Meal and oral glucose tests for assessment of -cell function: modeling analysis in normal subjects. Am J Physiol Endocrinol Metab 283: E1159-E1166, 2002. First published August 6, 2002 10.1152/ajpendo.00093.2002We investigated -cell function and its relationship to insulin sensitivity in 17 normal volunteers. For insulin secretion (derived by C-peptide deconvolution), a mathematical model was applied to 24-h triple-meal tests (MT) as well as oral glucose tolerance tests (OGTT); insulin sensitivity was assessed by the euglycemic insulin clamp technique. The -cell model featured a glucose concentration-insulin secretion dose response (characterized by secretion at 5 mM glucose and slope), a secretion component proportional to the glucose concentration derivative, and a time-dependent potentiation factor (modulating the dose response and accounting for effects of sustained hyperglycemia and incretins). The -cell dose-response functions estimated from the whole 24-h MT, the first 2 h of the MT, and the OGTT differed systematically, because a different potentiation factor was involved. In fact, potentiation was higher than average during meals (1.6 Ϯ 0.1-fold during the first meal) and had a different time course in the MT and OGTT. However, if potentiation was accounted for, the 24-and 2-h MT and the OGTT yielded similar dose responses, and most -cell function parameters were intercorrelated (r ϭ 0.50-0.86, P Յ 0.05). The potentiation factor was found to be related to plasma glucose-dependent insulin-releasing polypeptide concentrations (r ϭ 0.49, P Ͻ 0.0001). Among -cell function parameters, only insulin secretion at 5 mM glucose from MT correlated inversely with insulin sensitivity (24-h MT: r ϭ Ϫ0.74, P Ͻ 0.001; 2-h MT: r ϭ Ϫ0.52, P Ͻ 0.05), whereas the dose-response slope and the OGTT parameters did not. In nine other subjects, reproducibility of model parameters was evaluated from repeated MTs. Coefficients of variation were generally ϳ20%, but the derivative component was less reproducible. We conclude that our model for the multiple MT yields useful information on -cell function, particularly with regard to the role of potentiation. With cautious interpretation, a 2-h MT or a standard OGTT can be used as surrogates of 24-h tests in assessing spontaneous -cell function. insulin secretion; glucose-induced insulin release; potentiation of glucose-induced insulin release; insulin sensitivity
Turner's syndrome is associated with glucose intolerance, diminished first-phase insulin response, elevated blood pressure, reduced FFM, and physical fitness. Sex hormone administration causes a deterioration in glucose tolerance, increases FFM and physical fitness, and has beneficial effects on blood pressure. The deleterious effect on glucose tolerance may be mediated by norethisterone, a gestagen known to have androgenic effects.
Detection of insulin secretory bursts in peripheral blood is hampered by hepatic insulin extraction, dilution in the systemic insulin pool, and time-delayed damping of secretory burst amplitude. Previous studies in dogs in vivo and other experiments in vitro have shown that ∼70% of all insulin is released within distinct insulin secretory bursts. To establish a method for detection and quantification of pulsatile insulin release in humans on the basis of peripheral insulin concentration measurements, we used a high-sensitivity, -specificity, and -precision insulin enzyme-linked immunosorbent assay (ELISA) and optimized an established deconvolution methodology to quantify the frequency, mass, and amplitude of insulin secretory bursts as well as to estimate the relative contribution of pulsatile insulin release to overall insulin secretion. By use of minutely sampled serum insulin concentrations measured by a highly sensitive insulin ELISA, and insulin kinetics of 2.8 min (first half-life), 5.0 min (second half-life), and a fractional slow component of 0.28, the deconvolved insulin secretion rates in 20 healthy subjects during glucose infusion (4.5 mg ⋅ kg−1 ⋅ min−1) could be resolved into a series (4.7 ± 0.1 min/pulse) of approximately symmetric insulin secretory bursts with a mean mass of 87 ± 12 pmol ⋅ l−1 ⋅ pulse−1and a mean amplitude (maximal release rate) of 35 ± 4.7 pmol ⋅ l−1 ⋅ min−1. The relative contribution of pulsatile to overall insulin secretion was 75 ± 1.6% (range 59–85%). We conclude that in vivo insulin secretion in humans during nominal glucose stimulation consists of a series of punctuated insulin secretory bursts accounting for ≥75% of total insulin secretion.
Insulin resistance is a common feature in first-degree relatives of NIDDM patients. To explore the mechanism(s) behind this condition in more detail, a percutaneous muscle biopsy (vastus lateralis) was performed in 25 first-degree relatives of NIDDM patients and 21 control subjects to examine muscle fiber composition and capillary density. Insulin-stimulated glucose disposal (Rd) was determined employing a hyperinsulinemic-(insulin infusion rate 0.6 mU x kg[-1] x min[-1]) euglycemic clamp. Rd (5.76 +/- 0.35 vs. 8.06 +/- 0.36 mg x kg lean body weight [LBW]-1 x min[-], P < 0.001) and estimated VO2max (49.3 +/- 2.8 vs. 57.2 +/- 3.5 mg x kg LBW[-1] x min[-1], 0.05 < P < 0.10) were decreased in the relatives. The number of type IIb fibers (29.5 +/- 2.5 vs. 21.0 +/- 2.8%, P < 0.05) was increased in the relatives, whereas no significant differences were found in other fiber types or capillary density between the groups. Correlations were observed between number of type I fibers (positive), number of type IIb fibers (negative), and capillary density (positive) versus Rd as well as estimated VO2max (P < 0.05). In a multiple linear regression analysis with Rd as a dependent variable, estimated VO2max, family history of NIDDM, and number of type IIb fibers (P < 0.001, r2 = 0.64) significantly determined the level of Rd, whereas capillary density did not. In conclusion, insulin-resistant first-degree relatives of NIDDM patients are characterized by an increased number of type IIb muscle fibers. Whether this finding reflects a reduced physical activity level and fitness in the relatives or is of primary genetic origin remains to be determined.
To further explore the role of the beta-cell as a pathogenic factor behind non-insulin-dependent diabetes mellitus (NIDDM), insulin secretion at modest hyperglycemia was examined in 15 healthy first-degree relatives of NIDDM patients and 13 anthropometrically and age-matched controls. The oral glucose tolerance test was normal in all, but the relatives had impaired insulin-stimulated glucose uptake (P < 0.05). During a constant intravenous glucose infusion we performed a time-series analysis of serum insulin in samples obtained at 1-min intervals for 75 min (60-135 min). The recently introduced scale- and model-independent statistic approximate entropy (ApEn) and the coefficient of variation for a 6- (9 and 15) point moving average (MA) were applied to test regularity and stationarity, respectively, of insulin secretion. Both ApEn and 6-point MA were able to significantly discern the insulin time series of the two groups (P < 0.05), demonstrating a higher degree of irregularity and nonstationarity among the offspring. Moreover, when the two complementary sets of statistics were combined into a single "index of nonpulsatility," an even more notable distinction was available (P < 0.01). No relationship was found between altered insulin secretion and insulin resistance. In conclusion, this experimental and statistical model demonstrates that the stimulated insulin secretion of glucose-tolerant relatives of NIDDM patients is characterized by disorderliness. Whether the model can predict the risk for developing a clinically important beta-cell dysfunction remains to be clarified.
First degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM) are often reported to be insulin resistant. To examine the possible role of reduced physical fitness in this condition 21 first degree relatives of NIDDM patients and 22 control subjects without any history of diabetes were examined employing a 150-min hyperinsulinaemic (0.6 mU insulin. kg-1.min-1) euglycaemic clamp combined with the isotope dilution technique (3-(3)H-glucose, Hot GINF), the forearm technique and indirect calorimetry. During hyperinsulinaemia glucose disposal (Rd) and forearm glucose extraction were significantly diminished in the relatives (p < 0.01 and p < 0.05), but glucose oxidation and the suppressive effect on hepatic glucose production were normal. Arteriovenous differences across the forearm of the gluconeogenic precursors lactate, alanine and glycerol as well as the increments in forearm blood flow during hyperinsulinaemia were similar in the two groups. Maximal oxygen uptake (VO2 max) was lower in the relatives than in the control subjects (36.8 +/- 1.9 vs 42.1 +/- 2.0 ml.kg-1.min-1; p = 0.03). There was a highly significant correlation between Rd and VO2 max in both relatives and control subjects (r = 0.68 and 0.66, respectively; both p < 0.001). Comparison of the linear regression analyses of insulin-stimulated Rd on VO2 max in the two groups showed no significant differences between the slopes (0.10 +/- 0.03 vs 0.09 +/- 0.02) or the intercepts. In stepwise multiple linear regression analyses with insulin-stimulated Rd as the dependent variable VO2 max significantly determined the level of Rd (p < 0.01), whereas forearm blood flow and anthropometric data did not. In conclusion, the insulin resistance in healthy first degree relatives of patients with NIDDM is associated with a diminished physical work capacity. Whether, this finding is ascribable to environmental or genetic factors (e.g. differences in muscle fibre types, capillary density etc) remains to be determined.
First-degree relatives of type 2 diabetic patients (offspring) are often characterized by insulin resistance and reduced physical fitness (VO2 max). We determined the response of healthy first-degree relatives to a standardized 10-wk exercise program compared with an age-, sex-, and body mass index-matched control group. Improvements in VO2 max (14.1 +/- 11.3 and 16.1 +/- 14.2%; both P < 0.001) and insulin sensitivity (0.6 +/- 1.4 and 1.0 +/- 2.1 mg x kg(-1) x min(-1); both P < 0.05) were comparable in offspring and control subjects. However, VO2 max and insulin sensitivity in offspring were not related at baseline as in the controls (r = 0.009, P = 0.96 vs. r = 0.67, P = 0.002). Likewise, in offspring, exercise-induced changes in VO2 max did not correlate with changes in insulin sensitivity as opposed to controls (r = 0.06, P = 0.76 vs. r = 0.57, P = 0.01). Skeletal muscle oxidative capacity tended to be lower in offspring at baseline but improved equally in both offspring and controls in response to exercise training (delta citrate synthase enzyme activity 26 vs. 20%, and delta cyclooxygenase enzyme activity 25 vs. 23%. Skeletal muscle fiber morphology and capillary density were comparable between groups at baseline and did not change significantly with exercise training. In conclusion, this study shows that first-degree relatives of type 2 diabetic patients respond normally to endurance exercise in terms of changes in VO2 max and insulin sensitivity. However, the lack of a correlation between the VO2 max and insulin sensitivity in the first-degree relatives of type 2 diabetic patients indicates that skeletal muscle adaptations are dissociated from the improvement in VO2 max. This could indicate that, in first-degree relatives, improvement of insulin sensitivity is dissociated from muscle mitochondrial functions.
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