Background-Hypersecretion of insulinotropic factors such as glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-36)amide (GLP-1) have been postulated to account for the hyperinsulinaemia of obesity. Aims-To examine the role of GLP-1 and GIP in obese women and matched controls. Subjects-Six lean and six obese women subjects matched for age. Methods-The gut hormone, plasma glucose, and serum triglyceride responses were studied over 180 minutes after oral carbohydrate and fat meals. Heparin (10 000 units) was given intravenously at 120 minutes.Results-There was pronounced attenuation of plasma GLP-1 secretion to oral carbohydrate in the obese compared with lean subjects but no such difference in response to oral fat load. There were no differences in the plasma GIP responses to carbohydrate or fat feeding. There was an apparent fall in plasma GLP-1 values in all subjects after administration of heparin. Conclusion-Postprandial GLP-1 secretion in response to oral carbohydrate is considerably attenuated in obese subjects.The cause of this attenuation of GLP-1 secretion is not known although we suggest that both this fall and the overall reduction in GLP-1 values in obese subjects may be related to an increase in plasma non-esterified fatty acids. (Gut 1996; 38: 916-919) Keywords: GLP-1, obesity, carbohydrate meal, fat meal. strongly stimulates insulin secretion after carbohydrate, fat, and mixed meals. Molecular biology techniques have shown that posttranslational processing of proglucagon in the pancreas and ileum yields several novel glucagon-like peptides.67 Among these, the truncated fragment of GLP-1 (hitherto called GLP-1 in this paper), has been shown to be strongly insulinotropic and its secretion has been shown to increase after oral glucose and mixed meals.8 9 In addition to its insulinotropic effect, GLP-1 inhibits pancreatic glucagon secretion, decreases hepatic gluconeogenesis, and decreases insulin resistance.10 11 It has been postulated that an exaggerated 'incretin' factor may have a pathophysiological role in obesity. A role for GIP has been examined in this regard but has not been conclusively shown.5 In this context, it has been suggested that hypersecretion of GLP-1 may be the long sought 'incretin' factor in obesity. 12 Indeed, Fukase and colleagues have examined this hypothesis in a study where they showed increased secretion of glucagon-like peptide-1 in obese diabetic subjects but the responses in non-diabetic obese and matched controls were very similar.However, the methodology adopted by Fukase and workers for GLP-1 assay was indirect and less specific than that used in this study and included GLP-1(7-37), which is normally present at very low concentrations in plasma, and the two biologically inactive major proglucagon derived fragments. GLP-1 (7-36)amide, measured in this study, is the predominant circulating molecular species of glucagon-like peptides in humans. We undertook this study to clarify the conclusions of Fukase and colleagues that hypers...

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1. The effects of insulin (2 nM and 4 nM) upon oxygen consumption ( VoJ, lipolysis rates and indirectly derived rates of fatty acid utilization, by isolated brown adipocytes from warm-acclimated (W cells) and cold-acclimated (C cells) animals, induced by noradrenaline and glucagon separately and conjointly, are reported.2. Changes in interrelationships (coupling) between the parameters under different treatment regimes were assessed using bivariate regression analyses.3. Administration of glucagon with noradrenaline increased lipolysis/fatty acid utilization coupling without concomitant increase of Vo2 suggesting that glucagon may increase re-esterification through glycogenolytic generation of glycerol 3-phosphate, trapping intracellular fatty acid in excess of the capacity of disposal mechanisms, thus conserving respiratory substrate.4. W cells were unresponsive to glucagon in terms of lipolysis and po2'; C cells responded to glucagon with parallel increases in lipolysis rate and Both cell types responded to noradrenaline alone and conjointly with glucagon; C cells-were more sensitive to these agonists than W cells.5. Lipolysis/ Vo, coupling was reduced in C cells suggesting that in cold acclimation, noradrenaline-induced lipolysis rates are in excess of the capacity of cellular oxidation/re-esterification mechanisms.6. Insulin inhibited noradrenaline and glucagon-induced lipolysis, simultaneously increasing po2, supporting the hypothesis that glucose may be a thermogenic substrate in brown adipase tissue, permitting concurrent thermogenesis and lipogenesis. C cells were more insulin-sensitive than W cells.7. The data indicate that insulin may mediate its effects (additively with noradrenaline) by activation of pyruvate dehydrogenase, generating glycolytic flux and, in the presence of noradrenaline-inhibited lipogenesis, generate additional oxaloacetate, permitting increased P-oxidation.In homeotherms, non-shivering thermogenesis is mediated primarily by brown adipose tissue (BAT) [l]. The principal mechanism of activation is by means of increased sympathetic activity with liberation of noradrenaline from the dense adrenergic terminals with which the tissue is invested, and consequent activation of P-adrenergically mediated lipolysis leading to the liberation of free fatty acids from intracellular triacylglycerols. Subsequent P-oxidation of free fatty acids, associated with increased mitochondrial proton conductance induced by increased free fatty acid concentrations [2], leads to enhanced heat production by dissipation of the mitochondrial proton gradient [3]. A second effect attributed to noradrenaline release in chronic cold exposure is increased synthesis of mitochondrial protonophore [4].While noradrenaline appears to be the prime mediator of BAT thermogenesis [5], there is evidence that non-adrenergic factors such as glucagon [6, 71 may have permissive or

Arginine-stimulated insulin and glucagon outputs from isolated perfused pancreata of warm-acclimated and 2-, 4-, and 6-wk cold-acclimated rats (4 degrees C) were determined to assess whether observed changes in these parameters were a result of cold exposure per se or a part of the adaptive process of cold acclimation. Progressive and sequential changes were seen in both insulin and glucagon outputs. At 2 wk cold acclimation, glucagon rose and insulin output tended to fall, at 4 wk, glucagon output remained elevated and insulin output was further reduced, and at 6 wk, glucagon output had returned to control levels, whereas insulin output was substantially further reduced. These changes resulted in reduction of the insulin-to-glucagon molar ratio of the total arginine-induced output from 7.27 +/- 1.76 (SE) in the warm acclimate to 2.31 +/- 0.79 (SE) at 2 wk, 1.42 +/- 0.29 (SE) at 4 wk, and 1.26 +/- 0.21 (SE) at 6 wk cold acclimation. The data do not provide in vitro support for the hypothesis that changes in pancreatic hormone secretion in vivo are a consequence of cold exposure and not cold acclimation.