Insulin sensitivity and insulin clearance in human immunodeficiency virus-infected men.

To test whether clinically stable human immunodeficiency virus (HIV) infection, like other infections, is associated with insulin resistance and increased insulin clearance, we measured the sensitivity to insulin and insulin clearance using the euglycemic insulin clamp technique in 10 clinically stable outpatients with symptomatic HIV infection (Centers for Disease Control [CDC] group IV) and 10 healthy controls. During administration of 0.8 and 4 mU insulin.kg-1.min-1, HIV-infected men had 40% (P less than .02) and 83% (P less than .01) higher rates of insulin clearance when compared with healthy controls. Despite significantly lower steady-state insulin concentrations (42 +/- 2 v 52 +/- 4 microU/mL, P less than .05, and 255 +/- 17 v 392 +/- 14 microU/mL, P less than .001, patients v controls), patients and controls had similar total glucose uptake (7.99 +/- 0.81 v 7.92 +/- 0.44 mg.kg-1.min-1 and 14.00 +/- 0.81 v 13.65 +/- 0.65 mg.kg-1.min-1, patients v controls). In the postabsorptive state, no differences were found between patients and controls in insulin levels (7 +/- 1 microU/mL in both) and endogenous glucose production (2.52 +/- 0.07 and 2.24 +/- 0.17 mg.kg-1.min-1, respectively), but plasma glucose levels in the patients (5.02 +/- 0.15 mmol/L) were significantly lower when compared with controls (5.46 +/- 0.14 mmol/L, P less than .05). The results indicate that HIV-infected men have increased rates of insulin clearance and increased sensitivity of peripheral tissues to insulin, which makes HIV infection unique with regard to glucose and insulin metabolism.     

Insulin sensitivity and insulin clearance in cystic fibrosis patients with normal and diabetic glucose tolerance

OBJECTIVE We studied glucose metabolism and insulin kinetics in cystic fibrosis patients with diabetic and normal glucose tolerance. DESIGN Measurements of blood glucose and serum free insulin concentrations during hyperinsulinaemic normo-glycaemic clamp and post-clamp insulin decay, followed by the calculation of insulin sensitivity (M-value and M/1 ratio), insulin clearance rate, serum half-life and apparent distribution space for insulin. SUBJECTS Cystic fibrosis patients, age range 20–29 years, with diabetes mellitus (n= 10) and normal glucose tolerance (n= 10), and 10 age-matched control subjects. RESULTS During the glucose clamp, diabetic cystic fibrosis patients needed less glucose than cystic fibrosis patients with normal glucose tolerance and control subjects (M-value), and steady-state serum insulin concentrations were lower in cystic fibrosis patients with diabetic and normal glucose tolerance than in control subjects. The quantity of glucose metabolized per unit of serum insulin concentration (M/l ratio) was similar in the three study groups (median ～ 145 (μmol/kg/min)/(nmol/l); range 70–252). insulin clearance rates were higher in cystic fibrosis patients with diabetic (24·4 (19·3–29·9) mi/kg/min) and normal (22·6 (14·9–28·4) mi/kg/min) glucose tolerance than in control subjects (17·5 (15·9–24·2) ml/kg/min). Although Insulin clearance rates were inversely related to body mass index (R(S)=?0·59, P < 0·001), the higher insulin clearance rates in CF patients cannot be accounted for solely by differences in body mass index since the insulin clearance rates were similarly increased in patients with body mass index above and below 20kg/m²(22·7 (14·9–28·4) and 24·4 (19·3–29·9) ml/kg/min, respectively). Serum half-lives for Insulin were shorter in cystic fibrosis patients (～4·3 (3·2–7·2) min) than In control subjects (5·9 (3·8–12·5) min), whereas the apparent distribution spaces for Insulin were similar in the three study groups (～150 (88–391) ml/kg). CONCLUSIONS Insulin sensitivity, calculated as the quantity of glucose metabolized per kg body weight per unit of serum insulin concentration, is normal in cystic fibrosis patients with normal glucose tolerance and with well controlled diabetes mellitus. The insulin clearance rate is increased in cystic fibrosis patients with diabetic and normal glucose tolerance, owing to a shorter serum half-life of insulin, whereas the apparent distribution space for insulin is normal.     

The relationship of insulin sensitivity and metabolic clearance of insulin to adiposity and sex hormone binding globulin

Previous studies have shown that sex hormone binding globulin (SHBG) is negatively associated with insulin concentrations in premenopausal women. We determined insulin sensitivity (SI) and clearance (KI) in 8 non-obese men and 13 nonobese premenopausal women using the minimal model of Bergman and colleagues. Insulin clearance and insulin sensitivity were strongly correlated (p less than 0.05). SHBG was positively correlated with SI (i.e., individuals with high levels of SHBG had greater insulin sensitivity) in both men (r = .738, p less than 0.05) and women (r = .577, p less than 0.06). Insulin clearance was also positively correlated with SHBG in men (r = .619) and in women (r = .476) (0.05 less than p less than 0.10). Since obese subjects have both lower SHBG concentrations and decreased insulin sensitivity, we examined the effect of correcting for adiposity by partial correlation analyses. SHBG was not associated with KI after adjustment for BMI. SHBG was still positively correlated with SI in both men (r = .708) (p less than 0.06) and women (r = 0.541) (p less than 0.06), suggesting that the relationship between SHBG and insulin sensitivity is not confounded by obesity. Thus, the relationship of androgenicity with insulin sensitivity (but not insulin clearance) was independent of adiposity.     

Inverse relationship of metabolic clearance rate of insulin to body mass index

Twenty-five human subjects, whose body mass indices (BMI) ranged from 18.0 to 34.1 kg/m2, underwent euglycemic clamps at both low (1.5 mU/kg/min) and high (10 mU/kg/min) insulin infusion rates. Mean C-peptide concentrations were less than or equal to 0.5 ng/mL at the end of each two-hour period. The metabolic clearance rates (MCR) of insulin (mL/kg/min) were significantly (P less than .001) inversely correlated with BMI at both the low (r = -.65) and high (r = -.71) insulin infusion rates. The negative inverse correlations with BMI remained significant at both the low (r = -.42, P less than .05) and high (r = -.61, P less than .005) insulin infusion rates if the MCR were expressed as mL/m2/min. There were no significantly correlations (r less than .21) between the MCR at either rates of insulin infusion and age or tracer insulin binding to monocytes. Decreased MCR of insulin may contribute to the hyperinsulinemia seen in obese subjects.     

Insulin, insulin sensitivity and hypertension

The sensitivity of tissue to insulin is of physiological, pathophysiological and therapeutic relevance. The quantity of insulin and the response to insulin are paramount complementary factors in the regulation of glucose metabolism, and may, at least under certain pathophysiological conditions, also affect cardiovascular function. Hypertension has a high prevalence among subjects with decreased insulin sensitivity and/or hyperinsulinaemia due to obesity, impaired glucose tolerance, non-insulin-dependent diabetes mellitus, and certain other conditions. There is evidence that, even in the absence of obesity or diabetes mellitus, essential hypertension tends to be associated with insulin resistance. The latter elicits a compensatory increase in insulin secretion. Hyperinsulinaemia also occurs in diabetes type 1 as a consequence of insulin treatment. Considering the acute effects of insulin on sympathetic nervous activity, transmembranous cation transport, renal sodium reabsorption, cellular proliferation and lipid metabolism, insulin resistance and/or hyperinsulinaemia may possibly contribute to the genesis of essential, obesity-associated and diabetes-associated hypertension, and may also promote dyslipidaemia in these disorders.     

Changes in insulin sensitivity and clearance in anorexia nervosa

Anorexia nervosa (AN) is a state of self-induced malnutrition characterized by a marked pursuit of thinness and the fear of obesity. Although low fasting blood glucose and insulin have been demonstrated, there is contradictory data on insulin sensitivity and a lack of information about insulin metabolism and its metabolic effects in AN. Insulin sensitivity, kinetics, and metabolic effects were measured using the euglycemic clamp in nine females with AN (age 25.2 +/- 1.9 years and 70.6 +/- 2.2% ideal body weight), and the results compared with seven female normal controls (NC) (age 23.6 +/- 1.0 years and 92.7 +/- 2.5% ideal body weight). Fasting plasma glucose (FPG), immunoreactive insulin (IRI), and C-peptide were significantly lower in AN as compared to NC (84.3 +/- 1.5 v 91.5 +/- 1.7 mg dL-1, 9.3 +/- 1.0 v 13.5 +/- 1.4 microU mL-1, and 0.26 +/- 0.03 v 0.41 +/- 0.02 pmol mL-1) (P less than 0.05). During the glucose clamp, the glucose metabolized (M), the metabolic clearance rate of glucose (MCRg), and the glucose metabolized per unit of insulin (M/I ratio) were all higher in AN as compared to NC (M, 8.7 +/- 1.2 v 6.9 +/- 0.6 mg min-1 kg-1; MCRg, 9.9 +/- 1.5 v 7.4 +/- 0.6 mL min-1 kg-1; M/I ratio, 8.6 +/- 1.6 v 5.0 +/- 0.3 mg min-1 kg-1/microU mL-1 X 100), but only the M/I ratio attained statistical significance (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

A novel mechanism of glipizide sulfonylurea action: decreased metabolic clearance rate of insulin

To examine whether sulfonylureas inhibit the metabolic clearance rate (MCR) of insulin, 19 healthy young subjects participated in two experiments. In the first protocol (n=10), a 3-h oral glucose load was performed with and without 2 mg of glipizide given 30 min before glucose ingestion. The total insulin response was 60% greater with than without glipizide (5.9±0.6 vs 3.7±0.5 μU/ml;P<0.001). However, the total C-peptide responses were virtually identical (4.7±0.5 vs 4.8±0.4 nmol/l) in both studies. In the second protocol (n=9), the MCR of insulin was measured during 4-h euglycemic insulin clamps performed with and without glipizide. In the study with glipizide, the subjects ingested 5 mg of glipizide at 120 min. The steady-state plasma insulin concentration during the 4th h, i.e., 1–2 h after glipizide ingestion, was significantly higher than during the 2nd h, i.e., before glipizide ingestion (99±22 vs 78±17 μU/ml;P<0.01). In addition, glucose uptake during the 4th h was greater (8.0±1.6 vs 6.4±1.5 mg/kg·min) and the MCR of insulin was reduced (503±126 vs 621±176 ml/m²·min;P<0.01). We conclude that glipizide augments plasma insulin levels both by enhancing its secretion and by decreasing the MCR of insulin.     

对糖尿病合并急性感染时胰岛素代谢率变化的观察

对３４例ＮＩＤＤＭ合并急性感染而无肝、肾功能损害者，进行了感染期与感染后期胰岛素代谢率的观察，用胰岛素和葡萄糖同时输注，维持血糖相对稳定，根据稳定阶段血胰岛素、Ｃ肽值及胰岛素输注率计算出两期胰岛素降解代谢率。结果证明，感染期较非感染期胰岛素代谢率显著增加。     

Insulin secretion, adipocyte insulin binding and insulin sensitivity in thyrotoxicosis

The pattern of insulin secretion following an oral glucose load and the insulin receptor status and insulin sensitivity of adipocytes have been studied in patients with thyrotoxicosis and in matched controls. Thyrotoxic subjects showed normal basal and peak levels of serum immunoreactive insulin (peak, 69.0 +/- 6.8 vs 54.3 +/- 8.8 mU/l) and serum C-peptide (peak, 1.95 +/- 0.13 vs 1.71 +/- 0.12 nmol/l for thyrotoxic and control subjects, respectively). Peak serum proinsulin was higher in the thyrotoxic group (64.8 +/- 7.3 vs 39.0 +/- 3.7 pmol/l; P less than 0.01). Maximum specific insulin binding to adipocytes was decreased in the thyrotoxic group (1.80 +/- 0.18 vs 2.62 +/- 0.27%; P less than 0.025) and half-maximum displacement of tracer insulin was similar in the two groups, suggesting that reduced receptor number rather than reduced affinity accounted for the difference. However, adipocyte insulin sensitivity was normal as judged by half-maximal stimulation values of 13.9 +/- 3.6 vs 11.4 +/- 2.1 pmol/l, respectively for lipogenesis and 24.3 +/- 2.2 vs 24.6 +/- 3.6 pmol/l, respectively for glucose transport. Hence, thyroid hormone excess appears to affect adipocyte insulin receptor number directly, but change in receptor number is not associated with change in adipocyte insulin sensitivity in hyperthyroidism. The normal insulin secretion together with the failure to demonstrate abnormal insulin sensitivity of one of the major peripheral tissues suggests that disturbed hepatic rather than peripheral insulin responsiveness may be responsible for the glucose intolerance of hyperthyroidism.     

Insulin Wakayama: familial mutant insulin syndrome in Japan

Summary We describe a family from Japan displaying the mutant insulin syndrome with hyperinsulinaemia and an increased insulin: C-peptide molar ratio. Serum insulin isolated from several family members showed reduced in vitro biological activity, and analysis by high performance liquid chromatography revealed a peak co-eluting with human insulin and a second species of increased hydrophobicity co-migrating with the previously reported Insulin Wakayama. The insulin genes from the propositus were cloned and sequenced, revealing one normal allele; the second allele, encoding a leucine for valine amino acid substitution at position 3 of the insulin A chain, was similar to that previously described for Insulin Wakayama. Synthesized [Leu^A3] insulin showed 0.14% of receptor binding activity on rat adipocytes and a 10-fold prolonged half-life in a somatostatin-infused dog compared with human insulin. The finding of the same mutant gene in two unrelated Japanese families suggests that Insulin Wakayama may be discovered in additional Japanese families with hyperinsulinaemia and/or diabetes.     

Effects of massive obesity on insulin sensitivity and insulin clearance and the metabolic response to insulin as assessed by the euglycemic clamp technique

Insulin sensitivity was studied in nine nondiabetic massively obese patients (one male and eight females ages 39.0 +/- 2.7 years, body mass index 47.1 +/- 1) by the euglycemic clamp technique (40 microU/m2/min) and compared to seven lean control subjects (three males and three females, ages 34.8 +/- 2.5 years, body mass index 23 +/- 1.1). Fasting plasma glucose, immunoreactive insulin, and C-peptide concentrations were higher in the massively obese patients than in the controls (P less than 0.025). Following exogenous insulin infusion, immunoreactive glucagon and C-peptide concentrations decreased similarly in the massively obese patients and controls, indicating normal sensitivity of the alpha and beta cell to insulin. Glucose uptake (M) expressed either as mg X min-1 of fat free mass was significantly reduced in the massively obese patients compared to the controls (P less than 0.001). Similarly, the M/I ratio (glucose uptake per unit of insulin) was significantly reduced in the massively obese patients (P less than 0.001). Free fatty acids and glycerol concentrations measured in the fasting state were significantly elevated in the massively obese patients (free fatty acids 678 +/- 51 v 467 +/- 55 mumol/L, P less than 0.05; glycerol 97 +/- 9 v 59 +/- 11 mumol/L, P less than 0.02). The effects of insulin on antilipolysis was assessed by measuring the reductions in free fatty acids and glycerol concentration during the glucose clamp study. Although the absolute levels remained higher in the massively obese patients, inhibition of lipolysis was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins

Aims/hypothesis. To estimate the heritability of insulin sensitivity and insulin secretion, both of which are considered to contribute to the development of Type II (non-insulin-dependent) diabetes mellitus.¶Methods. Intraclass correlation coefficients and heritability estimates for insulin sensitivity (euglycaemic clamp) as well as first-phase and late-phase insulin secretion (intravenous glucose tolerance test) were calculated in 21 monozygotic and 20 dizygotic twin pairs of the same sex between 54 and 72 years of age.¶Results. Intrapair correlations for all traits were consistently higher in monozygotic than in dizygotic pairs. Insulin secretion correlated significantly only between monozygotic (first-phase r = 0.55; p = 0.003 and late-phase r = 0.66; p < 0.001) twins giving heritability estimates of 0.55 and 0.58, respectively. Insulin-stimulated glucose uptake showed a more modest correlation between monozygotic twins (r = 0.46; p = 0.015). The heritability estimate was 0.37. The heritability estimate for waist-to-hip ratio was 0.76 in female and 0.70 in male twins.¶Conclusion/interpretation. Genetic variability seems to contribute to the variance of insulin sensitivity as well as of insulin secretion. In the current study, genetic variance accounted almost 60 % for the variance in glucose-stimulated insulin secretion and almost 40 % for the variance in insulin-stimulated glucose uptake. Our data is also compatible with findings in monogenic forms of diabetes in which genetic defects in insulin secretion play a predominant part in the pathogenesis of hyperglycaemia. [Diabetologia (2000) 43: 285–293]     

Insulin binding to monocytes and insulin sensitivity in anorexia nervosa

In six female patients with anorexia nervosa, we examined specific binding of ¹²⁵I-insuIin to monocytes and in vivo sensitivity to insulin before and after treatment. Insulin sensitivity was determined by the rate of glucose disappearance during an intravenous insulin tolerance test (K_ITT).In the untreated state, the patients with anorexia nervosa were 26 to 41 per cent below ideal weight and amenorrheic. Fasting plasma glucose and insulin levels were, respectively, 20 per cent and 55 per cent below those observed in healthy controls. Insulin binding to monocytes was 70 per cent greater than that in controls. Scatchard analysis of the insulin binding data revealed an increase in binding capacity with no change in binding affinity. During the insulin tolerance test, K_ITT (9.7 ± 0.7 per cent · min^?1) was 50 per cent greater in untreated patients than in healthy controls.Following treatment with behavior modification, there was a gain in body weight to within 2 to 11 per cent of ideal body weight, and menstrual function returned. Plasma glucose and insulin levels rose to values similar to those in healthy controls. Insulin binding declined by 40 per cent to values comparable to those in the controls. The decrease in insulin binding was due to a reduction in binding capacity. The plasma glucose response to the insulin tolerance test (K_ITT) fell 50 per cent below pretreatment values to levels comparable to those in healthy controls.Both before and after treatment, an inverse correlation was observed between plasma insulin concentration and insulin binding to monocytes whereas a direct correlation was demonstrable between insulin binding to monocytes and k_ITT.The data indicate that in anorexia nervosa insulin binding to monocytes and in vivo sensitivity to insulin are increased. The increase in insulin binding may be a consequence of a decrease in plasma insulin and may, in turn, be responsible for the increase in insulin sensitivity. The increases in insulin binding and insulin sensitivity return to normal following regain of body weight.     

Increased insulin sensitivity is associated with reduced insulin and glucagon secretion and increased insulin clearance in man

Insulin secretion is increased in insulin resistance. In this study, we examined whether high insulin sensitivity results in low insulin secretion. Twelve male master athletes [age 25.6 +/- 4.1 (mean +/- SD) yr] and seven male sedentary students (age 25.0 +/- 2.0 yr) underwent a hyperinsulinemic, euglycemic clamp and a glucose-dependent arginine stimulation test. Athletes had high insulin sensitivity [230 +/- 18 vs. 92 +/- 12 (nmol glucose/kg.min)/(pmol insulin/liter), P < 0.001] and low insulin response to arginine (at fasting glucose 135 +/- 22 vs. 394 +/- 60 pmol/liter, P < 0.001), which resulted in unaltered disposition index (32.8 +/- 3.8 vs. 33.5 +/- 3.3 micro mol glucose/kg.min, NS). Also, the C-peptide response to arginine was reduced (at fasting glucose 0.71 +/- 0.09 vs. 0.89 +/- 0.09 nmol/liter, P = 0.034). However, the C-peptide reduction was not as large as the insulin reduction yielding increased disposition index in athletes when calculated from C-peptide data (184 +/- 9 vs. 76 +/- 11 micro mol glucose/kg.min, P < 0.001). This difference is explained by increased insulin clearance among the athletes during the first 5 min after arginine (81.1% +/- 1.8% vs. 53.6% +/- 4.7%, P < 0.001). Also, the glucagon response to arginine was reduced in the athletes (58.8 +/- 6.7 vs. 90.1 +/- 9.9 ng/liter at fasting glucose, P = 0.009). We conclude that high insulin sensitivity results in low islet hormone secretion and increased insulin clearance.     

Insulin receptors and insulin sensitivity in normo and hyperinsulinemic obese patients

The authors have studied insulin receptors on peripheral blood monocytes and insulin sensitivity, evaluated by simultaneous infusion of glucose, insulin and somatostatin in 10 control subjects and in 20 obese patients with normal glucose tolerance. The obese patients have been divided into two groups, normo (NO) and hyperinsulinemic (HO), according to the total insulin response during OGTT. We considered HO patients with insulin response higher than M + 2DS of controls. Obese patients showed, in comparison to the controls, a lower specific binding and higher degree of insulin resistance. The subdivision of obese patients allowed us to distinguish two groups. The first was characterized by basal hyperinsulinemia, normal insulin response to the stimulus, reduced number of insulin receptors and normal or slightly reduced sensitivity. The second group showed high basal and after stimulus insulinemic values, reduced number of insulin receptors and high level of insulin resistance. When we compared the two groups of obeses we found that the first has a shorter duration of obesity and lower blood glucose values after OGTT. However both groups show the same reduction of insulin bound and the same degree of basal hyperinsulinemia. These data suggest that a reduction of insulin receptors is not the main factor responsible for insulin resistance in obesity. Furthermore, the presence of basal hyperinsulinemia and normal insulin sensitivity in our first group suggests that the modification of basal insulin concentrations is not dependent on the presence of insulin resistance.     

Increased metabolic rate and insulin sensitivity in male mice lacking the carcino-embryonic antigen-related cell adhesion molecule 2

Aims/hypothesis

The carcino-embryonic antigen-related cell adhesion molecule (CEACAM)2 is produced in many feeding control centres in the brain, but not in peripheral insulin-targeted tissues. Global Ceacam2 null mutation causes insulin resistance and obesity resulting from hyperphagia and hypometabolism in female Ceacam2 homozygous null mutant mice (Cc2 [also known as Ceacam2]^?/?) mice. Because male mice are not obese, the current study examined their metabolic phenotype.

Methods

The phenotype of male Cc2 ^?/? mice was characterised by body fat composition, indirect calorimetry, hyperinsulinaemic?Ceuglycaemic clamp analysis and direct recording of sympathetic nerve activity.

Results

Despite hyperphagia, total fat mass was reduced, owing to the hypermetabolic state in male Cc2 ^?/? mice. In contrast to females, male mice also exhibited insulin sensitivity with elevated ??-oxidation in skeletal muscle, which is likely to offset the effects of increased food intake. Males and females had increased brown adipogenesis. However, only males had increased activation of sympathetic tone regulation of adipose tissue and increased spontaneous activity. The mechanisms underlying sexual dimorphism in energy balance with the loss of Ceacam2 remain unknown.

Conclusions/interpretation

These studies identified a novel role for CEACAM2 in the regulation of metabolic rate and insulin sensitivity via effects on brown adipogenesis, sympathetic nervous outflow to brown adipose tissue, spontaneous activity and energy expenditure in skeletal muscle.