Steady-state Plasma Insulin Levels Research Articles

Undercarboxylated osteocalcin does not correlate with insulin resistance as assessed by euglycemic hyperinsulinemic clamp technique in patients with type 2 diabetes mellitus

BackgroundRecent in vitro and in vivo studies have suggested a critical role of osteocalcin (OC), especially the undercarboxylated form (ucOC), in insulin secretion and insulin sensitivity. The objective of this study was to investigate the association between serum ucOC levels and insulin resistance in humans with type 2 diabetes mellitus.FindingsWe measured serum ucOC levels in 129 patients with type 2 diabetes. Insulin resistance was assessed using the euglycemic hyperinsulinemic clamp technique. The insulin resistance indices used were the M value, which is the total body glucose disposal rate, and the M/I value, which is the M value adjusted for the steady state plasma insulin level. ucOC levels were not correlated with the M value (ρ = −0.013, p = 0.886) or the M/I value (ρ = 0.001, p = 0.995).ConclusionsWe found no association between ucOC levels and insulin resistance in patients with type 2 diabetes mellitus.

Effects of Treatment With Testosterone Alone or in Combination With Estrogen on Insulin Sensitivity in Postmenopausal Women

Treatment with androgens such as testosterone has a number of salutary effects on postmenopausal women, including greater energy, improved sexual function, preservation of bone mass, and possibly a protective effect on the breast. There is concern, however, that excessive androgen may lead to an insulin-resistant state. This study addressed the issue of insulin sensitivity using testosterone undecenoate (TU), an orally active preparation with only minor liver-related side effects. Participants were 63 naturally postmenopausal women in good general health, 2 of whom were obese. The women were randomly assigned to receive 40 mg testosterone (T) in the form of TU every other day, 2 mg estradiol (E) valerate daily, or both treatments (T+E), all for 3 months. The euglycemic hyperinsulinemic clamp technique served to estimate insulin sensitivity. The 3 groups were similar in age, body weight, bone mass index, blood pressure, serum hormone levels, and a history of using conventional hormone therapy. Diastolic but not systolic blood pressure fell significantly in the T group but, in general, treatment was well tolerated. No hyperandrogenic signs such as acne or hirsutism developed. Total serum testosterone rose to median levels of 35 to 46 ng/dL in both the T and T+E groups-within the normal range for premenopausal women. Fasting blood glucose levels did not change significantly, but plasma insulin levels fell significantly in the E and T+E groups. Basal insulin sensitivity increased significantly in E-treated women only. Steady-state plasma insulin and blood glucose levels were similar in all groups before and after treatment. Whole-body glucose uptake fell significantly by approximately 20% in the T group and also after combined treatment. No significant correlation was found between changes in free T levels and altered anthropometric or metabolic variables. Body weight increased by approximately 1 kg, a small but significant change, in all treatment groups. Total body fat mass and fat distribution remained stable, but total lean body mass increased significantly in the T+E group. Total cholesterol fell significantly by approximately 20 mg/dL in the same group. High-density lipoprotein cholesterol decreased significantly in the T group but increased in the E group. Low-density lipoprotein cholesterol decreased significantly in both E-treated groups. It appears that short-term treatment with TU, alone or combined with estradiol, induces insulin resistance in postmenopausal women and also worsens the serum lipid profile. Treatment may, however, increase lean body mass. More work is needed to appreciate the clinical significance of these findings.

Primacy of hepatic insulin resistance in the development of the metabolic syndrome induced by an isocaloric moderate-fat diet in the dog.

Obesity is highly correlated with insulin resistance and the development of type 2 diabetes. Insulin resistance will result in a decrease in insulin's ability to stimulate glucose uptake into peripheral tissue and will suppress glucose production by the liver. However, the development of peripheral and hepatic insulin resistance relative to one another in the context of obesity-associated insulin resistance is not well understood. To examine this phenomena, we used the moderate fat-fed dog model, which has been shown to develop both subcutaneous and visceral adiposity and severe insulin resistance. Six normal dogs were fed an isocaloric diet with a modest increase in fat content for 12 weeks, and they were assessed at weeks 0, 6, and 12 for changes in insulin sensitivity and glucose turnover. By week 12 of the diet, there was a more than twofold increase in trunk adiposity as assessed by magnetic resonance imaging because of an accumulation in both subcutaneous and visceral fat depots with very little change in body weight. Fasting plasma insulin had increased by week 6 (150% of week 0) and remained increased up to week 12 of the study (170% of week 0). Surprisingly, there appeared to be no change in the rates of insulin-stimulated glucose uptake as measured by euglycemic-hyperinsulinemic clamps throughout the course of fat feeding. However, there was an increase in steady-state plasma insulin levels at weeks 6 and 12, indicating a moderate degree of peripheral insulin resistance. In contrast to the moderate defect seen in the periphery, there was a marked impairment in insulin's ability to suppress endogenous glucose production during the clamp such that by week 12 of the study, there was a complete inability of insulin to suppress glucose production. Our results indicate that a diet enriched with a moderate amount of fat results in the development of both subcutaneous and visceral adiposity, hyperinsulinemia, and a modest degree of peripheral insulin resistance. However, there is a complete inability of insulin to suppress hepatic glucose production during the clamp, suggesting that insulin resistance of the liver may be the primary defect in the development of insulin resistance associated with obesity.

Association of muscle glycogen synthase polymorphism with insulin resistance in type 2 diabetic patients

The aim of the present study is to investigate whether Met416Val (M416V) polymorphism of glycogen synthase (GYS1) gene is associated with insulin resistance in type 2 diabetes. In 100 type 2 diabetic subjects (66 men and 34 women), the M416V polymorphism of GYS1 gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) as previously reported, and insulin resistance was assessed by euglycemic hyperinsulinemic clamp represented as M/I value, the mean of glucose infusion rate (M value) adjusted by steady state plasma insulin level. The means of age and body mass index (BMI) of the subjects were 53.1 ± 11.6 (SD) years and 23.3 ± 3.5 kg/m 2. The allele frequencies of M416V polymorphism were 82.0% for MM, 16.0% for MV, and 2.0% for VV, and subjects were subsequently divided into V(+) group (n = 18) and V(-) group (n = 82) according to the presence or absence of V allele. There were no significant differences in age, BMI, blood pressure, fasting plasma glucose or insulin levels or glycosylated hemoglobin (HbA 1c) levels between the V(+) and V(-) groups. No significant differences in either M or M/I value were found between the V(+) and V(-) groups (M value, 5.06 ± 2.20 v 5.12 ± 2.04 mg · kg −1 · min −1, P = .841; M/I value, 5.24 ± 3.07 v 5.39 ± 2.87 mg · kg −1 · min −1 · mU −1 · L, P = .576). BMI showed the strongest independent contribution to M/I value, but the presence of V allele did not in multiple regression analysis. In conclusion, the M416V polymorphism of GYS1 gene is not associated with insulin resistance in type 2 diabetes.

Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: Possible role of reactive oxygen species

OBJECTIVESThis study was designed to examine the effect of antioxidant supplementation on the endothelial function and insulin sensitivity in patients with coronary spastic angina (CSA).BACKGROUNDInsulin resistance may play a key role in coronary heart disease, and there is a possible link between acetylcholine-induced coronary vasoconstriction and hyperinsulinemia in patients with CSA. Endothelial dysfunction is present in the systemic arteries in CSA patients, and reactive oxygen species may cause inactivation of nitric oxide in these patients.METHODSWe measured flow-mediated dilation of the brachial artery using ultrasound technique in 22 patients with CSA and 20 control subjects. We also evaluated glucose tolerance using a 75-g oral glucose tolerance test and insulin sensitivity using steady-state plasma glucose (SSPG) methods in the same patients.RESULTSThe incidence of impaired glucose tolerance was higher in the CSA group than in the control group. Vitamin C infusion augmented flow-mediated dilation and decreased SSPG levels in the CSA group (from 3.27 ± 0.77% to 7.00 ± 0.59% [p < 0.001 by analysis of variance (ANOVA)] and from 177.3 ± 13.3 to 143.1 ± 14.9 mg/dl [p = 0.047 by ANOVA], respectively) but not in the control group (from 6.47 ± 0.66% to 6.80 ± 0.60% and from 119.8 ± 11.7 mg/dl to 118.1 ± 11.3 mg/dl, respectively). The steady-state plasma insulin levels were not affected by vitamin C infusion in either group.CONCLUSIONSVitamin C improves both endothelial function and insulin sensitivity in patients with CSA. Thus, reactive oxygen species and/or decreased nitric oxide bioactivity may play an important role in the genesis of both endothelial dysfunction and insulin resistance in patients with CSA.

Differential timing for programming of glucose homoeostasis, sensitivity to insulin and blood pressure by in utero exposure to dexamethasone in sheep.

Numerous epidemiological studies have related an increased risk of adult-onset cardiovascular and metabolic disease to an adverse intra-uterine environment at critical periods. We have shown that fetal sheep exposed to dexamethasone for only 2 days at 27 days of gestation (term approximately 150 days) became hypertensive adults, whereas those exposed at 64 days of gestation remained normotensive, as did controls. In the same sheep, now nearly 5 years old, we performed glucose tolerance tests and hyperinsulinaemic euglycaemic clamps to study the insulin sensitivity of glucose, amino acid and non-esterified fatty acid metabolism. Glucose tolerance, calculated as the area under the curve, after intravenous administration of bolus glucose and insulin secretion in response to a glucose challenge were not altered in any group. There were no significant differences in the insulin sensitivity of net whole-body glucose or amino acid uptake. However, suppression of lipolysis by insulin, measured as the proportional decrease in the circulating concentration of non-esterified fatty acids during the hyperinsulinaemic clamp, was 69+/-1.2% at steady-state plasma insulin levels ( approximately 1000 m-units/l) in the group exposed to dexamethasone at 27 days of gestation, but only 50.8+/-6.5% in the controls (P<0.05). In the group exposed to dexamethasone at 64 days of gestation, the decrease was 66.4+/-5.1%, which did not reach significance compared with the controls (P=0.10). Thus brief dexamethasone exposure during early gestation programmed hypertension independently of insulin resistance of glucose or amino acid metabolism; however, it did lead to increased insulin sensitivity of the inhibition of lipolysis, which may increase susceptibility to the development of obesity postnatally.

Effect of obesity and insulin resistance on resting and glucose-induced thermogenesis in man

To assess the impact of obesity and insulin sensitivity on resting (REE) and glucose-induced thermogenesis (GIT). Data from 322 studies carried out in non-diabetic subjects of either gender, covering a wide range of age (18-80y) and body mass index (BMI, 18-50 kg/m2). Insulin sensitivity and thermogenesis were measured by combining the euglycaemic insulin clamp technique with indirect calorimetry. REE was inversely related to age (P = 0.001) and the respiratory quotient (P = 0.03), and positively related to BMI, lean body mass (LBM), fat mass, and percentage fat mass (all P<0.0001). In a multiple regression model, LBM-adjusted REE was estimated to decline by 9% between 18 and 80 y, independently of obesity and insulin sensitivity. In contrast, GIT was strongly associated with insulin sensitivity (P<0.0001) but not with gender, age or BMI. By multiple regression analysis, GIT was linearly related to insulin sensitivity after controlling for gender, age, BMI and steady-state plasma insulin levels. Furthermore, both of the main components of insulin-mediated glucose disposal (glucose oxidation and glycogen synthesis) correlated with GIT independently of one another. In the subset of subjects (n = 89) in whom waist-to-hip ratio (WHR) measurements were available, GIT was inversely associated with WHR (P<0.001 after adjustment by gender, age, BMI, insulin sensitivity and steady-state plasma insulin concentration). In this model, a significant interaction between WHR and gender indicated a stronger adverse effect on GIT of a high WHR in women than in men. In healthy humans, age, lean mass and respiratory quotient are the main independent determinants of resting thermogenesis. In contrast, insulin sensitivity and, to a lesser extent, abdominal obesity are the principal factors controlling glucose-induced thermogenesis.

Measurement of insulin resistance in vivo.

Insulin sensitivity, which can be impaired in both glucose-intolerant and non-glucose-intolerant individuals, is a valuable parameter because of its potential as a marker for the future development of diabetes and increased cardiovascular risk. Techniques available for the determination of insulin sensitivity include the glucose clamp, insulin tolerance test, insulin suppression test, the frequently sampled intravenous glucose tolerance test and the regional artero-venous balance. Model assessment methods are also available for the measurement of insulin sensitivity at steady-state plasma glucose and insulin levels or after a standardised glucose infusion. Methods vary in their complexity, and the choice between them depends on the nature of the information required. There is also evidence for a strong genetic contribution to insulin sensitivity; although identification of the relevant gene(s) has not yet been successful, accurate phenotyping should still be carried out as part of the assessment of a patient's clinical status.

Insulin resistance in patients with essential hypertension can occur in the absence of microalbuminuria

This study was initiated to see if the presence of resistance to insulin-mediated glucose disposal, glucose intolerance, and hyperinsulinemia in healthy patients with hypertension was dependent upon the coexistence of microalbuminuria. For this purpose we compared these variables in 68 individuals: 34 patients with hypertension and 34 normal volunteers. The two groups were similar in terms of age, gender distribution, body mass index, and ratio of waist to hip girth. Furthermore, although four patients with hypertension satisfied the criteria for microalbuminuria, as compared to one normal volunteer, the urinary albumin excretion (UAE) rates were similar in the two groups (8.07 +/- 1.08 v 7.67 +/- 1.12 micrograms/min). Despite the similarities, both the plasma glucose and insulin responses to a 75 g oral glucose challenge were significantly higher (P < .01) in those with high blood pressure. In addition, the steady-state plasma glucose (SSPG) concentrations at the end of a 180 min continuous infusion of somatostatin, insulin, and glucose was significantly higher in those with hypertension (156 +/- 13 v 107 +/- 10 mg/dL, P < .01). Since the steady-state plasma insulin levels were also somewhat higher in those with hypertension, the higher SSPG values indicate that these individuals were relatively insulin resistant as compared to the control population. Finally, UAE rates were not correlated with either the plasma glucose or insulin responses to oral glucose or to the SSPG concentrations--either in the entire group of 68, or when the 34 patients in each group were considered separately. These results demonstrate that insulin resistance, glucose intolerance, and hyperinsulinemia can occur independently of microalbuminuria in patients with hypertension.

Effect of insulin on urinary phosphate excretion in type II diabetes mellitus with or without renal insufficiency

We investigated the effect of insulin on urinary excretion of phosphate in type II diabetes mellitus (DM) with respect to the absence or presence of renal insufficiency. A euglycemic-hyperinsulinemic clamp was performed in 37 type II DM patients. Subjects were divided into two groups: group A consisted of patients with serum creatinine levels less than 1.5 mg/dL (n = 22), and group B consisted of patients with serum creatinine levels of 1.5 mg/dL or greater (n = 15). Blood and urine samples were collected at the beginning and end of the clamp, and urinary excretion of phosphate was evaluated by calculating fractional excretion (FE-P). Tissue sensitivity to insulin in the whole body was expressed as the glucose infusion rate (M value) and that divided by steady-state plasma insulin levels (M/I ratio) during the last 30 minutes of the clamp. FE-P in group A patients significantly decreased during the clamp (from 9.46 ± 0.67% before the clamp to 7.12 ± 0.73% after the clamp, P < .004), whereas FE-P in group B patients did not change significantly during the clamp. The percent decrease of FE-P (decrease of FE-P during the clamp divided by FE-P before the clamp) in group A patients was significantly higher than in group B patients (22.5 ± 7.0% and 2.5 ± 5.1%, respectively, P < .04). In all 37 patients, the percent decrease of FE-P was negatively correlated with blood urea nitrogen ([BUN] r = −.36, P < .05), serum creatinine ( r = −.34, P < .05), and serum β 2-microglobulin ( r = −.44, P < .01) and positively correlated with creatinine clearance ( r = .570, P < .004), but it was not correlated with the M value or M/I ratio. These results showed that the kidneys of diabetic patients with renal insufficiency are insulin-insensitive in terms of phosphate transport, and the insulin insensitivity is related to the glomerular filtration rate but not to systemic insulin insensitivity. The percent decrease of FE-P on clamp study could be useful for assessing the insulin insensitivity of the kidney, which probably occurs primarily in the renal tubules.

Role of bradykinin in insulin sensitivity and blood pressure regulation during hyperinsulinemia.

The purpose of these experiments was to determine in normotensive rats the role of endogenous bradykinin, prostaglandins, and nitric oxide in glucose metabolism and blood pressure response to hyperinsulinemia. Normotensive Wistar rats were treated with two different bradykinin antagonists, indomethacin or N omega-nitro-L-arginine methyl ester, concurrently with a euglycemic clamp with insulin infusion rates of 3 or 6 mU/kg per minute. Glucose uptake, steady-state plasma insulin levels, and insulin sensitivity index were determined over 2 hours. Bradykinin inhibition dramatically reduced glucose uptake and insulin sensitivity index during both the lower and higher insulin infusion rates to 30% and 32%, respectively, of values observed in control rats. Inhibition of prostaglandins or nitric oxide did not alter glucose metabolism in these rats. Blood pressure remained unchanged in the control group throughout the clamp but increased significantly in rats submitted to inhibition of bradykinin, prostaglandins, or nitric oxide, suggesting that these vasodilator systems tend to counteract the hypertensive effect of hyperinsulinemia. The counterregulatory component attributable to bradykinin was about twice as great as that attributable to nitric oxide. These findings suggest that insulin infusion in normotensive Wistar rats fails to raise blood pressure because its effects are offset by mobilization of vasodilator mechanisms, such as bradykinin, prostaglandins, and nitric oxide. Bradykinin seems to play the most important homeostatic role under these conditions, because its inhibition significantly reduces insulin sensitivity and allows blood pressure to rise.

Intracellular magnesium and insulin resistance: results in Pima Indians and Caucasians.

Intracellular magnesium is a cofactor for numerous enzymes involved in carbohydrate metabolism. Magnesium accumulation is dependent upon insulin action and correlates with insulin-mediated glucose uptake. As Pima Indians are known to be insulin resistant, we investigated whether, in response to insulin infusion, they have lower erythrocyte magnesium accumulation than Caucasians. Insulin-mediated glucose uptake was determined by a euglycemic hyperinsulinemic glucose clamp in 29 obese nondiabetic volunteers: 15 Caucasians (8 males and 7 females) and 14 Pima Indians (8 males and 6 females). Pima Indians were younger than Caucasians (mean +/- SD, 28 +/- 7 vs. 39 +/- 8 yr; P < 0.01), but had similar body mass index and fasting/2-h plasma glucose concentrations. Despite higher steady state plasma insulin levels (692 +/- 260 vs. 540 +/- 70 pmol/L; P < 0.03), Pima Indians had lower insulin-mediated glucose uptake than Caucasians (108 +/- 20 vs. 244 +/- 32 mg/m2.min; P < 0.0001). The mean fasting plasma magnesium concentration was lower in Pima Indians than in Caucasians (0.79 +/- 0.05 vs. 0.85 +/- 0.06 mmol/L; P < 0.01), whereas the mean fasting erythrocyte magnesium concentrations (1.98 +/- 0.10 vs. 2.03 +/- 0.14 mmol/L) were similar in the 2 groups. In response to insulin infusion, erythrocyte magnesium content increased less in Pima Indians than in Caucasians (0.15 +/- 0.07 vs. 0.28 +/- 0.21 mmol/L; P < 0.03). However, this increase was similar in the 2 groups when values were adjusted for insulin-mediated glucose uptake. In conclusion, nondiabetic Pima Indians have a lower erythrocyte magnesium accumulation in response to insulin infusion; this is probably due to their high degree of insulin resistance. The biochemical and physiological consequences of decreased intracellular magnesium uptake are discussed.

Hypertriglyceridemic mice transgenic for the human apolipoprotein C-III gene are neither insulin resistant nor hyperinsulinemic.

Plasma glucose and insulin concentrations and in vivo and in vitro estimates of insulin action were compared in hypertriglyceridemic apolipoprotein C-III transgenic mice (mean +/- SE triglyceride concentration = 11.8 +/- 0.9 mmol/l) and their normotriglyceridemic (1.1 +/- 0.1 mmol/l) littermates. There were no differences in the glucose (8.9 +/- 0.2 vs. 9.3 +/- 0.5 mmol/l) or insulin (172 +/- 21 vs. 203 +/- 17 pmol/l) concentrations of the transgenic and control mice, respectively. Steady-state plasma glucose concentrations at the end of a 150-min period of physiological hyperinsulinemia were also similar in transgenic (6.2 +/- 0.5 mmol/l) and control mice (6.7 +/- 0.5 mmol/l). As the steady-state plasma insulin levels were essentially identical in the two groups (approximately 1000 pmol/l), these results show that whole body insulin-mediated glucose disposal was unchanged in the transgenic mice. Finally, values for isoproterenol-stimulated lipolysis, insulin-inhibition of lipolysis, and insulin-stimulated glucose disposal were similar in adipocytes isolated from transgenic and control mice. It can be concluded from these data that insulin resistance does not develop in hypertriglyceridemic mice transgenic for the human apolipoprotein C-III gene.

Vanadyl sulfate prevents fructose-induced hyperinsulinemia and hypertension in rats.

To determine whether insulin resistance and hyperinsulinemia are causally related to fructose-induced hypertension, we used vanadyl sulfate, a drug that improves insulin sensitivity in rats. Chronic oral vanadyl treatment was initiated in 6-week-old male Sprague-Dawley rats. One week after vanadyl was started, rats were fed either normal rat chow or a fructose-enriched diet. Plasma glucose and insulin levels and systolic blood pressure were measured weekly for 4 weeks. Fructose feeding induced hyperinsulinemia (fructose-fed, 366.6 +/- 8.4 versus control, 276 +/- 10.8 pmol/L, P < .001) and increased blood pressure (fructose-fed, 160 +/- 3.0 versus control, 124 +/- 3.0 mm Hg, P < .001). Vanadyl (0.4 to 0.6 mmol/kg per day) prevented the rise in plasma insulin (treated, 211.2 +/- 6.0 pmol/L, P < .001) and blood pressure (treated, 127 +/- 3.0 mm Hg, P < .001) in the fructose-fed rats without a change in plasma glucose. No change in blood pressure was seen in the control group. After 4 weeks, euglycemic clamps were performed on 20-hour fasted, conscious, mobile rats. Low-dose porcine insulin infusion (14 pmol/kg per minute) with concomitant somatostatin infusion resulted in similar steady-state plasma glucose and insulin levels in the various groups. Hepatic glucose production was suppressed and similar among various groups under clamp conditions. Insulin sensitivity index (micromoles of glucose per kilogram per hour per picomole per liter of insulin) was reduced in the fructose-fed rats compared with controls (fructose-fed, 0.9 +/- 0.4 versus control, 5.4 +/- 1.2, P < .002).(ABSTRACT TRUNCATED AT 250 WORDS)

Counterregulatory hormone responses during graded hyperinsulinermic euglycemia in conscious rats

It has been suggested that hyperinsulinemia per se may affect the levels of some counterregulatory hormones in the absence of hypoglycemia. We studied the effect of graded hyperinsulinemia and concomitant increased glucose metabolism on the levels of counterregulatory hormones by means of the 5-step sequential hyperinsulinemic euglycemic clamp technique, combined with [3- 3H]-glucose infusion, in conscious rats. Insulin infusion rates (IIR) of 0, 0.5, 1, 3, and 16 mU/min, resulted in steady-state plasma insulin levels (mean ± SEM of 24±4, 44±3, 98±8, 418±48, and 6626±361 μU/ml, peripheral glucose uptake (PGU) of 3.1±0.2, 3.6±0.3, 5.4±0.3, 9.2±0.4, and 12.4±0.2 mg/min and hepatic glucose production (HGP) of 3.1±0.2, 2.4±0.4, 0.8±0.3, −0.1±0.2, and −0.5±0.3 mg/min, respectively. Plasma glucagon levels were half maximally suppressed between IIRs of 0.5 and 1 mU/min and maximally suppressed at 3 mU/min. The suppression exactly paralieled the inhibition of HGP ( r=0.87±0.04, p<0.02) but not the stimulation of PGU ( r=−0.66±0.12, p=NS). This suggests that the inhibition of HGP by insulin is at least partially mediated by a simultaneous suppression of plasma glucagon levels. The adrenal hormones corticosterone and epinephrine were not influenced during the clamp. Moreover, the circadian rhythm of corticosterone seemed unaffected. Plasma norepinephrine levels were increased (±50%, p<0.05) at IIRs of 1 mU/min and higher, suggesting an insulin-induced stimulation of the sympathetic nervous system when peripheral plasma insulin levels exceed 98±8 μU/ml. In conclusion, measurement of in vivo insulin action by means of the euglycemic clamp induces dose-dependent changes in the levels of glucagon and norepinephrine but not in epinephrine and corticosterone. This has to be taken into account because it is, in fact, the interaction between insulin and these counterregulatory hormones that determines the ultimate action of insulin on glucose metabolism in vivo.

Insulin Resistance in Spontaneously Hypertensive Rats: Difference in Interpretation Based on Insulin Infusion Rate or on Plasma Insulin in Glucose Clamp Studies

Isotopic glucose turnover was measured during euglycemic glucose clamp studies in spontaneously hypertensive rats and normotensive Wistar-Kyoto control rats, under pentobarbital sodium anesthesia. At an insulin infusion rate of 4 mU.kg-1 x min-1, glucose disposal rate and hepatic glucose output were not significantly different in either group, at a plasma glucose of 6 mM. However, steady-state plasma insulin levels in spontaneously hypertensive rats were more than double those in Wistar-Kyoto rats (2.34 +/- 0.16 [mean +/- SE] vs. 6.78 +/- 0.58 nM, P < 0.00005, n = 7 in each group). Additional studies (n = 30 in spontaneously hypertensive rats and n = 32 in Wistar-Kyoto control rats) were conducted to match insulin levels in the two groups over a wide range, using infusion rates of 0.5-10 mU.kg-1 x min-1. When the responses of glucose disposal rate and hepatic glucose output to insulin were analyzed from the standpoint of plasma insulin levels, a highly significant difference was seen in the response to insulin between spontaneously hypertensive rats and Wistar-Kyoto rats, for both glucose disposal rate (P < 0.000005) and hepatic glucose output (P = 0.00007). The slope of the regression line for glucose disposal rate versus plasma insulin was lower in spontaneously hypertensive rats compared with Wistar-Kyoto rats (2.652 vs. 4.864, P < 0.001), indicating that insulin stimulation of glucose disposal rate was reduced by 50% in spontaneously hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Prednisolone enhances β-cell function independently of ambient glycemic levels in type II diabetes

This study examined the changes in β-cell response and insulin sensitivity induced by a single overnight dose of 15 mg prednisolone in eight type II diabetic subjects, seven nondiabetic normal controls, and eight subjects with a first-degree type II diabetic relative who were therefore at risk of developing diabetes. β-Cell secretion was assessed by use of the hyperglycemic clamp technique, and insulin sensitivity was assessed with the clamp and the Continuous Infusion of Glucose with Model Assessment (CIGMA) technique. Subjects were studied in random order on two occasions, after placebo and after prednisolone administration. Normal subjects showed an increase of median fasting glucose level from 4.7 to 5.2 mmol · L −1 after prednisolone ( P < .02) and at-risk subjects showed an increase from 4.8 to 5.5 mmol · L −1 ( P < .005), whereas diabetic subjects showed no significant increase in median fasting plasma glucose level (7.0 mmol · L −1 after placebo and 6.3 mmol · L −1 after prednisolone). Six of these eight diabetic subjects showed a paradoxical decrease of fasting plasma glucose level after prednisolone therapy. All three groups showed a significant elevation of clamp steady-state plasma insulin levels following prednisolone, with a median percentage elevation of 46%, 66%, and 31% for normal, at-risk, and diabetic subjects, respectively. All three groups showed significant reduction in insulin sensitivity measured by CIGMA following prednisolone of 51%, 41%, and 25% of pre-prednisolone levels in normal, at-risk, and diabetic subjects, respectively, with a significantly greater reduction in normal subjects than in diabetics ( P < .02). Stimulation of insulin levels in the diabetic group, in the absence of an elevation of plasma glucose level and a minimal decrease in insulin sensitivity, suggests that prednisolone has an in vivo stimulatory effect on the β cell independent of changes in ambient glycemia and insulin sensitivity. The interaction between the different effects of prednisolone in nondiabetic groups was more complex, as fasting glucose levels were altered by prednisolone. The prednisolone-CIGMA test improved the distinction between normal and at-risk subjects, but the magnitude was not sufficient to be clinically useful.

Role of body fat distribution in the decline in insulin sensitivity and glucose tolerance with age.

The relationships of body composition and physical fitness [maximal aerobic capacity (VO2max)] to the decline in insulin sensitivity with age were examined in healthy older (47-73 yr; n = 36) and young (19-36 yr; n = 13) men. In 18 older men with normal glucose tolerance (OGTT), glucose disposal rates (M) during hyperinsulinemic euglycemic clamps correlated negatively with the waist to hip ratio (WHR; r = -0.77; P < .001) and percent body fat (r = -0.46; P < 0.05) and positively with VO2max (r = 0.54; P < 0.05), but not with age. Similar relationships existed in the 36 older men with a spectrum of OGTT responses; however, only WHR was independently related to M (r2 = 0.32; P < 0.01). In the older men with normal OGTT, M (mean +/- SEM, 7.88 +/- 0.43 mg/kg fat-free mass.min) was not different from that in the young men (8.56 +/- 0.47; P = NS). Furthermore, in older and young men with normal OGTT matched for WHR, percent fat, or VO2max, glucose disposal was comparable at sequential 15-min intervals during the clamp and in its relationship to insulin concentrations at the tissue level (multicompartmental analysis). In contrast, despite higher steady state plasma insulin levels during the clamp, M was significantly lower in the older men with a higher WHR, greater percent fat, lower VO2max, or impaired OGTT. Thus, in healthy older men up to the age of 73 yr, insulin sensitivity and glucose tolerance are affected primarily by the regional body fat distribution, not age, obesity, or VO2max.

Insulin resistance, hyperinsulinemia, and dyslipidemia in nonobese individuals with a family history of hypertension.

Various facets of glucose, insulin, and lipid metabolism were compared in 76 normal volunteers--38 with and 38 without a family history of hypertension. The two groups were comparable in terms of age, gender distribution, and degree of obesity (both generalized and abdominal). Although the plasma glucose response to oral glucose was similar in both groups, glucose-stimulated insulin concentrations were significantly greater in volunteers with a family history of hypertension (P < .001). Furthermore, the steady state plasma glucose concentration during a constant infusion of glucose, insulin and somatostatin was significantly greater in subjects with a family history of hypertension (8.1 +/- 0.6 v 6.2 +/- 0.6 mmol/L, P < .001). Since the steady-state plasma insulin levels during the infusion were similar, these results indicate that normotensive individuals with a family history of hypertension are relatively insulin resistant. Finally, plasma very low density lipoprotein (VLDL) triglyceride and VLDL cholesterol were higher in those with a family history of hypertension, as was the ratio of total to high density lipoprotein cholesterol. Thus, normotensive individuals with a family history of high blood pressure are insulin resistant, hyperinsulinemic and dyslipidemic when compared to a matched group of healthy volunteers without a family history of hypertension.

Decreased insulin clearance as a feature of essential hypertension.

Several studies report that essential hypertension is associated with hyperinsulinemia. This condition may depend on enhanced pancreatic insulin secretion and/or a decreased MCR of the circulating hormone. Twenty-five nonobese glucose-normotolerant patients with primary hypertension were divided into 5 groups, each consisting of 5 subjects. Each group was submitted to continuous 120-min double infusion of different doses of insulin (group I, 0.025; II, 0.05; III, 0.1; IV, 0.2; V, 0.4 U/kg.h) and glucose (I, 2; II, 3.5; III, 6; IV, 8; V, 10 mg/kg.min). The same procedures were applied to 25 healthy normotensive volunteers. Basal and steady state plasma levels of glucose, insulin, and C-peptide were significantly (P less than 0.05 or less) higher in hypertensive patients than in control subjects of all groups. The MCR of insulin (milliliters per kg/min) at all insulin-glucose infusion rates was significantly (P less than 0.05 or less) lower in hypertensive than normotensive subjects. Despite the significantly higher steady state plasma insulin levels in hypertensives, the MCR of glucose (milliliters per kg/min) was significantly (P less than 0.05 or less) lower in hypertensive than normotensive subjects. These results suggest that an altered insulin removal may contribute to the hyperinsulinemia found in the essential hypertensive subjects. In addition, a defect in insulin-stimulated glucose uptake which persists at supraphysiological insulin concentrations is confirmed in this population.