GLUCOSAMINE INFUSION IN RATS MIMICS THE BETA-CELL DYSFUNCTION OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS

Sustained hyperglycemia can cause peripheral insulin resistance and pa ncreatic beta-cell dysfunction and has been termed glucose toxicity or glucose-induced desensitization. Glucosamine, a product of glucose fl ux through the hexosamine biosynthetic pathway (HBP), causes insulin r esistance in peripheral tissues and has been shown to cause abnormal g lucose-insulin secretion coupling, and thus has been implicated in the pathogenesis of glucose toxicity. Here, we investigate whether glucos amine-induced insulin secretory dysfunction is specific to glucose or also extends to nonglucose secretagogues such as arginine. Two groups of 12 weight-matched Sprague-Dawley rats underwent hyperglycemic clamp studies (steady-state blood glucose, similar to 220 mg . dL(-1)) duri ng infusion of normal saline or glucosamine 3.5 mg . kg(-1) . min(-1) over a 100-minute period. Insulin levels were measured at baseline and between 90 and 100 minutes. One hundred minutes into the hyperglycemi c clamp, subgroups of seven rats each (saline-and glucosamine-infused rats) received a bolus of arginine (100 mg . kg(-1)) while the glucose infusion rate was unaltered. Glucose and insulin levels were measured at 1, 3, 5, 10, 15, and 30 minutes after the arginine bolus. Both gro ups had similar fasting glucose and insulin levels. At steady state (6 0 to 100 minutes), glucose levels were almost identical in both groups (223.58 +/- 3.94 v 224.58 +/- 4.34 mg . dL(-1)), but the glucose infu sion rate (26.55 +/- 1.60 v 8.83 +/- 1.35 mg . kg(-1) . min(-1), P <.0 001) and insulin level (41.36 +/- 6.47 v 18.04 +/- 2.95 mU . mL(-1), P <.0001) were markedly reduced in animals receiving glucosamine. Peak insulin levels 1 minute after the arginine bolus were lower in rats in fused with glucosamine versus saline (274.00 +/- 30.38 v 176.25 +/- 20 .12 mu U . ml(-1) ., P =.0319). Total insulin secretion in response to arginine was significantly lower in the glucosamine group as determin ed by the area under the curve (1,268.09 +/- 142.27 v 706.77 +/- 84.79 mu U . mL(-1) . min, P=.0054). In conclusion, glucosamine causes seve re impairment in glucose-induced insulin secretion. Further, glucosami ne-induced beta-cell secretory dysfunction extends to nonglycemic stim uli like arginine. This pattern of insulin secretory dysfunction is si milar to that observed in patients with non-insulin-dependent diabetes mellitus (NIDDM). These data suggest that glucosamine may participate in the pathogenesis of glucose toxicity at the level of the beta cell in NIDDM patients. Copyright (C) 1998 by W.B. Saunders Company.