Decrease in β-Cell Mass Leads to Impaired Pulsatile Insulin Secretion, Reduced Postprandial Hepatic Insulin Clearance, and Relative Hyperglucagonemia in the Minipig
- Lise L. Kjems1,
- Barbara M. Kirby1,
- Elizabeth M. Welsh1,
- Johannes D. Veldhuis2,
- Marty Straume2,
- Susan S. McIntyre1,
- Dongchang Yang1,
- Pierre Lefèbvre3 and
- Peter C. Butler1
- 1Diabetes Research Unit and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, Scotland
- 2Center for Biological Timing and Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, Virginia
- 3Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, University of Liege, Liege, Belgium
Most insulin is secreted in discrete pulses at an interval of ∼6 min. Increased insulin secretion after meal ingestion is achieved through the mechanism of amplification of the burst mass. Conversely, in type 2 diabetes, insulin secretion is impaired as a consequence of decreased insulin pulse mass. β-cell mass is reported to be deficient in type 2 diabetes. We tested the hypothesis that decreased β-cell mass leads to decreased insulin pulse mass. Insulin secretion was examined before and after an ∼60% decrease in β-cell mass achieved by a single injection of alloxan in a porcine model. Alloxan injection resulted in stable diabetes (fasting plasma glucose 7.4 ± 1.1 vs. 4.4 ± 0.1 mmol/l; P < 0.01) with impaired insulin secretion in the fasting and fed states and during a hyperglycemic clamp (decreased by 54, 80, and 90%, respectively). Deconvolution analysis revealed a selective decrease in insulin pulse mass (by 54, 60, and 90%) with no change in pulse frequency. Rhythm analysis revealed no change in the periodicity of regular oscillations after alloxan administration in the fasting state but was unable to detect stable rhythms reliably after enteric or intravenous glucose stimulation. After alloxan administration, insulin secretion and insulin pulse mass (but not insulin pulse interval) decreased in relation to β-cell mass. However, the decreased pulse mass (and pulse amplitude delivered to the liver) was associated with a decrease in hepatic insulin clearance, which partially offset the decreased insulin secretion. Despite hyperglycemia, postprandial glucagon concentrations were increased after alloxan administration (103.4 ± 6.3 vs. 92.2 ± 2.5 pg/ml; P < 0.01). We conclude that an alloxan-induced selective decrease in β-cell mass leads to deficient insulin secretion by attenuating insulin pulse mass, and that the latter is associated with decreased hepatic insulin clearance and relative hyperglucagonemia, thereby emulating the pattern of islet dysfunction observed in type 2 diabetes.
Address correspondence and reprint requests to Dr. Peter C. Butler, Division of Endocrinology and Diabetes, Keck School of Medicine, University of Southern California, 1333 San Pablo Street, BMT-B11, Los Angeles, CA 90033. E-mail:.
Received for publication 15 September 2000 and accepted in revised form 16 May 2001.
P.C.B. received an unrestricted grant from Novo Nordisk to assist in the development of the porcine model used in this study.
ELISA, enzyme-linked immunosorbent assay.