Teresa Salvatore

Improvement of insulin-induced glucose disposal in obese patients with NIDDM after 1-wk treatment with d-fenfluramine.

Objective To study the short-term effects of the serotoninergic anorectic drug d-fenfluramine on insulininduced glucose disposal. Research Design and Methods A randomized double-blind placebocontrolled crossover trial with 1-wk treatment periods (2 × 15 mg/day d-fenfluramine) was conducted. Twenty obese subjects, 10 with normal oral glucose tolerance and 10 with non-insulin-dependent diabetes mellitus (NIDDM), were all treated with a weight-maintaining diet. Euglycemic-hyperinsulinemic glucose clamps with measurement of glucose kinetics with D-[3-3H]glucose were performed at either two (patients without NIDDM, 0.05 and 0.10 U · kg−1 · h−1) or three (patients with NIDDM, 0.05, 0.10, and 0.50 U · kg−1 · h−1) insulin delivery rates. Results In the n·ndiabetic subjects, no significant changes in any metabolic or hormonal parameter were measured in the basal state or during the clamp despite a slight reduction in body weight (−1.2 ± 0.5 kg, P < 0.05). In the diabetic patients, no significant changes in body weight or basal plasma insulin levels were observed, but fasting blood glucose levels (8.0 ± 0.8 vs. 9.4 ± 1.1 mM, P < 0.005) and plasma free fatty acid concentrations (1150 ± 227 vs. 1640 ± 184 µM, P < 0.05) were significantly reduced after d-fenfluramine compared with placebo. During the clamp, insulin metabolic clearance rate (MCR) was similar after both placebo and d-fenfluramine; endogenous (hepatic) glucose production was similarly and almost completely suppressed, whereas glucose disposal was remarkably enhanced after cMenfluramine (average increase of glucose MCR 35 ± 12%, P < 0.02). Conclusions Whatever the mechanism(s) involved, a 1-wk treatment with d-fenfluramine induces better blood glucose control and improves insulin sensitivity in obese patients with NIDDM independent of significant weight reduction; this last effect is not present in obese subjects with normal oral glucose tolerance.

Effects of insulin-glucose infusion on left ventricular function at rest and during dynamic exercise in healthy subjects and noninsulin dependent diabetic patients: a radionuclide ventriculographic study.

OBJECTIVES The aim of this study was to evaluate: 1) the effects of insulin administration on left ventricular ejection fraction (LVEF) during exercise, and 2) the eventual impairment of the cardiovascular response to insulin in noninsulin dependent diabetes mellitus. BACKGROUND Insulin influences the cardiovascular system, but its effect on left ventricular function has yet to be established. METHODS The effects of normal saline (test A) and insulin-glucose (insulin = 1.7 mU x kg(-1) x min(-1); glucose = 6 mg x kg(-1)min(-1)) (test B) infusions on systolic and diastolic functions at rest and during dynamic exercise were examined by radionuclide ventriculography. Twenty-two noninsulin-dependent diabetic patients and 22 gender, age and body mass index matched healthy subjects were investigated. RESULTS Both groups had normal scintigraphic parameters at rest and during dynamic exercise. Rest- and stress-LVEF as well as rest- and stress-peak filling rate were significantly (p < 0.001) lower in diabetic than in healthy subjects, both in test A and B. Rest-LVEF was significantly higher during test B than it was in test A only in diabetic subjects (p < 0.01). Stress-LVEF was significantly higher (p < 0.05) during test B than it was in test A, in both groups. Insulin-glucose infusion did not modify rest- and stress-peak filling rate in either group. No difference in left ventricular end diastolic volume and in mean blood pressure was found between test A and B at rest and during exercise in either group. A significant linear correlation between LVEF and the index of insulin sensitivity was found in diabetic patients. CONCLUSIONS In both normal and diabetic humans, insulin induces a very important rise in LVEF after submaximal work. However, the rise is significantly lower in diabetic than in nondiabetic subjects. The increase in exercise-LVEF on insulin is likely due to an enhancement of ventricular contractility. Insulin resistance could justify the lower angioscintigraphic indexes in diabetic subjects.

Tolrestat for mild diabetic neuropathy: A 52-week, randomized, placebo-controlled trial

Diabetes mellitus causes widespread damage of the peripheral nervous system, involving chiefly the somatic sensory and autonomic nervous systems. Numerous attempts to halt the decrease in nerve function through improvement of diabetic control have resulted in limited benefits, and it therefore remains unclear whether or not strict control of hyperglycemia can prevent the occurrence and progression of polyneuropathy [1]. The increased conversion of glucose to sorbitol that occurs through the polyol pathway in the hyperglycemic state has been suggested to play an important role in the pathogenesis of diabetic neuropathy [2]. Reported benefits with aldose-reductase inhibitors, which act by interrupting the accumulation of sorbitol, have been disappointing [3-7]. These discouraging results may have occurred because patients with severe degrees of polyneuropathy, in whom a decrease of nerve function is likely to be too advanced, were investigated. To determine whether treatment for mild neuropathy results in benefit, we conducted a randomized, placebo-controlled, double-blind trial of the aldose-reductase inhibitor tolrestat (Alredase, Wyeth-Ayerst) in patients with asymptomatic diabetic autonomic neuropathy. Tolrestat significantly improved autonomic nerve function and peripheral neuropathy, when present. No important side effects were observed. Methods Patients All diabetic patients participating in this study were referred from the outpatient department of the Institute of General Medicine at the University of Naples, Italy and gave written, informed consent. The study, which began in early 1990, was carried out in accordance with the Helsinki Declaration II and was approved by the ethics committee of our institution. Men and postmenopausal women were included in the study if they had noninsulin-dependent diabetes mellitus with a known duration of disease of at least 1 year, stable diabetes (no change of therapy or stable glycated hemoglobin values during the previous six months), and asymptomatic diabetic autonomic neuropathy defined by the presence of at least one pathologic cardiovascular reflex test result. Patients with other possible causes of neuropathy, including liver and renal disease, thyroid hypofunction, low cobalamine levels, malignant disease, or excessive alcohol intake, were excluded. We also excluded patients affected by diseases known to interfere with cardiovascular reflexes (ischemic heart disease, heart failure, valvular heart disease, and major cardiac arrhythmias), as well as those receiving cardiac glycosides, anticholinergics, sympathomimetics, -blockers, or other drugs affecting heart-rate variability. Eligibility criteria were investigated during a 2-week period. Study Design A randomized, double-blind, parallel-group design was used. All patients were given placebo during a 4-week run-in period (single-blind). At the end of this period, baseline neurologic functions were measured, and patients were randomly assigned either to continue to receive placebo or to receive treatment with tolrestat (200 mg/d given in the morning). Patient compliance was assessed by counting of returned tablets; 85% of pills were taken in both patient groups. During the study, patients continued their standard antidiabetic therapy, diet, oral tablets, or insulin. Change of dosage was avoided during the study to prevent varying diabetic control from influencing nerve function [8]. No treatment for peripheral neuropathy, if present, was permitted except for occasional nonnarcotic analgesic drugs given as needed. Procedures All tests assessing autonomic and peripheral neuropathy were done by persons blinded to patient treatment regimen. Autonomic Neuropathy Autonomic nervous function was measured using four cardiovascular reflex tests, each done 3 hours after patients ate lunch: heart rate response to six forced respirations in 1 minute (deep breathing, maximum/minimum heart rate expressed by the expiration/inspiration ratio between the mean of the three longest R-R intervals in expiration and the mean of the three shortest R-R intervals in inspiration), heart rate response to standing (modified 30:15 ratio; ratio of the 30th to the 15th R-R interval after changing from supine to upright position), heart rate response to a standardized Valsalva maneuver (ratio of the longest R-R interval after the maneuver to the shortest interval during the maneuver), and blood pressure change after standing (change in systolic blood pressure beginning 30 seconds after assuming the upright posture) [9, 10]. Heart rate was recorded continuously with a Lifepak 6 (PhysioSystem, Milan, Italy) recorder. Each value was calculated as the mean of at least two consecutive tests that were done in the same sequence with a few minutes rest between each test. Results from each of these tests are known to worsen with age; reference values for a nondiabetic sample were used [11]. Peripheral Neuropathy The involvement, if any, of peripheral nerves was assessed by measuring vibration perception thresholds at four sites using a biothesiometer (Biomedical Instrument Company, Newborn, Ohio). The sites studied were the right and left medial malleoli and the right and left halluces. The presence of peripheral neuropathy was defined by vibration perception threshold values of more than two standard deviations above the age-related normal range at two or more sites [12]. Clinical Assessment A questionnaire was completed on symptoms of peripheral neuropathy if present. Patients were asked to grade the severity of neuropathic symptoms of either pain (burning, deep ache, tenderness) or paresthesiae (pins and needles, asleep feelings) using a visual analog scale graded from 0 to 10, in which 0 corresponded to the absence of symptoms, and 10 corresponded to very severe symptoms. Follow-up The study was conducted on an outpatient basis with visits at 1-month intervals. Clinical assessments described previously were repeated at 6, 9, and 12 months. Results of hemoglobin, full blood count, urea and electrolytes, liver function, creatinine, urinalysis, fasting and postprandial glucose, and glycated hemoglobin (HbA1c) tests were assessed each month. The diurnal plasma glucose profile represents the mean of the plasma glucose values measured every 2 hours during the day and every 4 hours during the night. Plasma glucose was measured using a glucose-oxidase method on a Beckman glucose analyzer. Glycated hemoglobin was measured by column chromatography (Auto A1c Analyzer, Kogaku Kioto, Menarini Diagnostici, Italy); normal values for our laboratory are 4.5% to 5.7%. Statistical Analysis All data are presented as mean SD; 95% confidence intervals (CIs) are provided where appropriate. Statistically significant differences in the vibration perception threshold at each site have been reported. Although the treatment by site interaction was not statistically significant for vibration perception thresholds (repeated measures analysis of variance), we decided to not use the mean value for the four sites; the values of the two different sites of the dominant leg are reported and used for analysis. Statistical significance was assessed by paired, two-tailed t-tests within groups (that is, for differences between baseline and follow-up measures in the tolrestat and the placebo groups) and the two-tailed test for a putative treatment effect (that is, comparison of the differences between baseline and follow-up values in the tolrestat and placebo groups). Results Of the fifty patients who entered the study, five dropped out: two for intercurrent disease apparently unrelated to the study drug (one in the tolrestat group and one in the placebo group), two for unstable diabetes (one in each group), and one in the tolrestat group for adverse reactions (nausea and diarrhea) that resolved rapidly after withdrawal of the study drug. Skin rashes, dizziness, and weight gain were not detected or reported by patients during treatment. Four of these five patients dropped out before randomization and the remaining patient, after randomization. Analysis of the results (both as randomized and as treated) did not differ whether the analysis was done according to intention to treat or according to actual treatment. Forty-five patients (25 in the tolrestat group and 20 in the placebo group) completed the trial. Their clinical and metabolic characteristics are presented in Table 1. The two groups were similar in the number of patients, duration of diabetes, and metabolic control. Table 1. Characteristics of Diabetic Patients Assigned to Tolrestat Therapy or Placebo* The baseline values of HbA1c were 8.2 1.1 (mean SD) in the tolrestat group and 8.4 1.1 in the placebo group (P = 0.2). Glycemic control remained stable during the study period (repeated measures analysis of variance) in both groups: at 12 months, changes in daily glycemic profile were 0.4 (CI, 0.1 to 0.7) in the tolrestat group and 0.1 (CI, 0.3 to 0.5) in the placebo group (P = 0.1). Both groups had comparable values of cardiovascular reflex tests in the basal state. Patients treated with tolrestat showed an improvement of all tests, which appeared to begin after 6 months of treatment and persisted until the end of the study (Table 2). In this group, deep breathing increased by 0.026 expiration/inspiration ratio (95% CI, 0.015 to 0.036, P = 0.001) from baseline to 12 months. In the placebo group, the same test decreased by a value of 0.012 expiration/inspiration ratio (95% CI, 0.024 to 0.004, P = 0.03). Table 2. Nerve Function at Randomization (Basal) and throughout the Study in the Tolrestat (n = 25) and Placebo (n = 20) Groups* Figure 1 shows the changes observed at the end of the study in the tolrestat and placebo groups, respectively. If one looks at the results of the deep breathing test, 20 patients improved, 3 deteriorated, and 2 remained unchanged compared with 4, 14, and 2 patients in the placebo group. Similar results wer

Cochlear dysfunction in type 2 diabetes: a complication independent of neuropathy and acute hyperglycemia.

The effects of type 2 diabetes on evoked otoacoustic emissions (e-OAEs) elicited by clicks in subjects with normal hearing and the involvement of the central (CNS) and peripheral nervous system and acute hyperglycemia were investigated. In study 1, 110 type 2 diabetic patients and 106 control subjects matched for age and gender were investigated by e-OAEs. Central and peripheral neuropathy were evaluated respectively by auditory brainstem responses (ABRs) and according to San Antonio Consensus Conference criteria. In study 2, 10 healthy and 10 type 2 diabetic men matched for age, all with normal e-OAEs, underwent a 5-hour hyperglycemic clamp study. e-OAE tests were performed before and during the hyperglycemic clamp. In study 1, e-OAEs were impaired in 51.8% (57 of 110) of the diabetic subjects, in comparison to 4.7% (five of 106) of the control group (P < .0001). Diabetics with impaired e-OAEs (e-OAEs-), in comparison to those with normal e-OAEs (e-OAEs+), were older (51.0+/-5.8 v 45.1+/-6.0 years, P < .001), had diabetes longer (11.5+/-4.4 v 7.0+/-3.9 years, P < .001), achieved poorer metabolic control as judged by hemoglobin A1c ([HbA1c] 6.9%+/-0.4% v 6.5%+/-0.3%, P < .001), and had more peripheral neuropathy (46% v 23%, P < .02). No difference was observed between e-OAEs- and e-OAEs+ subjects for retinopathy or nephropathy. Nevertheless, when the duration of diabetes was corrected by multiple regression analysis, the correlation between sensorineural damage and peripheral neuropathy lost significance (P = .12). Diabetic groups (e-OAEs+ and e-OAEs-) showed greater latency in waves I, III, and V and greater interwave latency for waves I to V than the control group, but there was no significant difference in ABRs between e-OAEs+ and e-OAEs- subjects. In study 2, there were no significant changes in e-OAE intensities compared with basal values during the entire hyperglycemic clamp in either type 2 diabetic or control subjects. No difference was observed between the two groups at each time of the clamp. Thus, type 2 diabetic subjects show a higher rate of compromised e-OAEs than healthy individuals. The e-OAE dysfunction does not associate with either an injury to the auditory nervous pathway or diabetic microvasculopathy. The apparent interference of peripheral neuropathy in e-OAEs loses significance when corrected for the duration of diabetes.

Sensitivity to β-endorphin as a cause of human obesity

Abstract Naloxone, an opiate antagonist, was given as an intravenous bolus (5 mg) in both lean and obese healthy subjects. In lean people, there was a slight trend for insulin and C-peptide concentrations to decrease below baseline values with no glucose change. Obese subjects showed an exaggerated suppression of insulin and C-peptide and a slight decrease of glucose. Glucagon was suppressed in both groups. An infusion of human β-endorphin (0.05 mg/h) produced only minor changes in plasma glucose, insulin, glucagon, and C-peptide concentrations in lean subjects, but caused marked increments in obese. Glucagon rose in both groups, but its response was greater in obese subjects. A ten-day treatment with naloxone (1.2 mg twice a day) did not change the metabolic and hormonal responses to an oral glucose load (75 g) in lean but significantly inhibited the insulin and C-peptide responses to glucose in obese people. These results suggest that an increased opiate drive to the pancreatic beta-cell and an increased responsiveness of insulin to β-endorphin are present in human obesity.

β-Endorphin–Induced Inhibition and Stimulation of Insulin Secretion in Normal Humans Is Glucose Dependent

This study evaluated the effect of human β-endorphin on pancreatic hormone levels and their responses to nutrient challenges in normal subjects. Infusion of 0.5 mg/h β-endorphin caused a significant rise in plasma glucose concentrations preceded by a significant increase in peripheral glucagon levels. No changes occurred in the plasma concentrations of insulin and C-peptide. Acute insulin and C-peptide responses to intravenous pulses of different glucose amounts (0.33 g/kg and 5 g) and arginine (3 g) were significantly reduced by β-endorphin infusion (P < .01). This effect was associated with a significant reduction of the glucose disappearance rates, suggesting that the inhibition of insulin was of biological relevance. β-Endorphin also inhibited glucose suppression of glucagon levels and augmented the glucagon response to arginine. To verify whether the modification of prestimulus glucose level could be important in these hormonal responses to β-endorphin, basal plasma glucose concentrations were raised by a primed (0.5 g/kg) continuous (20 mg kg−1 · min−1) glucose infusion. After stabilization of plasma glucose levels (350 ± 34 mg/dl, f = 120 min), β-endorphin infusion caused an immediate and marked increase in plasma insulin level (peak response 61 ± 9 μU/ml, P < .01), which remained elevated even after the discontinuation of opioid infusion. Moreover, the acute insulin response to a glucose pulse (0.33 g/kg i.v.) given during β-endorphin infusion during hyperglycemia was significantly higher than the response obtained during euglycemia (171 ± 32 vs. 41 ± 7 μU/ml, P < .01). Therefore, during euglycemia, β-endorphin infused at low pharmacological dose in normal humans inhibits basal and nutrient-stimulated insulin secretion, raises plasma glucose and glucagon concentrations, and increases the glucagon response to arginine. Also, during hyperglycemia (glucose clamp), β-endorphin stimulates basal and glucose-induced insulin secretion. Hyperglycemia alters the reactivity of the β-cells to β-endorphin.

Progress in the oral treatment of type 2 diabetes: update on DPP-IV inhibitors.

Glucagon-like peptide-1 (GLP-1) is a gut hormone that plays an important role in regulating glucose homeostasis by both its pancreatic and extrapancreatic activity. Defects of GLP-1 characterize type 2 diabetes as a primary or perhaps consequent phenomenon, resulting in inappropriately low insulin secretion after oral ingestion of nutrients. The discovery that cleavage by the ubiquitous enzyme dipeptidyl peptidase-IV (DPP-IV) is the primary route of GLP-1 metabolism formed the rationale behind the proposal to prevent degradation of endogenously released GLP-1 by DPP-IV inhibition as a novel approach to the management of type 2 diabetes. Enhanced insulin secretion as well as delayed gastric emptying, reduced glucagon secretion, and inhibited apoptosis of beta cells resulting from blockade of incretin degradation, have been proposed as the major actions of DPP-IV inhibitors as antidiabetic agents. Clinical studies to date indicate that DPP-IV inhibitors effectively ameliorate islet dysfunction and improve glucose control in patients with type 2 diabetes. They appear to have excellent therapeutic effectiveness as monotherapy in patients inadequately controlled with diet and exercise and as add-on therapy in combination with metformin, thiazolidinediones, and insulin. Their pharmacokinetic and pharmacodynamic profiles support once-daily dosing, with relatively few adverse effects.

Detection of Early Sympathetic Cardiovascular Neuropathy by Squatting Test in NIDDM

OBJECTIVE To determine the role of the squatting test in the detection of early sympathetic neuropathy in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS Three groups of nonsmoking, nonobese subjects were studied: 10 healthy subjects, 10 NIDDM patients without autonomic neuropathy (AN), and 10 NIDDM patients with AN defined by the presence of a pathological deep-breathing value. All subjects were given three postural tests: lying-to-standing, sitting-to-standing, and squatting test. Heart rate (HR) and finger arterial pressure were recorded with a noninvasive technique. RESULTS Blood pressure (BP) fall (expressed as decremental area) was not significantly different among the groups at standing up after sitting or lying. By contrast, a significantly greater BP drop occurred in NIDDM patients with AN (1,123 ± 245 mm2) compared with NIDDM patients without AN (460 ± 232 mm2) or normal subjects (429 ± 138 mm2, P < 0.001). The HR increase after all the orthostatic maneuvers was smaller in diabetic patients with AN (P < 0.01) compared with that recorded in other groups. Significant correlations were observed between BP fall after squatting and either the expiration:inspiration ratio at deep breathing (r = -0.77, P < 0.001) or the duration of diabetes (r = 0.76, P < 0.001). CONCLUSIONS The intrinsic orthostatic load of the squatting test, which is greater than conventional postural maneuvers, makes the squatting test an easy and useful test to detect early orthostatic dysregulation in NIDDM.

Hyperinsulinemia in offspring of non-insulin-dependent diabetes mellitus patients: The role played by abnormal clearance of insulin

Insulin resistance and hyperinsulinemia are often found in first-degree relatives of non-insulin-dependent diabetes mellitus (NIDDM) patients, and are currently considered a familial trait of this population at increased risk for diabetes. This study was undertaken to determine the role played by the metabolic clearance rate (MCR) of insulin (MCR-I) in the hyperinsulinism of these subjects. The proband population, consisting of 48 subjects aged 29.2 +/- 4.4 (mean +/- SD) years (18 men and 30 women; body mass index, 24.6 +/- 0.8 kg/m2; fasting plasma glucose, 4.54 +/- 0.37 mmol/L), was assigned in random order to four groups (I, II, III, and IV), each receiving a double insulin/glucose infusion (I, 0.025/2.0; II, 0.050/3.5; III, 0.100/6.0; and IV, 0.200/8.0 U/kg.h and mg/kg.min, respectively) to calculate MCR-I and MCR of glucose (MCR-G). Forty (14 men and 26 women) age- and body mass index-matched healthy individuals served as controls. All subjects had a normal response to an oral glucose tolerance test (75 g) according to World Health Organization criteria. Basal plasma insulin and C-peptide levels in probands were significantly (P < .05) higher than in controls in each study group; similarly, MCR-I was significantly (at least P < .05) lower in probands than in controls in all groups. MCR-G was significantly (at least P < .05) decreased in probands as compared with controls of groups III and IV.(ABSTRACT TRUNCATED AT 250 WORDS)

Liver biopsy in type 2 diabetes mellitus: Steatohepatitis represents the sole feature of liver damage

Recent studies report a prevalence of non-alcoholic fatty liver disease (NAFLD) of between 70% and 80% in patients with metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Nevertheless, it is not possible to differentiate between simple steatosis and non-alcoholic steatohepatitis (NASH) with non-invasive tests. The aim of this study was to differentiate between simple steatosis and NASH by liver biopsy in patients with hypertransaminasemia and MS or T2DM. Two hundred and fifteen patients with increased ALT levels and MS, and 136 patients at their first diagnosis of T2DM regardless of ALT values were consecutively admitted to a tertiary hepatology center between January 2004 and November 2014. Exclusion criteria were other causes of liver disease/ALT increase. Each patient underwent a clinical, laboratory and ultrasound evaluation, and a liver biopsy. Gender distribution, age, and body mass index were similar in the two groups of patients, whereas cholesterol levels, glycemia and blood pressure were significantly different between the two groups. The prevalence of NAFLD was 94.82% in MS patients and 100% in T2DM patients. NASH was present in 58.52% of MS patients and 96.82% of T2DM. Consequently, this study reveals that, by using liver biopsy, almost all patients with T2DM or MS have NAFLD, which in patients with T2DM means NASH. Importantly, it suggests that NASH may be one of the early complications of T2DM due to its pathophysiological correlation with insulin resistance.