Novel insulin sensitivity index derived from oral glucose tolerance test

The euglycemic hyperglycemic clamp is generally regarded as a reference method for assessing insulin sensitivity. However, this method is laborious and expensive. The oral glucose tolerance test (OGTT), the most commonly used method for evaluating whole body glucose tolerance, has often been used to assess insulin sensitivity. In the previous studies the correlation between the insulin sensitivity index (ISI) obtained from the OGTT (ISI(OGTT)) and those obtained from the glucose clamp (ISI(Clamp)) may not be satisfactory. This is because the glucose clamp study is designed for measuring peripheral glucose utilization, whereas plasma glucose responses during the OGTT are the results of peripheral glucose utilization and hepatic glucose production. Based on this problem, we developed a new equation, ISI(OGTT), [1.9/6 x body weight (kg) x fasting plasma glucose (mmol/liter) + 520 - 1.9/18 x body weight x area under the glucose curve (mmol/h.liter) - urinary glucose (mmol)/1.8] / [area under the insulin curve (pmol/h.liter) x body weight], which would represent peripheral glucose utilization only. We tested our equation with ISI(Clamp) and also compared with others. Thirty-three healthy volunteers (16 males) with normal glucose tolerance underwent a 75-g, 3-h OGTT on the morning of d 1 and a glucose clamp on the morning of d 2. Their mean (+/-SD) age and body mass index were 30.8 +/- 8.3 yr and 22.0 +/- 3.9 kg/m(2), respectively. The mean (+/-SD) glucose disposal rate and ISI determined by glucose clamp were 27.46 +/- 16.55 micro mol/kg.min and 7.39 +/- 2.72 micro mol/kg.min/pmol.liter, respectively. Pearson's correlation coefficient between our ISI(OGTT) and ISI(Clamp) was 0.869 (P < 0.0001) which was stronger than those corresponding values calculated from HOMA, QUICKI, Belfiore, Cederholm, Gutt, Matsuda, and Stumvoll, the respective values of which were 0.404, 0.434, 0.643, 0.533, 0.584, 0.734, and 0.508. In conclusion, the ISI(OGTT) derived from our equation is more suitable than others in assessing insulin sensitivity in subjects with normal glucose tolerance. Further studies in subjects with impaired glucose tolerance and diabetes mellitus should be performed to confirm the validity of this equation.     

Comparison of insulin sensitivity,clearance, and secretion estimates using euglycemic and hyperglycemic clamps in children

The euglycemic clamp is the gold standard for estimating insulin sensitivity. The hyperglycemic clamp is easier to perform and is the gold standard for estimating beta-cell secretion. Reports in adults suggest that hyperglycemic clamps can estimate insulin sensitivity with results equivalent to euglycemic clamps. We investigated whether insulin sensitivity measures from both clamps are equivalent in children. Thirty-one lean and obese children (mean body mass index, 25.1 +/- 4.9 kg/m(2); mean age, 8.7 +/- 1.4 yr; 15 girls and 16 boys; 12 black and 19 white) were studied. All subjects underwent hyperglycemic clamps, then euglycemic clamps 2-6 wk later. Body composition was estimated by dual energy x-ray absorptiometry. Visceral and sc abdominal fat was estimated by abdominal magnetic resonance imaging. Whole-body glucose disposal and insulin sensitivity (SI clamp) derived from both clamps and normalized for total or visceral fat and lean mass were significantly correlated (r, 0.45-0.65; P < 0.05). However, absolute SI clamp values were not equivalent. Bland-Altman comparisons found that SI clamp estimates from hyperglycemic clamps became less precise as SI clamp increased. There were significant correlations between indices of beta-cell secretion from the hyperglycemic clamp and mean C-peptide values from the euglycemic clamp (P < 0.05). However, no correlation was found between measures of total insulin clearance (derived from the euglycemic clamp) and surrogates of hepatic insulin clearance (derived from the hyperglycemic clamp). In this cohort of diverse children, SI clamp values from euglycemic and hyperglycemic clamps were significantly correlated but were not equivalent, whereas the insulin clearance measures were not correlated. It cannot be assumed that the hyperglycemic clamp obviates the need for euglycemic clamp studies to accurately estimate insulin sensitivity in children.     

Insulin and glucagon secretion are suppressed equally during both hyper- and euglycemia by moderate hyperinsulinemia in patients with diabetes mellitus

Hyper- and euglycemic clamp studies were performed in patients with noninsulin-dependent diabetes mellitus to examine the effects of exogenous insulin administration on insulin and glucagon secretion. Plasma glucose was kept at the fasting level [mean, 10.0 +/- 0.2 (+/- SE) mmol/L; hyperglycemic clamp], and graded doses of insulin (1, 3, and 10 mU/kg.min, each for 50 min) were infused. The plasma C-peptide level gradually decreased from 523 +/- 66 to 291 +/- 43 pmol/L (n = 13; P less than 0.005) by the end of the hyperglycemic clamp study. After 90 min of equilibration with euglycemia (5.4 +/- 0.1 mmol/L; euglycemic clamp), the same insulin infusion protocol caused a similar decrease in the plasma C-peptide level. With the same glucose clamp protocol, physiological hyperinsulinemia for 150 min (676 +/- 40 pmol/L), obtained by the infusion of 2 mU/kg.min insulin, caused suppression of the plasma C-peptide level from 536 +/- 119 to 273 +/- 65 pmol/L during hyperglycemia and from 268 +/- 41 to 151 +/- 23 pmol/L during euglycemia (n = 9; P less than 0.005 in each clamp). Plasma glucagon was suppressed to a similar degree in both glycemic states. These results demonstrate that 1) insulin secretion in non-insulin-dependent diabetes mellitus is suppressed by high physiological doses of exogenous insulin in both the hyper- and euglycemic states, the degree of inhibition being independent of the plasma glucose level; and 2) glucagon secretion is also inhibited by such doses of exogenous insulin.     

B cell secretion and insulin sensitivity in hypertensive and normotensive obese subjects

To test the hypothesis that in obesity hypertension is associated with more pronounced hyperinsulinaemia and insulin resistance we compared plasma insulin levels and insulin sensitivity in a group of 6 obese subjects with untreated hypertension and in a group of 6 obese subjects with normal blood pressure. The two groups were similar for sex, age, body mass index and glucose tolerance. Six nonobese subjects served as controls. The study consisted of a 2-h hyperglycaemic clamp (steady-state plasma glucose = 11 mmol/l) and a 15-min insulin tolerance test (0.1 U/kg body wt). During hyperglycaemic clamp, insulin and C-peptide plasma levels were similar in normotensive and hypertensive obese subjects: the area under the plasma insulin curve was 36,000 +/- 3000 pmol/l X 120 min in the former and 34,000 +/- 1000 pmol/l X 120 min in the latter; the area under the plasma C-peptide curve was 298,000 +/- 26,000 pmol/l X 120 min in the former and 246,000 +/- 26,000 pmol/l X 120 min in the latter (P = n.s.). The ratio M/I between the amount of glucose metabolized (M) and the mean plasma insulin levels (I) during hyperglycaemic clamp was similar in the two groups: 0.59 +/- 0.09 in normotensive and 0.58 +/- 0.08 mg/min X m2 per pmol/l in hypertensive obese subjects (P = n.s.). Also the rate coefficient of glucose disappearance from plasma (K(itt)) after i.v. insulin injection was similar in the two groups (4.08 +/- 0.51 vs. 3.87 +/- 0.53 per cent/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Ghrelin enhances glucose-induced insulin secretion in scheduled meal-fed sheep

The purpose of this study was to investigate the effects of physiologic levels of ghrelin on insulin secretion and insulin sensitivity (glucose disposal) in scheduled fed-sheep, using the hyperglycemic clamp and hyperinsulinemic euglycemic clamp respectively. Twelve castrated Suffolk rams (69.8 +/- 0.6 kg) were conditioned to be fed alfalfa hay cubes (2% of body weight) once a day. Three hours after the feeding, synthetic ovine ghrelin was intravenously administered to the animals at a rate of 0.025 and 0.05 mug/kg body weight (BW) per min for 3 h. Concomitantly, the hyperglycemic clamp or the hyperinsulinemic euglycemic clamp was carried out. In the hyperglycemic clamp, a target glucose concentration was clamped at 100 mg/100 ml above the initial level. In the hyperinsulinemic euglycemic clamp, insulin was intravenously administered to the animals for 3 h at a rate of 2 mU/kg BW per min. Basal glucose concentrations (44+/- 1 mg/dl) were maintained by variably infusing 100 mg/dl glucose solution. In both clamps, plasma ghrelin concentrations were dose-dependently elevated and maintained at a constant level within the physiologic range. Ghrelin infusions induced a significant (ANOVA; P < 0.01) increase in plasma GH concentrations. In the hyperglycemic clamp, plasma insulin levels were increased by glucose infusion and were significantly (P < 0.05) greater in ghrelin-infused animals. In the hyperinsulinemic euglycemic clamp, glucose infusion rate, an index of insulin sensitivity, was not affected by ghrelin infusion. In conclusion, the present study has demonstrated for the first time that ghrelin enhances glucose-induced insulin secretion in the ruminant animal.     

Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome

The obstructive sleep apnea syndrome is typically associated with conditions known to increase insulin resistance as hypertension, obesity, and diabetes. We investigated whether obstructive sleep apnea itself is an independent risk factor for increased insulin resistance and whether continuous positive airway pressure (CPAP) treatment improves insulin sensitivity. Forty patients (apnea-hypopnea index > 20) were treated with CPAP. Before, 2 days after, and after 3 months of effective CPAP treatment, hyperinsulinemic euglycemic clamp studies were performed. Insulin sensitivity significantly increased after 2 days (5.75 +/- 4.20 baseline versus 6.79 +/- 4.91 micromol/kg.min; p = 0.003) and remained stable after 3 months of treatment. The improvement in insulin sensitivity after 2 days was much greater in patients with a body mass index less than 30 kg/m2 than in more obese patients. The improved insulin sensitivity after 2 nights of treatment may reflect a decreasing sympathetic activity, indicating that sleep apnea is an independent risk factor for increased insulin resistance. The effect of CPAP on insulin sensitivity is smaller in obese patients than in nonobese patients, suggesting that in obese individuals insulin sensitivity is mainly determined by obesity and, to a smaller extent, by sleep apnea.     

The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance.

PC-1 is a membrane glycoprotein that impairs insulin receptor function. Its K121Q polymorphism is a genetic determinant of insulin resistance. We investigated whether the PC-1 gene modulates insulin sensitivity independently of weight status (i.e. both in nonobese and obese individuals). Nondiabetic subjects [164 males, 267 females; age, 37 +/- 0.6 yr, mean +/- SEM; body mass index (BMI), 32.7 +/- 0.5 kg/m(2)], who were subdivided into 220 nonobese (BMI < or = 29.9) and 211 obese, were studied. Although subjects were nondiabetic by selection criteria, plasma insulin concentrations during oral glucose tolerance test were higher (P < 0.05) in Q allele-carrying subjects (K121Q or Q121Q genotypes), compared with K121K individuals, in both the nonobese and obese groups. Insulin sensitivity, measured by euglycemic clamp in a representative subgroup of 131 of 431 randomly selected subjects, progressively decreased (P < 0.001) from nonobese K121K [n = 61; glucose disposal (M) = 34.9 +/- 1.1 micromol/kg/min] to nonobese Q (n = 21; M = 29.9 +/- 2.0), obese K121K (n = 31, M = 18.5 +/- 1.2), and obese Q (n = 18, M = 15.5 +/- 1.2) carriers. The K121Q polymorphism was correlated with insulin sensitivity independently (P < 0.05) of BMI, gender, age, and waist circumference. In conclusion, the Q121 PC-1 variant and obesity have independent and additive effects in causing insulin resistance.     

Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis

Hepatic insulin extraction is difficult to measure in humans; as a result, the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001), which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose, the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min), suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients, both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However, with oral glucose the rise in serum C-peptide concentration was relatively delayed, and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of insulin inhibition on insulin secretion in non-diabetic morbidly obese patients.

OBJECTIVE: Insulin inhibition of insulin secretion has been described in normal lean subjects. In this study, we examined whether this phenomenon also occurs in the morbidly obese who often have severe peripheral insulin resistance. SUBJECTS: Twelve obese patients, normotolerant to glucose (8 F/4 M, body mass index (BMI)=54.8+/-2.5 kg/m(2), 39 y) and 16 lean control subjects (10 F/6 M, BMI=22.0+/-0.5 kg/m(2), 31 y). DESIGN AND MEASUREMENTS: An experimental study using various parameters, including an euglycemic hyperinsulinemic clamp (280 pmol/min/m(2) of body surface), an oral glucose tolerance test (OGTT), electrical bioimpedance and indirect calorimetry. RESULTS: The obese subjects were insulin resistant (M=19.8+/-1.6 vs 48.7+/-2.6 micromol/min kg FFM, P<0.0001) and hyperinsulinemic in the fasted state and after glucose ingestion. Fasting plasma C-peptide levels (obese 1425+/-131 pmol/l vs lean 550+/-63 pmol/l; P<0.0001) decreased less during the clamp in the obese groups (-16.9+/-6.9% vs -43.0+/-5.6% relative to fasting values; P=0.007). In the lean group, the C-peptide decrease during the clamp (percentage variation) was related to insulin sensitivity, M/FFM (r=0.56, P=0.03), even after adjustment for the clamp glucose variation. CONCLUSION: We conclude that, in lean subjects, insulin inhibits its own secretion, and this may be related to insulin sensibility. This response is blunted in morbidly obese patients and may have a role in the pathogenesis of fasting hyperinsulinemia in these patients.     

Evidence for insulin resistance in black women from South Africa

OBJECTIVE: The rate of glucose disposal was determined in 10 black and 10 white obese nondiabetic urban women from South Africa to assess insulin resistance. DESIGN AND METHODS: Euglycemic hyperinsulinemic clamp and body composition analysis. RESULTS: Age, body mass index (BMI), anthropometric measurements and body composition were similar in both groups of women. A five-level computed tomography (CT) scan showed a similar mean subcutaneous fat mass in both groups of women (black obese women 555 +/- 9.0 vs white obese women 532 +/- 6.0 cm2), but less visceral fat in black obese women (90 +/- 3.0 vs 121 +/- 3.1 cm2; P< 0.05). Black obese women had higher fasting free fatty acid (997 +/- 69 vs 678 +/- 93 micromol/l; P < 0.05) and lactate concentrations (1,462 +/- 94 vs 1,038 +/- 39 micromol/l; P < 0.05), but lower fasting insulin levels (87 +/- 12 vs 155 +/- 9 pmol/l; P < 0.001). Black obese women also had a more favorable HDL: total cholesterol ratio (30.5% vs 23.0%; P< 0.04). The mean glucose disposal rate (M) and disposal expressed as glucose sensitivity index (M/I) were reduced in the black obese women vs white obese women (M: 7.1 +/- 0.8 vs 13.7 +/- 1.0 mmol/kg min(-1) x 100; P< 0.01, and M/I: 0.12 +/- 0.01 vs 0.24 +/- 0.02 mmol/kg x min(-1)/pmol/1 x 1,000; P < 0.01). Only black obese women showed a significant decrease in C-peptide levels during the clamp (2.9 +/- 0.22 vs 1.2 +/- 0.12 nmol/l; P<0.001). During the euglycemic period, the black obese women had higher lactate levels at all time points, but only the white obese women had increased lactate levels (918 +/- 66 to 1,300 +/- 53 micromol/l; P< 0.05). CONCLUSION: Black obese women demonstrate a higher degree of insulin resistance, despite less visceral fat and a higher HDL: total-cholesterol ratio. In addition, endogenous beta-cell secretory function in black obese women appears to be more sensitive to the suppressive effect of exogenous insulin administration. The significant increase in lactate levels in white obese women confirms that they are more insulin sensitive.     

Peripheral and hepatic insulin antagonism in hyperthyroidism

Eight hyperthyroid and eight normal subjects underwent 2-h oral glucose tolerance tests (OGTT) and euglycemic clamp studies to assess the presence of peripheral and hepatic insulin antagonism in hyperthyroidism. Although the mean total glucose area during the OGTT was similar in the hyperthyroid patients and normal subjects [16.4 +/- 0.8 (+/- SE) vs. 15.8 +/- 0.7 mmol/L.h], the mean insulin area was significantly elevated in the hyperthyroid group (1413 +/- 136 vs. 1004 +/- 122 pmol/L.h; P less than 0.05). Basal hepatic glucose production was measured during the second hour of a primed [3-3H]glucose infusion. A two-insulin dose euglycemic clamp study with [3-3H]glucose and somatostatin (500 micrograms/h) was carried out during the next 6 h. The insulin infusion rate was 0.05 mU/kg.min during the third, fourth, and fifth hours and 0.60 mU/kg.min during the sixth, seventh, and eighth hours. Hepatic glucose production and glucose utilization were measured during the final 0.5 h of each clamp period. Serum C-peptide concentrations were measured in the initial sample and in the last sample of each clamp period. The mean equilibrium serum insulin concentrations were similar in both groups during the final 0.5 h of the low (90 +/- 8 vs. 79 +/- 6 pmol/L) and high (367 +/- 11 vs. 367 +/- 15 pmol/L) insulin infusion rates. Basal serum C-peptide levels were significantly increased in the hyperthyroid patients (596 +/- 17 vs. 487 +/- 43 pmol/L; P less than 0.05) but were suppressed equally in both groups at the end of both clamp periods. The MCRs of insulin were similar in the hyperthyroid and normal subjects during the low (6.7 +/- 1.1 vs. 5.6 +/- 0.5 mL/kg.min) and high (11.9 +/- 0.4 vs. 12.1 +/- 0.5 mL/kg.mm) insulin infusion rates. Glucose production was significantly increased in the hyperthyroid patients during the basal state (17.6 +/- 0.9 vs. 11.5 +/- 0.5 mumol/kg.min; P less than 0.001) and remained elevated during the final 0.5 h of the low (12.1 +/- 1.1 vs. 5.9 +/- 1.7; P less than 0.01) and high (3.2 +/- 1.2 vs. 0.5 +/- 0.3; P less than 0.05) insulin infusion rates. Peripheral insulin action, assessed by Bergman's sensitivity index, was significantly decreased in the hyperthyroid patients (7.4 +/- 2.2 vs. 15.6 +/- 2.1 L/kg min-1/pmol/L; P less than 0.02). In conclusion, hyperthyroidism is characterized by 1) hyperinsulinemia after oral glucose loading, 2) increased basal hepatic glucose production, 3) impairment of insulin-mediated suppression of hepatic glucose production, and 4) antagonism to insulin-stimulated peripheral glucose utilization.     

Insulin secretion and insulin sensitivity in diabetic and non-diabetic subjects with hepatic nuclear factor-1alpha (maturity-onset diabetes of the young-3) mutations

OBJECTIVE: To evaluate insulin secretion and sensitivity in affected (diabetes mellitus or impaired glucose tolerance; n=7) and in unaffected (normal glucose tolerance; n=3) carriers of hepatocyte nuclear factor-1alpha (maturity-onset diabetes of the young-3 (MODY3)) gene mutations. METHODS: Insulin secretion was assessed by an i.v. glucose tolerance test (IVGTT), hyperglycemic clamp and arginine test, and insulin sensitivity by an euglycemic hyperinsulinemic clamp. Results were compared with those of diabetic MODY2 (glucokinase-deficient) and control subjects. RESULTS: The amount of insulin secreted during an IVGTT was decreased in affected MODY3 subjects (46+/-24 (s.d.) pmol/kg body weight (BW)) as compared with values in MODY2 (120+/-49pmol/kg BW) and control (173+/-37pmol/kg BW; P=0.0004) subjects. The amount of insulin secreted during a 10mmol/l glucose clamp was decreased in affected MODY3 subjects (171+/-78pmol/kg BW) and MODY2 subjects (302+/-104pmol/kg BW) as compared with control subjects (770+/-199pmol/kg BW; P=0.0001). Insulin secretion in response to arginine was decreased in affected MODY3 subjects. Milder and heterogeneous defects were observed in the unaffected MODY3 subjects; the amount of insulin secreted during the hyperglycemic clamp was 40-79% of that of controls. The response to arginine was abnormally delayed. Insulin sensitivity was decreased in diabetic but not in non-diabetic MODY3 subjects. CONCLUSIONS: Beta-cell dysfunction in response to glucose and arginine is observed in affected and unaffected MODY3 subjects. The MODY3 and MODY2 subtypes present different insulin secretion profiles. Secondary insulin resistance might contribute to the chronic hyperglycemia of MODY3 patients and modulate their glucose tolerance.     

Total ghrelin levels during acute insulin infusion in patients with polycystic ovary syndrome

Controversial data were reported concerning fasting ghrelin (decreased, normal or elevated) in polycystic ovary syndrome (PCOS). The aim of our study was to clarify ghrelin levels in non-obese, overweight, and obese PCOS patients; to investigate the effect of acute insulin infusion on ghrelin in PCOS as a chronic insulin-resistant state, with and without the impact of obesity, and to examine ghrelin-androgen interaction. In that order, we evaluated 1) ghrelin levels among 8 nonobese patients with PCOS [body mass index (BMI): 20.52+/-1.31 kg/m2], 8 overweight and obese patients with PCOS (BMI: 34.36+/-6.53 kg/m2) and their respective controls, 2) ghrelin suppression during euglycemic hyperinsulinemic clamp, and 3) ghrelin-androgen interrelationship. After overnight fast, 2-h euglycemic hyperinsulinemic clamp, was performed in all investigated women. Fasting ghrelin was significantly lower in non-obese PCOS than in controls (64.74+/-25.69 vs 108.36+/-52.60; p<0.05) as well as in overweight and obese PCOS in comparison with controls (38.71+/-14.18 vs 98.77+/-40.49; p<0.05). Insulin infusion significantly suppressed ghrelin in all subgroups of investigated women. Analysis of variance for repeatable measures confirmed that there was no significant difference in pattern of response between PCOS and controls. In conclusion, women with PCOS had lower fasting ghrelin and decreased insulin sensitivity independently of their BMI, compared to the controls. In addition, there were no differences between fasting ghrelin levels among non-obese, overweight, and obese women with PCOS. During euglycemic hyperinsulinemic clamp, ghrelin decreased in all studied groups to a similar extent, implying that, compared to chronic hyperinsulinemia, acute hyperinsulinemia reduces ghrelin levels independently of the degree of insulin resistance.     

The antilipolytic action of insulin in obese subjects with resistance to its glucoregulatory action

To compare the ability of insulin to regulate lipolysis in lean and obese subjects, free fatty acid (FFA) suppression was compared in groups of six lean [body mass index, 25.7 +/- 1.1 (+/-SEM) kg/m2] and six obese (body mass index, 48.8 +/- 3.1) Pima Indians during euglycemic hyperinsulinemic clamps which increased plasma insulin levels approximately 10, 20, and 100 microU/ml above basal concentrations. Basal FFA concentrations were slightly, but not significantly, elevated in the obese group (445 +/- 35 vs. 406 +/- 40 mu eg/liter). The mean decline in FFA from basal after 60-90 min of insulin infusion in the obese group was somewhat less than that in the lean group at the lower doses [67 +/- 23 vs. 132 +/- 32 (P = NS) during the 10-microU clamp, and 144 +/- 39 vs. 217 +/- 20 (P = NS) during the 20-microU clamp] and was almost identical in the two groups during the 100-microU clamp (226 +/- 29 vs. 229 +/- 51). In contrast, insulin-mediated glucose disposal at all insulin increments was much lower in the obese group (0.33 +/- 0.03, 0.56 +/- 0.04, and 1.39 +/- 0.04 mg/kg X min) than in the lean group (0.78 +/- 0.06, 1.67 +/- 0.12, and 4.96 +/- 0.26; P less than 0.001). The data suggest that although the obese subjects exhibited significant resistance to the glucoregulatory action of insulin, there were only small changes in insulin's antilipolytic effects. Relative maintenance of sensitivity to the antilipolytic action of insulin in the presence of resistance to insulin's glucoregulatory action could maintain fat deposition in obese individuals.     

Comparison of the inhibitory effect of insulin and hypoglycemia on insulin secretion in humans

Although both insulin and hypoglycemia are known to inhibit endogenous insulin secretion, their potency to suppress insulin secretion has not been directly compared thus far. The serum C-peptide concentration was measured during 28 euglycemic and 28 stepwise hypoglycemic (4.1,3.6, 3.1, and 2.6 mmol/L) clamp experiments using either a low-rate (1.5 mU x min(-1) x kg(-1)) or high-rate (15.0 mU x mU(-1) x kg(-1)) insulin infusion. The experiments lasted 6 hours and were performed in 28 lean healthy men. During both the euglycemic and hypoglycemic clamps, serum insulin was approximately 40-fold higher during the high-rates versus low-rate insulin infusion (euglycemia, 24,029 +/- 1,595 v 543 +/- 34 pmol/L; hypoglycemia, 23,624 +/- 1,587 v 622 +/- 32 pmol/L). Under euglycemic conditions, serum C-peptide decreased from 0.54 +/- 0.04 to 0.41 +/- 0.05 nmol/L during the low-rate insulin infusion (P < .05) and from 0.55 +/- 0.07 to 0.27 +/- 0.09 nmol/L during the high-rate insulin infusion (P < .001). Under hypoglycemic conditions, serum C-peptide decreased from 0.50 +/- 0.03 to 0.02 +/- 0.01 nmol/L during the low-rate insulin infusion (P< .001) and from 0.46 +/- 0.07 to 0.02 +/- 0.01 nmol/L during the high-rate insulin infusion (P< .001). In the euglycemic clamp condition, the high-rate insulin infusion reduced the C-peptide concentration more than the low-rate insulin infusion (P < .05). Independent of the rate of insulin infusion, the decrease in C-peptide was distinctly more pronounced during hypoglycemia versus euglycemia (P < .001). These data indicate that insulin inhibits insulin/C-peptide secretion in a dose-dependent manner. Hypoglycemia is a much stronger inhibitor of insulin secretion than insulin itself.     

Insulin resistance is a characteristic feature of primary hypertension independent of obesity

The relationship between abnormalities in carbohydrate metabolism and hypertension was studied in 143 newly detected hypertensive patients (59% obese) of both sexes (90 males, 53 females) and compared with 51 normotensive controls. Insulin-mediated glucose disposal assessed with the euglycemic insulin clamp technique was significantly decreased in both non-obese (7.2 +/- 2.1 mg/kg/min; P less than .05) and obese hypertensives (5.1 +/- 2.1 mg/kg/min; P less than .01) compared with the controls (8.4 +/- 1.8 mg/kg/min). The decrease in insulin sensitivity and increase in basal insulin as well as a decreased rate of glucose disposal after an intravenous glucose tolerance test (IVGTT) were verified also after statistical adjustment for sex, age, body mass index, and waist-hip ratio. The insulin index (ratio between peak and basal insulin) during IVGTT was significantly decreased in the hypertensive patients (P less than .001). After the statistical adjustment for the factors mentioned the following lipid abnormalities were still significant: total cholesterol (6.25 +/- 1.12 mmol/L non-obese; 6.06 +/- 1.20 mmol/L obese; 5.41 +/- 1.02 mmol/L controls), triglycerides (1.70 +/- 0.74 mmol/L nonobese; 2.26 +/- 1.13 mmol/L obese; 1.24 +/- 0.53 mmol/L controls) and free fatty acids (0.57 +/- 0.20 mmol/L nonobese; 0.59 +/- 0.20 mmol/L obese; 0.48 +/- 0.15 mmol/L controls). This study shows that after correction for a series of probable confounding variables, hypertension emerges as part of a syndrome characterized by major abnormalities of carbohydrate, insulin, and lipid metabolism, which independently or in concert may act as important risk factors for cardiovascular disease.     

Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies

We compared estimates of in vivo insulin action derived from insulin tolerance tests (ITT) and euglycemic and hyperglycemic glucose clamp studies in 17 normal subjects and 19 patients with various diseases characterized by insulin resistance. Fifteen subjects underwent an ITT and a euglycemic clamp study, 17 subjects underwent an ITT and a hyperglycemic clamp study, and 4 subjects underwent all 3 tests. The ITT consisted of a bolus iv injection of regular insulin (0.1 U/kg BW). The plasma glucose disappearance rate during the 3- to 15-min period following the insulin injection was taken as a measure of insulin action. In both euglycemic and hyperglycemic clamp studies, which were carried out with standard techniques, the ratio between the amount of glucose infused to maintain glycemia at the desired level and the mean plasma insulin concentration from 60-120 min (M) (euglycemic clamp studies) or 20-120 min (I) (hyperglycemic clamp studies) was used as a measure of insulin action. A close correlation was found between plasma glucose disappearance rate and the M/I ratio during either the euglycemic (r = 0.811; P less than 0.001) or the hyperglycemic (r = 0.826; P less than 0.001) clamp studies. These results suggest that the 15-min ITT is suitable as a simple and rapid estimation of in vivo insulin action when glucose clamp studies are not feasible, as in large series of subjects or serial studies.     

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 in women with polycystic ovary syndrome

The aim of our study was to compare insulin sensitivity in lean and obese European polycystic ovary syndrome (PCOS) women with lean healthy women. We performed the euglycemic hyperinsulinemic clamp in 83 women with PCOS [53 lean with body mass index (BMI) of 21.5 +/- 1.8 kg/m2 and 30 obese with BMI of 29.6 +/- 3.7 kg/m2] and in 15 healthy women with BMI of 21.6 +/- 1.8 kg/m2 to determine glucose disposal (M) and the insulin sensitivity index (ISI). Statistical evaluation was done using Kruskal-Wallis ANOVA followed by Kruskal-Wallis multiple-comparison z-value test. The basal blood glucose was significantly higher in lean and obese PCOS women than in controls (P < 0.02). Fasting insulin was significantly higher in both lean and obese PCOS women than in controls (P < 0.000001). Obese PCOS women were more insulin resistant than controls (P < 0.02 for M and P < 0.0008 for ISI); lean PCOS women did not differ from controls in M or ISI. Posthepatic insulin delivery was significantly higher in both lean and obese PCOS women compared with controls (P < 0.000008). We conclude that lean PCOS women are not more insulin resistant than healthy controls. Insulin hypersecretion, on the other hand, is present even in lean PCOS women.     

Chronic hyperinsulinemia decreases insulin action but not insulin sensitivity

Hyperinsulinemia and insulin resistance are commonly seen in obese and non-insulin-dependent diabetes mellitus (NIDDM) patients, suggesting a causal link exists between hyperinsulinemia and insulin resistance. In a previous study, we demonstrated that chronic (28 days) intraportal hyperinsulinemia (50% increase in basal insulin levels) resulted in a decrease in insulin action as assessed by a one-step euglycemic hyperinsulinemic clamp. Since only one dose of insulin was used during the clamp, it was not possible to determine if the decrease in insulin action was due to a change in insulin sensitivity and/or maximal insulin responsiveness. In the present study, insulin resistance was induced as before, but insulin action was assessed in overnight fasted conscious dogs using a four-step euglycemic hyperinsulinemic clamp (1, 2, 10, and 15 mU/kg/min). Insulin responsiveness was assessed before the induction of chronic hyperinsulinemia (day 0), and after 28 days of hyperinsulinemia (day 28). Transhepatic glucose balance and whole-body glucose utilization were measured to allow assessment of both the hepatic and peripheral effects of insulin. Chronic hyperinsulinemia increased basal insulin levels from 13 +/- 2 to 21 +/- 4 microU/mL. After 4 weeks of chronic hyperinsulinemia, maximal insulin-stimulated glucose utilization was decreased 23% +/- 4% (P less than .05) and insulin sensitivity (ED50) was not significantly altered. During the four-step clamp, the liver was a major site of glucose utilization. The liver was responsible for 13% of the total glucose disposal rate on day 0 (2.9 mg/kg/min) at the highest insulin infusion rate (15 mU/kg/min; 2,000 microU/mL).(ABSTRACT TRUNCATED AT 250 WORDS)