triacsin-c and Diabetes-Mellitus--Type-2

Increased glucose production is a hallmark of type 2 diabetes and alterations in lipid metabolism have a causative role in its pathophysiology. Here we postulate that physiological increments in plasma fatty acids can be sensed within the hypothalamus and that this sensing is required to balance their direct stimulatory action on hepatic gluconeogenesis. In the presence of physiologically-relevant increases in the levels of plasma fatty acids, negating their central action on hepatic glucose fluxes through (i) inhibition of the hypothalamic esterification of fatty acids, (ii) genetic deletion (Sur1-deficient mice) of hypothalamic K(ATP) channels or pharmacological blockade (K(ATP) blocker) of their activation by fatty acids, or (iii) surgical resection of the hepatic branch of the vagus nerve led to a marked increase in liver glucose production. These findings indicate that a physiological elevation in circulating lipids can be sensed within the hypothalamus and that a defect in hypothalamic lipid sensing disrupts glucose homeostasis.

Topics: Animals; Coenzyme A Ligases; Diabetes Mellitus, Type 2; Dietary Fats; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Glucose; Glucose-6-Phosphatase; Glyburide; Homeostasis; Hypothalamus; Injections, Intraventricular; Liver; Male; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; Rats; Rats, Sprague-Dawley; Triazenes; Vagotomy

Like obese humans, Zucker diabetic fatty (ZDF) rats exhibit early beta cell compensation for insulin resistance (4-fold beta cell hyperplasia) followed by decompensation (>50% loss of beta cells). In prediabetic and diabetic ZDF islets, apoptosis measured by DNA laddering is increased 3- and >7-fold, respectively, compared with lean ZDF controls. Ceramide, a fatty acid-containing messenger in cytokine-induced apoptosis, was significantly increased (P < 0.01) in prediabetic and diabetic islets. Free fatty acids (FFAs) in plasma are high (>1 mM) in prediabetic and diabetic ZDF rats; therefore, we cultured prediabetic islets in 1 mM FFA. DNA laddering rose to 19.6% vs. 4.6% in lean control islets, preceded by an 82% increase in ceramide. C2-Ceramide without FFA induced DNA laddering, but fumonisin B1, a ceramide synthetase inhibitor, completely blocked FFA-induced DNA laddering in cultured ZDF islets. [3H]Palmitate incorporation in [3H]ceramide in ZDF islets was twice that of controls, but [3H]palmitate oxidation was 77% less. Triacsin C, an inhibitor of fatty acyl-CoA synthetase, and troglitazone, an enhancer of FFA oxidation in ZDF islets, both blocked DNA laddering. These agents also reduced inducible nitric oxide (NO) synthase mRNA and NO production, which are involved in FFA-induced apoptosis. In ZDF obesity, beta cell apoptosis is induced by increased FFA via de novo ceramide formation and increased NO production.

Topics: Animals; Apoptosis; Cells, Cultured; Ceramides; Chromans; Coenzyme A Ligases; Diabetes Mellitus; Diabetes Mellitus, Type 2; DNA Fragmentation; Enzyme Induction; Enzyme Inhibitors; Fatty Acids, Nonesterified; Guanidines; Homozygote; Humans; Hypoglycemic Agents; Islets of Langerhans; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Obesity; Palmitic Acid; Prediabetic State; Rats; Rats, Zucker; Repressor Proteins; RNA, Messenger; Saccharomyces cerevisiae Proteins; Thiazoles; Thiazolidinediones; Transcription, Genetic; Triazenes; Troglitazone