Physiological Insulin Resistance Research Articles

Insulin-mediated vasorelaxation in pregnancy.

To investigate insulin-mediated vasorelaxation in pregnancy, and the role of nitric oxide in this response. In vitro study of isolated subcutaneous resistance arteries from pregnant and non-pregnant women. Small arteries (mean vessel diameter <300 microm) were isolated from biopsies of subcutaneous fat from 14 pregnant and seven non-pregnant women. Insulin-mediated attenuation of the vasoconstriction response to noradrenaline, before and after nitric oxide synthase inhibition, was studied in isolated arteries using wire myography. Vessel responses to noradrenaline following incubation with insulin were also tested after endothelial denudation. Maximum responses were compared using one-way ANOVA and Bonferroni's post hoc test for multiple comparisons. In pregnancy, the maximum vasoconstriction produced by noradrenaline was increased (P < 0.01). Insulin significantly reduced this response in pregnant women (P < 0.01), while inhibition of nitric oxide synthase with Nomega-nitro-L-arginine methyl ester (L-NAME) resulted in potentiation (P < 0.05). Following inhibition of nitric oxide synthase with L-NAME, addition of the insulin was still able to produce a significant attenuation in maximum vasoconstriction to noradrenaline in pregnant women (P < 0.01). Furthermore, the absence of functioning endothelium did not abolish the attenuating effect of the insulin on noradrenaline-induced vasoconstriction in pregnant women (P < 0.01). The vasodilatory effect of insulin is not diminished in pregnancy, despite the development of insulin resistance. Furthermore, the attenuation of vasoconstrictor tone is via an endothelium-independent mechanism. This suggests that the vascular dysfunction associated with diabetes mellitus does not occur with physiological insulin resistance.

Insulin-mediated vasorelaxation in pregnancy

Objective To investigate insulin-mediated vasorelaxation in pregnancy, and the role of nitric oxide in this response. Design In vitro study of isolated subcutaneous resistance arteries from pregnant and non-pregnant women. Methods Small arteries (mean vessel diameter <300μm) were isolated from biopsies of subcutaneous fat from 14 pregnant and seven non-pregnant women. Insulin-mediated attenuation of the vasoconstriction response to noradrenaline, before and after nitric oxide synthase inhibition, was studied in isolated arteries using wire myography. Vessel responses to noradrenaline following incubation with insulin were also tested after endothelial denudation. Maximum responses were compared using one-way ANOVA and Bonferroni's post hoc test for multiple comparisons. Results In pregnancy, the maximum vasoconstriction produced by noradrenaline was increased ( P <0.01). Insulin significantly reduced this response in pregnant women ( P <0.01), while inhibition of nitric oxide synthase with N ω -nitro-L-arginine methyl ester (L-NAME) resulted in potentiation ( P <0.05). Following inhibition of nitric oxide synthase with L-NAME, addition of the insulin was still able to produce a significant attenuation in maximum vasoconstriction to noradrenaline in pregnant women ( P <0.01). Furthermore, the absence of functioning endothelium did not abolish the attenuating effect of the insulin on noradrenaline-induced vasoconstriction in pregnant women ( P <0.01). Conclusions The vasodilatory effect of insulin is not diminished in pregnancy, despite the development of insulin resistance. Furthermore, the attenuation of vasoconstrictor tone is via an endothelium-independent mechanism. This suggests that the vascular dysfunction associated with diabetes mellitus does not occur with physiological insulin resistance.

Trp64Arg polymorphism of the beta3-adrenergic receptor gene in pregnancy: association with mild gestational diabetes mellitus.

A missense mutation of the beta3-adrenergic receptor gene (Trp64Arg) has been associated with obesity and increased capacity to gain weight in nonpregnant populations. Furthermore, the mutation is a potential modifying factor in the etiology of impaired glucose tolerance and type 2 diabetes. We studied the relation of the beta3-adrenergic receptor genotype to glucose tolerance during pregnancy, a state of physiological insulin resistance. In 179 pregnant women (mean age, 28.5 +/- 0.4 yr), a 2-h oral glucose tolerance test was performed between gestational weeks 20 and 31. The beta3-adrenergic receptor genotype was assessed using restriction fragment length polymorphism. The frequency of the Arg64 allele was 9.15%. In women with mild gestational diabetes (n = 70), as defined by 60 min postload glucose values, the Trp64Arg genotype was more frequent than in women with normal glucose tolerance (n = 109; 26% vs. 11%; P = 0.01). Furthermore, the Trp64Arg polymorphism was associated with increased weight gain during pregnancy (baseline to gestational weeks 20-31) and increased postload glucose, insulin, and C peptide values during the oral glucose tolerance test. The results of the present study extend current knowledge about the association of the Trp64Arg beta3-adrenergic receptor polymorphism with glucose tolerance to a pregnant population. The association with mild gestational diabetes suggests that the impact of the polymorphism may be clinically important during pregnancy, a state of physiological insulin resistance.

Longitudinal changes in pancreatic beta-cell function and metabolic clearance rate of insulin in pregnant women with normal and abnormal glucose tolerance.

To evaluate basal pancreatic beta-cell secretion and suppression during infused insulin and the metabolic clearance rate of insulin in women with normal and abnormal glucose tolerance prior to conception and during pregnancy. Seven women with normal glucose tolerance and nine women with abnormal glucose tolerance during gestation were evaluated prior to conception, in early (12-14 weeks) and late (34-36 weeks) gestation. Basal insulin and C-peptide were measured after an 11-h fast and during the last 40 min of a 2-h hyperinsulinemic-euglycemic clamp at 40 mU.m-2.m-1. Suppression of basal C-peptide was calculated as the steady-state C-peptide/basal C-peptide. The metabolic clearance rate of insulin was calculated by dividing the insulin infusion rate by the steady-state insulin concentration, which was corrected for residual beta-cell secretion. No significant differences were noted in the following parameters between women with normal and abnormal glucose tolerance with advancing gestation: increase in basal insulin (P = 0.20) and C-peptide (P = 0.12), ability of infused insulin to decrease basal C-peptide concentration (P = 0.22), and metabolic clearance rate of insulin (P = 0.76). There was a significant 65% increase in both basal insulin (P = 0.0005) and C-peptide (P = 0.0002) concentrations in all subjects with advancing gestation. There was a significant (P = 0.0001) decrease in the ability of the infused insulin to decrease basal C-peptide concentration. C-peptide as a percentage of the basal was 64% before conception, 74% in early pregnancy, and 108% in late pregnancy. The metabolic clearance rate of insulin significantly (P = 0.0005) increased with advancing gestation: pregravid 442 ml.m-2.min-1, early pregnancy 514 ml.m-2. min-1, and 526 ml.m-2.min-1 in late pregnancy. Pregnancy is accompanied by progressive alterations in insulin kinetics, which are partly responsible for the hyperinsulinemia of this condition. These alterations are more likely a homeostatic response to the increased physiological insulin resistance of pregnancy.

Abdominal obesity

The application of magnetic resonance imaging and computed tomography to obesity research has changed the focus from body mass and skinfold thickness to abdominal fat mass and visceral adiposity. Intra-abdominal fat constitutes less than 20% of total body fat but is a major determinant of fasting and postprandial lipid availability because of its physiological (lipolytic rate and insulin resistance) and anatomical (portal drainage) properties. High levels of serum free fatty acids, as a result of abdominal obesity, cause excessive tissue lipid accumulation and contribute to dyslipidaemia, beta cell dysfunction, and hepatic and peripheral insulin resistance. An individual's risk of non-insulin dependent diabetes mellitus and cardiovascular disease relates closely to the inheritance of central obesity and susceptibility to tissue lipotoxicity.

Regulation of cyclic AMP synthesis and degradation is modified in rat liver at late gestation.

Cyclic AMP (cAMP) is known to play a key role in regulating insulin action, and it is well documented that in several cases of physiological insulin resistance its concentration is increased. Since late pregnancy in the rat is associated with liver insulin resistance, we have studied possible alterations of some cellular mechanisms regulating the cAMP metabolism. (1) Liver cAMP concentration was shown to be increased by some 30% and 50% at 18 and 22 days of pregnancy respectively, compared with virgins. (2) Basal adenylate cyclase activity was higher only in the 18-days-pregnant rat, and the forskolin-stimulated maximal activity was similar in the three groups of animals. (3) alpha s protein is decreased in term-pregnant rats; however, coupling between Gs and adenylate cyclase is only impaired in the 18-days-pregnant animals, and stimulation by glucagon is impaired in both groups of pregnant animals. (4) Gi-2 protein was shown to be unable to elicit the tonic inhibition of adenylate cyclase in pregnant rats, although it was only decreased at 22 days of gestation. The increased alpha i-2 level detected by immunoblotting at 18 days of gestation did not correlate with its decreased ADP-ribosylation, suggesting that the protein is somehow modified at this stage. (5) Pregnancy is associated with a decrease in membrane phosphodiesterase activity. Our results show that late pregnancy is associated with increases in liver cAMP levels that might be involved in eliciting the characteristic insulin-resistant state, and suggest that mechanisms leading to these increments are changing during this phase of gestation.

Insulin receptor function is preserved in a physiological state of hypoinsulinemia and insulin resistance.

The suckling period in the rat is characterized by a continuously low plasma insulin concentration and a physiological insulin resistance, particularly in the adipose tissue. This insulin resistance disappears after weaning on the high-carbohydrate adult diet. We have studied the number, structure, and function of adipose tissue insulin receptors during the suckling-weaning transition. The insulin receptor number determined either on intact adipocytes or after partial purification was higher during suckling (15 days), whereas the affinity was similar when compared with weaned rats (30 days). The molecular weight of the alpha- and beta-subunits were identical in both groups and, when analyzed in nonreducing conditions, the alpha 2 beta 2-form was the unique detectable form of the receptor. Neither the basal and insulin-stimulated autophosphorylation of the insulin receptor beta-subunit nor the tyrosine kinase activity toward a synthetic substrate was decreased during the suckling period. Thus, in the adipose tissue of the suckling rat, a marked insulin resistance is concomitant with a normal insulin receptor number and function.