Measurements of Insulin Secretory Capacity and Glucose Tolerance to Predict Pancreatic β-Cell Mass In Vivo in the Nicotinamide/Streptozotocin Göttingen Minipig, a Model of Moderate Insulin Deficiency and Diabetes

  1. Marianne O. Larsen1,
  2. Bidda Rolin1,
  3. Michael Wilken2,
  4. Richard D. Carr1 and
  5. Carsten F. Gotfredsen3
  1. 1Department of Pharmacological Research I, Novo Nordisk A/S, Bagsvaerd, Denmark
  2. 2Department of Assay and Cell Technology, Novo Nordisk A/S, Bagsvaerd, Denmark
  3. 3Department of Histology, Novo Nordisk A/S, Bagsvaerd, Denmark

    Abstract

    Knowledge about β-cell mass and/or function could be of importance for the early diagnosis and treatment of diabetes. However, measurement of β-cell function as an estimate of β-cell mass is currently the only method possible in humans. The present study was performed to investigate different functional tests as predictors of β-cell mass in the Göttingen minipig. β-cell mass was reduced in the Göttingen minipig with a combination of nicotinamide (100 [n = 6], 67 [n = 25], 20 [n = 2], or 0 mg/kg [n = 4]) and streptozotocin (125 mg/kg). Six normal pigs were included. An oral glucose tolerance test (OGTT) (n = 43) and insulin secretion test (n = 30) were performed and pancreata obtained for stereological determination of β-cell mass. During OGTT, fasting glucose (r2 = 0.1744, P < 0.01), area under the curve for glucose (r2 = 0.2706, P < 0.001), maximum insulin secretion (r2 = 0.2160, P < 0.01), and maximum C-peptide secretion (r2 = 0.1992, P < 0.01) correlated with β-cell mass. During the insulin secretion test, acute insulin response to 0.3 g/kg (r2 = 0.6155, P < 0.0001) and 0.6 g/kg glucose (r2 = 0.7321, P < 0.0001) and arginine (67 mg/kg) (r2 = 0.7732, P < 0.0001) and maximum insulin secretion (r2 = 0.8192, P < 0.0001) correlated with β-cell mass. This study supports the use of functional tests to evaluate β-cell mass in vivo and has established a validated basis for developing a mathematical method for estimation of β-cell mass in vivo in the Göttingen minipig.

    Footnotes

    • Address correspondence and reprint requests to Marianne O. Larsen, Department of Pharmacological Research I, Pharmacology Research and Development, Novo Allé, 6A1.005, DK-2880 Bagsvaerd, Denmark. E-mail: mmla{at}novonordisk.com.

      Received for publication 29 July 2002 and accepted in revised form 14 October 2002.

      AIR, acute insulin response; AUC, area under the curve; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide 1; NIA, nicotinamide; OGTT, oral glucose tolerance test; STZ, streptozotocin.

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