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Effects of Weight Loss and Reduced Hyperglycemia on the Kinetics of Insulin Secretion in Obese Non-Insulin Dependent Diabetes Mellitus^*

BARRY GUMBINER, KENNETH S. POLONSKY, WILLIAM F. BELTZ, KAY GRIVER, PENNY WALLACE, GINGER BRECHTEL and ROBERT R. HENRY

Department of Medicine, University of California San Diego, California 92037
The Veterans Administration Medical Center San Diego, California 92161
The Department of Medicine, University of Chicago, Pritzker School of Medicine Chicago, Illinois 60637

Address requests for reprints to: Dr. Barry Gumbiner, Veterans Administration Medical Center (V-lllG), 3350 La Jolla Village Drive, San Diego, California 92161.

Impairment in pancreatic production of insulin, a cardinal feature of noninsulin dependent diabetes mellitus (NIDDM), was quantified and the kinetics of insulin secretion characterized in six obese individuals with NIDDM before and after weight loss (18.0 ± 3.0 kg, mean ± SEM) using a validated mathematical model that employs C-peptide as a marker of the in. vivo rate of insulin secretion. The metabolic clearance of Cpeptide, assessed by decay analysis after bolus injection of biosynthetic human C-peptide, was not changed by weight loss (0.143 ± 0.009 L/min-m² vs. 0.137 ± 0.010 L/min-m²). Kinetic parameters from each individual's decay curve before and after weight loss were used to derive accurate rates of secretion during the basal (postabsorptive) state, an oral glucose tolerance test and two hyperglycemic clamps. Basal rates of insulin secretion declined 20 ± 5 pmol/min-m² (96 ± 15 to 76 ± 15 pmol/minmz, P < 0.05) concomitant with decreases of 6.9 ± 0.9 mmol/L in fasting serum glucose (13.7 ± 1.0 to 6.8 ± 0.7 mmol/L, P < 0.05), 60 ± 14 pmol/L in serum insulin (134 ± 30 to 74 ± 15 pmol/L, P < 0.05), and 0.15 ± 0.03 pmol/ml in plasma C-peptide (0.67 ± 0.11 to 0.52 ± 0.08 pmol/ml, P < 0.05) concentrations. As expected, weight loss resulted in improved glucose tolerance as measured by the glycemic profiles during the oral glucose tolerance test (P < 0.05 analysis of variance). The insulin secretory response before weight loss showed a markedly reduced ability to respond appropriately to an increase in the ambient serum glucose. After weight loss, the pancreatic response was more dynamic (P < 0.05, analysis of variance) and parralleled the moment-to-moment changes in glycemia. Insulin production above basal doubled (11.2 ± 3.2 to 24.5 ± 5.8 nmol/6h-m², P < 0.05) and peak rates of insulin secretion above basal tripled (55 ± 16 to 157 ± 32 pmol/min/m², P < 0.05).

To assess the /3-cell response to glucose per se and the changes associated with weight reduction, two hyperglycemic clamps were performed at steady state glucose levels in the range characteristic of individuals with severe NIDDM. At a fixed glycemia of 20 mmol/L, average rates of insulin secretion increased almost 2-fold with treatment (161 ± 41 to 277 ± 60 pmol/min-m², P < 0.05). At an increment of 6 mmol/L glucose above prevailing fasting glucose levels, the average rate of insulin secretion increased 53% (120 ± 21 to 183 ± 39 pmol/min-m², P < 0.05). Changes in the kinetics of insulin production were further characterized by comparing the prevailing level of glycemia (basal and two clamps) to the rate of insulin secretion. Before weight loss, there was no association between the steady state glucose levels and insulin secretion rates (r = 0.08). After weight loss, however, these parameters were strongly correlated (P = 0.58, P < 0.02) indicating improved responsivity of the β-cell over the physiological range of serum glucose concentrations.

In conclusion, weight loss in obese individuals with severe NIDDM results in: 1) no change in the metabolic clearance rate of C-peptide and 2) improvement of impaired β-cell responsivity to both the absolute and incremental changes in glycemia such that the β-cell response is more coordinated with changes in the prevailing serum glucose level.

^* This work was supported in part by grants from the Advanced Healthcare Division of Avadyne, Inc, the Medical Research Service of the Veterans Administration Medical Center, National Institutes of Health (MOl RR-00827 General Clinical Research Branch, Division of Research; Resources, Diabetes and Research Training Center DK-20595; 5-T32 DK-07494-04, DK-38949) and the Whitaker Foundation.

Recipient of an American Diabetes Association (California Affiliate) Fellowship Award.

Recipient of a Research Career Development Award from the NIH (DK-01234).

Recipient of an NIH FIRST Award (DK-38949) and a Research Associate Career Development Award from the Veterans Administration.

Received July 13, 1989.

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