In outbred Sprague-Dawley rats, about one-half develop diet-induced obesity (DIO) on a diet relatively high in fat and energy (HE diet). The rest are diet resistant (DR), gaining weight and fat at the same rate as chow-fed controls. Here we selectively bred for high (DIO) and low (DR) weight gainers after 2 wk on HE diet. By the F5 generation, both male and female inbred DIO rats gained > 90% more weight than inbred DR rats on HE diets. Even on low-fat chow diet, DIO males were 31% and females were 22% heavier than their respective DR rats. Full metabolic characterization in male rats showed that weight-matched, chow-fed DIO-prone rats had similar energy intakes and feed efficiency [body weight (kg0.75)/energy intake (kcal)] but 44% more carcass fat than comparable DR-prone rats. Their basal plasma insulin and glucose levels in the fed state were 70 and 14% higher, respectively. But, when fasted, DIO-prone oral glucose tolerance results were comparable to DR-prone rats. Chow-fed DIO-prone males also had 42% greater 24-h urine norepinephrine levels than DR-prone males. During 2 wk on HE diet, DIO rats ate 25% more, gained 115% more weight, had 36% more carcass fat, and were 42% more feed efficient than comparable DR rats. Fasted HE diet-fed DIO rats developed frank glucose intolerance during a glucose tolerance test with 55 and 158% greater insulin and glucose areas under the curve, respectively. Thus the DIO and DR traits in the outbred Sprague-Dawley population appear to be due to a polygenic pattern of inheritance.

Control of prandial plasma concentrations of substrates, particularly glucose, is aided by incretins. Incretins are hormones released by the digestive tract in response to ingested nutrients [1]. The role of incretins is to sensitize beta cells to stimulation by glucose, leading to an accelerated and augmented insulin response to absorbed glucose. The two most prominent incretins are gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The first is released by K cells in the duodenum and jejunum [2] whereas GLP-1 is produced in L cells in the distal small intestine and in the colon [3]. Both GLP-1 and GIP augment glucose-stimulated insulin secretion [4,5] and increase intracellular cAMP concentrations in beta cells [6]. Although some controversy exists regarding the relative importance of each of these incretins, both hormones have strong priming effects on the beta cells [7]. Several studies have shown that Diabetologia (1999) Abstract Aims/hypothesis. The potent incretin hormone glucagon-like peptide 1 (GLP-1) plays a pivotal role in prandial insulin secretion. In the circulation GLP-1 (7±36) amide is, however, rapidly (t 1/2 :1±2 min) inactivated by the protease dipeptidyl peptidase IV (DPP-IV). We therefore investigated whether DPP-IV inhibition is a feasible approach to improve glucose homeostasis in insulin resistant, glucose intolerant fatty Zucker rats, a model of mild Type II (non-insulin-dependent) diabetes mellitus.Methods. An oral glucose tolerance test was done in lean and obese male Zucker rats while plasma DPP-IV was inhibited by the specific and selective inhibitor NVP-DPP728 given orally.Results. Inhibition of DPP-IV resulted in a significantly amplified early phase of the insulin response to an oral glucose load in obese fa/fa rats and restoration of glucose excursions to normal. In contrast, DPP-IV inhibition produced only minor effects in lean FA/? rats. Inactivation of GLP-1 (7±36) amide was completely prevented by DPP-IV inhibition suggesting that the effects of this compound on oral glucose tolerance are mediated by increased circulating concentrations of GLP-1 (7±36) amide. Reduced gastric emptying, as monitored by paracetamol appearance in the circulation after an oral bolus, did not appear to have contributed to the reduced glucose excursion. Conclusion/interpretation. It is concluded that NVP-DPP728 inhibits DPP-IV and improves insulin secretion and glucose tolerance, probably through augmentation of the effects of endogenous GLP-1. The improvement observed in prandial glucose homeostasis during DPP-IV inhibition suggests that inhibition of this enzyme is a promising treatment for Type II diabetes. [Diabetologia (1999

The incretin glucagon-like peptide-1 (GLP-1)-(7---36) amide is an important factor in prandial glucose homeostasis. Findings that GLP-1 is rapidly inactivated led to the hypothesis that the target of GLP-1 is close to the site of release. To investigate whether the target tissue is located in the hepatoportal system, we administered GLP-1 with glucose into the portal vein of rats and compared this with peripheral GLP-1 administration (jugular vein) and studied the effects of blockers of the nervous system. Portal GLP-1 augmented the insulin response to a portal glucose bolus by 81% (P < 0.01) and markedly improved the glucose disposal rate (P < 0.05). Peripheral administration of GLP-1 produced a similar augmentation of the insulin response (88%) and of the glucose disposal rate. However, only the effect of portal GLP-1 on insulin secretion was blocked by the ganglionic blocker chlorisondamine. The data suggest that prandial beta-cell stimulation by GLP-1 is evoked via a neural reflex triggered in the hepatoportal system. Because absorbed nutrients and GLP-1 first appear in the portal system, this mechanism may constitute a major pathway of GLP-1 action during meals.

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The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). Because GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined acute (single dose) and chronic (once-a-day dosing for 21 days) effects of the DPP-4 inhibitor vildagliptin (0.03-10 mg/kg) on plasma DPP-4 activity, intact GLP-1, glucose, and insulin after an oral glucose load in insulin-resistant Zucker fatty rats and acute effects in mildly insulin-resistant high-fat-fed normal rats. A single oral dose of vildagliptin in Zucker rats produced a rapid and dose-related inhibition of DPP-4: the minimum effective dose (MED) was 0.3 mg/kg. Glucose-induced increases of intact GLP-1 were greatly but similarly enhanced by vildagliptin at doses Ն0.3 mg/kg. Postload glucose excursions decreased, and the insulinogenic index (⌬insulin/⌬glucose at 10 min) increased, with an MED of 0.3 mg/kg and a maximally effective dose of 3 mg/kg. The effects of vildagliptin after chronic treatment were nearly identical to those of acute administration, and vildagliptin had no effect on body weight. In fat-fed normal rats, vildagliptin (3 mg/kg) also decreased postload glucose excursions and increased the insulinogenic index, but these effects were smaller than those in Zucker rats. Thus, vildagliptin is an orally effective incretin enhancer with antihyperglycemic activity in insulin-resistant rats and exhibits no tachyphylaxis. GLP-1-mediated augmentation of glucose-induced insulin release seems to make the major contribution to the antidiabetic properties of vildagliptin.