TY - JOUR
T1 - Assessment of insulin secretion in relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus
T2 - Evidence of early β-cell dysfunction
AU - Nyholm, B.
AU - Pørksen, N.
AU - Juhl, C. B.
AU - Gravholt, C. H.
AU - Butler, P. C.
AU - Weeke, J.
AU - Veldhuis, J. D.
AU - Pincus, S.
AU - Schmitz, O.
N1 - Funding Information:
From the Department of Medicine M (Endocrinology and Diabetes), University Hospital of Aarhus, Aarhus, Denmark; Department of Endocrinology, University of Edinburgh, Edinburgh, Scotland; and National Science Foundation Center for Biological Timing, Endocrinology Division, University of Virginia, Charlottesville, VA. Submitted August 23, 1999; accepted December 16, 1999. Supported by the Institute of Clinical Experimental Research, University of Aarhus, the Danish Diabetes Association, Novo Nordisk Farmaka (Copenhagen, Denmark), the National Science Foundation, Science and Technology Center for Biological Timing, and a National Institutes of Health Research Career Development Award (IK04 HD006). Address reprint requests to B. Nyholm, MD, PhD, Department of Medicine M (Endocrinology and Diabetes), Kommunehospitalet, University Hospital of Aarhus, DK-8000 Aarhus C, Denmark. Copyright r 2000 by W.B. Saunders Company 0026-0495/00/4907-0004$10.00/0 doi:10.1053/mt.2000.6737
PY - 2000/7
Y1 - 2000/7
N2 - 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.
AB - 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.
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U2 - 10.1053/meta.2000.6737
DO - 10.1053/meta.2000.6737
M3 - Article
C2 - 10910002
AN - SCOPUS:0034235095
SN - 0026-0495
VL - 49
SP - 896
EP - 905
JO - Metabolism: Clinical and Experimental
JF - Metabolism: Clinical and Experimental
IS - 7
ER -