabolized GLP-1. Augmentation of glucose-stimulated insulin secretion by GLP-1-(7-36)NH(2) was not altered by the coadministration of GLP-1-(9-36)NH(2). Based on these results we conclude that GLP-1-(9-36)NH(2) does not regulate insulin release or glucose metabolism in healthy humans.