. 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)...

OBJECTIVE -The purpose of this study was to determine whether an extended infusion of the incretin hormone glucagon-like peptide 1 (GLP-1) has a greater effect to promote insulin secretion in type 2 diabetic subjects than acute administration of the peptide.RESEARCH DESIGN AND METHODS -Nine diabetic subjects and nine nondiabetic volunteers of similar age and weight were studied in identical protocols. First-phase insulin release (FPIR; the incremental insulin response in the first 10 min after the intravenous glucose bolus) and second-phase insulin release (SPIR; the incremental insulin response from 10 -60 min after intravenous glucose) were measured during three separate intravenous glucose tolerance tests (IVGTTs): 1) without GLP-1 (control); 2) with acute administration of GLP-1 as a square wave starting just before glucose administration; and 3) with an extended infusion of GLP-1 for 3 h before and during the IVGTT.RESULTS -In the subjects with diabetes, FPIR was severely impaired-a defect that was only modestly improved by acute administration of GLP-1 (197 Ϯ 97 vs. 539 Ϯ 218 pmol/l ⅐ min, P Ͻ 0.05), while SPIR was substantially increased (1,952 Ϯ 512 vs. 8,072 Ϯ 1,664 pmol/l ⅐ min, P Ͻ 0.05). In contrast, the 3-h preinfusion of GLP-1 normalized fasting hyperglycemia (7.9 Ϯ 0.5 vs. 5.2 Ϯ 0.6, P Ͻ 0.05), increased FPIR by 5-to 6-fold (197 Ϯ 97 vs. 1,141 Ϯ 409 pmol/l ⅐ min, P Ͻ 0.05), and augmented SPIR significantly (1,952 Ϯ 512 vs. 4,026 Ϯ 851 pmol/l ⅐ min, P Ͻ 0.05), but to a lesser degree than the acute administration of GLP-1. In addition, only the 3-h GLP-1 preinfusion significantly improved intravenous glucose tolerance (K g control 0.61 Ϯ 0.04, acute infusion 0.71 Ϯ 0.04, P ϭ NS; 3-h infusion 0.92 Ϯ 0.08%/min, P Ͻ 0.05). These findings were also noted in the nondiabetic subjects in whom acute administration of GLP-1 significantly increased SPIR relative to the control IVGTT (9,439 Ϯ 2,885 vs. 31,553 Ϯ 11660 pmol/l ⅐ min, P Ͻ 0.001) with less effect on FPIR (3,221 Ϯ 918 vs. 4,917 Ϯ 1,614 pmol/l ⅐ min, P ϭ 0.075), while the 3-h preinfusion of GLP-1 significantly increased both FPIR (3,221 Ϯ 918 vs. 7,948 Ϯ 2,647 pmol/l ⅐ min, P Ͻ 0.01) and SPIR (9,439 Ϯ 2,885 vs. 21,997 Ϯ 9,849 pmol/l ⅐ min, P Ͻ 0.03).CONCLUSIONS -Extended administration of GLP-1 not only augments glucosestimulated insulin secretion, but also shifts the dynamics of the insulin response to earlier release in both diabetic and nondiabetic humans. The restitution of some FPIR in subjects with type 2 diabetes is associated with significantly improved glucose tolerance. These findings demonstrate the benefits of a 3-h infusion of GLP-1 on ␤-cell function beyond those of an acute insulin secretagogue, and support the development of strategies using continuous or prolonged GLP-1 receptor agonism for treating diabetic patients. Diabetes Care 26:791-798, 2003G lucagon-like peptide 1(GLP-1) amide is one of the principle hormones that contribute to the incretin effect, i.e., the augmentation of insulin secretion that occurs when glucose is taken ...

We report a case of subtle Cushing syndrome in a Pakistani man who self-treated his asthma with a potent long-acting oral glucocorticoid (betamethasone disodium phosphate [Bentelan]) for more than 30 years. He presented with cushingoid features, insulin resistance, and refractory hypertension. Laboratory evaluation revealed undetectable cortisol levels and suppression of the hypothalamic-pituitary-adrenal axis. The patient obtained the drug from his country of origin, with no understanding of the potential adverse effects imposed by long-term use of steroids. He is now being slowly weaned off the drug. The apparent widespread availability, access, and abuse of such potent steroids are a cause of concern in developing countries. We suggest that physicians in the United States be aware of the potential abuse of such potent drugs in all populations, including immigrants.

Although glucocorticoid therapy carries a risk of promoting or exacerbating hyperglycemia, there are currently no established medical guidelines for detecting or managing diabetes in patients starting such therapy. The authors use three case reports to illustrate a relatively simple strategy that can be used to manage preexisting and new-onset diabetes in the primary care setting.

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