Hyperglycemia counterbalances the antihypertensive effect of glutathione in diabetic patients: evidence linking hypertension and glycemia through the oxidative stress in diabetes mellitus.

Diabetes mellitus is associated with hypertension. An antihypertensive effect of the antioxidant glutathione has been recently demonstrated. It has been suggested that hyperglycemia may contribute to the pathophysiology of hypertension in diabetes by generating an oxidative stress. In this study, three different tests were performed in ten hypertensive and ten nonhypertensive diabetic subjects: (1) an oral glucose tolerance test, (2) glutathione i.v. administration (1 g/m2 bolus + 1 g/m2 in 2 h), and (3) oral glucose tolerance test + glutathione administration. At -15', 0', 30', 60', 90', 120', and 180' systolic and diastolic blood pressure, plasma glucose, and insulin were measured. Variations in plasma glucose and insulin levels were not different during each test in the two groups of patients and in test (1) compared to (3). Glutathione administration reduced systolic and diastolic blood pressure in both hypertensive and nonhypertensive diabetic subjects from 30' to 120'. This phenomenon was abolished as glycemia increased after oral glucose loading. In hypertensive, but not in nonhypertensive diabetic subjects, a significant increase of systolic and diastolic blood pressure was observed at 90' and 120' of the oral glucose tolerance test (p < 0.01). These data show that hyperglycemia can counteract the hypotensive effects of the antioxidant glutathione, suggesting that glucose may impair arterial relaxation by producing free radicals. Also, it appears that hypertension in diabetic patients is aggravated by high glucose plasma levels.

Abnormal rheologic effects of glyceryl trinitrate in patients with non-insulin-dependent diabetes mellitus and reversal by antioxidants.

OBJECTIVE: To evaluate 1) the hemorrheologic and hemodynamic effects of glyceryl trinitrate in patients with non-insulin-dependent diabetes mellitus and 2) the influence of antioxidants on these effects. DESIGN: Case-control study. SETTING: University hospital clinic. PATIENTS: 40 patients with diabetes and no evidence of cardiovascular complications and 40 controls matched for demographic variables and body habitus. INTERVENTIONS: Sublingual glyceryl trinitrate (0.3 mg) and transdermal glyceryl trinitrate patches (10 mg/d). Vitamin E, 300 mg/d orally for 7 days, and glutathione, 600 mg intravenously or intramuscularly, were given to test the effects of antioxidant supplementation. MEASUREMENTS: Systolic, diastolic, and mean arterial pressure and heart rate; left ventricular ejection fraction; platelet aggregation, blood viscosity, and blood filterability in vitro and ex vivo. RESULTS: Compared with controls, patients with diabetes had increased platelet aggregation to adenosine diphosphate (P < 0.005), increased blood viscosity (P < 0.001), and decreased blood filterability (P = 0.041) at baseline; blood pressure, heart rate, and ejection fraction were similar in the two groups. In controls, both sublingual glyceryl trinitrate and transdermal glyceryl trinitrate patches significantly reduced platelet aggregation (-38%; 95% CI, -49% to -27%) and blood viscosity (-8%; CI, -11% to -5%) and increased blood filterability (10%; CI, 7.0% to 13.1%). Slight but significant decreases in blood pressure and ejection fraction and an increase in heart rate were also seen in controls after administration of glyceryl trinitrate (both preparations). In patients with diabetes, glyceryl trinitrate paradoxically increased platelet aggregation (24%; CI, 15% to 33%) and blood viscosity (6%; CI, 2.9% to 8.8%) and decreased blood filterability (-7%; CI, -9.5% to -4.4%); hemodynamic values did not change significantly. In both groups, rheologic responses to glyceryl trinitrate (end concentration, 100 and 200 ng/mL) in vitro were similar to those seen in ex vivo studies. Vitamin E and glutathione normalized rheologic responses to glyceryl trinitrate in patients with diabetes. CONCLUSIONS: Organic nitrates have beneficial effects on blood rheology in controls but not in patients with diabetes, in whom a paradoxical deterioration is seen. Antioxidant supplementation can normalize primary tolerance to the rheologic effects of nitrates in diabetes.

Tolrestat in the primary prevention of diabetic neuropathy.

OBJECTIVE: To compare the effects of tolrestat and placebo in patients with subclinical diabetic neuropathy. RESEARCH DESIGN AND METHODS: Non-insulin-dependent diabetes mellitus (NIDDM) patients with early involvement of the autonomic nervous system were identified by only one pathological (outside the 99% confidence interval of the normal population) squatting test (vagal or sympathetic). Fifty-seven patients entered a randomized, placebo-controlled, double-blind, parallel 52-week study of tolrestat at a dose of 200 mg/day. Cardiovascular reflex tests (squatting vagal and sympathetic tests, pressure gain, deep breathing, lying-to-standing, Valsalva maneuver, and orthostatic hypertension), vibration thresholds, tendon reflexes, and muscle strength were assessed throughout the study. RESULTS: At 12 months, nerve function significantly improved in patients receiving tolrestat and deteriorated in patients taking placebo. At baseline, the squatting vagal test was normal in 16 patients in the tolrestat group and in 15 patients in the placebo group. At 12 months, 25 patients taking tolrestat had a normalized squatting test, but only 6 patients taking placebo did (P = 0.02). Vibration perception threshold improved by a value of 6 +/- 3 V in the tolrestat group (P < 0.001) and deteriorated by a value of 3 +/- 1.8 V (P < 0.001) in the placebo group. CONCLUSIONS: Tolrestat may be useful in the primary prevention of diabetic neuropathy.

Hyperinsulinemia in glucose intolerance: is it true?

To evaluate whether beta-cell hyperfunction characterizes glucose intolerant states per se independent of fasting glycemia, we conducted a case-control study among 430 subjects who were classified, by NDGG criteria, as having normal glucose tolerance (n = 230, 130M/130F), nondiagnostic tolerance (NDT, n = 100, 50M/50F) and impaired glucose tolerance (IGT, n = 100, 50M/50F). Thirty-four subjects (17M/17F) with normal glucose tolerance were matched by age, sex, body mass index (BMI), waist-to-hip ratio (WHR), fasting glucose and HbA1c with 30 NDT (15M/15F) and 30 IGT (15M/15F) subjects. The continuous and significant increase in insulin and C-peptide levels across categories of glucose tolerance (from normal to NDT to IGT) was no longer evident in the case-control study: at a fasting plasma glucose ranging from 5.2-5.5 mmol/L (HbA1c was 5%) the concentration of fasting C-peptide was 0.793 +/- 225 nmol/L (mean +/- SD) in subjects with normal glucose tolerance, 0.805 +/- 200 nmol/L in NDT and 0.807 +/- 231 nmol/L in IGT subjects (p = NS). Similarly, plasma concentrations of triglycerides and blood pressure values were similar when subjects of different categories were compared at the same level of glycemia. Sixteen normal subjects were rendered mildly hyperglycemic by a 24-h glucose infusion to match the fasting glucose level of NDT (1 mg/kg/min) and IGT (2 mg/kg/min) subjects. At the same fasting glucose level, normal subjects presented elevations of fasting C-peptide significantly (p < 0.01) higher than subjects belonging to the NDT and IGT categories.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of nitrendipine and cilazapril in patients with hypertension and non-insulin-dependent diabetes mellitus.

The metabolic and cardiovascular effects of nitrendipine and cilazapril in patients who have elevated blood pressure and non-insulin-dependent diabetes mellitus (NIDDM) were compared. After at least 6 weeks of a washout period, 20 NIDDM patients who had diastolic blood pressure in the range of 90-105 mm Hg received a single-blind placebo for 4 weeks and then were randomized to receive 20 mg nitrendipine once daily and 5 mg cilazapril once daily each for 12 weeks according to a crossover, double-blind procedure. Nitrendipine and cilazapril reduced diastolic blood pressure levels 12% and 13%, left ventricular mass index (LVMI) levels 13% and 12%, and raised whole glucose disposal levels 18% and 19.5%, respectively. Only nitrendipine reduced glucose-stimulated insulin levels. Nitrendipine is as effective as cilazapril in lowering diastolic blood pressure and LVMI levels and in increasing glucose disposal levels in these patients.

Coronary artery disease in type-2 diabetes mellitus: a scintigraphic study.

This study was aimed at evaluating the level of metabolic control and cardiovascular risk factors in a population of Type 2 diabetic patients with coronary artery disease. We used myocardial thallium-201 scintigraphy as a measure of coronary perfusion integrity. One hundred and forty six diabetic patients presenting with chest pain, ischaemic ECG changes or a positive exercise test underwent myocardial thallium-201 imaging perfusion in conjunction with exercise stress. Scintigrams were assessed by a computer assisted image analysis. The cardiovascular risk factors considered were sex, age, BMI and waist-hip ratio, smoking, systolic and diastolic blood pressure, serum lipids (total cholesterol and triglycerides), glycated haemoglobin A1, urinary albumin excretion, white blood cell count, and diabetes duration. The proportion of male diabetic subjects with a positive scintigraphy was 63% while that of diabetic women was 45% (p < 0.05). Mean age, anthropometric measures and diabetes indices were similar when diabetic patients with positive or negative scintigraphy were compared. The prevalence of patients with microalbuminuria and retinopathy (both non-proliferative and proliferative) was higher in positive (26% and 27%, respectively) than in negative (10% and 11%, respectively, p = 0.01) diabetic patients. Total cholesterol and white blood cell counts were also higher in positive diabetics (p < 0.05-0.01). These findings suggest that a cluster of risk factors (cholesterol, white blood cells, microalbuminuria) may be implicated in the development of coronary artery disease in Type 2 diabetes mellitus.

Hyperinsulinemia in hypertension: increased secretion, reduced clearance or both?

Peripheral hyperinsulinism is said to be associated and perhaps implicated in the pathogenesis of hypertension. There is however some inconsistency in the evidence of the relationship between insulin and blood pressure. We prospectively investigated glucose metabolism, insulin and C-peptide values and serum lipids in a large sample of hypertensive as compared with age and body habitus-matched normotensive subjects. As a group, the 145 hypertensives (blood pressure: 160/99 +/- 8.5/6.5 mmHg, mean +/- SD) had significantly elevated fasting plasma insulin (p < 0.02), total and LDL-cholesterol (p < 0.01) than 132 normotensive control subjects. The fasting HbA1c (glycated hemoglobin A1c)/insulin ratio, an estimate of insulin sensitivity, was significantly lower (5.15 +/- 1.45) in the hypertensives than normotensives (5.8 +/- 1.5, p < 0.001). Hypertensives had normal fasting C-peptide levels and lower C-peptide/insulin molar ratios, indicating low hepatic insulin extraction. There was no correlation between mean blood pressure (1/3 systolic + 2/3 diastolic) and fasting serum C-peptide (p = 0.14), insulin (p = 0.11), HbA1c/insulin ratio (p = 0.6), C-peptide/insulin ratio (p = 0.22) and HbA1c (p = 0.19), even after adjusting for age, BMI and family history of diabetes. The differences between hypertensives and normotensives persisted after dividing the subjects according to the presence/absence of either obesity or impaired glucose tolerance, but the significance was lost due to the smaller samples of the subgroups. The obese hypertensives with impaired glucose tolerance had the lowest values of insulin sensitivity and clearance in the fasting state.(ABSTRACT TRUNCATED AT 250 WORDS)

Is a family history of diabetes associated with an increased level of cardiovascular risk factors? Studies in healthy people and in subjects with different degree of glucose intolerance.

In order to evaluate whether the presence of a positive family history of diabetes (PFH) may have a negative impact on both glucose metabolism and cardiovascular risk factors, we studied parameters of carbohydrate metabolism (fasting and 2h-plasma glucose, HbA1c) and beta-cell function (fasting insulin and C-peptide), as well as the levels of some established cardiovascular risk factors (total cholesterol and triglycerides, HDL-cholesterol, blood pressure) in 729 subjects who were seen within the frame of a Regional Health Program in Taranto, South Italy. According to the NDDG criteria, 147 men and 235 women had normal glucose tolerance, 54 men and 66 women non-diagnostic OGTT, 65 men and 79 women impaired glucose tolerance, and 45 men and 58 women newly-diagnosed Type 2 diabetes. There was a continuous increase of PFH across the categories of glucose intolerance (p < 0.001). Subjects with PFH were younger (4 years on the average) than subjects without PFH. After adjustment for age, there was no difference in the clinical and metabolic parameters considered across the categories of glucose tolerance between subjects with or without PFH. Only in OGTT-diagnosed diabetics, was the presence of PFH associated with significantly greater levels of total cholesterol and 2h-plasma glucose, as well as a trend for triglycerides and HbA1c to be higher. There was a continuous increase in fasting glucose, HbA1c, insulin and C-peptide across the categories; however, the C-peptide/insulin molar ratio was lowest in OGTT-diagnosed diabetics. There was a graded and significant increase in the levels of cardiovascular risk factors across the categories.(ABSTRACT TRUNCATED AT 250 WORDS)

The combination of insulin and oral hypoglycaemic drugs: a continuous challenge.

A large number of studies have demonstrated the efficacy and usefulness of combining insulin and sulfonylurea therapy in Type 2 diabetic patients with secondary therapeutic failure. Better glycaemic profiles and/or decreased insulin needs, which are shown to persist after a maximum of 5 years, have been reported in diabetic patients on combination therapy. Residual beta-cell function appears to be a prerequisite for a favourable effect of combined therapy since the diabetics who continued to benefit from this were those whose C-peptide levels (both fasting and stimulated) remained greater than baseline. The concept of combined therapy might not be confined to sulfonylurea: the biguanide, metformin, has been found useful in obese diabetic patients with secondary failure. The combination of insulin with other new promising drugs or triple associations (insulin+sulfonylurea+biguanide) are also worth considering.

Impaired fibrinolytic response to increased thrombin activation in type 1 diabetes mellitus: effects of the glycosaminoglycan sulodexide.

Data on fibrinolysis in diabetes mellitus are still unclear, as is the role of hyperglycaemia on this topic and the possibility of any therapeutic intervention. In this study we examined fibrinopeptide A, tissue plasminogen activator and plasminogen activator inhibitor plasma levels in Type 1 diabetic patients compared to matched healthy normal controls, and the effect of induced hyperglycaemia on these parameters. At the same time the effect of a glycosaminoglycan, Sulodexide, administration during hyperglycaemia was evaluated. Fibrinopeptide A and plasminogen activator inhibitor were increased while tissue plasminogen activator was decreased in Type 1 diabetic patients, in the basal state. Induced hyperglycaemia increases fibrinopeptide A formation and tissue plasminogen activator concentrations, while it decreases plasminogen activator inhibitor levels more in normal subjects than in diabetic patients. Sulodexide consistently reduces this phenomenon. This study shows an altered fibrinolytic response to increased thrombin activation in Type 1 diabetic patients and suggests that the administration of the glycosaminoglycan, Sulodexide, may help to reduce this phenomenon.

Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors.

The efficacy and safety of metformin in the treatment of obese, non-insulin-dependent, diabetic subjects poorly controlled by insulin after secondary failure to respond to sulphonylureas has been investigated. Fifty insulin-treated, obese diabetics participated in this prospective, randomised double-blind six-month trial. After a four-week run-in period, during which all patients were given placebo (single-blind), patients were randomly assigned to continue to receive placebo or to active treatment with metformin. At six months, there was a relevant and significant improvement in glycaemic control in diabetics receiving the combined insulin-metformin treatment (decrease in glucose -4.1 mmol.l-1; glycosylated haemoglobin A1 decrease -1.84%). No significant changes were seen in diabetics receiving insulin and placebo. There was a significant decrease in blood lipids (trygliceride and cholesterol), an increase in HDL-cholesterol and a reduction in blood pressure in diabetics taking metformin. These positive findings were most marked in the 14 diabetics who experienced a good response to metformin (glucose profile < 10 mmol.l-1), and were less marked but still significant in the remaining 13 diabetics, whose response to therapy was not so good (glucose profile > 10 mmol.l-1). The fasting insulin level was significantly lower after six months of combined insulin-metformin treatment as shown by a 25% reduction in the daily dose of insulin (-21.6 U/day). Metformin was well tolerated by all diabetics.(ABSTRACT TRUNCATED AT 250 WORDS)

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

OBJECTIVE: To evaluate the effectiveness and safety of tolrestat, an aldose-reductase inhibitor, in patients with mild diabetic autonomic and peripheral neuropathy. DESIGN: Randomized, placebo-controlled, double-blind 52-week trial. SETTING: University hospital clinic. PATIENTS: Forty-five diabetic patients with asymptomatic autonomic neuropathy identified by at least one pathologic cardiovascular reflex test result. INTERVENTIONS: All patients were given placebo during a 4-week run-in period (single-blind). Twenty patients were randomly assigned to continue to receive placebo, and 25 were assigned to treatment with tolrestat (200 mg/d given in the morning). MEASUREMENTS AND RESULTS: At 12 months, improvements in nerve functions occurred in patients receiving tolrestat. Compared with baseline values, postural hypotension decreased by a value of 5.9 mm Hg (95% Cl, 1.6 to 8.7); deep-breathing, maximum/minimum heart rate (expiration/inspiration ratio) increased by a value of 0.026 (Cl, 0.015 to 0.036); and lying-to-standing heart rate ratio (30:15 ratio) increased by a value of 0.032 (Cl, 0.027 to 0.052). In the placebo group, all test results except postural hypotension deteriorated. Vibration perception threshold at the malleolus and great toe of the dominant leg improved in the tolrestat group (-1.4; Cl, -3.69 to -1.09) but tended to worsen in the placebo group during the study period. No important side effects were detected in either group. CONCLUSIONS: The progression of mild diabetic autonomic and peripheral neuropathy may be halted or even reversed by pharmacologic intervention with the aldose-reductase inhibitor tolrestat.

New insights on non-enzymatic glycosylation may lead to therapeutic approaches for the prevention of diabetic complications.

It is generally accepted that chronic hyperglycaemia is responsible for most of the long-term complications of diabetes. Several studies suggest that accelerated non-enzymatic glycosylation may be the underlying mechanism by which hyperglycaemia causes complications. More recently, glucose auto-oxidation has been linked to non-enzymatic glycosylation, and glycosylated proteins have been shown to be a source of free radicals. These findings suggest the possibility that oxidative stress may be related to the development of diabetic complications. Anti-oxidants such as vitamins C and E have recently been demonstrated to reduce protein glycosylation both in vivo and in vitro. In addition they also act as scavengers of free radicals generated by non-enzymatic glycosylation of protein. These findings may lead to new therapeutic approaches for the prevention of complications by limiting the damage caused by non-enzymatic glycosylation and oxidant stress. Such therapies may also be useful in complementing existing treatment in those with the long-term complications of diabetes.