Greater efficacy of pulsatile insulin in type I diabetics critically depends on plasma glucagon levels.

The aim of this study was to investigate the role of plasma glucagon levels on the blood glucose response to intravenous insulin administered continuously or in a pulsatile manner. Six type I diabetic patients proven to have no residual insulin secretion were investigated. Endogenous glucagon secretion was inhibited by a continuous intravenous infusion of somatostatin (100 micrograms/h) and replaced by exogenous infusions of the hormone at three different rates (7.5, 4.5, and 2.5 micrograms/h), resulting in three different plasma glucagon steady-state levels (i.e., approximately equal to 200, approximately equal to 130, and approximately equal to 75 pg/ml, respectively). Each subject, in random order and on different days, was infused intravenously with regular human insulin either continuously (0.17 mU X kg-1 X min-1) or with the same amount of insulin infused in a pulsatile manner (0.85 mU X kg-1 X min-1 during 2 min followed by 8 min during which no insulin was infused). At plasma glucagon levels approximately equal to 200 pg/ml, blood glucose rose from approximately 10 to approximately 13 mM without any difference between the two modalities of insulin infusion. For plasma glucagon levels approximately equal to 130 pg/ml, plasma glucose remained steady throughout the experiments, but during the last 40 min, plasma glucose levels were significantly lower when insulin was administered intermittently. This greater blood glucose-lowering effect of pulsatile insulin occurred earlier and was more pronounced for plasma glucagon levels averaging 75 pg/ml. We conclude that the greater hypoglycemic effect of insulin administered intravenously in a pulsatile manner in type I diabetics critically depends on plasma glucagon circulating levels.

Colchicine and insulin secretion in man.

The present study is aimed at investigating the effect of acute and chronic colchicine administration on insulin secretion in humans. Acute insulin response to glucose (0.33 g/kg) was significantly decreased by colchicine (3 mg i.v.). In fact, this response (mean change 2-10 min insulin) was 44 +/- 8 microunits/ml before and 32 +/- 6 microunits/ml after colchicine administration (P less than 0.01). As a consequence of this, glucose disappearance rates were reduced (P less than 0.05). Infusion of lysine acetylsalicylate (LAS), an inhibitor of endogenous PG synthesis, completely reversed the inhibitory effect of colchicine upon insulin secretion and also augmented acute insulin response to glucose (response before colchicine + LAS = 45 +/- 8 microunits/ml; response after colchicine + LAS = 51 +/- 9 microunits/ml, P less than 0.05). This effect was associated with an increase in glucose disappearance rates (P less than 0.05). The 10-day treatment with colchicine (2 mg daily) caused a significant suppression of insulin secretion induced by oral glucose (100 g) and significantly increased the plasma glucose concentrations following the test (P less than 0.05). These findings demonstrate that (1) both acute and chronic colchicine administration inhibit glucose-induced insulin secretion and deteriorate glucose tolerance in humans, and (2) LAS completely reverses these negative effects of colchicine. An increased synthesis of endogenous PGE, which are known to inhibit insulin secretion in humans, might account for the inhibiting effect of colchicine on insulin secretion.

Repaglinide has more beneficial effect on cardiovascular risk factors than glimepiride: data from meal-test study.

Aim our study is to compare the effects of repaglinide vs glimepiride administration on cardiovascular risk factors after meal test. Thus, after 2 weeks washout period, a 3-month randomised, cross-over parallel group trial of repaglinide (1 mg x 2/day) vs glimepiride (2 mg/day) in 14 patients with type 2 diabetes "naive" on diet treatment was made. Both treatments significantly declined plasma glucose, total-cholesterol, LDL-cholesterol, triglycerides, PAI-1, PAP levels and increased HDL-cholesterol. Lowering in plasma PAI-1 and PAP levels was significantly greater in repaglinide group. Furthermore, repaglinide administration resulted in a significant decrease in fasting plasma free fatty acids, fibrinogen, thrombin-antithrombin complex and reaction product of malondialdehyde with thiobarbituric acid (TBARS) levels, in absence of significant difference in fasting plasma insulin levels. Decrease in plasma TBARS levels correlated with the decrease in Plasminogen Activator Inhibitor-1 (r = 0.72; P < 0.003) and free fatty acids concentrations (r = 0.62; P < 0.01). Analysis of the insulin and glucose concentrations throughout the meal test revealed that AUC for glucose (758 +/- 19 vs 780 +/- 28 mg/Lxmin; P = 0.02) was significantly lower after repaglinide than glimepiride administration despite similar AUC for insulin (2327 +/- 269 vs 2148 +/- 292 mU/Lxmin; P = 0.105). At time 120' of meal test, repaglinide vs glimepiride administration was associated with a significant decline in plasma triglycerides, free fatty acids, fibrinogen, Plasminogen Activator Inhibitor-1, plasmin-alpha(2)-antiplasmin complex, thrombin-antithrombin complex, TBARS levels and increase in plasma HDL-cholesterol levels. In repaglinide group a negative correlation between insulin secretion during 1st phase of meal-test and plasma TBARS levels (r = -0.55; P < 0.03) at time 120' was found. Such correlation was lost after adjusting for changes in postprandial hyperglycaemia (r = -0.48; P < 0.09). In conclusion, our results support the hypothesis that repaglinide is more efficient than glimepiride on controlling for postprandial glucose excursion and may have beneficial effect on reducing cardiovascular risk factors.

Metabolic control may alter antithrombin III activity but not its plasma concentration in diabetes: a possible role for nonenzymatic glycosylation.

The effects of metabolic control on both antithrombin III (AT III) activity and AT III plasma concentration in 20 insulin-treated diabetic subjects have been evaluated. Basal AT III activity was significantly lower in diabetic subjects versus healthy controls (P less than 0.001), whereas no difference was found in AT III concentration. A good correlation was found between AT III activity and AT III concentration (r = 0.81; P less than 0.001) in healthy controls, but this correlation was not significant in diabetic subjects (r = 0.12; P = NS). In those subjects a linear inverse correlation was found to exist between AT III activity and level of glycosylated proteins (r = -0.43; P less than 0.05). Diabetic subjects were also examined after 1 and 2 mo of restored metabolic control, obtained by human insulin (DNA-recombinant) therapy. Improved metabolic control was characterized by an increase of AT III activity (P less than 0.05), a decrease of mean daily blood glucose, and stable HbA1 and glycosylated proteins (P less than 0.05), while AT III concentration did not vary. On the other hand, a significant inverse correlation between AT III activity and glycosylated proteins was found during both the first and second months (r = -0.54 and r = -0.53, respectively; P less than 0.01). Moreover, no correlation between AT III activity and AT III concentration was found. These data suggest that impaired metabolic control may alter the biologic activity of AT III in diabetes, but not its plasma concentration.

Improved insulin response and action by chronic magnesium administration in aged NIDDM subjects.

In eight aged non-insulin-dependent diabetes mellitus (NIDDM) subjects, insulin response and action were studied before and after chronic magnesium supplementation (2 g/day) to diet. Chronic magnesium supplementation to diet versus placebo produced 1) a significant increase in plasma (0.83 +/- 0.05 vs. 0.78 +/- 0.06 mM, P less than .05) and erythrocyte (2.03 +/- 0.06 vs. 1.88 +/- 0.09 mM, P less than .01) magnesium levels, 2) an increase in acute insulin response (AIR) (4.0 +/- 0.6 vs. -1.6 +/- 0.6 mU/L, P less than .05) to glucose pulse, and 3) an increase in glucose infusion rate (GIR) (3.6 +/- 0.6 vs. 2.9 +/- 0.5 mg.kg-1.min-1, P less than .025) calculated in the last 60 min of a euglycemic-hyperinsulinemic (100 mU.m2.min-1 during 180 min) glucose clamp. Net increase in AIR, glucose disappearance rate after glucose pulse, and GIR were significantly and positively correlated to the net increase in erythrocyte magnesium content calculated after chronic magnesium supplementation to diet. In conclusion, our data suggest that NIDDM subjects may benefit from therapeutic chronic administration of magnesium salts.

Effect of aldose reductase inhibitor (tolrestat) on urinary albumin excretion rate and glomerular filtration rate in IDDM subjects with nephropathy.

OBJECTIVE: To explore the possible link between diabetic nephropathy and the enhanced activity of the polyol pathway, known to occur in IDDM subjects. RESEARCH DESIGN AND METHODS: We studied the effects of the aldose reductase inhibitor tolrestat (200 mg/day) on urinary albumin excretion rate and glomerular filtration rate in 20 IDDM patients with diabetic nephropathy. RESULTS: Six months of placebo treatment produced no significant changes in glomerular filtration rate, urinary albumin excretion rate, and renal plasma flow. Consequently, filtration fraction remained unchanged. During tolrestat treatment, glomerular filtration rate decreased from the basal value of 156 +/- 14 ml.min-1.1.73 m2 to 142 +/- 13.7 ml.min-1.1.73 m2 (P < 0.001) at 2 mo; 128 +/- 12.4 ml.min-1.1.73 m2 (P < 0.001) at 4 mo; and 123.7 +/- 13.0 ml.min-1.1.73 m2 at 6 mo. A significant decrease of urinary albumin excretion rate was observed during the trial (basal values 219 +/- 32.5 vs. 196.9 +/- 28.5 micrograms/min at 2 mo [P < 0.05]; 171.6 +/- 25.5 micrograms/min at 4 mo [P < 0.001]; and 58.6 +/- 19.3 micrograms/min at 6 mo [P < 0.001]). No significant change in renal plasma flow was seen during tolrestat treatment. Filtration fraction significantly decreased in the tolrestat group from the basal value of 0.23 +/- 0.02 to 0.21 +/- 0.01 at 2 mo (P < 0.005); 0.18 +/- 0.02 at 4 mo (P < 0.001); and 0.17 +/- 0.02 at 6 mo (P < 0.001). CONCLUSIONS: The polyol pathway is implicated in hemodynamic changes associated with early diabetic nephropathy, and aldose reductase treatment can positively influence these parameters.

Low-dose iloprost infusion improves insulin action in aged healthy subjects and NIDDM patients.

OBJECTIVE: To investigate the effect of iloprost infusion on insulin action. RESEARCH DESIGN AND METHODS: Thirteen healthy subjects and 13 non-insulin-dependent diabetes mellitus (NIDDM) patients matched for age (68.2 +/- 0.5 vs. 67.9 +/- 0.5 years, NS), gender ratio (7 men:6 women vs. 6 men:7 women), body weight, body fat distribution, arterial blood pressure, and plasma triglyceride levels (1.89 +/- 0.09 vs. 1.87 +/- 0.08 mmol/l, NS) were studied. In eight healthy subjects and eight NIDDM patients, we studied insulin action by euglycemic glucose clamp (insulin infusion rate 2 mU.kg-1.min-1) along with saline and iloprost delivery (0.7 ng.kg-1.min-1). In the other five subjects of each group, forearm blood flow and insulin-mediated glucose uptake during saline and iloprost infusion (0.7 ng.kg-1.min-1) were investigated. RESULTS: Iloprost infusion improved insulin-stimulated whole-body glucose uptake and oxidative and nonoxidative glucose metabolism in both study groups. Forearm blood flow under basal conditions and with insulin infusion (2 mU.kg-1.min-1) did not show any significant difference from that during saline and iloprost infusion (0.7 ng.kg-1.min-1) in healthy subjects and diabetic patients. CONCLUSIONS: Iloprost infusion improves insulin action in healthy subjects and NIDDM patients.

Glucagon secretion in patients with hypoparathyroidism: effect of serum calcium on glucagon release.

The aim of the present study was to evaluate the influence of changes in the serum calcium concentration upon glucagon secretion in man. For this purpose, a group of subjects with either idiopathic (four cases) or secondary (two cases) hypoparathyroidism was submitted to an arginine test (0.5 g/kg) before and after the correction of hypocalcemia. In the presence of hypocalcemia, the glucagon response to the amino acid was modest and delayed (glucagon peak, 150 +/- 28 pg/ml). The acute correction of hypocalcemia produced a striking increase in basal glucagon levels (125 +/- 24 vs. 75 +/- 15 pg/ml; P less than 0.01) and restored the glucagon peak in response to arginine (270 +/- 50 pg/ml; P less than 0.01). The increase in plasma glucose triggered by arginine was augmented under normocalcemic conditions, while the pattern of plasma insulin response was quite similar. These results indicate that glucagon secretion in man is critically dependent on the serum calcium concentration.

Calcitonin, a diabetogenic hormone?

The effect of calcitonin on oral glucose tolerance and on insulin, C-peptide, glucagon, and GH secretion has been investigated in man. Eight subjects with normal glucose tolerance and eight with impaired glucose tolerance (IGT) were studied. Each subject received two oral glucose tolerance tests (100 g) in random order, one under basal conditions and the other during the simultaneous in administration of salmon calcitonin (100 Medical Research Council Units). In all subjects, calcitonin exaggerated the rise in plasma glucose after oral sugar. The integrated areas under the plasma glucose curves were 4,400 +/- 840 mg/dl.min (normals) and 8,708 +/- 1,840 mg/dl.min (IGT) without calcitonin, and 8,208 +/- 1,700 mg/dl. min (normals) and 19,500 +/- 3,500 mg/dl. min (IGT) with calcitonin (P less than 0.01). Plasma insulin and C-peptide responses to glucose were significantly reduced (P less than 0.01) by calcitonin at all times after the start of the test in both normal and IGT groups. The inhibitory action of oral glucose on glucagon secretion was partially prevented by calcitonin (P less than 0.01). Moreover, calcitonin completely blunted the GH rebound occurring at the end of the test. These findings demonstrate that calcitonin impairs glucose tolerance in man by both inhibiting glucose-induced insulin secretion (primary effect) and reducing glucose-mediated glucagon suppression (accessory effect). These effects of calcitonin could be explained by a decrease in the cytosolic Ca2+ concentration in both alpha- and beta-cells.

A possible role of gamma-aminobutyric acid in the control of the endocrine pancreas.

This study examines the effect of baclofen, a specific gamma-aminobutyric acid analog which crosses the blood-brain barrier freely, upon insulin, glucagon, and GH responses to iv glucose in normal man. Normal subjects received two consecutive iv glucose tolerance tests (0.33 g/kg) before and after the acute oral administration of 5, or 10 or 20 mg baclofen, respectively, (10 subjects for each group). The dose of baclofen was divided and given 8 and 1 h before the performance of the posttreatment test. A fourth group of normal subjects served as placebo group (8 subjects). The highest dose of baclofen significantly increased insulin responses to glucose and raised basal glucagon levels (P less than 0.01). No significant change occurred with the other doses. Baclofen produced a dose-related increase in basal GH levels; a 10-fold increase was observed with the 20-mg dose. However, glucose-induced glucagon and GH suppression were not affected by baclofen. Despite the increased hormonal secretions, glucose tolerance did not change after baclofen. These results seem to indicate that gamma-aminobutyric acid may play a role in the neuroendocrine control of the pancreatic islets.

Role of free fatty acids on cardiac autonomic nervous system in noninsulin-dependent diabetic patients: effects of metabolic control.

Decreased heart rate variability (HRV) is a risk factor for cardiovascular mortality. Elevated plasma free fatty acid (FFA) levels decrease HRV in healthy subjects. Thus, we investigated the effect of changes in plasma FFA levels on HRV, in non-insulin-dependent diabetes (NIDDM) patients. Thirty NIDDM patients free from diabetic neuropathy volunteered for a study made by two phases. In study A, changes in HRV along a 10% lipid emulsion infusion + heparin (n = 15) or saline infusion (control study; n = 15) were investigated. In study B, all patients (n = 30) underwent further determination of HRV after 3 months of improved metabolic control achieved by intensified insulin treatment. In study A, lipid emulsion infusion increased plasma FFA (P < 0.001) and catecholamine concentrations (P < 0.005), mean arterial blood pressure (P < 0.005), low frequency/high frequency (LF/HF) ratio (P < 0.001). Delta plasma FFA levels correlated with delta LF/HF ratio (r = 0.57; P < 0.02). Along with saline infusion, metabolic and cardiovascular parameters remained unchanged throughout the test. In study B, improved metabolic control lowered fasting plasma glucose (P < 0.005), FFA (P < 0.001), norepinephrine (P < 0.02), epinephrine (P < 0.04), and glycosylated hemoglobin levels (P < 0.001), mean arterial blood pressure(P < 0.05), and LF/HF ratio (P < 0.001). Again percent decline in plasma FFA correlated with the percent change in LF/HF ratio (r = 0.72; P < 0.001). In a multivariate analysis, percent changes in LF/HF ratio were associated with percent changes in plasma FFA independently of gender and percent changes in body mass index, waist/hip ratio, plasma norepinephrine, epinephrine, glycosylated hemoglobin, and daily insulin therapy. Our study demonstrates that changes in plasma FFA levels may have a parallel effect on cardiac sympathetic/parasympathetic nervous system balance in NIDDM patients.

Glucose tolerance and hormonal responses in heroin addicts. A possible role for endogenous opiates in the pathogenesis of non-insulin-dependent diabetes.

Plasma glucose, insulin, glucagon, and growth hormone responses to intravenous glucose stimulation were investigated in 15 heroin-dependent men and in 15 control subjects matched for age, sex, and weight. Although the fasting concentrations of insulin, glucagon, and GH were significantly higher in the heroin addicts, they had markedly reduced plasma insulin responses to intravenous glucose (acute insulin response, calculated as the mean change in insulin levels over 3 to 10 minutes: 10 +/- 5 microU/mL in the addicts v 44 +/- 9 microU/mL in the controls, P less than 0.001) and glucose utilization rates in the diabetic range (KG: 0.96 +/- 0.09%/min in the addicts v 1.65 +/- 0.10%/min in the controls, P less than 0.01). These results show that chronic heroin administration produces a state of fasting hyperinsulinemia even in the absence of obesity, glucose intolerance, and a marked reduction of the first phase of insulin secretion. A possible role for endogenous opiates in the pathogenesis of non-insulin-dependent diabetes is hypothesized.

Further studies on the significance of circulating platelet aggregates induced by somatostatin in man.

The aim of the present study was to further evaluate the significance of circulating platelet aggregates induced by somatostatin in insulin-dependent diabetic subjects. Eight insulin-dependent diabetics and eight normals were infused with somatostatin at increasing doses (250, 500, and 750 microgram/h), each dose for 30 min. In diabetics, somatostatin induced the appearance in blood of platelet aggregates in a dose-dependent fashion, the highest level being observed with the highest dose (750 microgram/h), p less than 0.005). In normals, circulating platelet aggregates were detected only with the infusion of the highest rate of somatostatin (p less than 0.025). This effect of somatostatin was reversible, since it tended to disappear 30 min after the infusion was stopped. In six additional insulin-dependent diabetics, a previous infusion of phentolamine (0.5 mg/min) completely prevented the appearance of platelet aggregates by somatostatin. No significant variation of the aggregation response to both ADP and collagen and the platelet count was seen in both experiments. Somatostatin, as expected, reduced the basal concentration of plasma glucose, glucagon, and C-peptide in both diabetics and normals. On the basis of these results, we suggest that somatostatin has some proaggregating capacity in vivo, probably by interacting with adrenergic mechanisms.

Repaglinide is more efficient than glimepiride on insulin secretion and post-prandial glucose excursions in patients with type 2 diabetes. A short term study.

OBJECTIVES: To compare the effect of Repaglinide vs Glimepiride on glucose- and meal-induced insulin secretion and on meal-test induced postprandial glucose excursions. METHODS: After 2 weeks washout period, a 3-Month randomised, cross-over parallel group trial of R (1 mg x 2/die) vs G (2 mg/die) in 14 patients with type 2 diabetes "naive" in diet treatment was made. RESULTS: Both R and G significantly but similarly lowered fasting glucose levels and improved fasting plasma insulin levels vs baseline. Hyperglycemic clamp showed that both 1st (129.15 +/- 23.6 vs 106.90 +/- 18.6 pmol/L; p=0.01) and 2nd phase (189.42 +/- 34.4 vs 144.21 +/- 37.3 pmol/L; p=0.003) B-cell response to glucose as well as area under the curve (52.07 +/- 10.86 vs 39.54 +/- 10.27 micromol/L x 120'; p=0.005) were greater in R than G groups. Insulin action (4.0 +/- 1.1 vs 3.2 +/- 0.9 mg x Kg x 60'/microU/mL; p=0.046) was also improved by R than G administration. In the meal test, R therapy produced a more rapId induction of insulin secretion during the first part. In fact, the mean rise in insulin secretion peaked at 45 min in R (p=0.001 vs G) and at 60 min in G (p=0.001 vs R). Consequently, glucose spike at 60 min was higher in G group compared to glucose spike at 45 min in R group (p=0.002). CONCLUSIONS: Our study demonstrates that R is more efficient that G on improving glucose- and meal- induced insulin secretion as well as on controlling for postprandial glucose excursion.

[Treatment of chronic hepatitis C with lymphoblastic interferon. Long-term follow-up]. / Traitement par l'interféron lymphoblastique humain de l'hépatite virale C chronique. Suivi à distance.

OBJECTIVES: A randomized controlled trial was set up to assess the effect of two different therapy regimens with lymphoblastoid interferon on the treatment and follow-up of patients with chronic C hepatitis. METHODS: Eighty-five patients with chronic hepatitis C were randomized into two treatment groups (n = 30 respectively) and one control group (no treatment: n = 25). In one treatment group patients received three million units of alpha-lymphoblastoid interferon. The other received six million units. RESULTS: A rapid decline in both alanine aminotransferase and aspartataminotransferase levels was seen in most treated patients (a complete response in 51% from group A and 55% from group B; partial response 29% from group A, 25% from group B). In five partial responders and six complete responders from group A and in seven partial responders and six complete responders in group B serum aminotransferase levels returned to baseline values in the follow-up. No change in serum bilirubin, albumin, IgG and prothrombin time during interferon treatment were seen. The histologic staging remained unchanged throughout the entire study. CONCLUSION: alpha-interferon treatment improves the clinical picture, biochemical parameters and histologic pattern in a large percentage of patients with hepatitis C. Long-term remission was seen in only 37% of treated patients. Using six million units of alpha-interferon has not proven to be significantly better than three million units. Protracted treatment for nine months seems to increase the percentage of patients in biochemical and histologic remission.

[Hypertrophy of the masseter: a rare case associated with hypertrophic cardiomyopathy]. / Ipertrofia dei masseteri: un raro caso, associato a cardiomiopatia ipertrofica.

Masseteric hypertrophy is a rare, monolateral or bilateral lesion. The aetiology is often unknown and both congenital and acquired forms are reported in the literature. The authors report a case of masseteric hypertrophy associated with hypertrophic cardiomyopathy. Family history shows two brothers suffering from the same cardiac disease. Echography, computed tomography, EMG test and aspiration biopsy of masseteric muscle were performed. Echocardiography and HLA, B and C antigens of 16 relatives were also performed. In the report case the authors hypothesized a multifactorial background on a genetic basis.