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, Johannes D Veldhuis, S. Pincus, O. Schmitz

Research output: Contribution to journalArticle

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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
Externally publishedYes

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Type 2 Diabetes Mellitus
Insulin
Glucose Tolerance Test
Glucose
Rain
Area Under Curve
Insulin Resistance
Serum
Glucose Clamp Technique
Entropy
Intravenous Infusions
Theoretical Models
Control Groups

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Assessment of insulin secretion in relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus : Evidence of early β-cell dysfunction. / Nyholm, B.; Pørksen, N.; Juhl, C. B.; Gravholt, C. H.; Butler, P. C.; Weeke, J.; Veldhuis, Johannes D; Pincus, S.; Schmitz, O.

In: Metabolism: Clinical and Experimental, Vol. 49, No. 7, 07.2000, p. 896-905.

Research output: Contribution to journalArticle

Nyholm, B. ; Pørksen, N. ; Juhl, C. B. ; Gravholt, C. H. ; Butler, P. C. ; Weeke, J. ; Veldhuis, Johannes D ; Pincus, S. ; Schmitz, O. / Assessment of insulin secretion in relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus : Evidence of early β-cell dysfunction. In: Metabolism: Clinical and Experimental. 2000 ; Vol. 49, No. 7. pp. 896-905.
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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.",
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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, Johannes D

AU - Pincus, S.

AU - Schmitz, O.

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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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