Predictors of insulin sensitivity in Type 2 diabetes mellitus.

AIMS: To identify the independent predictors of insulin sensitivity in Type 2 diabetes, and to establish whether isolated Type 2 diabetes (i.e. diabetes without overweight, dyslipidaemia and hypertension) is a condition of insulin resistance. METHODS: We examined 45 patients with non-insulin-treated Type 2 diabetes undergoing a 4-h euglycaemic hyperinsulinaemic clamp (20 mU/m2 per min) combined with 3H-3-D-glucose and 14C-U-glucose infusions and indirect calorimetry. We also examined 1366 patients with non-insulin-treated Type 2 diabetes randomly selected among those attending the Diabetes Clinic and in whom insulin resistance was estimated by Homeostasis Model Assessment (HOMA-IR). RESULTS: In the 45 patients undergoing glucose clamp studies, insulin-mediated total glucose disposal (TGD) was independently and negatively associated with systolic blood pressure (standardized beta coefficient = -0.407, P = 0.003), plasma triglycerides (beta= -0.355, P = 0.007), and HbA1c (beta= -0.350, P = 0.008). The overall variability of TGD explained by these variables was 53%. Overweight diabetic subjects with central fat distribution, hypertension, hypertriglyceridaemia and poor glycometabolic control had insulin-mediated TGD values markedly lower than their lean counterparts without hypertension, with normal triglycerides, and with good glycometabolic control (16 +/- 5 vs. 31 +/- 10 micromol/min per kg lean body mass, P < 0.01). Nevertheless, the latter still were markedly insulin-resistant when compared with sex- and age-matched non-diabetic control subjects (31 +/- 10 vs. 54 +/- 13 micromol/min per kg lean body mass, P < 0.01). In the 1366 Type 2 diabetic patients of the epidemiological study, HOMA-IR value was independently associated with HbA1c (beta = 0.283, P < 0.0001), plasma triglycerides (beta = 0.246, P < 0.0001), body mass index (beta = 0.139, P < 0.001), waist girth (beta = 0.124, P < 0.001) and hypertension (beta = 0.066, P = 0.006). CONCLUSION: Overweight, central fat distribution, dyslipidaemia, hypertension and poor glycometabolic control are strong independent predictors of insulin resistance in Type 2 diabetes. However, reduced insulin sensitivity can be found even when Type 2 diabetes is isolated and well controlled.

Relation between soluble adhesion molecules and insulin sensitivity in type 2 diabetic individuals: role of adipose tissue.

OBJECTIVE: The purpose of this study was to explore the relation between insulin resistance and plasma levels of soluble adhesion molecules and to examine the effects of acute hyperinsulinemia on these molecules in type 2 diabetic individuals. RESEARCH DESIGN AND METHODS: Intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E- and P-selectin plasma concentrations were measured in 36 nonobese type 2 diabetic patients without cardiovascular disease and in 7 healthy subjects. Insulin sensitivity was assessed by a 4-h euglycemic ( approximately 5 mmol/l)-hyperinsulinemic ( approximately 300 pmol/l) clamp performed in combination with [(3)H]3-D-glucose infusion. RESULTS: Diabetic subjects were insulin resistant but did not show plasma concentrations of adhesion molecules that were significantly higher than control subjects. In diabetic subjects, plasma ICAM-1 and E-selectin were negatively correlated with total glucose disposal during the insulin clamp (r = -0.432, P < 0.01; and r = -0.375, P < 0.05, respectively), whereas plasma VCAM-1 and P-selectin were not. Plasma ICAM-1 as well as E- and P-selectin were positively correlated with BMI, total body fat (TBF), and waist girth (P < 0.05-0.001). In multiple regression analyses, the relation of plasma ICAM-1 and E-selectin with insulin sensitivity was lost after adjustment for potential confounders, including HbA(1c), blood pressure, and/or LDL cholesterol. In these analyses, BMI was the only independent predictor of plasma ICAM-1 (R(2) = 0.244, P < 0.002), whereas TBF was the only independent predictor of plasma E-selectin (R(2) = 0.202, P = 0.01). The 4-h insulin infusion during the glucose clamp did not significantly change plasma levels of adhesion molecules. CONCLUSIONS: Overall adiposity, rather than insulin resistance, may be a determinant of plasma levels of ICAM-1 and E-selectin in type 2 diabetic individuals. In these patients, acute hyperinsulinemia does not exert any significant effect on plasma adhesion molecules. These findings support the possibility that adipose tissue releases one or more factors that may adversely affect endothelial function on one hand and insulin sensitivity on the other.

Intracellular partition of plasma glucose disposal in hypertensive and normotensive subjects with type 2 diabetes mellitus.

The aim of this study was to ascertain whether the presence of hypertension conveys a more severe degree of insulin resistance in type 2 diabetes mellitus and, if so, which biochemical pathways are involved. We quantitated the rates of total glucose disposal, glycogen synthesis (GS), glycolysis, glucose oxidation, endogenous glucose production, and LOX in the basal state and during a 4-h euglycemic ( approximately 5 mM) hyperinsulinemic ( approximately 300 pM) clamp carried out in combination with a dual-tracer infusion ([(3)H]-3- and [(14)C]-U-D-glucose) and indirect calorimetry in 42 nonobese noninsulin-treated type 2 diabetic subjects (22 hypertensive and 20 normotensive) and 23 nonobese nondiabetic subjects (9 without and 14 with essential hypertension). Compared with normotensive controls, both groups of diabetic subjects were markedly insulin resistant. In the basal state, all glucose fluxes were similar in diabetic subjects with or without hypertension. During insulin infusion, total glucose disposal was significantly reduced in hypertensive diabetic subjects, compared with their normotensive counterparts (18.7 +/- 1.0 vs. 28.6 +/- 3.0 micromol/min.kg lean body mass; P < 0.01). This difference was almost entirely explained by a marked reduction in GS (4.5 +/- 2.0 vs. 12.5 +/- 3.3 micromol/min.kg lean body mass; P < 0.01). Endogenous glucose production was not different in the two diabetic groups during insulin infusion and was significantly higher than in normotensive controls. Lipid oxidation was less suppressed by hyperinsulinemia in hypertensive than in normotensive diabetic subjects (1.46 +/- 0.1 vs. 0.91 +/- 0.1 micromol/min.kg lean body mass; P < 0.01). Glucose fluxes were not significantly different in nondiabetic subjects with essential hypertension and in normotensive diabetic individuals. These results indicate that hypertension markedly aggravates insulin resistance featuring type 2 diabetes mellitus. The molecular defects underlying this phenomenon involve primarily GS.

Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity.

OBJECTIVE: To evaluate whether the homeostasis model assessment (HOMA) is a reliable surrogate measure of in vivo insulin sensitivity in humans. RESEARCH DESIGN AND METHODS: In the present study, we compared insulin sensitivity as assessed by a 4-h euglycemic (approximately 5 mmol/l) hyperinsulinemic (approximately 300 pmol/l) clamp with HOMA in 115 subjects with various degrees of glucose tolerance and insulin sensitivity. RESULTS: We found a strong correlation between clamp-measured total glucose disposal and HOMA-estimated insulin sensitivity (r = -0.820, P<0.0001), with no substantial differences between men (r = -0.800) and women (r = -0.796), younger (aged <50 years, r = -0.832) and older (r = -0.800) subjects, nonobese (BMI <27 kg/m2, r = -0.800) and obese (r = -0.765) subjects, nondiabetic (r = -0.754) and diabetic (r = -0.695) subjects, and normotensive ( r = -0.786) and hypertensive (r = -0.762) subjects. Also, we found good agreement between the two methods in the categorization of subjects according to insulin sensitivity (weighted k = 0.63). CONCLUSIONS: We conclude that the HOMA can be reliably used in large-scale or epidemiological studies in which only a fasting blood sample is available to assess insulin sensitivity

Effect of chronic treatment with lacidipine or lisinopril on intracellular partitioning of glucose metabolism in type 2 diabetes mellitus.

Antihypertensive treatment is frequently needed in type 2 diabetes. In this study we measured the rates of total, oxidative, and nonoxidative glucose disposal, glycogen synthesis, glycolysis, endogenous glucose production, and lipid oxidation using a 4-h euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 300 pmol/L) clamp in combination with a dual glucose tracer infusion ([3-(3)H]- and [U-14C] D-glucose) and indirect calorimetry in 40 nonobese subjects with type 2 diabetes. Subjects were studied twice: after a 4-week run-in period and after a 16-week period of double blind, randomized treatment with 4-6 mg/day lacidipine, a calcium channel blocker (n = 19), or 10-20 mg/day lisinopril, an angiotensin-converting enzyme inhibitor (n = 21). Antihypertensive treatment resulted in a significant increase in total glucose disposal during insulin clamp as well as in basal and insulin-stimulated nonoxidative glucose disposal rates. On the contrary, oxidative glucose disposal was significantly decreased by antihypertensive treatment, mainly in the basal state. The changes in glucose disposal rates were not significantly different in subjects treated with lacidipine and in those treated with lisinopril. The suppression of endogenous glucose production during insulin clamp was significantly greater after lacidipine than after lisinopril. These results suggest that treatment of subjects with type 2 diabetes with either lacidipine or lisinopril has no adverse effect on glucose metabolism. Conversely, both drugs seem to improve insulin sensitivity.

Cigarette smoking and insulin resistance in patients with noninsulin-dependent diabetes mellitus.

To evaluate the effects of chronic cigarette smoking on insulin sensitivity in patients with noninsulin-dependent diabetes mellitus (NIDDM), we examined 28 smokers and 12 nonsmokers with NIDDM, of similar sex, age, body mass index, waist/hip ratio, alcohol consumption, physical activity level, glycometabolic control, diabetes duration, and treatment. Insulin and C-peptide responses to oral glucose load were significantly higher in smokers than nonsmokers, whereas glucose levels were not substantially different. During insulin clamp (20 mU/min.m2), carried out in combination with tritiated glucose infusion and indirect calorimetry, total glucose disposal was markedly reduced in smokers vs. nonsmokers [19 +/- 1.2 vs. 33 +/- 5 mumol/min.kg fat-free mass (FFM); P < 0.001], in a dose-dependent fashion (F = 6.8, P < 0.001 by ANOVA when subjects were categorized for number of cigarettes smoked per day). Oxidative (9 +/- 1 vs. 14 +/- 2 mumol/min.kg FFM; P < 0.01) and nonoxidative (10 +/- 1 vs. 19 +/- 4 mumol/min.kg FFM; P < 0.01) pathways of insulin-mediated intracellular glucose metabolism were similarly reduced in smokers vs. nonsmokers. Plasma free fatty acid levels (240 +/- 33 vs. 130 +/- 23 microEq/L; P < 0.05) and lipid oxidation rate (1.39 +/- 0.1 vs. 0.95 +/- 0.2 mumol/ min.kg FFM; P < 0.05) were less suppressed by hyperinsulinemia in smokers than nonsmokers. In conclusion, chronic cigarette smoking seems to markedly aggravate insulin resistance in patients with NIDDM.

Obesity worsens cardiovascular risk profiles independently of hyperinsulinaemia.

OBJECTIVE: To investigate whether human obesity is characterized by a worse cardiovascular risk profile (than no obesity) even in the absence of hyperinsulinaemia. SUBJECTS AND DESIGN: A total of 367 healthy subjects (247 nonobese and 120 obese) with normal glucose tolerance and without family history of diabetes mellitus. INTERVENTIONS: A 75-g oral glucose tolerance test was performed in all participants. MAIN OUTCOME MEASURES: Anthropometry, blood pressure, fasting plasma lipids and urate, plasma glucose and insulin concentrations at fasting, 1 h and 2 h after oral glucose load. RESULTS: In a multivariate linear regression analysis, body mass index was strongly related to all cardiovascular risk factors, independently of sex, age and plasma insulin. When risk factors were compared in 37 normoinsulinaemic obese subjects (plasma insulin within one standard deviation of the mean values observed in the 247 nonobese subjects), and in 37 sex- and age-matched normoinsulinaemic nonobese subjects, we found that plasma glucose levels were similar in the two groups, whereas plasma triglyceride (1.50 +/- 0.13 vs. 1.13 +/- 0.08 mmol L-1; mean +/- SE), low-density lipoprotein cholesterol (3.42 +/- 0.25 vs. 2.77 +/- 0.18 mmol L-1) and urate (290 +/- 12 vs. 255 +/- 12 mumol L-1) levels were significantly higher, and plasma high-density lipoprotein cholesterol concentrations were lower (1.27 +/- 0.04 vs. 1.46 +/- 0.06 mmol L-1) in obese than in nonobese subjects with normal plasma insulin levels (P < 0.01). Also systolic (132 +/- 2 vs. 124 +/- 2 mmHg) and diastolic (86 +/- 1 vs. 81 +/- 1 mmHg) blood pressure values were significantly higher in normoinsulinaemic obese subjects than in normoinsulinaemic nonobese individuals (P < 0.001). CONCLUSIONS: These results suggest that in human obesity a worse cardiovascular risk profile is found (than in the nonobese) independently of the presence of hyperinsulinaemia.

Intimal-medial thickness of the carotid artery in nondiabetic and NIDDM patients. Relationship with insulin resistance.

OBJECTIVE: The aim of this study was 1) to compare intimal-medial thickness (IMT) of the carotid artery in nondiabetic and NIDDM patients and 2) to evaluate the association of this early marker of atherosclerosis with several cardiovascular risk factors, including plasma insulin and insulin resistance. RESEARCH DESIGN AND METHODS: A total of 58 nondiabetic and 56 NIDDM patients, randomly selected among those attending the outpatient Diabetes Clinic or the Clinic for Internal Medicine were examined. BMI, waist-to-hip ratio (WHR), blood pressure, glycohemoglobin (HbA1c), and fasting concentrations of plasma glucose, serum lipids (total and HDL cholesterol, triglycerides), and serum insulin were measured. Insulin resistance was assessed by computing glucose disappearance rate from plasma after intravenous insulin injection (Kitt). IMT of the carotid artery was measured by ultrasonography. RESULTS: IMT was significantly higher in diabetic patients, and the difference remained highly significant after adjusting for sex, age, BMI, WHR, presence of hypertension and dyslipidemia, and smoking status (1.39 vs. 1.24 mm, common SD 0.12, P < 0.001). Univariate regression analyses showed that IMT was negatively correlated with Kitt in either nondiabetic (r = -0.348, P < 0.01) or diabetic patients (r = -0.492, P < 0.001). However, multiple regression analyses showed that IMT was independently associated with age and WHR in nondiabetic subjects, whereas in diabetic patients, IMT was independently predicted by Kitt and hypertension. These two variables explained approximately 62% and approximately 35% of the variability of IMT in nondiabetic and diabetic patients, respectively. Plasma insulin was not independently associated with IMT in either groups. CONCLUSIONS: These results indicate that 1) diabetes is characterized by a greater thickness of the carotid artery independently of other established risk factor of atherosclerosis, 2) early atherosclerosis is independently associated with insulin resistance in diabetic but not in nondiabetic patients, 3) central adiposity is an independent predictor of IMT in nondiabetic individuals.

Relationship between fasting insulin and cardiovascular risk factors is already present in young men: the Verona Young Men Atherosclerosis Risk Factors Study.

The associations between fasting plasma insulin concentration and risk factors for cardiovascular disease were examined in 979 18-year-old men participating in the Verona Young Men Atherosclerosis Risk Factors Study, a cross-sectional population-based study. Body mass index (BMI), waist-to-hip ratio (WHR), plasma triglycerides and uric acid concentrations, and blood pressure values significantly increased, and the high-density lipoprotein (HDL)-total cholesterol ratio decreased, across quartiles of fasting insulin. Total and low-density lipoprotein cholesterol, concentrations did not change significantly with the increase in fasting insulin levels. After adjustment for BMI, WHR, smoking, alcohol intake and physical activity, only plasma triglycerides significantly increased across insulin quartiles (F = 7.1; P < 0.001). However, systolic blood pressure and uric acid were close to statistical significance (P = 0.06-0.07). Multiple linear regression analysis confirmed that plasma insulin was independently correlated with plasma triglycerides and, to a lesser extent, with blood pressure and uric acid concentration. This analysis pointed out that BMI was a stronger independent predictor of all cardiovascular disease risk factors than fasting insulin. When subjects were categorized according to the number of metabolic and haemodynamic disorders occurring within the same individual, subjects with multiple disorders (i.e, three or four) had higher plasma insulin levels than those with none or few disorders, even after adjusting for BMI, WHR and behavioural variables (F = 4.0; P < 0.01). These results indicate that hyperinsulinaemia is already associated with a cluster of cardiovascular disease risk factors in young adulthood, the strongest independent association being with plasma triglycerides.

Relationship of uric acid concentration to cardiovascular risk factors in young men. Role of obesity and central fat distribution. The Verona Young Men Atherosclerosis Risk Factors Study.

OBJECTIVE: To examine the relationships of serum uric acid concentration with several risk factors of cardiovascular diseases (CVD). SUBJECTS: 957 men 18 y old participating in the Verona Young Men Atherosclerosis Risk Factors Study, a cross-sectional population-based study. MEASUREMENTS: Body mass index (BMI), waist/hip ratio (WHR), serum uric acid, serum lipids, blood pressure, fasting insulin and behavioural variables. RESULTS: Serum uric acid concentration showed positive associations with BMI (r = 0.24; P < 0.0001), WHR (r = 0.19; P < 0.0001) and serum triglyceride levels (r = 0.19; P < 0.0001); it was also significantly correlated to systolic (r = 0.08; P < 0.01) and diastolic (r = 0.11; P < 0.001) blood pressure, fasting insulin (r = 0.11; P < 0.001), total (r = 0.12; P < 0.001) and LDL cholesterol (r = 0.10; P < 0.01) plasma concentrations. Life-style characteristics, such as smoking and physical activity did not show any significant association, while daily alcohol intake was positively associated with uric acid concentration (r = 0.09; P < 0.01). While the adjustment for fasting insulin did not substantially change these results, the magnitude of the correlations between uric acid and CVD risk factors markedly decreased when allowance was made for BMI and WHR. Only triglycerides maintained an independent correlation with uric acid levels (r = 0.17; P < 0.0001). In multivariate regression analysis, serum triglycerides, BMI and WHR (at borderline significance) were independent positive predictors of uric acid (R2 of the model 0.122, P < 0.001), while fasting insulin concentration did not give any independent contribution to explain the variability uric acid levels. CONCLUSIONS: These data indicate that, already in young, essentially health subjects, hyperuricaemia associates with several components of the so-called insulin resistance syndrome, thus suggesting that increased levels of uric acid might be another member of this syndrome. In addition, these data suggest that obesity and central body fat distribution, rather than hyperinsulinaemia/insulin resistance, play a major role in linking hyperuricaemia with CVD risk factors clustering in the insulin resistance syndrome. Nevertheless, hypertrigliceridemia is related to hyperuricemia independently of obesity and central body fat distribution.

Cardiovascular risk profile in 38-year and 18-year-old men. Contribution of body fat content and regional fat distribution.

OBJECTIVE: To evaluate whether young and middle-age men differ in blood pressure and serum lipid profiles and, if so, to what extent these differences are dependent on total body fat, regional fat distribution, plasma insulin and behavioural variables. SUBJECTS: Random samples of 94 young (18 year-old) and 94 middle-age (38 year-old) healthy men matched for body mass index (BMI). MEASUREMENTS: BMI, total body fat (by bioelectrical impedance), regional fat distribution (by anthropometry), serum lipids, blood pressure, fasting insulin and some behavioural variables. RESULTS: Total body fat was similar in the two groups (mean +/- s.e.: 16.6 +/- 0.5 vs 16.0 +/- 0.6 kg and 20.8 +/- 0.5 vs 20 +/- 0.5%), while waist/hip circumference ratio (WHR) was significantly higher in middle-age as compared to young men (0.96 +/- 0.001 vs 0.92 +/- 0.003, P < 0.0001). The former also had significantly higher serum concentrations of total cholesterol (6.21 +/- 0.13 vs 4.10 +/- 0.10 mmol/l; P < 0.0001). LDL-cholesterol (4.24 +/- 0.11 vs 2.34 +/- 0.10 mmol/l; P < 0.0001), triglycerides 1.40 +/- 0.09 vs 1.02 +/- 0.06 mmol/l; P < 0.01) as well as higher systolic (134.0 +/- 1.6 vs 126.3 +/- 1.4 mmHg; P < 0.0001) and diastolic (86.8 +/- 0.9 vs 82.0 +/- 1.1 mmHg; P < 0.001) blood pressure values. HDL-cholesterol and fasting insulin concentrations were similar in the two groups (1.33 +/- 0.03 vs 1.28 +/- 0.03 mmol/l and 13.7 +/- 0.6 vs 14.7 +/- 0.7 mU/l, respectively). Significant differences in the two groups also were found in daily alcohol consumption (49.6 +/- 5.7 vs 20.0 +/- 3.4 g/day; P < 0.0001), whereas no significant differences were found in smoking and physical activity level. The comparison of subgroups (n = 41) of young and middle-age men matched for both BMI and WHR showed virtually unchanged differences in serum lipids and blood pressure. When age, BMI, WHR, fasting insulin and behavioural variables were included as independent variables in a multiple linear regression analysis in which subjects of the two groups were pooled, age was a significant predictor of total and LDL cholesterol, triglycerides and systolic blood pressure, insulin predicted HDL cholesterol and systolic blood pressure, BMI predicted triglycerides and diastolic blood pressure and WHR was not an independent predictor of any risk factor. CONCLUSIONS: These results indicate that middle-age men have a cardiovascular risk profile less favourable than young men, which is largely independent of differences in total body fat content, regional fat distribution and behavioural variables.

The Verona diabetes study: a population-based survey on known diabetes mellitus prevalence and 5-year all-cause mortality.

This population-based survey aimed to determine the prevalence of known diabetes mellitus on 31 December 1986, and to assess all-cause mortality in the subsequent 5 years (1987-1991) in Verona, Italy. In the study of prevalence, 5996 patients were identified by three independent sources: family physicians, diabetes clinics, and drug prescriptions for diabetes. Mortality was assessed by matching all death certificates of Verona in 1987-1991 with the diabetic cohort. Overall diabetes prevalence was 2.61% (95% confidence interval 2.56-2.67). Prevalence of insulin-dependent and non-insulin-dependent diabetes mellitus was 0.069% (0.059-0.078) and 2.49% (2.43-2.54), respectively. Diabetes prevalence sharply increased after age 35 years up to age 75-79, and finally declined. Prevalence was higher in men up to age 69 years, in women after age 75 years. Of the diabetic cohort 1260 patients (592 men, 668 women) died by 31 December 1991, yielding an overall standardized mortality ratio of 1.46 (CI 1.38-1.54). Even though the differences narrowed with age, mortality rates in the diabetic cohort were higher than in the non-diabetic population at all ages. Women aged 65-74 years showed observed/expected ratio higher than men (2.27, CI 1.92-2.66, vs 1.50, CI 1.30-1.72), while in other age groups the sex-related differences were not significant. Pharmacological treatment of diabetes was associated with an excess mortality, while treatment with diet alone showed an apparent protective effect on mortality (observed/expected ratio 0.73, CI 0.58-0.92).(ABSTRACT TRUNCATED AT 250 WORDS)

Mononuclear leukocytes from obese patients with type II diabetes have reduced activity of hexokinase, 6-phosphofructokinase and glucose-6-phosphate dehydrogenase.

In the present study we measured the activity of some cytosolic enzymes involved in intracellular glucose metabolism in mononuclear leukocytes from 77 obese subjects of which 39 were nondiabetic and 38 had newly-diagnosed untreated type II diabetes mellitus. 28 subjects (19 nondiabetic and 18 diabetic) had also a study of insulin binding to monocytes. 35 subjects (14 nondiabetic, 21 diabetic) underwent an insulin tolerance test for the evaluation of in vivo insulin action. Mononuclear leukocytes from diabetic obese patients showed significantly lower activities of hexokinase (HK), 6-phosphofructokinase (PFK) and glucose-6-phosphate dehydrogenase (G6PDH), while pyruvate kinase (PK) and 6-phosphogluconate dehydrogenase (6PGDH) activities were similar in the two groups. In the whole population HK and G6PDH activities inversely correlated with fasting and 2-h OGTT plasma glucose levels. Neither plasma insulin levels nor maximal specific insulin binding to monocytes were significantly correlated with any of the enzyme activities measured. Conversely, the parameter of insulin action generated by insulin tolerance test significantly correlated with HK, G6PDH and 6PGDH. These results indicate that in obese subjects the presence of diabetes is associated with a reduced activity of some enzymes of glucose metabolism in mononuclear leukocytes. This multiple enzymatic defect is correlated with the impairment of in vivo insulin action.

Influence of body fat and its regional localization on risk factors for atherosclerosis in young men.

A study was carried out in 1988 in Verona, Italy, to examine the relation of body fat and its localization to several risk factors for atherosclerosis in young men. Total body fat (bioelectrical impedance), waist and hip circumferences, and waist/hip circumference ratio were measured in 1,293 18-year-old men. Fasting serum levels of total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, and insulin, as well as systolic and diastolic blood pressure, were also measured. Significant differences were found in all metabolic and hemodynamic variables among quartiles of total body fat. Most of these differences remained significant after the authors controlled for the independent effect of fat localization and behavioral factors such as smoking, alcohol intake, and physical activity. Triglycerides, insulin, and blood pressure were significantly different among quartiles of waist/hip ratio, but these differences disappeared after the authors controlled for the independent effect of total body fat. These results indicate that in young men, irrespective of its regional localization, an excess of body fat is associated with a poor profile of risk for atherosclerosis. On the other hand, the prevalent localization of fat in the central part of the body is not independently associated with any risk factor.

Studies on the mechanism of action of sulphonylureas in type II diabetic subjects: gliquidone.

The mechanism of action of sulphonylureas is not completely understood. In the present study we evaluated the effects of gliquidone, a second-generation compound, on several metabolic parameters in 22 patients with untreated newly-diagnosed type II (noninsulin-dependent) diabetes mellitus. After either 1 or 6 months of treatment with gliquidone plus isocaloric diet we observed: 1) a significant decrease in fasting plasma glucose and glycemic profile after oral glucose load; 2) unchanged fasting and postglucose plasma insulin levels; 3) no change in fasting C-peptide levels but a significant increase in C-peptide concentrations after glucose challenge; 4) a significant increase in glucose disappearance rate from plasma following iv insulin injection; 5) an increase in the insulin-induced reduction of plasma levels of free-fatty acids; 6) no change in plasma C-peptide levels following iv insulin injection; 7) a significant increase in specific insulin binding to monocytes. After 6 but not 1 month of gliquidone therapy we also found an increase in the activity of hexokinase in circulating mononuclear leukocytes. These results suggest that the hypoglycemic effect of gliquidone occurs through either an increased beta cell response to glucose stimulus or an enhanced insulin sensitivity. The latter effect seems to depend on both receptor and postreceptor mechanisms.

Normal inhibition by somatostatin of glucose-stimulated B cell secretion in the obese subjects.

Aim of the present study was to evaluate whether the inhibitory effect of somatostatin on pancreatic B-cell secretion is normal in nondiabetic obese subjects. For this purpose plasma C-peptide concentrations were measured in 10 nondiabetic obese subjects and 10 nonobese healthy controls during a 4-h hyperglycemic (11 mmol/l) glucose clamp. Somatostatin was infused (2.5 nmol/min) during the third hour of the study period in order to inhibit glucose-stimulated B-cell secretion. Fasting C-peptide averaged 0.46 +/- 0.04 nmol/l (mean +/- SEM) in nonobese subjects, and 0.85 +/- 0.08 nmol/l in obese patients (P less than 0.001). In the period 0-120 min the area under the plasma C-peptide curve was significantly higher in obese than in nonobese subjects (292 +/- 23 vs. 230 +/- 17 nmol/l x 120 min, P less than 0.05), however, in the last 20 min of the glucose infusion period without somatostatin (100-120 min) plasma C-peptide was not significantly different in the two groups (2.94 +/- 0.32 nmol/l in nonobese subjects and 3.21 +/- 0.19 nmol/l in obese patients, p = NS). During somatostatin infusion while maintaining hyperglycemia, plasma C-peptide decreased in both groups, and in the period 160-180 min it averaged 0.89 +/- 0.12 nmol/l in control subjects and 0.93 +/- 0.08 nmol/l in obese patients (P = NS), with a percent reduction similar in the two groups (70 +/- 2% in controls and 71 +/- 2% in obese patients). After discontinuing somatostatin infusion, plasma C-peptide increased to concentrations which were higher in obese than in nonobese subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma concentrations of glucagon during hyperglycemic clamp with or without somatostatin infusion in obese subjects.

The aim of the present study was to evaluate whether the inhibitory effect on pancreatic A-cell exerted by hyperglycemic hyperinsulinemia and/or by somatostatin administration is impaired in human obesity. For this purpose plasma glucagon concentrations were measured in 8 obese and 8 nonobese nondiabetic subjects during a 4-h hyperglycemic clamp. Synthetic cyclic somatostatin-14 was infused at the rate of 2.5 nmol/min during the third hour of the study. Fasting plasma glucagon was higher in obese than in nonobese subjects (242 +/- 32 vs 163 +/- 15 pg/ml, p less than 0.05) (mean +/- SEM). In the last 20 min of the glucose infusion period preceding somatostatin administration (100-120 min of the study) plasma glucagon averaged 195 +/- 26 pg/ml in obese and 122 +/- 13 pg/ml in nonobese subjects (p less than 0.05), with a reduction of 19 +/- 3% in the former and 28 +/- 4% in the latter (p = n.s.). In both groups somatostatin infusion did not result in a further decrease in plasma glucagon, which averaged 192 +/- 27 pg/ml in obese and 123 +/- 16 pg/ml in nonobese subjects (p less than 0.05) in the 160-180 min period of the study. Also after discontinuing somatostatin infusion plasma glucagon levels did not change. These results suggest that in human obesity hyperglycemic hyperinsulinemia has a normal inhibitory effect on pancreatic A-cell and that somatostatin administration has no additive effect on hyperglycemia and hyperinsulinemia in either obese or nonobese nondiabetic subjects.

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)

Plasma C-peptide response to oral glucose load in hyperthyroidism.

Aim of the present study was to evaluate the pancreatic beta cell response to oral glucose load in a group of patients with hyperthyroidism. For this purpose plasma C-peptide at fasting and after a 100 g oral glucose load was measured in 8 newly-diagnosed untreated hyperthyroid patients with fasting normoglycemia, and 8 sex-, age-, and weight-matched healthy controls. As compared to healthy subjects, patients with hyperthyroidism showed higher plasma glucose levels (incremental area 5405 +/- 742 vs 2729 +/- 539 mg/dl x 180 min, p less than 0.05), and slightly reduced plasma C-peptide concentrations (incremental area 166 +/- 12 vs 182 +/- 36 pmol/ml x 180 min, p = NS) following oral glucose load. The ratios between plasma C-peptide and plasma glucose incremental areas were lower in hyperthyroid patients than in controls (3.66 +/- 0.85 vs 10.41 +/- 3.08, p less than 0.05). These data suggest that hyperthyroidism is characterized by a decreased pancreatic beta cell response to oral glucose load.

Plasma concentrations of growth hormone during hyperglycemic clamp with or without somatostatin infusion in obese subjects.

It is known that obese subjects have a blunted GH secretory response to stimulation, but little is known about the inhibition of GH secretion in obesity. The present study was designed to evaluate the effects of obesity on the suppression of GH by hyperglycemia and/or somatostatin. Plasma GH concentrations were measured in eight nondiabetic obese subjects and eight nonobese healthy controls during a 4-h hyperglycemic clamp. During the third hour synthetic cyclic somatostatin-14 was infused at the rate of 2.5 nmol/min. Baseline plasma GH levels were similar in obese and nonobese subjects (0.9 +/- 0.1 vs. 0.8 +/- 0.2 micrograms/L; mean +/- SEM). In the last 20 min of the glucose infusion period preceding somatostatin administration (100-120 min of the study) plasma GH averaged 0.8 +/- 0.1 micrograms/L in obese patients and 0.4 +/- 0.1 micrograms/L in control subjects (P less than 0.01), with a reduction of 6 +/- 5% in the former and 35 +/- 10% in the latter (P less than 0.01). In both groups somatostatin infusion did not result in a further decrease in plasma GH. Discontinuation of the somatostatin infusion resulted in a rise in both groups; the increase was higher in nonobese subjects (8.1 +/- 3.8 vs. 2.3 +/- 0.9 micrograms/L in the period 220-240 min; P = NS). These results suggest that in human obesity, hyperglycemia has a diminished inhibitory effect on GH secretion, and somatostatin administration has no additional effect in either obese or nonobese nondiabetic subjects.