A multicenter observational study on the management of hyperglycemia in patients with acute coronary syndrome.

AIM: To assess the prevalence, risk and management of hyperglycemia in patients with acute coronary syndrome (ACS). DESIGN: a multicenter prospective observational study of a representative sample of patients with ACS consecutively admitted to intensive cardiac care units (ICCU). SETTING: 31 out of 61 ICCUs in Lombardy, the most heavily populated Italian region. From May 2009 to April 2010 1260 patients (69.4% male; mean age 68 ± 13 years) were included in the study: 301 (23.9%) were known diabetic patients (D) and 265 (21.0%) had hyperglycemia (H) (blood glucose >180 mg/dL) at hospital admission, 174 with a history of diabetes (D+H+) and 91 without (D-H+). On the first day after admission intravenous insulin infusion was prescribed to 72 D+H+ (41.4%) and 10 D-H+ (11.0%), according to different protocols. Approximately one third of D+H+ patients (59) and one fifth (17) of D-H+ maintained mean blood glucose higher than 180 mg/dL during the first day in the ICCU. Patients with diabetes or hyperglycemia had a higher incidence of major adverse cardiovascular events or death in hospital. However, at multivariable analysis neither diabetes nor blood glucose at admission was associated with a poor prognosis whereas mean blood glucose on the first day was an independent negative prognostic predictor (OR 1.010, 95% CI 1.002-1.018, p = 0.016). CONCLUSION: Hyperglycemia is frequent in patients with ACS and is independently associated with a poor in-hospital prognosis if it persists in first day. Unfortunately, however, this condition is still poorly treated, with far from optimal blood glucose control.

Effect of a long-term oral l-arginine supplementation on glucose metabolism: a randomized, double-blind, placebo-controlled trial.

AIM: This study assessed the efficacy of long-term l-arginine (l-arg) therapy in preventing or delaying type 2 diabetes mellitus. METHODS: A mono-centre, randomized, double-blind, parallel-group, placebo-controlled, phase III trial (l-arg trial) was conducted on 144 individuals affected by impaired glucose tolerance (IGT) and metabolic syndrome (MS). l-Arg/placebo was administered (6.4 g/day) on a background structured lifestyle intervention for 18 months plus a 12-month extended follow-up period after study drug termination. Fasting glucose levels and glucose tolerance after oral glucose tolerance test were evaluated throughout the study. RESULTS: After 18 months, l-arg as compared with placebo did not reduce the cumulative incidence of diabetes [21.4 and 20.8%, respectively, hazard ratio (HR), 1.04; 95% confidence interval (CI), 0.58-1.86] while the cumulative probability to become normal glucose tolerant (NGT) increased (42.4 and 22.1%, respectively, HR, 2.60; 95% CI, 1.51-4.46, p < 0.001). The higher cumulative probability to become of NGT was maintained during the extended period in subjects previously treated with l-arg (HR, 3.21; 95% CI, 1.87-5.51; p < 0.001). At the end of the extended period, the cumulative incidence of diabetes in subjects previously treated with l-arg was reduced as compared with placebo (27.2 and 47.1%, respectively, HR, 0.42; 95% CI, 0.24-0.75, p < 0.05). During both periods, l-arg significantly improved insulin sensitivity and ß-cell function. CONCLUSION: Among persons with IGT and MS, the supplementation of l-arg for 18 months does not significantly reduce the incidence of diabetes but does significantly increase regression to NGT.

Food selection based on high total antioxidant capacity improves endothelial function in a low cardiovascular risk population.

BACKGROUND AND AIMS: Oxidative stress has been advocated as a major cause for cardiovascular disease (CVD), and low plasma antioxidant concentrations are associated with endothelial dysfunction, the first step towards atherosclerosis. However, although the antioxidant content in fruits and vegetables may explain at least in part their protective effect against CVD, supplementation with antioxidant vitamins fails to improve endothelial function and reduce CVD risk. The aim of this study was to investigate the impact of a diet rich in antioxidants on endothelial function measured by flow-mediated dilatation (FMD) in volunteers at low cardiovascular risk. METHODS AND RESULTS: In a crossover trial, 24 subjects (13 women, mean age 61 ± 3 years), received, in a randomised order, a 14-day high (HT) and a 14-day low (LT) antioxidant diets, with a 2-week wash-out (WO) in between. Both diets were comparable in daily portions of fruits and vegetables, and in alcohol, fibre and macronutrient intake, but differed in their total antioxidant capacity. Before and after each diet, anthropometrics, blood pressure, fasting plasma glucose, lipid profile, hepatic enzymes, circulating antioxidant concentrations, high sensitivity C-reactive protein (hs-CRP) and FMD were assessed. FMD increased significantly during the HT diet compared to the LT (p < 0.000). FMD values were 2.3% higher after HT compared with LT (p < 0.001) after adjustment for age, gender and diet order. α-tocopherol increased significantly (p < 0.05) and hs-CRP and of γ-glutamyltranspeptidase decreased significantly (p < 0.05 and p < 0.01, respectively) during the HT diet, compared with the LT diet. CONCLUSIONS: A short-term HT diet improves endothelial function in volunteers at low cardiovascular risk, which may further reduce their risk of CVD.

Effects of chronic elevation of atrial natriuretic peptide and free fatty acid levels in the induction of type 2 diabetes mellitus and insulin resistance in patients with mitral valve disease.

BACKGROUND AND AIMS: The relationship between atrial natriuretic peptide (ANP), increased free fatty acid (FFA) and insulin resistance in patients with mitral valve disease (MVD), a group characterised by elevated atrial pressure and increased ANP levels, is not defined. The present study was performed to evaluate, in MVD patients, the relationship between increased ANP and FFA levels and insulin resistance and the role of mitral valve replacement/repair in ameliorating these metabolic alterations. Conversely, coronary heart disease (CHD) patients were evaluated before and after coronary artery bypass grafting (CABG), since they are known to be insulin resistant in the presence of chronic FFA increase. METHODS AND RESULTS: Fifty MVD patients and 55 CHD patients were studied before and 2 months after surgery and compared with 166 normal subjects. Before surgery, 56% of MVD patients had impaired glucose tolerance or newly diagnosed type 2 diabetes after a standard oral glucose load and this percentage decreased to 46% after surgery. In CHD, impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetic patients were 67% of patients before and after CABG. In MVD, left atrial (LA) volume, ANP, FFA incremental area and insulin levels were higher and Insulin Sensitivity (IS) index significantly reduced while after surgery, LA volume, ANP and FFA significantly decreased and IS index significantly improved. In CHD, insulin resistance and hyperinsulinaemia were present both before and after surgery with increased tumour necrosis factor (TNF)-α and interleukin (IL)-6 levels. CONCLUSION: In MVD, a higher degree of abnormal glucose tolerance and insulin resistance are associated to increased levels of ANP and FFA, while these metabolic alterations are improved by mitral valve replacement/repair surgery. Clinical Trial.gov registration number NCT 00520962.

Consensus on: Screening and therapy of coronary heart disease in diabetic patients.

The screening and best treatment for coronary heart disease in diabetic patients is still a matter of debate. For this reason the main Italian scientific societies dealing with diabetes and cardiovascular diseases have tried to finalize a document providing shared recommendations based on the available evidence on : 1) how and who to screen for coronary heart disease, 2) methodologies for the characterization of existing coronary heart disease 3) evaluation of the optimal treatment of cardiovascular risk factors and 4) appropriate revascularization procedures. For each of these points, the levels of evidence and strength of recommendations used in the Italian Standard of Care were adopted.

Intake of the plant lignans matairesinol, secoisolariciresinol, pinoresinol, and lariciresinol in relation to vascular inflammation and endothelial dysfunction in middle age-elderly men and post-menopausal women living in Northern Italy.

BACKGROUND AND AIMS: It has been suggested that lignan intake may decrease the risk for cardiovascular disease (CVD) by modifying traditional risk factors as well as aortic stiffness. However, the role of dietary lignans on the vascular system is largely unknown. The objective was to investigate whether dietary intake of plant lignans in a free-living population was associated with markers of vascular inflammation and function. METHODS AND RESULTS: We performed a cross-sectional study in 242 (151 males) men and post-menopausal women. Anthropometric characteristics and lignan intake were evaluated. Soluble intercellular adhesion molecule-1 (sICAM-1), insulin, high-sensitive C-reactive protein, glucose, total cholesterol, HDL-cholesterol and triacylglycerols were measured in fasting blood samples. Brachial flow-mediated dilation (FMD) measurements were available for 101 subjects (56 males). Median (interquartile range) daily intake of matairesinol (MAT), secoisolariciresinol (SECO), pinoresinol (PINO), lariciresinol (LARI), and total lignans was 20.9 microg (17.4), 335.3 microg (289.1), 96.7 microg (91.1), 175.7 microg (135.8), and 665.5 microg (413.7), respectively, as assessed by 3-day weighed food record. Plasma concentrations of sICAM-1 (whole sample) significantly decreased (mean (95%CI) = 358 microg/L (320-401), 276 microg/L (252-303), 298 microg/L (271-326), and 269 microg/L (239-303), P per trend 0.013) and FMD values (FMD sub-group) significantly increased (4.1% (2.2-6.0), 5.7% (4.3-7.2), 6.4% (4.9-7.8), and 8.1% (6.3-10.0), P per trend 0.016) across quartiles of energy-adjusted MAT intake, even after adjustment for relevant clinical and dietary variables. Intake of SECO was also inversely related to plasma sICAM-1 (P per trend 0.018), but not to FMD values. No relationship between intake of PINO, LARI or total lignans and either sICAM-1 or FMD values was observed. CONCLUSIONS: Higher MAT intakes in the context of a typical Northern Italian diet are associated to lower vascular inflammation and endothelial dysfunction, which could have some implications in CVD prevention.

Beneficial role of L-arginine in cardiac matrix remodelling in insulin resistant rats.

BACKGROUND: The study was performed to determine whether sucrose-induced insulin resistance could increase the expression of cardiac matrix metalloproteinases (MMPs), indices of matrix remodelling, and whether the addition of 1.25 g day(-1) of L-arginine (ARG) to a sucrose diet could prevent both the sucrose-induced metabolic abnormalities and elevated cardiac expression of matrix metalloproteinases in an insulin resistant stage that precedes frank type 2 diabetes. MATERIALS AND METHODS: Experiments were performed on 38 male Sprague-Dawley rats, 16 rats maintained a standard chow diet (ST), 12 rats were switched to a sucrose enriched diet (SU) and 10 rats to a sucrose plus L-arginine (1.25 g day(-1)) enriched diet (SU + ARG) for a period of 8 weeks. After 8 weeks of different diets, an intravenous glucose tolerance test (IVGTT) was performed and samples were drawn for the measurements of insulin, glucose, triglycerides, free fatty acids (FFA), plasma cyclic guanosine-monophosphate (c-GMP) and retroperitoneal, omental, epididymal fat pad and heart were dissected and weighed. RESULTS: At the end of the study, retroperitoneal fat, heart weight/body weight ratio, fasting plasma glucose, serum insulin, and serum triglyceride levels and integrated insulin area after IVGTT were significantly higher in SU than in SU + ARG and ST. All these parameters were comparable between SU + ARG and ST animals. FFA levels were significantly different among groups, with highest levels in SU and lowest levels in ST. Fasting plasma c-GMP levels and the integrated c-GMP area after IVGTT, an index of nitric oxide activity, were significantly lower in SU than in SU + ARG and ST, the result was similar in SU + ARG and in ST MMP-9 protein expression increased 10.5-fold, MMP-2 protein expression increased 2.4-fold and the expression of tissue inhibitors of metalloproteinase (TIMP-1) increased 1.7-fold in SU rats as compared to ST animals. This was accompanied with a significant increase of cardiac triglyceride concentrations. In contrast, cardiac MMP-9, MMP-2, and TIMP-1 protein expressions were not different between SU + ARG and ST animals. Cardiac triglyceride levels were not significantly different between SU + ARG and ST rats. CONCLUSIONS: SU rats developed insulin resistance and hyperlipidaemia, accompanied with increased fat deposition in the heart and enhanced MMP protein expression. Conversely, ARG supplementation prevents these metabolic abnormalities and restored MMP/TIMP-1 balance.

The total antioxidant capacity of the diet is an independent predictor of plasma beta-carotene.

OBJECTIVE: To investigate the contribution of the total antioxidant capacity (TAC) of the diet to plasma concentrations of beta-carotene. DESIGN: Cross-sectional study. SETTING: Department of Public Health and Department of Internal Medicine and Biomedical Sciences, University of Parma. SUBJECTS: A total of 247 apparently healthy adult men (n=140) and women (n=107). METHODS: A medical history, a physical exam including height, weight, waist circumference and blood pressure measurements, a fasting blood draw, an oral glucose tolerance test and a 3-day food record. RESULTS: We observe a negative trend across quartiles of plasma beta-carotene for most biological variables clustering in the insulin resistance syndrome, as well as for traditional and new risk factors for type II diabetes and cardiovascular disease (CVD), including C-reactive protein and gamma-glutamyltranspeptidase (P<0.05). Regarding dietary characteristics, energy-adjusted intake of fat, fiber, fruits, vegetables, beta-carotene, vitamin C, vitamin E and dietary TAC significantly increased with increasing plasma beta-carotene (P<0.05), whereas alcohol intake decreased (P=0.013). Adjusted geometric means (95% confidence interval) of plasma beta-carotene significantly increased across quartiles of dietary TAC, even when single dietary antioxidants were considered in the model (QI=0.087 mg/dl (0.073-0.102); QII=0.087 mg/dl (0.075-0.103); QIII=0.114 mg/dl (0.098-0.132) and QIV=0.110 mg/dl (0.093-0.130); P for linear trend=0.026). When the population was divided on the basis of alcohol consumption, this trend was also observed in subjects drinking <20 g alcohol/day (P=0.034), but not in those with higher alcohol intake (P=0.448). CONCLUSIONS: Dietary TAC is an independent predictor of plasma beta-carotene, especially in moderate alcohol drinkers. This may explain, at least in part, the inverse relationship observed between plasma beta-carotene and risk of chronic diseases associated to high levels of oxidative stress (i.e., diabetes and CVD), as well as the failure of beta-carotene supplements alone in reducing such risk.

Basal insulin therapy is associated with beneficial effects on postoperative infective complications, independently from circulating glucose levels in patients admitted for cardiac surgery.

BACKGROUND: Although hyperglycemia is a strong predictor of postoperative infective complications (PIC), little is known about the effect of basal insulin therapy (BIT) per se on PIC. AIM: To evaluate if there is an association between BIT, independent of glucose levels, and a possible improvement of PIC during the perioperative cardiosurgery period (PCP). METHODS: In 812 patients admitted for cardiac intervention and treated with a continuous intravenous insulin infusion (CIII) for hyperglycemic levels (>130 mg/dl), a retrospective analysis was performed during the PCP (January 2009-December 2011). Upon transfer to the cardiac surgery division, if fasting glucose was ≥130 mg/dl, a basal + premeal insulin therapy was initiated (121 patients, group 1); for <130 mg/dl, a premeal insulin alone was initiated (691 patients, group 2). FINDINGS: Compared with group 2, group 1 showed reductions in PIC (2.48% vs 7.96%, p < 0.049; odds ratio: 0.294; 95% CI: 0.110-0.780), C-Reactive Protein (p < 0.05) and white blood cell (p < 0.05) levels despite glucose levels and CIII that were higher during the first two days after surgery (179.8 ± 25.3 vs 169.5 ± 10.6 mg/dl, p < 0.01; 0.046 ± 0.008 vs 0.037 ± 0.015 U/kg/h, p < 0.05, respectively). Normal glucose levels were achieved in both groups from day 3 before the discharge. The mean length of hospital duration was 18% lower in group 1 than in group 2 (7.21 ± 05.08 vs 8.76 ± 9.08 days, p < 0.007), providing a significant impact on public health costs. CONCLUSIONS: Basal + preprandial insulin therapy was associated with a lower frequency of PIC than preprandial insulin therapy alone, suggesting a beneficial effect of basal insulin therapy on post-surgery outcome.

Hyperinsulinemia decreases second-phase but not first-phase arginine-induced insulin release in humans.

The aim of this study was to investigate the effect of hyperinsulinemia on the first and second phase of arginine-induced insulin release in humans. Seven healthy subjects underwent three studies (lasting 360 min): a control study using saline infusion and two euglycemic clamps using a low-dose (0.33 mU.kg-1.min-1) and a high-dose (1.20 mU.kg-1.min-1) insulin infusion. After a 3-h equilibration period, arginine (25 g) was infused for 30 min, and insulin and C-peptide responses to arginine were followed for 180 min. At the end of the equilibration period, before arginine administration, steady-state insulin levels were (means +/- SE) 60.0 +/- 2.4, 165.6 +/- 1.8, and 455.4 +/- 7.8 pmol/l during saline, low-dose, and high-dose insulin infusions, respectively. The time course of insulin release during the arginine test was calculated from C-peptide concentrations by using C-peptide kinetic modeling and deconvolution. In particular, first-phase and second-phase insulin response was obtained by integrating the time course of the insulin release during either the first 5 min or the following 40 min of the arginine test, respectively. Whereas first-phase insulin release was independent of any effect induced by either insulin infusion, second-phase insulin release was reduced in a similar degree by both insulin infusion doses. First phase was 75.5 +/- 10.1, 73.7 +/- 12.8, and 73.4 +/- 10.3 pmol/kg, whereas second phase was 266.1 +/- 46.0, 143.1 +/- 33.5, and 133.0 +/- 30.2 pmol/kg for saline, low-dose, and high-dose insulin infusions, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertriglyceridemia and hyperinsulinemia are potent inducers of endothelin-1 release in humans.

The purpose of the study was to evaluate fasting endothelin-1 levels in subjects with syndrome X, in subjects with insulinoma, and in normal subjects. The single and synergistic contributions of insulin and triglyceride levels to endothelin-1 release were studied in normal subjects. This was achieved by the evaluation of endothelin-1 levels in response to an insulin bolus combined with a euglycemic clamp (protocol A) and during intralipid (test 1) or saline (test 2) infusions lasting 360 min (protocol B). In protocol B, a euglycemic two-step hyperinsulinemic (25 and 125 mU x kg-1 x h-1) clamp was started at 120 min. Subjects with syndrome X showed significantly higher endothelin-1 levels than normal subjects and subjects with insulinoma (7.22 +/- 0.89 vs. 2.61 +/- 0.38 and 2.49 +/- 0.24 pg/ml, P < 0.01). After an insulin bolus, endothelin-1 levels peaked at 10 min (3.71 +/- 0.96 pg/ml). The incremental area of endothelin-1 was significantly higher after insulin than after a saline bolus. In test 1, an acute increase in triglyceride levels significantly enhanced endothelin-1 levels, with were further increased by the synergistic contribution of high insulin and triglyceride levels. In test 2, endothelin-1 release was achieved at high insulin levels but remained significantly lower than in test 1. In conclusion, subjects with syndrome X showed higher endothelin-1 levels than normal subjects and subjects with insulinoma. These levels were reproduced in normal subjects by a simultaneous increase in insulin and triglyceride levels.

Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients.

UNLABELLED: The aim of this study was to evaluate whether long-term administration of arginine acting through a normalization of NO/cyclic-guanosine-3' 5'-cyclic monophosphate (cGMP) pathway was able to ameliorate peripheral and hepatic insulin sensitivity in 12 lean type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A double-blind study was performed for 3 months. In the first month, patients were treated with their usual diet. Then they were randomly allocated into to groups. In group 1, patients were treated with diet plus placebo (orally three times per day) for 2 months. In group 2 patients were treated for 1 month with diet plus placebo orally, three times per day) and then for 1 month with diet plus L-arginine (3 g three times per day). At the end of the first and the second month of therapy, patients underwent a euglycemic-hyperinsulinemic clamp combined with [6,6-2H2] glucose infusion. A total of 10 normal subjects underwent the same test as control subjects. RESULTS: In group 1, no changes in basal cGMP levels, systolic blood pressure, forearm blood flow, glucose disposal, and endogenous glucose production were observed throughout. In group 2, L-arginine normalized basal cGMP levels and significantly increased forearm blood flow by 36% and glucose disposal during the clamp by 34% whereas it decreased systolic blood pressure and endogenous glucose production by 14 and 29%, respectively. However, compared with normal subjects, L-arginine treatment was not able to completely overcome the defect in glucose disposal. CONCLUSIONS: L-Arginine treatment significantly improves but does not completely normalizc peripheral and hepatic insulin sensitivity in type 2 diabetic patients.

Benfluorex in obese noninsulin dependent diabetes mellitus patients poorly controlled by insulin: a double blind study versus placebo.

Most obese patients with noninsulin-dependent diabetes mellitus (NIDDM) are initially treated with diet, then with oral hypoglycemic agents, eventually with insulin. However several reports indicate that in these patients insulin therapy has little chance to control glucose metabolism, promotes weight gain and arterial hypertension, and is likely to aggravate insulin resistance. In this randomized, double-blind trial vs. placebo (P) we evaluated in 29 obese NIDDM patients poorly controlled by insulin (daily insulin doses 48.7 +/- 4.0 U/day, HbA1c 10 +/- 0.27%, mean daily blood glucose levels 12.3 +/- 0.3 mmol/L, fasting C-peptide 1.8 +/- 0.2, C-peptide after 1 mg iv glucagon 3.2 +/- 0.3 ng/mL, means +/- SE), the clinical and metabolic effects of benfluorex (B), a lipid-lowering drug able to improve insulin sensitivity. After a 2-3 week run-in period (1 tablet P at dinner and diet 800 cal/day to lose 5% of the initial body weight (BWi), patients received a 1000 kcal/day diet and were randomized to B, 150 mg/ tablet, or P (3 tablets/day); the time limit was set at a 10% decrease of BWi or at 90 days. At the end of run-in there was a significant reduction of BWi (P < 0.001), fasting (P = 0.002) and mean daily blood glucose levels (P < 0.001), triglycerides (P = 0.02), cholesterol (P < 0.001) and daily insulin doses (P < 0.001). At the end of the double-blind trial, weight-loss was greater (P < 0.05), faster (P = 0.018), and more frequent (P < 0.05) with B than with P, and systolic blood pressure (P < 0.05) decreased only with B. Considering only patients with a 10% decrease of BWi (B = 15, P = 10), HbA1c (P < 0.001) decreased only with B, while fasting insulin levels decreased with both B (P < 0.01) and with P (P < 0.05). Insulin sensitivity was evaluated by means of a double infusion test (LDIGIT, insulin 25 mU/Kg/h plus glucose 4 mg/kg/min, lasting 150 min) at the end of run-in and at the end of the double-blind trial; at the end of the double-blind trial steady state blood glucose (SSBG, P < 0.05), free fatty acids (FFA, P < 0.05) and blood beta-hydroxybutyrate (P < 0.05) decreased only with B, while blood glycerol decreased both with both P (P < 0.05) and B (P < 0.06). At the end of the double-blind trial, C-peptide release was unchanged with either P or B. In conclusion, benfluorex potentiates the effects of hypocaloric diet on weight loss and on glycemic control in obese NIDDM patients treated with insulin, and this effect seems to be the result of an improved insulin sensitivity.

The continuous low dose insulin and glucose infusion test: a simplified and accurate method for the evaluation of insulin sensitivity and insulin secretion in population studies.

In this study we investigated a simple nonlabor-intensive method to evaluate insulin sensitivity and beta-cell function which is suitable for application in population studies. The method is a refinement of the modified Harano test and consists of a continuous low dose insulin (25 mU/kg.h) and glucose (4 mg/kg.min) infusion test (LDIGIT) lasting 150 min. Insulin sensitivity was evaluated as the MCR of glucose divided by the steady state serum insulin level achieved at the end of the test. Insulin secretion was expressed as the incremental area for C-peptide concentration during the first 15 min of the test. We compared the indices of insulin sensitivity and insulin secretion yielded by LDIGIT with those derived from the euglycemic clamp and the hyperglycemic clamp, respectively. Fifty-four subjects underwent a LDIGIT (33 with normal glucose tolerance and 21 with impaired glucose tolerance); of the 54, 19 were submitted to a euglycemic clamp, 18 to a hyperglycemic clamp, and 10 to a modified Harano test (insulin infusion, 50 mU/kg.h; glucose infusion, 6 mg/kg.min). LDIGIT overcame the drawbacks associated with the modified Harano test because it resulted in more stable final glucose levels and prevented the occurrence of hypoglycemic episodes. No significant differences were found between the insulin sensitivity index (ISI) of the LDIGIT and that of the euglycemic clamp for each group of subjects. Moreover, there was a strong correlation between the ISI determined by LDIGIT and the ISI determined by clamp (r = 0.90; P < 0.0001), and the best regression line was not different from the identity line, suggesting that the two indices are equivalent. The index of insulin secretion provided by LDIGIT correlated well with that of the hyperglycemic clamp (r = 0.82; P < 0.001) and was significantly higher in overweight subjects than in normal weight subjects. In conclusion, LDIGIT is a simple and accurate method to assess insulin sensitivity and secretion. It can be useful in population studies and in situations when more complex techniques are not feasible.

Mediation of the hepatic effects of growth hormone by its lipolytic activity.

The aim of the study was to investigate the acute effect of GH per se, independent from its lipolytic activity, on glucose and lipid oxidation and glucose turnover in seven healthy subjects. Five tests lasting 360 min were performed. Each test consisted of a 4-h equilibration period followed by a euglycemic hyperinsulinemic (25 mU/kg x h) clamp lasting 2 h. In test 1 (control experiment) saline was infused, leaving GH and FFA at basal levels. In tests 2, 3, and 4, GH was infused (80 ng/kg x min) to increase GH levels. Whereas in test 2 FFA levels were free to increase due to GH lipolytic activity, in test 3 FFA elevation was prevented by using an antilipolytic compound (Acipimox) that allowed evaluation of the effect of GH at low FFA levels. In test 4 (GH+Acipimox+heparin) GH infusion was associated with the administration of Acipimox and heparin to maintain FFA at the basal level to evaluate the effect of GH per se independent from GH lipolytic activity. In test 5 Acipimox and a variable heparin infusion were given to evaluate possible effects of Acipimox other than the inhibition of lipolysis. During the euglycemic hyperinsulinemic clamp in the presence of high GH and FFA levels (test 2), glucose oxidation was significantly lower and lipid oxidation was significantly higher than in tests 1, 3, 4, and 5. During the same period, hepatic glucose production was completely suppressed in the control study (test 1; 94%) and in test 5 (99.6%), whereas it was significantly less inhibited (65%, 74%, and 73%) when GH was administered in tests 2, 3, and 4. In conclusion, these results suggest that GH directly mediates the reduction of insulin's effect on the liver. In addition, the effect of GH on glucose and lipid oxidation is not direct, but is mediated by its lipolytic activity.

Alterations in nitric oxide/cyclic-GMP pathway in nondiabetic siblings of patients with type 2 diabetes.

In this study, we have compared resistance to insulin-mediated glucose disposal and plasma concentrations of nitric oxide (NO) and cyclic-GMP in healthy volunteers with (n = 35) or without (n = 27) at least one sibling and one parent with type 2 diabetes. The 62 volunteers were further divided into groups of those with normal glucose tolerance or impaired glucose tolerance. Insulin-mediated glucose disposal was quantified by determining the insulin sensitivity index (ISI) in response to a low-dose, constant infusion of insulin (25 mU/kg x h) and glucose (4 mg/kg x min) for 150 min. The mean (+/-SEM) ISI [(mL kg(-1) min(-1)/pmol/L) x 10(3)] was significantly greater in those without a family history (30.3 +/- 2.3) as compared with nondiabetic volunteers with a family history of type 2 diabetes, whether they had normal glucose tolerance (17.0 +/- 7.2) or impaired glucose tolerance (9.5 +/- 1.4). In addition, basal NO levels, evaluated by the measurement of its stable end products [i.e. nitrite and nitrate levels (NO2-/ NO3-)], were significantly higher, and cyclic-GMP levels, its effector messenger, were significantly lower in those with a family history, irrespective of their degree of glucose tolerance, when compared with healthy volunteers without a family history of type 2 diabetes. Furthermore, when the 62 volunteers were analyzed as one group, there was a negative correlation between ISI and NO2-/NO3- levels (r = -0.35; P < 0.005) and a positive correlation between ISI and cyclic-GMP levels (r = 0.30; P < 0.02). These results have shown that alterations of the NO/cyclic-GMP pathway seem to be an early event in nondiabetic individuals with a family history of type 2 diabetes and these changes are correlated with the degree of insulin resistance.

In middle-aged siblings of patients with type 2 diabetes mellitus normal glucose tolerance is associated with insulin resistance and with increased insulin secretion. The SPIDER study.

OBJECTIVES: To evaluate the frequency of impaired glucose tolerance (IGT) and of Type 2 diabetes mellitus (Type 2 DM) in siblings of patients with Type 2 DM, and to assess insulin release and insulin sensitivity in siblings with normal glucose tolerance (NGT), compared with NGT spouses of probands without family history of Type 2 DM. DESIGN AND METHODS: We evaluated 87 families including 103 Type 2 DM patients (87 probands), and we carried out an oral glucose tolerance test (OGTT) in 130 siblings and in 60 spouses. Among NGT subjects, 12 siblings and 16 spouses underwent a low-dose insulin-glucose infusion test (LDIGIT) to evaluate C-peptide release and insulin sensitivity. RESULTS: After the OGTT, 24 siblings were classified as having Type 2 DM, 31 as IGT, and only 14 spouses as IGT (P=0.0012 vs siblings). NGT siblings (n=75) showed higher insulin levels at 120 min than NGT spouses (n=46) at OGTT, in spite of identical blood glucose levels; at LDIGIT, NGT siblings secreted more C-peptide and showed a lower insulin sensitivity than NGT spouses. CONCLUSIONS: These data indicate that middle-aged siblings of probands with Type 2 DM have a high frequency of IGT and Type 2 DM, and that NGT siblings have increased insulin resistance and increased insulin secretion when compared with adequate controls.

Forearm insulin- and non-insulin-mediated glucose uptake and muscle metabolism in man: role of free fatty acids and blood glucose levels.

Muscle can utilize glucose by two different mechanisms, one non-insulin-mediated and the other insulin-mediated. The aim of this study was to investigate and to quantify the influence of high and low free fatty acids (FFA) levels on muscle non-insulin-mediated glucose uptake (MNIMGU) and muscle insulin-mediated glucose uptake (MIMGU) and on muscle metabolism during euglycemia and hyperglycemia. Six healthy volunteers were submitted, in a random order, to a 2-hour euglycemic clamp (EC) followed by a 2-hour hyperglycemic (11 mmol/L) clamp (HC) under five different conditions: (1) somatostatin infusion (SRIF, 500 micrograms/h); (2) SRIF infusion preceded by a nicotinic acid analogue (acipimox, 250 mg orally, (3) SRIF plus insulin infusion; (4) SRIF plus insulin plus intralipid infusion; and (5) SRIF plus insulin infusion plus acipimox. In the postabsorptive state MNIMGU represented 71% of the total muscle glucose uptake (MGU) and during the EC a sharp reduction of FFA levels increased the MNIMGU by 10% (P less than .05), and an acute increase in FFA levels decreased the MNIMGU by 26% (P less than .05). MIMGU was significantly increased by 103% after acipimox administration (P less than .05) and was decreased by 65% during intralipid infusion (P less than .05). During HC, MNIMGU was not significantly influenced by low or high FFA levels, and MIMGU was not affected by a sharp lowering of FFA levels, but was significantly decreased (85%) during intralipid infusion. There was no significant difference in the lactate, pyruvate, and alanine balance across the forearm during EC and HC.(ABSTRACT TRUNCATED AT 250 WORDS)

Proinsulin and insulin concentrations following intravenous glucose challenges in normal, obese, and non-insulin-dependent diabetic subjects.

We investigated the effects of different intravenous (IV) glucose challenges on insulin and proinsulin secretion. On separate occasions, seven normal controls and five obese and five non-insulin-dependent diabetic (NIDDM) subjects each received an IV glucose tolerance test (IVGTT), a hyperglycemic clamp (HY), and a 60-minute, standardized, low-dose, continuous infusion of glucose (CIG) in a randomized fashion. Basal proinsulin concentrations in NIDDM subjects (8.4 +/- 5.0 pmol/L) were significantly higher compared with those of normal (1.1 +/- 0.2) and obese subjects (1.5 +/- 0.4; both P < .05). Basal molar proinsulin:insulin ratio (P:I) was also significantly higher in NIDDM subjects (22% +/- 12%) compared with normal (1.0%) and obese subjects (1.6% +/- 0.8%; both P < .01). Proinsulin concentrations did not increase significantly in any group during the first 10 minutes of the IV glucose challenges. However, during HY, significant increases in proinsulin concentration occurred after 60 minutes in each group. In normal and obese subjects, IV glucose administration resulted in significant acute increases in insulin concentrations compared with the characteristic blunted response in NIDDM subjects. The P:I ratio in normal and obese subjects did not change in the first 10 minutes after IV glucose administration. However, by the end of HY, the P:I ratio had increased significantly in normal subjects by 1% to 5% +/- 2% (P < .05), and in obese subjects by 1% to 5% +/- 1% (P < .02). In NIDDM subjects, both HY (19% +/- 10% to 27% +/- 12%) and IVGTT (18% +/- 9% to 43% +/- 16%) resulted in a transient increase in the basal P:I ratio by 5 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)