Experimental NIDDM: development of a new model in adult rats administered streptozotocin and nicotinamide

Abstract

We took advantage of thè partial protection exerted by suitable dosages of nicotinamide against thè p-cytotoxic effect of Streptozotocin (STZ) to create a new experimental diabetic syndrome in adult rats that appears closer to NIDDM than other available animai models with regard to insulin responsiveness to gincose and sulfonylureas. Among thè various dosages of nicotinamide tested in 3-month-old Wistar rats (100-350 mg/kg body wt), thè dosage of 230 mg/kg, given intraperitoneally 15 min before STZ administration (65 mg/kg i.v.) yielded a maximum of animals with moderate and stable nonfasting hyperglycemia (155 ± 3 vs. 121 ± 3 mg/dl in controls; P < 0.05) and 40% preservation of pancreatic insulin stores. We also evaluated liceli function both in vitro and in vivo 4-9 weeks after inducing diabetes. In thè isolated perfused pancreas, insulin response to glucose elevation (5-11 mmol/1) was clearly present, although significantly reduced with respect to controls (P < 0.01). Moreover, thè insulin response to tolbutamide (0.19 mmol/1) was similar to that observed in normal pancreases. Perfused pancreases from diabetic animals also exhibited a striking hypersensitivity to arginine infusìon (7 mmol/1). In rats administered STZ plus nicotinamide, intravenous glucose tolerance tests revealed clear abnormalities in glucose tolerance and insulin responsiveness, which were interestingly reversed by tolbutamide administration (40 mg/kg i.v.). In conclusion, this novel NIDDM syndrome with reduced pancreatic insulin stores, which is similar to human NIDDM in that it has a significant response to glucose (although abnormal in kinetics) and preserved sensitivity to tolbutamide, may provide a particularly advantageous tool for pharmacological investigations of new insulinotropic agents.

Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

“…This indicates that the remaining beta cells were only partially able to compensate in the isolated organ. Similarly, in the perfused pancreas from rats dosed with NIA+STZ [28], insulin responses to glucose, tolbutamide and arginine indicate that secretory responses are related to pancreatic insulin content but, as in the present study, some compensation for the reduced beta cell mass seems to occur.…”

“…Male Göttingen minipigs (aged 11-14 months, weight 26±3 kg [range [21][22][23][24][25][26][27][28][29][30], n=12) were obtained from the barrier unit at Ellegaard Göttingen minipigs (Dalmose, Denmark) and housed in single pens under controlled conditions as described previously [19]. Pigs were allowed at least 2 weeks recovery after surgery and were trained carefully in all experimental procedures prior to the start of the experiments.…”

GLUT2 protein at the rat proximal tubule brush border membrane correlates with protein kinase C (PKC)-βl and plasma glucose concentration

“…In order to study as wide a range of glucose concentrations as possible, we used normal animals and STZ-diabetic animals, with or without prior treatment with low or high doses of nicotinamide. Nicotinamide protects pancreatic beta cells from STZ cytotoxicity [15] and makes it possible to modulate blood glucose concentrations more effectively than by using graded doses of STZ.…”

SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats

“…To accomplish SirT1 knockdown, we used an ASO that causes specific reduction of SirT1 mRNA in liver and adipose tissue. Four weeks of fructose and high-fat feeding combined with an initial streptozotocin injection created a rat model that mimics T2DM (16). To evaluate peripheral and hepatic insulin sensitivity, we performed hyperinsulinemiceuglycemic clamps in combination within infusions of [6, H] glucose and [2-14 C] deoxyglucose to assess rates of whole-body glucose turnover and tissue-specific rates of glucose uptake.…”