Basal insulin hypersecretion in insulin-resistant Zucker diabetic and Zucker fatty rats: Role of enhanced fuel metabolism

Zhou, Yinggang; Cockburn, Brian N.; Pugh, William; Polonsky, Kenneth S.

doi:10.1016/s0026-0495(99)90219-6

Cited by 56 publications

(49 citation statements)

References 31 publications

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“…Previously it has been shown that inhibition of fatty acid oxidation by an inhibitor of CPT1 reduces basal hypersecretion in ZDF rats, such that the maintenance of fatty acid oxidation may also be important in compensation processes [38]. Islets of the ZF rat displayed none of the well-described features of lipotoxicity [7,[39][40][41][42][43].…”

Section: Discussionmentioning

confidence: 96%

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

et al. 2006

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Aims/hypothesis The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes. Materials and methods NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats. Results Exogenous palmitate markedly potentiated glucosestimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l).Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent. Conclusions/interpretationThe results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity.

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Section: Discussionmentioning

confidence: 96%

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

et al. 2006

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“…The factors determining whether an individual with NGT is hyper-or hypoinsulinemic relative to the degree of insulin sensitivity and adiposity remain to be fully identified, but differences in ␤-cell size and mass (31), in plasma free fatty acid concentration and/or tissue (islet and muscle) triglyceride or glycogen content (28), in ␤-cell insulin receptor expression (42), in the constitutive secretory pathway (31), in the metabolic clearance rate of insulin (32), in central (hypothalamic) regulatory pathways (27,30), and/or in the activity of the parasympathetic nervous system (27,29,30) have been suggested. The latter mechanism is of particular interest because recent evidence suggests that the marked hyperinsulinemia in Pima Indians may, at least in part, be due to an increased vagal cholinergic drive to the pancreas (34).…”

Section: Discussionmentioning

confidence: 99%

“…Second, basal hypersecretion of insulin was found to be a more common abnormality than insulin resistance in a large group of nondiabetic obese Caucasians (26). Third, hypersecretion of insulin is one of the earliest detectable abnormalities in various animal models of type 2 diabetes (27)(28)(29)(30)(31), such as in rats with lesions of the ventromedial hypothalamus (28). In this model, amelioration of insulin hypersecretion by vagotomy largely delays or even prevents the development of diabetes (28).…”

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confidence: 99%

A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia.

et al. 2000

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Fasting hyperinsulinemia is a widely used surrogate measure of insulin resistance and predicts type 2 diabetes in various populations. Whether fasting hyperinsulinemia predicts diabetes independent of insulin resistance is unknown. In 319 Pima Indians with normal glucose tolerance, fasting plasma insulin concentration and insulin-stimulated glucose disposal (M) (hyperinsulinemic clamp) were inversely related, but at any given M, there was substantial variation, with some subjects being hyperinsulinemic and others being hypoinsulinemic relative to their degree of insulin sensitivity. In 262 of the 319 subjects followed prospectively over 6.4 ± 3.9 years, a high fasting plasma insulin concentration was a significant independent predictor of diabetes, in addition to low M and low acute insulin response (AIR) (intravenous glucose challenge). In 161 of the 319 subjects with follow-up measurements of M and AIR (5.1 ± 3.9 years), a high relative fasting plasma insulin concentration predicted a decline in AIR but not in M before the onset of diabetes. The adjusted fasting plasma insulin concentration was a familial trait (heritability of 0.52) and in a genomewide scan, there was suggestive evidence of linkage (logarithm of odds score 1.77) to a region on chromosome 3q, which harbors the gene encoding GLUT2. These results provide the first prospective evidence in humans that fasting hyperinsulinemia itself has a primary role in the pathogenesis of diabetes, independent of insulin resistance. Whether amelioration of basal insulin hypersecretion will prevent diabetes remains to be elucidated.

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“…Cross-sectional support for these changes has been shown in other models of insulin resistance. Increased insulin secretion has been observed in animal (26) and human (4,27) obesity. Insulin clearance was reduced in obesity (28)(29)(30)(31), insulin resistance without obesity (31), impaired glucose tolerance (IGT) (32), and diabetes (33).…”

Section: Longitudinal Compensation For Fat Feedingmentioning

confidence: 99%

Longitudinal compensation for fat-induced insulin resistance includes reduced insulin clearance and enhanced beta-cell response.

et al. 2000

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Central adiposity is highly correlated with insulin resistance, which is an important risk factor for type 2 diabetes and other chronic diseases. However, in normal individuals, central adiposity can be tolerated for many years without development of impaired glucose tolerance or diabetes. Here we examine longitudinally the mechanisms by which glucose tolerance can be maintained in the face of substantial insulin resistance. Normal dogs were fed a diet enriched with moderate amounts of fat (2 g · kg -1 · day -1 ), similar to that seen in modern "cafeteria" diets, and the time course of metabolic changes in these animals was examined over 12 weeks. Trunk adiposity as assessed by magnetic resonance imaging increased from 12 to 19%, but body weight remained unchanged. Insulin sensitivity (S I ) as determined by frequently sampled intravenous glucose tolerance tests was measured over a 12-week period. S I decreased 35% by week 1 and remained impaired for the entire 12 weeks. Intravenous glucose tolerance was reduced transiently for 1 week, recovered to baseline, and then again began to decline after 8 weeks. Firstphase insulin response began to increase after week 2, peaked by week 6 (190% of basal), and then declined. The increase in insulin response was due partially to enhanced ␤-cell function (22%) but due also to añ 50% reduction in insulin clearance. This compensation by insulin clearance was also confirmed with insulin clamps performed in fat-fed versus control dogs. The present study confirms the ability of the normal individual to compensate for fat-induced insulin resistance by enhanced insulin response, such that the product of insulin sensitivity ؋ secretion is little changed. However, the compensation is due as much to reduced insulin clearance as increased ␤-cell sensitivity to glucose. Reduced hepatic extraction of insulin may be the first line of defense providing a higher proportion of secreted insulin to the periphery and sparing the ␤-cells during compensation for the insulin-resistant state. Diabetes 49:2116-2125, 2000 T here is abundant evidence that diabetes and obesity are increasing in the U.S. population (1-3). Because adiposity is related to insulin resistance (4-6), and insulin resistance is a risk factor for type 2 diabetes and cardiovascular disease, a consensus has emerged that increased adiposity is responsible for the increased incidence of type 2 diabetes and its associated morbidity (metabolic syndrome or syndrome X [7]). In addition, evidence has accumulated indicating that visceral adiposity in particular is associated with insulin resistance and the metabolic syndrome (8,9).Despite overwhelming evidence demonstrating association between insulin resistance, visceral adiposity, and metabolic risk, there is little evidence directly demonstrating that central adiposity in fact causes insulin resistance. In addition, there is little understanding of the mechanisms underlying the relationship among visceral adiposity, insulin resistance, and risk.To examine the acute effects of adiposi...

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Basal insulin hypersecretion in insulin-resistant Zucker diabetic and Zucker fatty rats: Role of enhanced fuel metabolism

Cited by 56 publications

References 31 publications

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia.

Longitudinal compensation for fat-induced insulin resistance includes reduced insulin clearance and enhanced beta-cell response.

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