The mechanism by which long-term exposure of the ␤-cell to elevated concentrations of fatty acid alters glucose-induced insulin secretion has been examined. Exposure of INS-1 ␤-cells to 0.4 mmol/l oleate for 72 h increased basal insulin secretion and decreased insulin release in response to high glucose, but not in response to agents acting at the level of the K ATP channel (tolbutamide) or beyond (elevated KCl). This also suppressed the glucose-induced increase in the cellular ATP-to-ADP ratio. The depolarization of the plasma membrane promoted by glucose was decreased after oleate exposure, whereas the response to KCl was unchanged. Cells exposed to free fatty acids displayed a lower mitochondrial membrane potential and a decreased glucose-induced hyperpolarization. The possible implication of uncoupling protein (UCP)-2 in the altered secretory response was examined by measuring UCP2 gene expression after chronic exposure of the cells to fatty acids. UCP2 mRNA and protein were increased twofold by oleate. Palmitate and the nonoxidizable fatty acid bromopalmitate had similar effects on UCP2 mRNA, suggesting that UCP2 gene induction by fatty acids does not require their metabolism. The data are compatible with a role of UCP2 and partial mitochondrial uncoupling in the decreased secretory response to glucose observed after chronic exposure of the ␤-cell to elevated fatty acids, and suggest that the expression and/or activity of the protein may modulate insulin secretion in response to glucose. Diabetes 50:803-809, 2001

A comprehensive metabolic study was carried out to understand how chronic exposure of pancreatic β-cells to fatty acids causes high basal secretion and impairs glucose-induced insulin release. INS-1 β-cells were exposed to 0.4 mM oleate for 3 days and subsequently incubated at 5 or 25 mM glucose, after which various parameters were measured. Chronic oleate promoted triglyceride deposition, increased fatty acid oxidation and esterification, and reduced malonyl-CoA at low glucose in association with elevated basal O2 consumption and redox state. Oleate caused a modest (25%) reduction in glucose oxidation but did not affect glucose usage, the glucose 6-phosphate and citrate contents, and the activity of pyruvate dehydrogenase of INS-1 cells. Thus changes in glucose metabolism and a Randle-glucose/fatty acid cycle do not explain the altered secretory properties of β-cells exposed to fatty acids. The main response of INS-1 cells to chronic oleate, which is to increase the oxidation and esterification of fatty acids, may contribute to cause high basal insulin secretion via increased production of reducing equivalents and/or the generation of complex lipid messenger molecule(s).

Objective: We earlier reported marked qualitative differences between the effect of 3,5,3H -triiodothyroacetic acid (Triac) and tri-iodothyronine (T 3 ) on cardiac hypertrophy at equivalent thyroidstimulating hormone (TSH)-suppressive doses. We have now extended these studies to specific cardiac parameters. Due to its rapid metabolic clearance rate, Triac is not suitable for TSH suppression and therefore the slowly metabolized 3,5,3H ,5 H -tetraiodothyroacetic acid (Tetrac), the precursor of Triac, was studied. Methods: Hypothyroid rats were infused over 13 days with 1.5±40.5 nmol Tetrac/day per 100 g body weight (BW) or with 0.5±13.5 nmol thyroxine (T 4 )/day per 100 g BW. Results: The responses of serum TSH and of hepatic monodeiodinase type 1 were parallel for both hormones, their potency ratios could therefore be compared. Tetrac was revealed as being only half as active on hepatic monoiodinase type 1 despite a similar serum TSH levels. Tetrac can therefore be considered to have a preferential action on serum TSH suppression. The cardiac effects on Ca 2+ -ATPase (SERCA 2a) and monodeiodinase type 1 activity were qualitatively different and therefore one cannot give an overall quantitative estimate of these differences. The results showed clearly, however, that Tetrac is less efficient for all parameters studied, namely induction of cardiac hypertrophy, amyosin heavy chain mRNA, monodeiodinase type 1 activity and mRNA levels of the sarcoplasmic SERCA 2a. Conclusion:We postulate therefore that, in the rat and possibly in man, Tetrac could represent a favorable alternative for suppression of serum TSH levels.