[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.

Plasma vitamin C affects glucose homeostasis in healthy subjects and in non-insulin-dependent diabetics.

In aged healthy (n = 10) and non-insulin-dependent (type II) diabetic (n = 10) subjects matched for age [67.3 +/- 0.5 vs. 68.0 +/- 0.4 yr, P = not significant (NS)], body mass index (25.7 +/- 0.7 vs. 26.0 +/- 0.2 kg/m2, P = NS), gender ratio [6 males (M)/4 females (F) vs. 5 M/5 F], and mean arterial blood pressure (104 +/- 6 vs. 105 +/- 9 mmHg, P = NS), we determined the changes in insulin secretion and action after vitamin C infusion and the relative increase in plasma vitamin C levels. At the highest vitamin C infusion rate (0.9 mmol/min) the increase in plasma vitamin C levels did not affect B cell response to glucose, but it improved Conard's K values and whole body glucose disposal in healthy subjects and in diabetic patients. In both groups of subjects vitamin C-mediated increase in insulin action was mainly due to an improvement in nonoxidative glucose metabolism. After fasting, plasma vitamin C levels correlated with basal whole body glucose disposal (r = -0.44, P < 0.05; n = 20). After vitamin C infusion, percent change in plasma vitamin C level correlated with the percent decline in membrane microviscosity (r = 0.53, P < 0.01; n = 20) and increase in whole body glucose disposal (r = 0.63, P < 0.003; n = 20). In conclusion, plasma vitamin C levels seem to play a role in the modulation of insulin action in aged healthy and diabetic subjects.

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.

Hyperinsulinemia in patients with hypercholesterolemia.

An independent association between hypercholesterolemia and high insulin levels has not consistently emerged from large-scale epidemiologic observations. We selected 39 patients with elevated low-density (LDL) cholesterol levels but normal body weight, blood pressure, and glucose tolerance, and compared them to 36 normocholesterolemic, healthy control subjects accurately matched to the patients for age, gender, body mass index, and mean arterial blood pressure. Fasting serum total cholesterol concentrations and levels of LDL cholesterol, triglycerides, and apoprotein B were all higher in the patients with hypercholesterolemia than in controls (P < 0.025 or less), whereas high-density lipoprotein cholesterol and apoprotein A levels were significantly lower (P < 0.05 or less). Plasma insulin concentrations were elevated in hypercholesterolemic patients vs. controls both in the fasting state (86 +/- 6 vs. 59 +/- 8 pmol/L) and 2 h after a 75-g oral glucose load (412 +/- 16 vs. 276 +/- 18 pmol/L, P < 0.02 for both). Two-hour plasma glucose concentrations were also significantly raised in the patients (7.8 +/- 0.2 mmol/L) compared to controls (6.4 +/- 0.1 mmol/L, P < 0.025). In a multiple regression model including serum triglyceride concentrations, LDL cholesterol was still significantly related to both fasting and 2-h plasma insulin concentrations, contributing approximately 20% to the overall variability of these measures. Thus, in this group of patients with type IIa familial combined hyperlipoproteinemia hypercholesterolemia was associated with hyperinsulinemia even when controlling for other confounders (age, gender, body mass, glucose tolerance, and blood pressure).

Plasma GSH/GSSG affects glucose homeostasis in healthy subjects and non-insulin-dependent diabetics.

In healthy subjects (n = 10) and non-insulin-dependent (type II) diabetics (n = 10) matched for age [43.1 +/- 2.2 vs. 41 +/- 4.4 yr, P = not significant (NS)], body mass index (25.1 +/- 1.1 vs. 26 +/- 0.8 kg/m2, P = NS), gender ratio [5 males (M)/5 females (F) vs. 5M/5F], and mean arterial blood pressure (105 +/- 7 vs. 106 +/- 9 mmHg, P = NS), we determined the changes in insulin secretion and action after glutathione infusion (15 mg/min) and the relative increase in the plasma reduced (GSH)/oxidized (GSSG) glutathione ratio. The rise in the plasma GSH/GSSG ratio significantly improved total body glucose disposal in healthy subjects and in diabetic patients. In this latter group, GSH infusion potentiated the beta-cell response to glucose slightly. In controls and diabetics, insulin infusion with a simultaneous increase in the plasma GSH/GSSG ratio significantly enhanced nonoxidative glucose disposal without affecting oxidative glucose metabolism. After glutathione infusion, all metabolic and hormonal changes correlated with a significant decline in plasma membrane microviscosity. In conclusion, the plasma GSH/GSSG ratio seems to play a major role in the modulation of glucose homeostasis mainly in diabetics.

Insulin effects on glucose kinetics in non-insulin-dependent diabetic patients with secondary failure to hypoglycaemic agents: role of different modes and rates of delivery.

OBJECTIVES: This study aimed at investigating the effects of pulsatile and continuous insulin delivery on glucose kinetics in non-insulin-dependent (type 2) diabetic patients with secondary failure to oral hypoglycaemic agents. METHODS: Seven type 2 diabetic patients underwent a 585 minute glucose-controlled glucose intravenous infusion using the Biostator. The endogenous pancreas secretion was inhibited by somatostatin. Three experiments were performed in each patient on different days and in random order. In all cases, glucagon was replaced (58 ng/min). The amounts of insulin infused were: a) 0.15 mU/kg x min continuously; b) 0.20 mU/kg x min continuously and c) 1.0 mU/kg x min in 2 minute pulses every 13 minutes. D-[3-3H]-glucose infusion allowed determination of glucose kinetics. RESULTS: Infusion of identical amounts of insulin (A vs C) demonstrated that pulsatile insulin delivery exerted greater metabolic effects (higher glucose infusion rate and, mainly at the beginning of the experiment, lower endogenous glucose production) than continuous infusion; furthermore pulsatile insulin delivery (C) exerted metabolic effects similar to those of a greater dose of insulin (B) infused continuously. CONCLUSIONS: In type 2 diabetic patients with secondary failure to oral hypoglycaemic agents, pulsatile insulin delivery exerts greater metabolic effects than continuous hormone delivery.

Daily magnesium supplements improve glucose handling in elderly subjects.

We demonstrated similar plasma concentrations and urinary losses but lower erythrocyte magnesium concentrations (2.18 +/- 0.04 vs 1.86 +/- 0.03 mmol/L, P less than 0.01) in twelve aged (77.8 +/- 2.1 y) vs 25 young (36.1 +/- 0.4 y), nonobese subjects. Subsequently, aged subjects were enrolled in a double-blind, randomized, crossover study in which placebo (for 4 wk) and chronic magnesium administration (CMA) (4.5 g/d for 4 wk) were provided. At the end of each treatment period an intravenous glucose tolerance test (0.33 g/kg body wt) and a euglycemic glucose clamp with simultaneous [D-3H]glucose infusion and indirect calorimetry were performed. CMA vs placebo significantly increased erythrocyte magnesium concentration and improved insulin response and action. Net increase in erythrocyte magnesium significantly and positively correlated with the decrease in erythrocyte membrane microviscosity and with the net increase in both insulin secretion and action. In aged patients, correction of a low erythrocyte magnesium concentration may allow an improvement of glucose handling.

ACE inhibition improves insulin-sensitivity in aged insulin-resistant hypertensive patients.

We have compared the cardiovascular and metabolic responses to five different ACE inhibitors in 86 patients matched for age, body mass index, blood pressure, fasting plasma glucose and insulin levels in a placebo-controlled, double-blind, crossover, randomised trial. In the active drug treatment phase the patients were randomly assigned to one of five ACE inhibitors: captopril (75 mg/day; n = 16); enalapril (20 mg/day; n = 14); quinapril (20 mg/day; n = 17); ramipril (5 mg/day; n = 21) and lisinopril (20 mg/day; n = 18). Placebo and ACE inhibition phases lasted two weeks and were separated by a one week wash-out period. At the end of each treatment period blood pressure and heart rate were recorded and a fasting sample intravenous glucose tolerance test was conducted. Our study demonstrated that ACE inhibition significantly reduces blood pressure and improves insulin sensitivity. All the ACE inhibitors studied had similar cardiovascular responses but lisinopril displayed the larger metabolic response.

Effects of mild-to-moderate hyperglycaemia per se on glucose production and uptake in the elderly.

OBJECTIVES: In order to better understand the mechanisms responsible for the diminished glucose tolerance that occurs in the elderly, the present study aimed at investigating the effect of mild hyperglycaemia on glucose production and uptake in a group of aged subjects. For comparison, a group of young subjects was simultaneously investigated. METHODS: Seven aged (71.8 +/- 2.3 yrs) and seven young (25.5 +/- 1.7 yrs) healthy non-obese subjects underwent two hyperglycaemic glucose-clamps having as targets plasma glucose levels 7.5 and 10.0 mmol/L. Contemporary infusion of D-[3-3H]-glucose allowed determination of glucose turnover parameters in basal conditions and during the clamps. Endogenous pancreatic secretion was inhibited by somatostatin (8.3 micrograms/min) while glucagon (67 ng/min) and insulin (0.15 mU/kg/min) were replaced by exogenous infusions. RESULTS: In basal conditions, glucose uptake (12.9 +/- 0.5 vs 14.4 +/- 0.4 mumol/kg/min; p < 0.05) and glucose metabolic clearance rate (2.58 +/- 0.15 vs 3.35 +/- 0.10 ml/kg/min; p < 0.01) were lower in elderly vs young subjects. In the hyperglycaemic glucose-clamps, we observed, in the elderly subjects, the persistence of a greater glucose production during mild (7.5 mmol/L) (11.6 +/- 0.4 vs 9.7 +/- 0.2 mumol/kg/min; p < 0.005) but not moderate (10 mmol/L) (3.5 +/- 0.1 vs 3.4 +/- 0.1 mumol/kg/min; NS) hyperglycaemia. In contrast, glucose-induced glucose uptake and glucose metabolic clearance rate were similarly affected by glucose infusions in both groups of subjects. Moreover, in elderly but not in young subjects, basal glucose disappearance rate was significantly negatively correlated with fasting plasma glucose levels (r = -0.84; p < 0.01). CONCLUSIONS: In the basal state, glucose uptake and glucose metabolic clearance rate are slightly impaired in elderly, compared to young subjects. Furthermore, in the elderly, endogenous glucose production is less suppressed by mild hyperglycaemia i.e. 7.5 mmol/L, than it is in young people. Such impairment in the inhibition of endogenous glucose production is not seen when blood glucose attains 10 mmol/L. We suggest that impairment in glucose tolerance in the elderly results from both reduced glucose uptake (in basal conditions) and excessive glucose production (at mild hyperglycaemic levels).

Pulsatile insulin delivery has greater metabolic effects than continuous hormone administration in man: importance of pulse frequency.

The aim of this study was to see if the greater effect of insulin on hepatic glucose output when insulin is given using 13-min pulses in man remains when the same amount of insulin is delivered using 26-min pulses. The study was performed on nine male healthy volunteers submitted to a 325 min glucose-controlled glucose iv infusion using the Biostator. The endogenous secretion of pancreatic hormones was inhibited by somatostatin. Three experiments were performed in each subject on different days and in random order. In all cases glucagon was replaced (58 ng min-1). The amounts of insulin infused were identical in all instances and were 0.2 mU kg-1 min-1 (continuous), 1.3 mU kg-1 min-1, 2 min on and 11 min off (13-min pulses) or 2.6 mU kg-1 min-1, 2 min on and 24 min off (26-min pulses). Blood glucose levels and glucose infusion rate were monitored continuously by the Biostator, and classic methodology using D-[3-3H] glucose infusion allowed to study glucose turnover. When compared with continuous insulin, 13-min insulin pulses induced a significantly greater inhibition of endogenous glucose production. This effect disappeared when insulin was delivered in 26-min pulses. We conclude that, in man, an adequate pulse frequency is required to allow the appearance of the greater inhibition of pulsatile insulin on endogenous glucose production.

Simvastatin reduces plasma lipid levels and improves insulin action in elderly, non-insulin dependent diabetics.

Twelve elderly non-insulin dependent diabetic patients took part in a double-blind, cross-over, randomized study comparing simvastatin 30 mg/day and placebo. Each treatment period lasted 3 weeks and was separated by a 3 week wash-out period. At the end of each treatment period all subjects underwent in randomized order an oral glucose tolerance test (OGTT; 75 g) and an euglycaemic hyperinsulinaemic (50 mU/kg.h) glucose clamp. Simvastatin compared to placebo significantly reduced plasma total cholesterol (7.9 vs 5.3 mmol.l-1), LDL-cholesterol (7.2 vs 4.3 mmol.l-1), triglycerides (2.9 vs 2.1 mmol.l-1), free fatty acids (1106 vs 818 mmol-1) and glucose (7.4 vs 6.6 mmol.l-1) levels. After simvastatin, and in the last 60 min of the glucose clamp, there was an improvement in the action of insulin as demonstrated by stronger inhibition of hepatic glucose output (2.7 vs 5.2 mumol.kg-1.min-1) and stimulation both of the glucose disappearance rate (26.3 vs 19.5 mumol.kg-1.min-1) and glucose metabolic clearance rate (4.3 vs 3.6 ml.kg-1.min-1). The changes in glucose turnover parameters were significantly correlated with basal plasma free fatty acids and were independent of plasma glucoregulatory hormones. In conclusion, simvastatin seems to exert beneficial effects both on lipid and glucose metabolism.

Effects of oxytocin upon the endocrine pancreas secretion and glucose turnover in normal man.

In normal man oxytocin infusion under basal conditions and at pharmacological doses evoked a rapid surge in plasma glucose and glucagon levels followed by a later increase in plasma insulin levels. Simultaneous [D-3H]glucose infusion indicated that oxytocin also produced a prompt and significant increase in hepatic glucose output with a secondary increase in glucose disappearance rate. Eight healthy volunteers were studied during euglycemic glucose clamp and simultaneous [D-3H]glucose infusion, during suppression of endogenous pancreatic secretion by cyclic somatostatin (250 micrograms/h) and during exogenous glucagon (67 ng/min) and insulin (0.15 mU.kg-1.min-1 from 0 to 120 min and 0.40 mU.kg-1.min-1 from 121 to 240 min) replacement. During the first 60 min oxytocin (0.2 U/min) evoked a transient but significant increase in plasma glucose levels and hepatic glucose output with a simultaneous suppression of the glucose infusion rate. No difference in glucose disappearance and metabolic clearance rates were recorded throughout the clamp irrespective of whether oxytocin was infused or not. So we conclude that oxytocin exerts a hyperglycemic effect through an A-cell stimulation and a glycogenolytic action.

Impaired insulin-mediated erythrocyte magnesium accumulation is correlated to impaired insulin-mediated glucose diposal in aged non-diabetic obese patients.

Basal erythrocyte magnesium levels were significantly lower in obese than lean subjects. In vitro incubation in the presence of 100 mU/l insulin significantly increased magnesium erythrocyte levels in both groups of subjects. However, even in the presence of 100 mU/l, the erythrocyte magnesium content of obese patients was lower than that of control subjects. The in vitro dose-response curve of the effect of insulin on magnesium erythrocyte accumulation was shifted to the right when the red cells of obese were used, with a highly significant reduction of the maximal effect. Such reduction of the maximal effect of insulin suggests that the impairment of insulin-induced erythrocyte magnesium accumulation observed in obese patients results essentially from a post-receptor defect. In obese patients, net increase in erythrocyte magnesium levels (calculated as the difference between basal and 100 mU/l insulin-induced erythrocyte magnesium levels) was negatively correlated with basal plasma insulin levels (r = 0.79 p less than 0.01), and with body mass index (r = 0.81 p less than 0.01) while it was positively correlated with the glucose disappearance rate after glucose load (r = 0.67 p less than 0.05) and glucose metabolic clearance rate (r = 0.71 p less than 0.01). These results demonstrate that insulin-induced erythrocyte magnesium accumulation is impaired in patients with obesity and that such defect is correlated to impaired -- mediated glucosal disposal in the patients.

Insulin resistance as cause of increased blood pressure in the elderly: effects on intracellular ion contents.

Previous reports have evidenced a strong relationship between high plasma insulin levels and blood pressure in diabetic and obese subjects but not in the elderly. During aging many patho-physiological changes in cardiovascular functions and autonomic nervous system occur, so that aging per se might be a cause of a 'physiological' increase in blood pressure. Nevertheless, an insulin resistance also develops during aging. The present study investigates the possible role of age-dependent insulin resistance in the genesis of increased blood pressure. Our data show that insulin resistance calculated by the glucose infusion rate during a euglycemic hyperinsulinemic glucose clamp procedure is significantly correlated with the insulin-mediated net decrease in erythrocyte Na+ content (r = 0.58, P < 0.05), as well as with net increase in erythrocyte K+ (r = 0.64, P < 0.05) and Mg2+ (r = 0.67, P < 0.01) content and to basal diastolic blood pressure (r = -0.63, P < 0.05). We conclude that in elderly subjects the age-related and normally occurring insulin resistance might contribute to the increase of arterial blood pressure through its effect on cell cation content.

Metabolic effects of pulsatile insulin infusion in the elderly.

The present study investigated the metabolic effects of pulsatile insulin delivery at a pulse rate of 2 + 11 and 2 + 18 min in 7 healthy, elderly subjects (71.4 +/- 2.1 years), submitted to 260 min controlled iv glucose infusion via the Biostator. The endogenous secretion of pancreatic hormones was inhibited by somatostain (3 micrograms/min) and glucagon was replaced (67 ng/min) to basal levels. The same total insulin dose was delivered on both occasions. Insulin infusion rate was 1.3 and 2.0 mIU. kg-1. min-1 during switching on/off of 2 + 11 and 2 + 18 min, respectively. Blood glucose levels and glucose infusion rate were monitored continuously by the Biostator; [D-3-3H]glucose infusion allowed determination of glucose turnover. During the last 60 min of the experiment, pulsatile insulin at a pulse rate of 2 + 11 vs 2 + 18 min produced a stronger inhibition of endogenous glucose production, whereas glucose disappearance rate and glucose metabolic clearance rate were similarly affected. Plasma triglycerides, apolipoprotein B, and free fatty acids levels were also more suppressed during insulin delivery at pulse rate of 2 + 11 than at 2 + 18 min.

Pulsatile glucagon has greater hyperglycaemic, lipolytic and ketogenic effects than continuous hormone delivery in man: effect of age.

The present study aimed at investigating the hyperglycaemic, lipolytic and ketogenic effects of small doses of glucagon delivered continuously or in a pulsatile manner. The study was performed in eight healthy young volunteers (24.2 +/- 1.2 years) and in eight healthy aged subjects (69.4 +/- 2.0 years). In all the subjects, endogenous pancreatic hormone secretion was inhibited by somatostatin and only glucagon was replaced. Consequently, the effects of pulsatile and continuous glucagon delivery were studied in conditions of progressive somatostatin-induced insulin deficiency. In both the young and the aged subjects, pulsatile glucagon delivery resulted in increases in plasma glucose, non-esterified fatty acid, glycerol and beta-hydroxybutyrate levels greater than those observed when the same amount of glucagon was delivered in a continuous manner. The net increases in plasma glucose, glycerol and non-esterified fatty acid levels were similar between the young and the aged subjects when glucagon was infused continuously; in contrast, the rise in plasma beta-hydroxybutyrate in the aged was only about half that observed in the young subjects. Surprisingly, when glucagon was infused in a pulsatile manner, the rises in plasma glycerol, non-esterified fatty acid and beta-hydroxybutyrate levels were all significantly smaller in the aged subjects, while no significant differences were observed in the blood glucose responses. We conclude that, in the presence of somatostatin-induced insulin deficiency, pulsatile glucagon exerts greater effects on blood glucose, plasma non-esterified fatty acid, glycerol and beta-hydroxybutyrate levels than its continuous delivery. In the elderly, the lipolytic and ketogenic, but not the hyperglycaemic, responses to pulsatile glucagon are significantly reduced.

Pulsatile rather than continuous glucagon infusion leads to greater metabolic derangements in insulin-dependent diabetic subjects.

The present study aimed at investigating the respective effects of continuous and pulsatile intravenous delivery of glucagon in insulin-dependent diabetic subjects. The study was performed in seven insulin-dependent diabetic subjects proven to have no residual insulin secretion. In random order and in different days each subject was submitted to glucagon delivery given continuously (58 ng/min) and in a pulsatile (377 ng/min during 2 min followed by 11 min during which no glucagon was infused) manner. In this conditions plasma glucose levels were significantly higher during pulsatile glucagon delivery. In particular in the last 65 min plasma glucose levels reached 10.8 +/- 0.3 vs 12.9 +/- 0.4 mmol/l (p less than 0.05) during continuous and pulsatile glucagon delivery respectively. Similarly plasma lipid changes also evidenced a greater effects of pulsatile rather than continuous hormone administration in producing the metabolic derangements classically encountered in insulin-dependent diabetic subjects. In conclusion, pulsatile glucagon delivery seem to produce greater metabolic effects than continuous hormone delivery.

Exaggerated orthostatic hypotension as first sign of diabetic autonomic neuropathy in the elderly.

Long-standing diabetic subjects have an impaired sympathetic nervous system activity as a consequence of autonomic neuropathy. Moreover, in this latter group of subjects the parasympathetic rather than the sympathetic nervous system seems firstly impaired by glucose metabolism derangements. In the present study we show that, in aged diabetic subjects with a short duration of the disease (less than 5 years), and who are free from diabetic complications, it is possible to evidence a primary compromise of sympathetic rather than parasympathetic nervous system activity since a greater rate of orthostatic hypotension occurred. In the light of the well-known age-related changes in the physiopathology of cardiovascular activity, we hypothesize that in aged diabetic patients, even after a short duration of disease, sympathetic compromise precedes the derangement of parasympathetic nervous system activity.

Dietary magnesium supplements improve B-cell response to glucose and arginine in elderly non-insulin dependent diabetic subjects.

Hypomagnesemia and low erythrocyte magnesium content are both common findings in non-insulin-dependent diabetic subjects. Moreover, intracellular magnesium may play a crucial role in modulating B-cell response to glucose by interfering with potassium permeability. Eight elderly, moderately obese, non-insulin-dependent diabetic subjects were treated with either magnesium supplementation (3 g/day) to the diet or placebo. Both treatment schemes lasted 4-weeks and were separated by a 'wash-out' of 3 weeks. At the end of each treatment period, in glucose test (0.33 g/kg for 3 min) and an iv arginine (5 g) test were performed to determine the B-and A-cell responses. Dietary magnesium supplementation vs placebo produced a slight but significant decrease in basal plasma glucose (8.6 +/- 0.3 vs 8.0 +/- 0.1 mmol/l, p less than 0.05) and an increase in acute insulin response after iv glucose (3.7 +/- 2.3 vs - 14.7 +/- 0.9 pmol.l 1. (10 min)-1, p less than 0.01) and after iv arginine (151 +/- vs 81 +/- 15 pmol.l-1. (10 min)-1, p less than 0.01), respectively. Plasma glucagon levels were unaffected by chronic dietary magnesium supplementation as well under basal conditions as in response to arginine. Net increase in acute insulin response after iv glucose and after iv arginine was significantly correlated to the net increase in erythrocyte magnesium content after dietary magnesium supplementation. We conclude that magnesium administration may be a useful adjuvant to the classic hypoglycemic agents in the treatment of non-insulin-dependent diabetic subjects.

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.