. Longterm high-fat feeding leads to severe insulin resistance but not diabetes in Wistar rats. Am J Physiol Endocrinol Metab 282: E1231-E1238, 2002. First published January 15, 2002 10.1152/ajpendo.00173.2001.-Although lipid excess can impair -cell function in vitro, short-term high-fat feeding in normal rats produces insulin resistance but not hyperglycemia. This study examines the effect of long-term (10-mo) high polyunsaturated fat feeding on glucose tolerance in Wistar rats. The high fat-fed compared with the chow-fed group was 30% heavier and 60% fatter, with approximately doubled fasting hyperinsulinemia (P Ͻ 0.001) but only marginal fasting hyperglycemia (7.5 Ϯ 0.1 vs. 7.2 Ϯ 0.1 mmol/l, P Ͻ 0.01). Insulin sensitivity was ϳ67% lower in the high-fat group (P Ͻ 0.01). The acute insulin response to intravenous arginine was approximately double in the insulin-resistant highfat group (P Ͻ 0.001), but that to intravenous glucose was similar in the two groups. After the intravenous glucose bolus, plasma glucose decline was slower in the high fat-fed group, confirming mild glucose intolerance. Therefore, despite severe insulin resistance, there was only a mildly elevated fasting glucose level and a relative deficiency in glucose-stimulated insulin secretion; this suggests that a genetic or congenital susceptibility to -cell impairment is required for overt hyperglycemia to develop in the presence of severe insulin resistance. insulin secretion; arginine; long-chain acyl-coenzyme A; body composition; glucose tolerance DIETARY FACTORS such as high-fat feeding can induce insulin resistance, but it is generally assumed that, without a genetic predisposition, diet alone will not suffice to induce diabetes mellitus. This notion has been challenged by recent work suggesting a toxic effect of excess lipid on -cell function. Although shortterm exposure (Ͻ6 h) to elevated fatty acids potentiates glucose-stimulated insulin secretion, longer-term exposure (24-48 h) can inhibit insulin secretion in rat -cells in vitro (41), in perifused pancreata (32), and in humans (6,28).Previous studies from our institution with shortterm (3 wk-1 mo) high polyunsaturated fat-fed rats showed no metabolically significant hyperglycemia despite the induction of insulin resistance (23,26,37). One other study of long-term (32 wk) high-fat feeding produced a wider variation in fasting plasma glucose levels with some hyperglycemia (15). However, that study differed in method from our usual model of high-fat feeding, in that there was a greater proportion of saturated fat and a longer period of fasting (24 h).This current study extends our previous short-term high-fat feeding in normal rats for a 10-mo period to determine whether long-term high-fat feeding adversely affects glucose tolerance. We examine this in the context of lipid levels, insulin sensitivity, and body composition.
MATERIALS AND METHODSExperimental animals. Male Wistar rats obtained from an in-house breeding colony were randomized at ϳ2 mo of age into two groups; one group rec...
To clarify roles of amylin, we investigated metabolic responses to rat amylin-(8—37), a specific amylin antagonist, in normal and insulin-resistant, human growth hormone (hGH)-infused rats. Fasting conscious rats were infused with saline or hGH, each with and without amylin-(8—37) (0.125 μmol/h), over 5.75 h. At 3.75 h, a hyperinsulinemic (100 mU/l) clamp with bolus 2-deoxy-d-[3H]glucose and [14C]glucose was started. hGH infusion led to prompt (2- to 3-fold) basal hyperamylinemia ( P < 0.02) and hyperinsulinemia. Amylin-(8—37) reduced plasma insulin ( P < 0.001) and enhanced several measures of whole body and muscle insulin sensitivity ( P < 0.05) in both saline- and hGH-infused rats. Amylin-(8—37) corrected hGH-induced liver insulin resistance, increased basal plasma triglycerides and lowered plasma nonesterified fatty acids in both groups, and reduced muscle triglyceride and total long-chain acyl-CoA content in saline-treated rats ( P < 0.05). In isolated soleus muscle, amylin-(8—37) blocked amylin-induced inhibition of glycogen synthesis but had no effect in the absence of amylin. Thus 1) hyperamylinemia accompanies insulin resistance induced by hGH infusion; 2) amylin-(8—37) increases whole body and muscle insulin sensitivity and consistently reduces basal insulin levels in normal and hGH-induced insulin-resistant rats; and 3) amylin-(8—37) elicits a significant alteration of in vivo lipid metabolism. These findings support a role of amylin in modulating insulin action and suggest that this could be mediated by effects on lipid metabolism.
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