Exenatide (Exendin-4) Improves Insulin Sensitivity and β-Cell Mass in Insulin-Resistant Obese fa/fa Zucker Rats Independent of Glycemia and Body Weight (original) (raw)

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1Amylin Pharmaceuticals, Inc., San Diego, California 92121

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1Amylin Pharmaceuticals, Inc., San Diego, California 92121

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1Amylin Pharmaceuticals, Inc., San Diego, California 92121

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1Amylin Pharmaceuticals, Inc., San Diego, California 92121

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1Amylin Pharmaceuticals, Inc., San Diego, California 92121

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1Amylin Pharmaceuticals, Inc., San Diego, California 92121

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1Amylin Pharmaceuticals, Inc., San Diego, California 92121

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1Amylin Pharmaceuticals, Inc., San Diego, California 92121

*Address all correspondence and requests for reprints to: Andrew A. Young, M.D., Ph.D., Amylin Pharmaceuticals, Inc., 9360 Towne Centre Drive, Suite 110, San Diego, California 92121.

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Received:

13 October 2004

Accepted:

14 December 2004

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Bronislava R. Gedulin, Svetlana E. Nikoulina, Pamela A. Smith, George Gedulin, Loretta L. Nielsen, Alain D. Baron, David G. Parkes, Andrew A. Young, Exenatide (Exendin-4) Improves Insulin Sensitivity and β-Cell Mass in Insulin-Resistant Obese fa/fa Zucker Rats Independent of Glycemia and Body Weight, Endocrinology, Volume 146, Issue 4, 1 April 2005, Pages 2069–2076, https://doi.org/10.1210/en.2004-1349
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Abstract

The effects of the incretin mimetic exenatide (exendin-4) on metabolic parameters, insulin sensitivity, and β-cell mass were examined in nondiabetic, insulin-resistant obese fa/fa Zucker rats. After 6 wk of treatment, _ad libitum_-fed exenatide-treated (EX) and pair-fed vehicle control (PF) rats had comparable food intake, body weight, hemoglobin A1c (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 to plasma insulin concentration) measured during a hyperinsulinemic euglycemic clamp was 224% higher in EX rats than CON rats (P < 0.001) and 61% higher in EX rats than PF rats (P < 0.004). The latter difference was despite comparable HbA1c, fasting glucose, fasting insulin, total cholesterol, high-density lipoprotein, and daily food consumption between EX and PF animals. In the absence of exenatide, β-cell mass was hyperbolically related to ISI (β-cell mass ∗ ISI was constant). Analogous to the disposition index, the β-cell mass ∗ ISI product was 63% greater in EX than PF rats (P < 0.05). Thus, exenatide increased β-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.

Copyright © 2005 by The Endocrine Society

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