Defective Fatty Acid-mediated β-Cell Compensation in Zucker Diabetic Fatty Rats

Abstract

Although obesity is associated with insulin resistance, most obese humans and rodents remain normoglycemic because of compensatory hyperinsulinemia. This has been attributed to ␤-cell hyperplasia and increased low K m glucose metabolism of islets. Since free fatty acids (FFA) can induce these same ␤-cell changes in normal islets of Wistar rats and since plasma FFA are increased in obesity, FFA could be the signal from adipocytes that elicits ␤-cell compensation sufficient to prevent diabetes. To determine if FFA-induced compensation is impaired in islets of rats with a diabetogenic mutation, the Zucker diabetic fatty (ZDF) rat, we cultured islets from 6-week-old obese (fa/fa) rats that had compensated for obesity and apparently normal islets from lean ZDF rats (fa/؉) in 0, 1, or 2 mM FFA. Low K m glucose usage rose 2.5-fold in FFA-cultured control islets from age-matched Wistar rats, but failed to rise in either the precompensated islets of ZDF rats or in islets of lean ZDF rats. Bromodeoxyuridine incorporation increased 3.2-fold in Wistar islets but not in islets from obese or lean ZDF rats. Insulin secretion doubled in normal islets cultured in 2 mM FFA (p < 0.01) but increased only slightly in islets from lean ZDF rats (not significant) and declined in islets from obese ZDF rats (p < 0.05). We conclude that, unlike the islets of age-matched Wistar rats, islets of 6-week-old heterozygous and homozygous ZDF rats lack the capacity for FFA-induced enhancement of ␤-cell function.Pancreatic islets from obese rodents are enlarged and exhibit a marked increase in low K m glucose metabolism (1), which may account for their high output of insulin even at low concentrations of glucose (1-3). The hyperinsulinemia is regarded as a compensatory response that prevents hyperglycemia despite the insulin resistance that invariably accompanies obesity.There is evidence that free fatty acids (FFA) 1 may be the signal from adipocytes that mediates this compensatory insulin secretion (1). Plasma FFA are elevated in obesity (4, 5) and have long been known to stimulate insulin secretion (6 -8).Moreover, the compensatory triad observed in islets from obese rats can be induced in normal islets by culturing them for 7 days in the presence of 1 or 2 mM FFA; low K m glucose metabolism rises dramatically (1), there is evidence of increased ␤-cell replication (1), and insulin secretion increases (1), confirming the earlier description of FFA-induced hyperinsulinemia (9). If the FFA-induced compensation in obesity is, at least in part, responsible for preventing diabetes, it follows that FFAinduced compensation may be impaired at or before the onset of diabetes. In this study we assess the ability of FFA to induce the compensatory triad of enhanced low K m glucose metabolism, increased ␤-cell replication, and insulin hypersecretion in islets from obese rats with a diabetogenic mutation, the Zucker diabetic fatty rat (ZDF-drt). We observe that FFA induction of these compensatory changes is impaired, not only in islets from obese homozygous r...

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

“…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]. The TG content was mildly decreased rather than dramatically increased [7,40].…”

Pleiotropic effects of fatty acids on pancreatic β‐cells

“…An additional increase in islet fat reverses the foregoing compensatory changes and causes b-cell disfunction, a reduction in the b-cell proliferation, and diabetes (Milburn et al, 1995;Hirose et al, 1996;Shimabukuro et al, 1998b). The b-cell descompensation in this type of diabetes may involve excessive nitric oxide (NO) generation through inducible NO synthase .…”

LncRNA NONRATT021972 siRNA attenuates P2X7 receptor expression and inflammatory cytokine production induced by combined high glucose and free fatty acids in PC12 cells

“…However, there is no effective therapy for inflammation or for DNP. LncRNAs, typically defined as transcripts longer than 200 nucleotides, are recently regarded as a potential therapeutic target for inflammatory relevant diseases, including diabetes and DNP [26][27][28][29][30][31][32][33][34][35][36][37][38]. However, the functional question of massive lncRNAs in DNP has not been characterized [26,27,30].…”

“…The cells were grouped into control (25 mM Dglucose), HG 50 mM (50 mM D-glucose), and HG 75 mM (75 mM D-glucose). FFAs were a mixture of oleate and palmitate, 2:1 (w/w) [34]. For HF experiment, the cells were grouped into control (1 % BSA), HF 0.25 mM, HF 0.5 mM, and HF 1.0 mM [6].…”