Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships.

TLDR

Hyperinsulinemia, loss of glucose‑stimulated insulin secretion, and peripheral insulin resistance coexist in non‑insulin‑dependent diabetes mellitus. The study aimed to determine whether free fatty acids contribute to the development of NIDDM in obese Zucker diabetic fatty rats. Researchers followed obese ZDF‑drt rats from 5 to 14 weeks of age, a period before hyperglycemia onset, to assess the effects of rising plasma free fatty acids. Plasma free fatty acids rose before hyperglycemia, coinciding with loss of GSIS, decreased GLUT‑2, and a tenfold increase in islet triacylglycerol that correlated with FFA and glucose; reducing FFA by pair‑feeding prevented beta‑cell dysfunction and hyperglycemia, and in vitro FFA exposure replicated these defects, indicating hyperlipidemia drives NIDDM through insulin‑antilipolysis resistance and beta‑cell sensitivity.

Abstract

Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM). Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDF-drt) rats from 5 weeks of age (before the onset of hyperglycemia) until 14 weeks. Two weeks prior to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 +/- 0.06 mM at the onset of hyperglycemia (P < 0.001 vs. controls). At this time GSIS was absent and beta-cell GLUT-2 glucose transporter was decreased. The triacylglycerol content of prediabetic islets rose to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P < 0.001), which, in turn, was correlated with the plasma glucose concentration (r = 0.873; P < 0.001). Reduction of hyperlipacidemia to 1.3 +/- 0.07 mM by pair feeding with lean littermates reduced all beta-cell abnormalities and prevented hyperglycemia. Normal rat islets that had been cultured for 7 days in medium containing 2 mM FFA exhibited increased basal insulin secretion at 3 mM glucose, and first-phase GSIS was reduced by 68%; in prediabetic islets, first-phase GSIS was reduced by 69% by FFA. The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of beta cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS.