We tested effects of long-term exposure of pancreatic islets to free fatty acids (FFA) in vitro on B cell function. Islets isolated from male Sprague-Dawley rats were exposed to palmitate (0.125 or 0.25 mM), oleate (0.125 mM), or octanoate (2.0 mM) during culture. Insulin responses were subsequently tested in the absence of FFA. After a 48-h exposure to FFA, insulin secretion during basal glucose (3.3 mM) was severalfold increased. However, during stimulation with 27 mM glucose, secretion was inhibited by 30-50% and proinsulin biosynthesis by 3040%. Total protein synthesis was similarly affected. Conversely, previous palmitate did not impair a-ketoisocaproic acid (5 mM)-induced insulin release. Induction and reversibility of the inhibitory effect on glucose-induced insulin secretion required between 6 and 24 h. Addition of the carnitine palmitoyltransferase I inhibitor etomoxir (1 ,uM) partially reversed (by > 50%) FFA-associated decrease in secretory as well as proinsulin biosynthetic responses to 27 mM glucose. The inhibitory effect of previous palmitate was similar when co-culture was performed with 5.5, 11, or 27 mM glucose. Exposure to palmitate or oleate reduced the production of 14CO2 from D-[U-14C1 glucose, and of "4CO2 from D-13,4-"CIglucose, both effects being reversed by etomoxir. Conclusions: long-term exposure to FFA inhibits glucose-induced insulin secretion and biosynthesis probably through a glucose fatty acid cycle. (J.

In most populations studied, birth weight was inversely related to type 2 diabetes risk.

Short- and long-term effects of hyperlipidemia with elevated FFA on insulin secretion were investigated. Male Sprague-Dawley rats were fed ad libitum and additionally infused with Intralipid 10%, 1.0 ml/h. After 3 h of Intralipid the response to 27 mM glucose in isolated perfused pancreas was enhanced by 86%, P less than 0.02. After 6 h of Intralipid enhancement had subsided. After 48 h of Intralipid glucose-induced insulin release was inhibited by 49%, from 1950 +/- 177 microU/min after saline to 1003 +/- 232 microU/min after Intralipid, P less than 0.02. Inhibition was glucose-selective since responses to other secretagogues (1 mM 3-isobutyl-1 methylxanthine, 10 mM octanoate, or 5 mM alpha-ketoisocaproic acid) were unaffected as were pancreatic contents of insulin (2284 +/- 111 mU/pancreas after saline, 2566 +/- 131 mU/pancreas after Intralipid). In isolated islets from 48 h lipid infused rats production of [14-C]CO2 from D[U-14-C]glucose was decreased (P less than 0.02) in parallel with the insulin response to 27 mM glucose. Glucose-induced secretion was partially normalized by in vitro exposure to a carnitine palmitoyl-transferase I inhibitor (Etomoxir). Effects of a 48 h lipid infusion were also tested during hyperglycemia. Rats were infused with glucose, and hyperglycemia was enhanced by dexamethasone (25 micrograms/24 h). Hyperglycemia depressed glucose-induced secretion from perfused pancreas from 2072 +/- 22 microU/min after saline + dexamethasone to 1185 +/- 155 microU/min after glucose + dexamethasone, P less than 0.01). Intralipid, added to the latter protocol, further inhibited glucose-induced secretion to 437 +/- 87 microU/min, P less than 0.005. Hyperlipidemia is concluded to be associated with short term stimulation but long term inhibition of glucose-induced insulin secretion. Evidence indicates that inhibition depends on fatty acid oxidation, is coupled to decreased glucose oxidation and operates both during normo- and hyperglycemia.

A B S T R A C T Glucose-induced insulin secretion is enhanced by a preceeding glucose stimulus. The characteristics of this action of glucose were investigated in perfused pancreas and collagenase-isolated islets of Langerhans. A 20-to 30-min pulse of 27.7 mM glucose enhanced both the first and second phase of insulin release in response to a second glucose stimulus by 76-201%. This enhancement was apparent as an augmented maximal insulin release response to glucose. The effect of priming with glucose was seen irrespective of whether the pancreatic tissue was obtained from fed or fasted rats. Separating the two pulses of hexose by a 60-min time interval of exposure to 3.3 mM glucose did not abolish the potentiation of the second pulse. Omission of Ca++ as well as the inclusion of somatostatin or mannoheptulose during the first pulse abolished insulin secretion during this time period; however, only the inclusion of mannoheptulose deleted the potentiation of the second pulse. D-Glyceraldehyde, but not pyruvate, D-galactose, or 3-isobutyl-l-methylxanthine, could substitute for glucose in inducing potentiation.In islets labeled with [2-3H]adenine, the [3H]-cyclic AMP response to glucose was increased by 35% when measured after 1 min, but was increased only marginally after 2-10 min of stimulation with a second pulse of glucose. The production of 3H2O from glucose was not affected by glucose priming.It is concluded that (a) the induction of the glucoseinduced, time-dependent potentiation described here is dependent on glucose metabolism but not on stimulation of cyclic AMP, calcium fluxes, or insulin release per se; (b) the mechanisms that mediate the Dr. Cerasi's present address is Department of Endocrinology and Metabolism, Hadassah Medical School, Jerusalem, Israel.

OBJECTIVE -The aim of this study was to investigate alcohol consumption in relation to the incidence of type 2 diabetes. 1975, 1981, and 1990. By record linkage to national registers of hospital discharge and prescribed medication, 580 incident cases of type 2 diabetes were identified during 20 years of follow-up. RESEARCH DESIGN AND METHODSRESULTS -Moderate alcohol consumption (5-29.9 g/day in men and 5-19.9 g/day in women) tended to be associated with a reduced incidence of type 2 diabetes compared with low consumption (Ͻ5 g/day). The estimates were lower in overweight (BMI Ն25.0 kg/m 2 ) subjects (relative risk 0.7, 95% CI 0.5-1.0 [men]; 0.6, 0.3-1.1 [women]). High alcohol consumption (Ն20 g/day) was associated with an increased incidence of type 2 diabetes in lean women (2.9, 1.1-7.5) but not in overweight women or in men. In women, binge drinking was associated with an increased incidence of type 2 diabetes (2.1, 1.0 -4.4). Analyses of alcohol-discordant twin pairs supported a reduced risk in moderate consuming twins compared with their lowconsuming cotwins (odds ratio 0.5, 95% CI 0.2-1.5).CONCLUSIONS -The results of this study suggested that moderate alcohol consumption may reduce the risk of type 2 diabetes. On the other hand, binge drinking and high alcohol consumption may increase the risk of type 2 diabetes in women.