The roles of insulin resistance and fl-cell dysfunction in glucocorticoid-induced diabetes were determined in Wistar and Zucker (fa/fa) rats. All Wistar rats treated with 5 mg/kg per d of dexamethasone for 24 d exhibited increased f-cell mass and basal and arginine-stimulated insulin secretion, indicating insulin resistance, but only 16% became diabetic. The insulin response to 20 mM glucose was normal in the perfused pancreas of all normoglycemic dexamethasone-treated rats but absent in every diabetic rat. Immunostainable high K. f-cell transporter, GLUT-2, was present in -100% of f-cells of normoglycemic rats, but in only 25% of f, cells of diabetic rats.GLUT-2 mRNA was not reduced. All Zucker (fia/fa) rats treated with 0.2-0.4 mg/kg per d of dexamethasone for 24 d became diabetic and glucose-stimulated insulin secretion was absent in all. High K. glucose transport in islets was 50% below nondiabetic controls. Only 25% of cells of diabetic rats were GLUT-2-positive compared with -100% in controls. Total pancreatic GLUT-2 mRNA was increased twofold suggesting a posttranscriptional abnormality. We conclude that dexamethasone induces insulin resistance, whether or not it induces hyperglycemia. Whenever hyperglycemia is present, GLUT-2-positive fi cells are reduced, high K. glucose transport into cells is attenuated and the insulin response to glucose is absent. (J. Clin. Invest. 1992. 90:497-504.)

Although obesity is associated with insulin resistance, most obese humans and rodents remain normoglycemic because of compensatory hyperinsulinemia. This has been attributed to ␤-cell hyperplasia and increased low K m glucose metabolism of islets. Since free fatty acids (FFA) can induce these same ␤-cell changes in normal islets of Wistar rats and since plasma FFA are increased in obesity, FFA could be the signal from adipocytes that elicits ␤-cell compensation sufficient to prevent diabetes. To determine if FFA-induced compensation is impaired in islets of rats with a diabetogenic mutation, the Zucker diabetic fatty (ZDF) rat, we cultured islets from 6-week-old obese (fa/fa) rats that had compensated for obesity and apparently normal islets from lean ZDF rats (fa/؉) in 0, 1, or 2 mM FFA. Low K m glucose usage rose 2.5-fold in FFA-cultured control islets from age-matched Wistar rats, but failed to rise in either the precompensated islets of ZDF rats or in islets of lean ZDF rats. Bromodeoxyuridine incorporation increased 3.2-fold in Wistar islets but not in islets from obese or lean ZDF rats. Insulin secretion doubled in normal islets cultured in 2 mM FFA (p < 0.01) but increased only slightly in islets from lean ZDF rats (not significant) and declined in islets from obese ZDF rats (p < 0.05). We conclude that, unlike the islets of age-matched Wistar rats, islets of 6-week-old heterozygous and homozygous ZDF rats lack the capacity for FFA-induced enhancement of ␤-cell function.Pancreatic islets from obese rodents are enlarged and exhibit a marked increase in low K m glucose metabolism (1), which may account for their high output of insulin even at low concentrations of glucose (1-3). The hyperinsulinemia is regarded as a compensatory response that prevents hyperglycemia despite the insulin resistance that invariably accompanies obesity.There is evidence that free fatty acids (FFA) 1 may be the signal from adipocytes that mediates this compensatory insulin secretion (1). Plasma FFA are elevated in obesity (4, 5) and have long been known to stimulate insulin secretion (6 -8).Moreover, the compensatory triad observed in islets from obese rats can be induced in normal islets by culturing them for 7 days in the presence of 1 or 2 mM FFA; low K m glucose metabolism rises dramatically (1), there is evidence of increased ␤-cell replication (1), and insulin secretion increases (1), confirming the earlier description of FFA-induced hyperinsulinemia (9). If the FFA-induced compensation in obesity is, at least in part, responsible for preventing diabetes, it follows that FFAinduced compensation may be impaired at or before the onset of diabetes. In this study we assess the ability of FFA to induce the compensatory triad of enhanced low K m glucose metabolism, increased ␤-cell replication, and insulin hypersecretion in islets from obese rats with a diabetogenic mutation, the Zucker diabetic fatty rat (ZDF-drt). We observe that FFA induction of these compensatory changes is impaired, not only in islets from obese homozygous r...

Non-insulin-dependent diabetes mellitus (NIDDM) is attributed to a failure of pancreatic . cells to maintain insulin secretion at a level sufficient to compensate for underlying insulin resistance. In the ZDF rat, a model of

Gliotoxin is a natural mycotoxin with immunosuppressive and antimicrobial activity. Inhibition of farnesyltransferase (IC50 80 microM) and geranylgeranyltransferase I (IC50 17 microM) stimulated interest in the potential antitumor activity of this epidithiodioxopiperazine. Gliotoxin inhibited proliferation of six breast cancer cell lines in culture with mean +/- SD IC50 289 +/- 328 microM (range 38-985 microM); intracellular farnesylation of Lamin B and geranylgeranylation of Rap1A were inhibited in a dose-dependent manner. In randomized controlled studies using the N-methyl-N-nitrosourea rat mammary carcinoma model, gliotoxin had pronounced antitumor activity in vitro and little systemic toxicity when administered to 10 animals at 10 mg/kg by subcutaneous injection weekly for 4 wk compared with 10 controls. Single doses up to 25 mg/kg were well tolerated. The present studies confirm that gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with pronounced antitumor activity and favorable toxicity profile against breast cancer in vitro and in vivo.