Search

The effects of 3 weeks of treatment with the beta-receptor blocking agent propranolol and a placebo on glucose tolerance, insulin secretion and peripheral insulin sensitivity have been evaluated in 7 normoglycaemic hypertensive patients by an oral glucose tolerance test and the insulin clamp technique. Significant changes in systolic and diastolic blood pressure and heart rate were observed at the end of propranolol treatment, but there were no associated changes in glucose tolerance, insulin secretion or peripheral insulin sensitivity. No difference was observed in glucagon, growth hormone and free fatty acids between propranolol and placebo treatment. The results support the view that the hypothetical pancreatic glucoreceptor, at least in non-acute studies, is not affected by beta blockade. In addition, there was no effect on tissue sensitivity to insulin.

Although it has been reported that bezafibrate influences carbohydrate metabolism, this possibility has never been properly evaluated in a controlled clinical trial. In this study we attempted to evaluate the effects of bezafibrate on plasma lipoproteins, glucose tolerance, insulin secretion and peripheral insulin sensitivity in a group of hypertriglyceridemic patients with and without diabetes. Sixteen hyperlipidemic patients (10 males and 6 females) participated in the study. Eight had type IIB and 8 type IV hyperlipoproteinemia; 6 of them also had non-insulin dependent diabetes mellitus. The study was performed according to a double blind, crossover design: after 1 month wash-out period in which patients were on diet alone, they underwent, in a random order, a period of placebo therapy and another period in which they received a single daily dose of a long-acting bezafibrate preparation (400 mg) administered in the evening. Each treatment lasted 2 months. Total plasma and VLDL triglyceride concentrations were consistently reduced by bezafibrate (-46%, P less than 0.001; and -50%, P less than 0.001). Total and VLDL-cholesterol were also reduced by bezafibrate. The effects of bezafibrate on lipoproteins were similar in diabetic and non-diabetic subjects. Bezafibrate treatment did not influence fasting blood glucose concentration, glucose tolerance, peripheral insulin sensitivity or insulin secretion. In conclusion, the results of this controlled trial clearly indicate that bezafibrate can be successfully employed to lower plasma lipid levels in patients with non-insulin dependent diabetes mellitus and hyperlipidemia.

Twenty-four hour plasma free insulin and blood glucose and intermediary metabolite profiles have been measured in 6 C-peptide deficient 'brittle' diabetic patients, during continuous sc and im insulin infusion. During sc infusion free insulin profiles were erratic and unpredictable. Mean 24 h blood glucose levels were raised at 12.6 ± 2.1 (se) mmol/l, and 3-hydroxybutyrate at 0.24 ± 0.08 mmol/1. Blood lactate (1.88 ± 0.18 mmol/l) and glycerol (0.084 ± 0.007) were also elevated. Insulin (im) restored free insulin profiles to the normal pattern as found in 'stable' diabetics on sc infusion, with characteristic post-meal peaks (49 ± 7, 103 ± 35, and 95 ± 34 mU/l) and stable night-time levels. Mean 24 h blood glucose was 6.7 ± 1.1 mmol/l (P < 0.05 compared to sc infusion) and 3-hydroxybutyrate 0.07 ± 0.02 mmol/l (P < 0.05). Blood lactate (1.67 ± 0.08 mmol/l) and glycerol (0.10 ± 0.02 mmol/l) levels remained abnormal. The ratio of plasma free insulin to insulin dose administered was significantly higher during im infusion. In the 6 'stable' diabetics on sc insulin infusion good blood glucose control (7.1 ± 0.9 mmol/l) was accompanied by clear post-prandial insulin peaks, and stable nocturnal levels. The results strongly suggest that in one category of 'brittle' diabetics there is defective and erratic sc insulin absorption.

Ten insulin-dependent C-peptide-negative diabetic subjects, whose control had been optimized on twice-daily injection therapy, were treated for periods of 10 wk in a crossover study, with either a thrice-daily subcutaneous insulin injection regimen (Actrapid + Ultratard) or by continuous subcutaneous insulin infusion (CSII). On CSII insulin dose stabilized at 51 +/- 5 U/day, compared with 80 +/- 9 U/day (P = 0.004) on the thrice-daily injection regimen, having been 60 +/- 6 U/day on twice-daily therapy. After 10 wk glycosylated hemoglobin was 11.7 +/- 0.6% on injection therapy and 10.0 +/- 0.7% (P = 0.026) on CSII. Mean blood glucose concentration and urinary glucose excretion were lower at most points during the study on CSII than on injection therapy. Patients on pumps gained weight compared with the thrice-daily injection regimen (P = 0.023 at 10 wk) and the previous twice-daily regimen, despite the reduction in insulin dose. Considering individual patients, four markedly improved on CSII compared with the previous twice-daily regimen and five compared with Actrapid + Ultratard. No patient showed impaired control on CSII compared with either injection regimen. The benefits of portable insulin infusion pumps over injection therapy are thus clearly demonstrable under outpatient conditions even with equal and intensive medical attention.

Certain acute and chronic metabolic effects of nicardipine have been studied in 20 patients with non-insulin dependent diabetes (NIDD). An intravenous glucose tolerance test (i.v. GTT, glucose 0.33 g/kg as a bolus) and the corresponding insulin response were assessed at the end of a 4 week placebo period, after the first dose and on administration for 12 weeks of nicardipine 20 mg t.i.d. The glucose and insulin responses to the i.v.GTT, evaluated as incremental AUCs, did not change significantly (glucose 30.5 mg/dl.90 min on placebo, 33.1 mg/dl.90 min acutely and 31.4 mg/dl.90 min on chronic administration of nicardipine; insulin 2.08 microU/ml.90 min on placebo, 1.87 microU/ml.90 min acutely and 1.93 microU/ml.90 min after chronic nicardipine). Glucose removal rate (KG) following the i.v.GTT was 0.73%/min on placebo 0.75%/min on acute administration and 0.8%.min-1 with chronic nicardipine. Active treatment produced a significant reduction of blood pressure (from 187/96 mm Hg on placebo to 166/89 mm Hg acutely and 152/83 mm Hg after 12 weeks of nicardipine treatment). It is concluded that the calcium antagonist nicardipine was an effective antihypertensive drug, and that it did not cause deterioration of metabolic control in hypertensive patients with NIDD.

Plasma lipoprotein and lipoprotein lipase activity have been evaluated in young diabetics with and without ketonuria and in healthy controls of the same age. Fifteen (age range 7-23 years) newly detected diabetics (8 with ketonuria, 7 non ketonuric) have been examined before starting the treatment. Five healthy medical students (age range 19-21 years) have also been studied. Both ketotic and non ketotic patients showed an impaired insulin and C-peptide response to the glucose load in comparison to controls. Ketotic patients had low lipoprotein lipase activity (p less than 0.01) and high density lipoprotein (p less than 0.01); total plasma Triglycerides and VLDL Triglyceride and Cholesterol were higher than in controls. Plasma Triglyceride and VLDL Triglyceride and Cholesterol were inversely related to lipoprotein lipase activity. Low lipoprotein lipase activity, from adipose tissue and muscle, has been found to be associated with hypertriglyceridemia and reduced HDL Cholesterol in young diabetic patients with ketonuria.

The activity of biosynthetic human insulin (BHI) has been compared with that of pork insulin using the glucose clamp technique in normal subjects. After a baseline period, insulin was infused at 0.02 U/kg/h for 2 h, then 0.032 U/kg/h for 2 h, and finally 0.05 U/kg/h for 2 h. Glucose was clamped at baseline values using a glucose-controlled insulin infusion system (Biostator) and the amount of glucose infused to maintain normoglycemia calculated for each insulin dose for the two insulins. C-peptide levels decreased with both insulins, suggesting suppression of endogenous insulin secretion. Serum insulin levels attained were the same for both insulins. There were no significant differences in either total glucose infused or glucose infused during the last 30 or 60 min at each insulin dose for the two insulins. Intermediary metabolite responses to the infusion of the two insulins were similar. We conclude that in normal human beings, BHI shows identical metabolic activity with pork insulin.

Bezafibrate (2-[4-(2-(4-chlorobenzamido)-ethyl-phenoxy]2-methyl propionic acid) is a new hypolipidemic drug which is more effective than its analogue Clofibrate in reducing plasma lipid levels. Fully adsorbed in the gut it binds by 95% to plasma proteins, has a mean half-life of 2 h and is excreted through urine within 24–48 h (Abshagen et al. 1979). Bezafibrate increases hepatic and extra-hepatic lipoprotein lipase activity, thus enhancing the plasma removal of triglyceride-rich lipoproteins. The increase of lipoprotein lipase activity takes place at the muscle tissue level but not in the adipose tissue.

This study was designed to quantitate glucose and FFA disposal by muscle tissue in patients with type II diabetes and to investigate the relationship between FFA metabolism and insulin resistance. The forearm perfusion technique was used in six normal subjects and two groups of normal weight diabetic patients, i.e. untreated (n = 8) and insulin-treated (n = 6). The latter received 2 weeks of intensive insulin therapy before the study. Plasma insulin levels were raised acutely [950-1110 pmol/L) (130-150 microU/mL)], while the blood glucose concentration was clamped at its basal value [4.9 +/- 0.1 (+/- SE) mmol/L in the normal subjects, 5.7 +/- 0.5 in the insulin-treated diabetic patients, and 5.5 +/- 0.3 in the untreated diabetic patients] by a variable glucose infusion. During the control period, arterial FFA concentrations were similar in the three groups, and they decreased to a comparable extent (less than 0.1 mmol/L) in response to insulin infusion. During the control period, the mean forearm FFA uptake was 2.5 +/- 0.5 mumol/L.min in the normal subjects, 2.9 +/- 0.5 in the insulin-treated patients, and 2.1 +/- 0.5 in the untreated diabetic patients. During the insulin infusion, FFA uptake was profoundly suppressed to similar levels in the normal subjects (0.9 +/- 0.1 mumol/L.min), the insulin-treated diabetic patients (1.1 +/- 0.3), and the untreated diabetic patients (0.9 +/- 0.1; P less than 0.001). Forearm glucose uptake was similar in the three groups during the control period. It increased during the insulin infusion, but the response in both diabetic groups was less than that in the normal subjects. The total amounts of glucose taken up by the forearm during the study period were 5.2 +/- 0.7, 2.6 +/- 0.5, and 2.1 +/- 0.6 mmol/L.min in the normal subjects, the insulin-treated diabetic patients, and the untreated diabetic patients, respectively (P less than 0.01). We conclude that 1) insulin-mediated glucose uptake by forearm skeletal muscle is markedly impaired in type II diabetes and improves only marginally after 2 weeks of intensive insulin therapy; 2) in contrast, no appreciable abnormality in forearm FFA metabolism is demonstrable in insulin-treated type II diabetic patients; and 3) FFA do not contribute to the insulin-treated skeletal muscle insulin resistance that occurs in patients with type II diabetes mellitus.

This study attempts to evaluate whether the putative excess risk of cardiovascular disease in individuals with impaired glucose tolerance (IGT) can be explained by the clustering of other major cardiovascular risk factors after controlling for obesity. The study population was 1376 male and female employees of a Naples telephone company who had participated in a health survey in which an oral glucose tolerance test (OGTT) was given. After excluding treated hypertensives, we recruited all 65 individuals with IGT and 125 euglycemic controls matched for gender, age, and weight. Systolic and diastolic blood pressure was significantly higher in individuals with IGT (134 +/- 16 vs 127 +/- 15 mm Hg, p less than 0.001; 87 +/- 10 vs 84 +/- 8 mm Hg, p less than 0.05 (M +/- SD). Blood lipids were similar in the two groups (total cholesterol was 214 +/- 34 vs 218 +/- 40 mg/dl; HDL cholesterol was 39 +/- 9 vs 40 +/- 10 mg/dl; total triglyceride was 145 +/- 58 vs 135 +/- 63 mg/dl). Serum insulin values (fasting or at 1 or 2 hours after 75 g of oral glucose) were also similar. The number of persons currently smoking was significantly lower among individuals with IGT (30% vs 47%, p less than 0.025) but the percentage of exsmokers was identical in the two groups. We conclude that, among the possible cardiovascular risk factors investigated, blood pressure is the only one significantly associated with IGT independent of matched variables and antihypertensive treatment.

The relationship between impaired glucose tolerance (IGT) and blood lipid levels was examined in 65 IGT individuals and in two control groups: control group I, composed of age-, sex-, and body weight-matched controls, and control group II, including normal subjects matched for sex and age but with normal body mass index. IGT individuals were found to have significantly higher total triglyceride (Tg) values compared with normal weight controls (P < 0.001), while no difference was found between IGT and control group I. Total cholesterol levels were similar in IGT and each of the control groups. No significant correlation was found between serum lipoproteins and blood glucose levels either fasting or after load.

We assessed in normal subjects the effects of an acute increase in forearm norepinephrine (NE) release, evoked by -20 mmHg lower body negative pressure (LBNP), on insulin-mediated muscle glucose uptake. Seven normal subjects underwent the following two insulin euglycemic clamps in random sequence: one during application of LBNP and the other without LBNP (control study). In the control study, hyperinsulinemia (approximately 60 microU/ml) produced a significant increment in forearm NE release, measured by using the forearm perfusion technique combined with infusion of tritiated NE (from 4.91 +/- 1 to 7.94 +/- 1.33 ng.l-1.min-1; P < 0.05). Forearm glucose uptake rose from 0.97 +/- 0.13 to 5.2 +/- 0.2 mg.l-1.min-1 in response to insulin infusion. When the insulin clamp was performed during LBNP, forearm NE release rose to significantly higher values than those of the control study (from 4.33 +/- 0.52 to 12.7 +/- 1.46 ng.l-1.min-1; P < 0.01 vs. control). Under these conditions, the stimulatory effect of insulin on forearm glucose uptake was markedly reduced (from 0.78 +/- 0.10 to 3.2 +/- 0.7 mg.l-1.min-1; P < 0.02 vs. control). Forearm blood flow and plasma epinephrine and free fatty acid concentrations were comparable in the two study sessions. These data demonstrate that an acute activation of endogenous NE release antagonizes insulin-mediated glucose uptake in forearm skeletal muscle, probably accounted for by a direct metabolic effect of NE.

Muscle sympathetic nerve activity was measured in nine acromegalic patients (age, 35 ± 4 yr; body mass index, 28 ± 2 kg/m2) and eight healthy subjects (age, 32 ± 3 yr; body mass index, 25 ± 2 kg/m2) by combining the forearm arterial-venous difference technique with the tracer method[ infusion of tritiated norepinephrine (NE)]. Muscle NE release was quantified both at rest and during physiological hyperinsulinemia while maintaining euglycemia (∼90 mg/dL) by means of the euglycemic clamp. Arterial plasma NE was similar in the two groups at rest (197 ± 28 and 200 ± 27 pg/mL−1) and slightly increased during insulin infusion. Forearm NE release was 2.33 ± 0.55 ng·liter−1·min−1 in healthy subjects and 2.67 ± 0.61 ng·liter−1·min−1 in acromegalic subjects in the basal state and increased to a similar extent during insulin infusion in both groups (3.13 ± 0.71 and 3.32 ± 0.75 ng·L−1· min−1, P < 0.05 vs. basal), indicating a normal stimulatory effect of insulin on muscle sympathetic activity. In contrast, insulin-stimulated forearm glucose uptake was markedly lower in acromegalic patients (2.3 ± 0.4 mg·L−1·min−1) than in control subjects (7.9 ± 1.3 mg·L−1·min−1, P < 0.001), indicating the presence of severe insulin resistance involving glucose metabolism. Our data demonstrate that patients with long-term acromegaly have normal sympathetic activity in the skeletal muscle in the basal, postabsorptive state and normal increments in NE spillover in response to the sympatho-excitatory effect of insulin. Thus, the presence of severe insulin resistance in acromegaly is not accounted for by adrenergic mechanisms.

The effect of hyperglycemia per se on glucose uptake by muscle tissue was quantitated in six controls and six type II diabetics by the forearm technique, under conditions of insulin deficiency induced by somatostatin (SRIF) infusion (0.7 mg/h). Blood glucose concentration was clamped at its basal value during the first 60 min of SRIF infusion and then raised to approximately 200 mg/dl by a variable glucose infusion. Plasma insulin levels remained at or below 5 microU/ml during SRIF infusion, including the hyperglycemic period. No appreciable difference between controls and diabetics was present in the basal state as to forearm glucose metabolism. After 60 min of SRIF infusion and euglycemia, forearm glucose uptake fell consistently from 2.1 +/- 0.7 mg X liter-1 X min-1 to 1.0 +/- 0.6 (P less than 0.05) and from 1.7 +/- .2 to 0.4 +/- 0.3 (P less than 0.02) in the control and diabetic groups, respectively. The subsequent induction of hyperglycemia caused a marked increase in both the arterial-deep venous blood glucose difference (P less than 0.02-0.01) and forearm glucose uptake (P less than 0.01-0.005). However, the response in the diabetic group was significantly greater than that observed in controls. The incremental area of forearm glucose uptake was 276 +/- 31 mg X liter-1 X 90 min and 532 +/- 81 in the control and diabetic groups, respectively (P less than 0.02). In the basal state, the forearm released lactate and alanine both in controls and diabetic subjects at comparable rates. No increment was observed after hyperglycemia, despite the elevated rates of glucose uptake. It is concluded that (1) hyperglycemia per se stimulates forearm glucose disposal to a greater extent in type II diabetics than in normal subjects; and (2) the resulting increment of glucose disposal does not accelerate the forearm release of three carbon compounds. The data support the hypothesis that hyperglycemia per se may play a compensatory role for the defective glucose disposal in type II diabetes.

The forearm perfusion technique was used 1) to quantify the muscle metabolism of glucose and gluconeogenic precursors in response to insulin-induced hypoglycemia and 2) to assess the role of catecholamines and glucose concentration, pe se. Insulin (0.5 mU.kg-1.min-1) was infused for 4 h in three groups of healthy volunteers. In group I (n = 6), blood glucose (BG) was maintained at its basal level (4.5 +/- 0.1 mmol/l). In group II (n = 7), BG was allowed to fall to approximately 3 mmol/l. Group III (n = 6) was similar to group II except that propranolol was infused also. In addition, at 240 min, hypoglycemia was locally corrected by intrabrachial glucose infusion while maintaining the systemic milieu unperturbed. In group I, forearm glucose uptake (FGU) increased from 4.7 +/- 1.3 to a mean value of 37.8 +/- 5.0 mumol.l-1.min-1, whereas in group II it remained unchanged (8.3 +/- 2.0 mumol.l-1.min-1). In group III, propranolol partially prevented the suppression of FGU that increased to 21.6 +/- 5.2 mumol.l-1.min-1 (P < 0.05 vs. group II). Local correction of hypoglycemia normalized the FGU response (36.5 +/- 8.0 mumol.l-1.min-1). Muscle release of lactate, but not of alanine, was slightly higher during hypoglycemia (P = not significant). Forearm blood flow remained unchanged in groups I and III, whereas it increased by approximately 40% in group II (P < 0.05). It is concluded that, during mild hypoglycemia 1) extreme insulin resistance develops in the skeletal muscle, mediated by beta-adrenergic stimulation and reduced glucose mass effect and 2) mobilization of gluconeogenic precursors is only weakly activated.