In vivo effects of polyunsaturated, monounsaturated, and saturated fatty acids on hepatic and peripheral insulin sensitivity.

OBJECTIVE: Free fatty acids (FFAs) cause insulin resistance and are often elevated in obesity. Chronic ingestion of diets rich in saturated fat induces more insulin resistance than diets rich in unsaturated fat, however, it remains unclear whether different FFAs cause distinct levels of insulin resistance in the short-term, which is relevant to the feeding and fasting cycle. Protein kinase C (PKC)-δ is implicated in hepatic insulin resistance. Therefore, we investigated the effects of short-term elevation of fatty acids with different degrees of unsaturation on hepatic insulin action and liver PKC-δ membrane translocation, a marker of activation. MATERIALS/METHODS: Triglyceride emulsions of Soybean Oil+Heparin (polyunsaturated (POLY)), Olive Oil+Heparin (monounsaturated (MONO)), Lard Oil+Heparin (saturated (SATU)), or saline (SAL) were infused intravenously for 7h to elevate plasma FFA concentrations ~3-4 fold in rats. During the last 2h of infusion, a hyperinsulinemic-euglycemic clamp with tritiated glucose methodology was performed to examine hepatic and peripheral insulin sensitivity. RESULTS: Surprisingly, SATU, MONO, and POLY impaired peripheral insulin sensitivity (glucose utilization divided by insulin) to a similar extent. Furthermore, all lipids induced a similar degree of hepatic insulin resistance compared to SAL. Although there were changes in hepatic content of lipid metabolites, there were no significant differences in liver PKC-δ membrane translocation across fat groups. CONCLUSIONS: In summary, in the short-term, FFAs with different degrees of unsaturation impair peripheral insulin sensitivity and induce hepatic insulin resistance as well as hepatic PKC-δ translocation to the same extent.

Susceptibility to fatty acid-induced ß-cell dysfunction is enhanced in prediabetic diabetes-prone biobreeding rats: a potential link between ß-cell lipotoxicity and islet inflammation.

ß-Cell lipotoxicity is thought to play an important role in the development of type 2 diabetes. However, no study has examined its role in type 1 diabetes, which could be clinically relevant for slow-onset type 1 diabetes. Reports of enhanced cytokine toxicity in fat-laden islets are consistent with the hypothesis that lipid and cytokine toxicity may be synergistic. Thus, ß-cell lipotoxicity could be enhanced in models of autoimmune diabetes. To determine this, we examined the effects of prolonged free fatty acids elevation on ß-cell secretory function in the prediabetic diabetes-prone BioBreeding (dp-BB) rat, its diabetes-resistant BioBreeding (dr-BB) control, and normal Wistar-Furth (WF) rats. Rats received a 48-h iv infusion of saline or Intralipid plus heparin (IH) (to elevate free fatty acid levels ~2-fold) followed by hyperglycemic clamp or islet secretion studies ex vivo. IH significantly decreased ß-cell function, assessed both by the disposition index (insulin secretion corrected for IH-induced insulin resistance) and in isolated islets, in dp-BB, but not in dr-BB or WF, rats, and the effect of IH was inhibited by the antioxidant N-acetylcysteine. Furthermore, IH significantly increased islet cytokine mRNA and plasma cytokine levels (monocyte chemoattractant protein-1 and IL-10) in dp-BB, but not in dr-BB or WF, rats. All dp-BB rats had mononuclear infiltration of islets, which was absent in dr-BB and WF rats. In conclusion, the presence of insulitis was permissive for IH-induced ß-cell dysfunction in the BB rat, which suggests a link between ß-cell lipotoxicity and islet inflammation.

Free fatty acid-induced reduction in glucose-stimulated insulin secretion: evidence for a role of oxidative stress in vitro and in vivo.

OBJECTIVE: An important mechanism in the pathogenesis of type 2 diabetes in obese individuals is elevation of plasma free fatty acids (FFAs), which induce insulin resistance and chronically decrease beta-cell function and mass. Our objective was to investigate the role of oxidative stress in FFA-induced decrease in beta-cell function. RESEARCH DESIGN AND METHODS: We used an in vivo model of 48-h intravenous oleate infusion in Wistar rats followed by hyperglycemic clamps or islet secretion studies ex vivo and in vitro models of 48-h exposure to oleate in islets and MIN6 cells. RESULTS: Forty-eight-hour infusion of oleate decreased the insulin and C-peptide responses to a hyperglycemic clamp (P < 0.01), an effect prevented by coinfusion of the antioxidants N-acetylcysteine (NAC) and taurine. Similar to the findings in vivo, 48-h infusion of oleate decreased glucose-stimulated insulin secretion ex vivo (P < 0.01) and induced oxidative stress (P < 0.001) in isolated islets, effects prevented by coinfusion of the antioxidants NAC, taurine, or tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl). Forty-eight-hour infusion of olive oil induced oxidative stress (P < 0.001) and decreased the insulin response of isolated islets similar to oleate (P < 0.01). Islets exposed to oleate or palmitate and MIN6 cells exposed to oleate showed a decreased insulin response to high glucose and increased levels of oxidative stress (both P < 0.001), effects prevented by taurine. Real-time RT-PCR showed increased mRNA levels of antioxidant genes in MIN6 cells after oleate exposure, an effect partially prevented by taurine. CONCLUSIONS: Our data are the first demonstration that oxidative stress plays a role in the decrease in beta-cell secretory function induced by prolonged exposure to FFAs in vitro and in vivo.