Dynamic Changes in β-Cell Mass and Pancreatic Insulin During the Evolution of Nutrition-Dependent Diabetes in Psammomys obesus

Impact of Glycemic Control

  1. Nurit Kaiser1,
  2. Michal Yuli1,
  3. Gökhan Üçkaya1,
  4. Andrei I. Oprescu1,
  5. Marie-France Berthault2,
  6. Catherine Kargar2,
  7. Marc Y. Donath3,
  8. Erol Cerasi1 and
  9. Alain Ktorza2
  1. 1Endocrinology and Metabolism Service, Department of Medicine, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
  2. 2Laboratoire de Physiopathologie de la Nutrition, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7059, Universite Paris 7, Paris, France
  3. 3Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, Zurich, Switzerland
  1. Address correspondence and reprint requests to Nurit Kaiser, Endocrinology and Metabolism Service, Department of Medicine, Hadassah—Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel. E-mail: kaiser{at}md.huji.ac.il

Abstract

Recent studies ascribe a major role to pancreatic β-cell loss in type 2 diabetes. We investigated the dynamics of β-cell mass during diabetes evolution in Psammomys obesus, a model for nutrition-dependent type 2 diabetes, focusing on the very early and the advanced stages of the disease. P. obesus fed a high-calorie diet for 26 days developed severe hyperglycemia, β-cell degranulation, and markedly reduced pancreatic insulin content. Reducing calories for 7 days induced normoglycemia in 90% of the animals, restoring β-cell granulation and insulin content. To dissociate effects of diet from blood glucose reduction, diabetic animals received phlorizin for 2 days, which normalized glycemia and increased the pancreatic insulin reserve to 50% of control, despite a calorie-rich diet. During diabetes progression, β-cell mass decreased initially but recovered spontaneously to control levels, despite persistent hyperglycemia. Strikingly, however, β-cell mass did not correlate with degree of hyperglycemia or pancreatic insulin content. We conclude that reduced insulin reserve is the main cause of diabetes progression, whereas irreversible β-cell mass reduction is a late event in P. obesus. The rapid recovery of the pancreas by phlorizin-induced normoglycemia implies a causal relationship between hyperglycemia and islet dysfunction. Similar mechanisms could be operative during the evolution of type 2 diabetes in humans.

Footnotes

    • Accepted September 22, 2004.
    • Received August 1, 2004.
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