Long-term high-fat feeding leads to severe insulin resistance but not diabetes in Wistar rats

Abstract

. 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...

Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding

“…This suggests that adipose tissue insulin resistance was specific with respect to glucose metabolism, but not to the control of lipolysis. Similar findings have been described in other studies [25,29,34]. This notion of selective insulin resistance has recently been described in liver [17,35].…”

“…Here, we show that whole-body insulin sensitivity does not deteriorate further beyond 3 weeks of HFD in mice, indicating that insulin resistance develops rapidly but reaches a plateau that is maintained over the course of further fat feeding. When comparing short-(3 week) [28] and long-term (10 months) [29] HFD protocols in rats, whole-body insulin sensitivity is reduced by ∼60% when compared with lean chow-fed controls, irrespective of how long the rats are maintained on the HFD. This supports the notion that insulin resistance has a limit that, once reached, is not exacerbated by further HFD and subsequent gains in adiposity.…”

Combined effects of high-fat feeding and circadian desynchronization

“…The increase in body fat was associated with higher levels of basal blood glucose and plasma leptin, a hormone signaling metabolic status from the adipocyte to peripheral tissues and the brain. There was no indication that high-fat feeding in our Long-Evans rats led to impaired glucose tolerance as previously found in Wistar and Sprague-Dawley rats, 20,21 in contrast to what others found in Wistar Imamichi rats. 21 Plasma insulin in response to high-fat diet has been shown to be either unchanged 21 or increased, 19,22 while a decrease was noted in the present study (Table 1).…”

Interactive influences of peroxisome proliferator-activated receptor α activation and glucocorticoids on pancreatic beta cell compensation in insulin resistance induced by dietary saturated fat in the rat

“…This is reiterated in Wistar rats fed a high level of saturated fats. Although very long-term (10 months) high-saturated-fat feeding of Wistar rats leads to severe insulin resistance, overt diabetes does not develop [26]. In the highsaturated-fat feeding protocol of Wistar rats used in the present study (female Wistar rats; moderate lipid content; 4 weeks of dietary manipulation), euglycaemic-hyperinsulinaemic clamp studies have demonstrated peripheral insulin resistance, but unimpaired hepatic insulin sensitivity [11], and enhanced insulin secretion that allows maintenance of glucose tolerance [15].…”