Kim G. Stanton

The effect of combined aerobic and resistance exercise training on vascular function in Type 2 diabetes

OBJECTIVES The purpose of this study was to examine whether exercise training stimulates a generalized improvement in vascular function in patients with type 2 diabetes mellitus. BACKGROUND Exercise is often recommended for patients with type 2 diabetes to improve physical conditioning and glycemic control. This study examined the effect of eight weeks of exercise training on conduit and resistance vessel function in patients with type 2 diabetes, using a randomized crossover design. METHODS Both resistance vessel endothelium-dependent and -independent functions were determined by forearm plethysmography and intrabrachial infusions of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, in 16 patients with type 2 diabetes. Conduit vessel endothelial function was assessed in 15 of these patients using high-resolution ultrasound and flow-mediated dilation of the brachial artery; glyceryl trinitrate (GTN) was used as an endothelium-independent dilator. RESULTS Flow-mediated dilation increased from 1.7 +/- 0.5% to 5.0 +/- 0.4% following training (p < 0.001). The forearm blood flow ratio to ACh was significantly improved (analysis of variance, p < 0.05). Responses to SNP and GTN were unchanged. Endothelium-dependent vasodilation was enhanced in both conduit and resistance vessels. CONCLUSIONS If endothelial dysfunction is an integral component of the pathogenesis of vascular disease, as currently believed, this study supports the value of an exercise program in the management of type 2 diabetes.

Improvement in endothelial function by angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus.

OBJECTIVES The aim of this study was to assess the effect of angiotensin-converting enzyme (ACE) inhibition with enalapril on forearm endothelial function in subjects with type II diabetes mellitus. BACKGROUND Endothelial function is depressed in the presence of conventional risk factors for atherosclerosis, and various therapies, such as lipid-lowering therapy in hypercholesterolemia, can improve endothelial-mediated vasodilation. ACE inhibition has improved such function in several conditions including type I diabetes, but there is no evidence for a beneficial effect in type II diabetes. METHODS The influence of enalapril (10 mg twice daily for 4 weeks) on endothelium-dependent and -independent vasodilator function was determined in 10 type II diabetic subjects using a double-blinded placebo-controlled crossover protocol. Forearm blood flow was measured using strain-gage plethysmography and graded intrabrachial infusion of acetylcholine (ACh), N(G)-monomethyl-L-arginine (LNMMA) and sodium nitroprusside (SNP). RESULTS Enalapril increased the response to the endothelium-dependent vasodilator, ACh (p < 0.02) and the vasoconstrictor response to the nitric oxide (NO) synthase inhibitor, LNMMA (p < 0.002). No difference was evident in the response to SNP. CONCLUSIONS In type II diabetic subjects without evidence of vascular disease, the ACE inhibitor enalapril improved stimulated and basal NO-dependent endothelial function. The study extends the spectrum of beneficial effects demonstrated to result from ACE inhibition in diabetes.

Effects of a short-term circuit weight training program on glycaemic control in NIDDM

This study assessed the effects of short-term circuit weight training (CWT) on glycaemic control in NIDDM. Twenty-seven untrained, sedentary subjects (mean age, 51) with NIDDM participated in an 8-week randomised, controlled study, involving either CWT 3 days/week (n = 15) or no formal exercise (control) (n = 12). All subjects performed regular self-blood glucose monitoring throughout. Fasting serum glucose and insulin were measured following a 12-h fast and during an oral glucose tolerance test (75 g) before and after 8 weeks. Twenty-one subjects completed the study (CWT, n = 11) (Control, n = 10). Strength for all exercises improved significantly after CWT. Pooled time-series analysis, using a random effects model, revealed an overall decrease in self-monitored glucose levels with CWT compared to controls. Significant reductions from baseline values were observed in both the glucose (-213 mmol l-1 per 120 min, P < 0.05) and insulin (-6130 pmol l-1 per 120 min, P < 0.05) area under the curve following CWT relative to controls. After adjustment for body mass changes, the change in self-monitored glucose levels and insulin area under the curve, but not glucose area under the curve, remained significant. Short-term CWT therefore may provide a practical exercise alternative in the lifestyle management of this condition.

The Independent and Combined Effects of Aerobic Exercise and Dietary Fish Intake on Serum Lipids and Glycemic Control in NIDDM: A randomized controlled study

OBJECTIVE The triglyceride-lowering effects of ω-3 fats and HDL cholesterol-raising effects of exercise may be appropriate management for dyslipidemia in NIDDM. However, fish oil may impair glycemic control in NIDDM. The present study examined the effects of moderate aerobic exercise and the incorporation of fish into a low-fat (30% total energy) diet on serum lipids and glycemic control in dyslipidemic NIDDM patients. RESEARCH DESIGN AND METHODS In a controlled, 8-week intervention, 55 sedentary NIDDM subjects with serum triglycerides > 1.8 mmol/l and/or HDL cholesterol < 1.0 mmol/l were randomly assigned to a low-fat diet (30% daily energy intake) with or without one fish meal daily (3.6 g ω-3/day) and further randomized to a moderate (55–65% VO2max) or light (heart rate < 100 bpm) exercise program. An oral glucose tolerance test (75 g), fasting serum glucose, insulin, lipids, and GHb were measured before and after intervention. Self-monitoring of blood glucose was performed throughout. RESULTS In the 49 subjects who completed the study, moderate exercise improved aerobic fitness (VO2max) by 12% (from 1.87 to 2.07 l/min, P = 0.0001). Fish consumption reduced triglycerides (0.80 mmol/l, P = 0.03) and HDL3 cholesterol (0.05 mmol/l, P = 0.02) and increased HDL2 cholesterol (0.06 mmol/l, P = 0.01). After adjustment for age, sex, and changes in body weight, fish diets were associated with increases in GHb (0.50%, P = 0.05) and self-monitored glucose (0.57 mmol/l, P = 0.0002), which were prevented by moderate exercise. CONCLUSIONS A reduced fat diet incorporating one daily fish meal reduces serum triglycerides and increases HDL2 cholesterol in dyslipidemic NIDDM patients. Associated deterioration in glycemic control can be prevented by a concomitant program of moderate exercise.

Losartan, an angiotensin type 1 receptor antagonist, improves endothelial function in non-insulin-dependent diabetes.

OBJECTIVES The present study examined the effect on forearm endothelial function of an angiotensin II type 1 receptor antagonist, losartan, in subjects with non-insulin-dependent diabetes mellitus (NIDDM). BACKGROUND Angiotensin-converting enzyme (ACE) inhibition with enalapril improves acetylcholine (ACh)-dependent endothelial function in patients with NIDDM. This could be mediated through angiotensin II and the type 1 receptor or could be due to inhibition of kininase II and a bradykinin preserving effect. It is therefore relevant to determine whether a type 1 receptor antagonist improves endothelial function. METHODS The influence of losartan (50 mg daily for four weeks) on endothelium-dependent and independent vasodilator function was determined in 9 NIDDM subjects using a double-blinded placebo-controlled crossover protocol. Forearm blood flow was measured using strain-gauge plethysmography. RESULTS Losartan significantly decreased infused arm vascular resistance in response to three incremental doses of intrabrachial acetylcholine (p < 0.05, ANOVA). The forearm blood flow ratio (flow in infused to noninfused arm) was also increased (p < 0.01). Responses to sodium nitroprusside and monomethyl arginine were not significantly changed. CONCLUSIONS Losartan administration at 50 mg per day improved endothelium-dependent dilation of resistance vessels in patients with NIDDM. That is, blockade of the angiotensin II type 1 receptors improves endothelial function in NIDDM. At least some of the similarly beneficial effect of ACE inhibition is probably mediated also through the angiotensin II-type 1 receptor pathway. The use of a type 1 receptor antagonist seems a reasonable alternative to an ACE inhibitor to maintain endothelial function in NIDDM subjects.

Benefits and Safety of Long-Term Fenofibrate Therapy in People With Type 2 Diabetes and Renal Impairment The FIELD study

OBJECTIVE Diabetic patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) are at particular cardiovascular risk. Fenofibrate’s safety in these patients is an issue because it may elevate plasma creatinine. Furthermore, guidelines regarding fenofibrate dosing in renal impairment vary internationally. We investigated fenofibrate’s effects on cardiovascular and end-stage renal disease (ESRD) events, according to eGFR, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. RESEARCH DESIGN AND METHODS Type 2 diabetic patients (aged 50–75 years) with eGFR ≥30 mL/min/1.73 m2 were randomly allocated to a fixed dose of fenofibrate (200 mg daily) (n = 4,895) or placebo (n = 4,900) for 5 years. Baseline renal function (Modification of Diet in Renal Disease equation) was grouped by eGFR (30–59, 60–89, and ≥90 mL/min/1.73 m2). The prespecified outcome was total cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary/carotid revascularization). Serious adverse events and instances of ESRD (plasma creatinine >400 μmol/L, dialysis, renal transplant, or renal death) were recorded. Analysis was by intention to treat. RESULTS Overall, fenofibrate reduced total cardiovascular events, compared with placebo (hazard ratio 0.89 [95% CI 0.80–0.99]; P = 0.035). This benefit was not statistically different across eGFR groupings (P = 0.2 for interaction) (eGFR 30–59 mL/min/1.73 m2: 0.68 [0.47–0.97], P = 0.035; eGFR ≥90 mL/min/1.73 m2: 0.85 [0.70–1.02], P = 0.08). ESRD rates were similar between treatment arms, without adverse safety signals of fenofibrate use in renal impairment. CONCLUSIONS Patients with type 2 diabetes and moderate renal impairment benefit from long-term fenofibrate, without excess drug-related safety concerns compared with those with no or mild renal impairment. Fenofibrate treatment should not be contraindicated in moderate renal impairment, suggesting that current guidelines may be too restrictive.

Losartan, an angiotensin type I receptor antagonist, improves conduit vessel endothelial function in Type II diabetes.

We have demonstrated previously that inhibition of angiotensin-converting enzyme (ACE) with enalapril and angiotensin II blockade with losartan improve acetylcholine-dependent endothelial function in resistance vessels of patients with Type II diabetes. It was therefore of interest to examine the effect of losartan on conduit vessel function in this group. The influence of losartan (50 mg daily for 4 weeks) on endothelium-dependent and -independent vasodilator function was determined in 12 subjects with Type II diabetes using a randomized, double-blind, placebo-controlled crossover protocol. Conduit vessel endothelial function was assessed using high-resolution ultrasound and the brachial artery response to reactive hyperaemia (flow-mediated dilation; FMD); glyceryl trinitrate (GTN) was used as a non-endothelium-dependent dilator. Losartan administration significantly increased the FMD response from 5.2+/-0.7% (mean+/-S.E.M.) to 7.4+/-0.6% of vessel diameter (P<0.05; paired t-test). There was no effect of losartan on the endothelium-independent responses to GTN (17.8+/-1.8% to 17.6+/-1.2%). Consistent with our previous findings in resistance vessels, administration of 50 mg of losartan daily improves NO-mediated dilation in the conduit vessels of subjects with Type II diabetes. Together with the findings that both ACE inhibition and angiotensin II blockade improve resistance vessel function in this group, it is likely that at least some of the beneficial effect is mediated through the angiotensin II/type I receptor pathway. A type I receptor antagonist seems a reasonable alternative to an ACE inhibitor to maintain conduit vessel endothelial function in Type II diabetic subjects.

Homocysteine, folate, methylene tetrahydrofolate reductase genotype and vascular morbidity in diabetic subjects.

In the present study, the determinants of fasting plasma homocysteine in diabetic subjects were examined; whether plasma homocysteine and vascular disease are related and the influence of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene on serum and erythrocyte folate, plasma homocysteine and vascular disease. Diabetic clinic subjects (Type I, n=354; Type II, n=392) were recalled for a cross-sectional survey. Standard methods were used to measure biochemical variables and to characterize vascular disease and MTHFR genotype. Plasma homocysteine was significantly and directly related to age, male sex and serum urea, and inversely related to serum folate and vitamin B12, independently in stepwise regression. When corrected for age and sex, homocysteine was significantly related to hard end points of coronary artery disease and stroke (each P<0.01), remaining significant when additionally adjusted for serum folate (P=0.043 and P=0.019 respectively). Serum folate was not clearly related to these events, although there was a trend to associate with the lower quintile of serum folate. The MTHFR genotype was not a determinant of plasma homocysteine, even in those in the lowest quintile of serum folate, nor of vascular disease. TT homozygosity at residue 677 was associated with elevation of total erythrocyte folate compared with both other genotypes (P<0.0001), almost certainly due to the diversion of 5,10-methylenetetrahydrofolate into derivates subsequent to the partial metabolic block that results from the MTHFR enzyme defect. In conclusion, in this clinic cohort of people with diabetes, vascular disease is related to plasma homocysteine, which is correlated with serum folate. The MTHFR genotype does not significantly influence either plasma homocysteine or vascular disease, despite it being a determinant of erythrocyte folate, which reflects its effect on folate metabolism.

Dietary fish oils increase serum lipids in insulin-dependent diabetics compared with healthy controls

The effect of daily dietary supplementation with fish oil on serum lipids and platelet total phospholipid fatty acids was examined in male normolipidemic insulin-dependent diabetics and normal controls. They were given 15 g/d of fish oil as Max EPA (equivalent to 2.7 g/d of eicosapentaenoic acid) for 3 weeks. The diabetics showed a rise in total cholesterol, attributable to increases in LDL- and HDL-cholesterol. The increase in HDL-cholesterol was largely due to a rise in its HDL2 subclass. There was also a decrease in triglycerides in both groups. Similar changes in lipids were seen in the normal controls, although these were not significant. The more pronounced effect in diabetics suggests an altered metabolic response to omega-3 fatty acids in that disorder. However, the results indicate that the possible detrimental effect of the rise in total and LDL-cholesterol following fish oil may be offset by the increase in the protective HDL2 subclass.

Risk factors for cardiovascular disease in a diabetic population

&NA; A study of the associations with cardiovascular disease (CVD) was made in subjects attending the Diabetic Clinic at Royal Perth Hospital. The variables examined were sex, age at time of study, age of onset of diabetes, duration of diabetes, mode of treatment, control (as assessed by fasting and post‐prandial plasma glucose concentrations and glycosylated hemoglobin concentration), insulin levels in subjects not on insulin, obesity, blood pressure, total‐ and high‐density lipoprotein and triglyceride concentrations, and smoking habit. CVD was diagnosed on the basis of (a) past history of myocardial infarction, (b) definite angina, (c) diagnostic ECG abnormality, and (d) cardiornegaly. A multiple logistic regression model identified the variables showing independent, significant associations with CVD as age, high‐density lipoprotein cholesterol, diastolic blood pressure, an interaction between smoking and age and an interaction between treatment mode and blood pressure. As in the population generally, high‐density lipoprotein cholesterol is the lipid variable showing the most significant association with prevalence of cardiovascular disease. Smoking is associated with a substantially increased risk of CVD in diabetics up to the age of about 70 yr. The use of oral hypoglycemic agents is associated with a lower prevalence of CVD in normotensive subjects, but with an increased risk in those who have systolic hypertension.