Assessment of insulin secretion in relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus: Evidence of early β-cell dysfunction

B. Nyholm, N. Pørksen, C. B. Juhl, C. H. Gravholt, P. C. Butler, J. Weeke, J. D. Veldhuis, S. Pincus, O. Schmitz

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Abstract

To examine β-cell function in glucose-tolerant offspring of type 2 diabetic families, 41 insulin-resistant (hyperinsulinemic-euglycemic clamp, P < .001) first-degree relatives and 32 controls underwent oral (OGTT) and intravenous (IVGTT) glucose tolerance tests and a constant intravenous glucose infusion (4.0 or 4.5 mg/kg/min) with blood sampling every minute for insulin determinations. Insulin concentration time-series were analyzed with complementary mathematical models (deconvolution and autocorrelation analysis, approximate entropy [ApEn], and coefficient of variation [CV] for a 6-point moving average, together with a combined index for regularity and stationarity [RaS] based on the last 2 measures). During the OGTT the area under the curve (AUC) for plasma glucose was moderately (11%) but significantly (P < .01) elevated in the relatives despite a trend for increased serum insulin (AUC, P = .14). The acute-phase serum insulin response (IVGTT) did not differ between groups (2,055 ± 330 v 1,765 ± 229 pmol/L - 10 rain, P = .84) but was inappropriately low (individually, P < .05 v control group) for the degree of insulin resistance in 16 relatives. Deconvolution analysis of the insulin time-series did not uncover differences in either the intersecretory pulse interval (5.8 ± 0.2 v 5.7 ± 0.2 rain/pulse) or the fractional secretory burst amplitude (133% ± 10% v 116% ± 7% over basal) between the 2 groups. Similarly, significant autocorrelation coefficients were observed in a comparable number of relatives and control subjects (P = .74). In contrast, the RaS index was significantly higher (ie, insulin time-series was more irregular and nonstationary) in the relatives (0.221 ± 0.194) than in the controls (-0.318 ± 0.176, P < .05), primarily attributed to the pattern of insulin secretion in relatives with a strong genetic burden. In conclusion, nonstationary and disorderly insulin secretion patterns during glucose stimulation and a low acute-phase serum insulin response associated with significant insulin resistance suggest early β-cell regulatory dysfunction in individuals genetically predisposed to type 2 diabetes mellitus prior to any evident alterations in insulin secretory burst frequency or mass. Copyright (C) 2000 by W.B. Saunders Company.

Original languageEnglish (US)
Pages (from-to)896-905
Number of pages10
JournalMetabolism: Clinical and Experimental
Volume49
Issue number7
DOIs
StatePublished - Jul 2000

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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    Nyholm, B., Pørksen, N., Juhl, C. B., Gravholt, C. H., Butler, P. C., Weeke, J., Veldhuis, J. D., Pincus, S., & Schmitz, O. (2000). Assessment of insulin secretion in relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus: Evidence of early β-cell dysfunction. Metabolism: Clinical and Experimental, 49(7), 896-905. https://doi.org/10.1053/meta.2000.6737