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Submitted on October 13, 2004
Accepted on December 14, 2004
-Cell Mass in Insulin-Resistant Obese Fa/Fa Zucker Rats Independent of Glycemia and Body Weight
Amylin Pharmaceuticals, Inc., San Diego CA 92121
* To whom correspondence should be addressed. E-mail: ayoung{at}amylin.com.
The effects of the incretin mimetic exenatide (exendin-4) on metabolic parameters, insulin-sensitivity, and 
-cell mass were examined in nondiabetic, insulin-resistant obese fa/fa Zucker rats. After 6 weeks of treatment, ad libitum-fed exenatide-treated (EX) and pair-fed vehicle control (PF) rats had comparable food intake, body weight, HbA1c, and fasting plasma concentrations of glucose, insulin, and lipids. Concurrent decreases in food intake and weight gain were observed in EX and PF rats compared with ad libitum-fed vehicle control (CON) rats (P < 0.001). The increases in HbA1c and fasting plasma insulin concentrations that occur during the normal progression of this disease model were significantly reduced in EX and PF rats compared with CON rats (P < 0.001). The insulin-sensitivity index (ISI; glucose infusion rate/plasma insulin concentration) measured during a hyperinsulinemic euglycemic clamp was 224% higher in EX rats than in CON rats (P < 0.001) and 61% higher in EX rats than in PF rats (P < 0.004). The latter difference was despite comparable HbA1c, fasting glucose, fasting insulin, total cholesterol, HDL, and daily food consumption between EX and PF animals. In the absence of exenatide, -cell mass was hyperbolically related to ISI (-cell mass • ISI was constant). Analogous to "Disposition Index", the -cell mass • ISI product was 63% greater in EX than in PF rats (P < 0.05). Thus, exenatide increased -cell mass to a greater extent than would be expected in animals of comparable insulin-resistance, suggesting a direct trophic effect on islet neogenesis in obese fa/fa rats independent of body weight and glycemia.
-cell mass •
obesity
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