Skin reactive hyperemia in diabetic patients. A study by laser Doppler flowmetry.

OBJECTIVE: To assess whether laser Doppler flowmetry could detect differences in the cutaneous response to postischemic reactive hyperemia between patients with non-insulin-dependent diabetes mellitus (NIDDM) and nondiabetic controls and among subgroups of NIDDM patients. RESEARCH DESIGN AND METHODS: We measured the cutaneous blood flow on the forearms during the postischemic reactive hyperemia test in diabetic patients and nondiabetic controls. Subjects were 25 patients with NIDDM from the outpatient clinics of dermatology, ophthalmology, and endocrinology and 25 nondiabetic volunteers matched for sex and age. Of the patients with NIDDM, 14 had proliferative retinopathy, and 13 were obese. Cutaneous postischemic reactive hyperemia test monitored by measuring the cutaneous blood flow with laser Doppler flowmetry was used. Peak blood flow (P) after arterial occlusion, the time required to reach this peak (Tp) and the ratio (K) between these two quantities (K = P/Tp) were measured. RESULTS: In diabetic patients, P was significantly lower (P less than 0.02) than in nondiabetic control subjects. In diabetic patients with proliferative retinopathy, K was lower (P less than 0.05) than in diabetic patients without retinopathy. Diabetic patients with a body mass index (BMI; wt/ht2) less than 25 kg/m2 had a longer Tp (P less than 0.002), whereas the control group BMI did not affect this parameter. The combination of retinopathy and BMI less than 25 gave the longest Tp values (P less than 0.0001). CONCLUSIONS: Postischemic hyperemia tests in diabetic patients reveal cutaneous microcirculatory changes in the forearm (lower P). Advanced retinopathy is associated with functional disturbances (lower K), especially when combined with a low BMI (less than 25; longer Tp).     

Microcirculatory effects of KATP channel blockade by sulphonylurea derivatives in humans

BACKGROUND: Recent investigations have shown that glibenclamide inhibits the opening of vascular ATP-sensitive potassium channels during ischemia. This observation may implicate cardiovascular effects of sulphonylurea derivatives when used under conditions of ischemia in patients with Type 2 diabetes mellitus. In addition to resistance arteries, the (pre) capillary vessels also contain ATP-dependent potassium channels. Closure of these channels by sulphonylurea derivatives might affect the development of microvascular disease in Type 2 diabetes mellitus. Therefore, we investigated the microcirculatory effects of sulphonylurea derivatives in Type 2 diabetic patients as compared with healthy volunteers. MATERIALS AND METHODS: Arteriovenous blood flow (skin temperature and laser Doppler flux) and capillary blood cell velocity were measured before and during infusion of four doses of glibenclamide (0.1, 0.3, 1.0 and 3.0 microg min-1 dL-1) into the brachial artery of 14 Type 2 diabetic patients and 13 healthy controls. The experiments included appropriate time control studies. RESULTS: Both skin temperature and laser Doppler flux decreased in response to glibenclamide in healthy volunteers (-7 +/- 2%, P < 0.0005 and -31 +/- 11%, P = 0.001, respectively), but did not change in Type 2 diabetic patients (1 +/- 3%, P = 0.29 and 4 +/- 14%, P = 0.97). However, capillary blood cell velocity decreased in Type 2 diabetic patients (-38 +/- 18%, P = 0.04), but did not change in healthy volunteers (-1 +/- 11%, P = 0.28). CONCLUSIONS: The results of the present study indicate that glibenclamide indeed affects microvascular blood flow. Glibenclamide may induce redistribution of the microvascular skin flow from nutritive flow to arteriovenous shunt flow in Type 2 diabetic patients. Therefore, closure of ATP-dependent potassium channels by glibenclamide possibly plays a role in the development of microangiopathy in Type 2 diabetic patients.     

ACE inhibitors improve endothelial function in type 1 diabetic patients with normal arterial pressure and microalbuminuria.

OBJECTIVE: The purpose of this study was to test whether a short-course treatment with ACE inhibitors may restore endothelium-dependent and/or -independent vasodilation in the femoral artery of microalbuminuric patients with type 1 diabetes and normal arterial pressure. RESEARCH DESIGN AND METHODS: We studied nine normotensive microalbuminuric type 1 diabetic patients and two groups of control subjects matched for femoral artery diameter to type 1 diabetic patients after placebo (control group A, n = 17) and ACE inhibitor (control group B, n = 18) treatment, respectively. The patients were enrolled in a double-blind cross-over study with a 1-week trial of either placebo, captopril (25 mg t.i.d.), or enalapril (10 mg/day) in randomized order to ascertain whether short-term ACE inhibition obtained with (captopril) or without (enalapril) a sulfhydryl donor molecule ameliorates vessel wall function. Endothelium-mediated flow-dependent vasodilation and endothelium-independent vasodilation were evaluated in the right common femoral artery by echo Doppler. RESULTS: Both captopril and enalapril normalized (control group B 22.9+/-3.2% per 8 min) endothelium-dependent response (19.6+/-7.5 and 18.0+/-5.3 vs. -10.4+/-4.1% per 8 min, P < 0.01, for both captopril and enalapril versus placebo, respectively) in the type 1 diabetic patients. Captopril (28.4+/-3.5 vs. 17.1+/-3.5% per 5 min during placebo, P < 0.05) but not enalapril (20.1+/-3.0 vs. 31.7+/-2.8% per 5 min, P < 0.05 for enalapril versus control group B, and NS for captopril vs. control group B) ameliorated endothelium-independent vasodilation in type 1 diabetic patients. CONCLUSIONS: ACE inhibition improves endothelium-dependent vasodilation in the femoral artery of normotensive microalbuminuric type 1 diabetic patients. Captopril also ameliorates endothelium-independent vasodilation, possibly through its sulfhydryl donor properties. These results may be of pathophysiological relevance to prevent cardiovascular complications in these patients.     

L-arginine-induced vasodilation of the renal vasculature is preserved in uremic type 1 diabetic patients after kidney and pancreas but not after kidney-alone transplantation

OBJECTIVE: In uremic type 1 diabetic patients, kidney and pancreas transplantation (KP) and kidney-alone transplantation (KD) provide full restoration of normal renal function; however, only KP, i.e., curing diabetes, is expected to prevent endothelial damages. Our aim was to study L-arginine-induced vasodilation of the renal vasculature in uremic type 1 diabetic patients after KP or KD using magnetic resonance (MR). RESEARCH DESIGN AND METHODS: MR quantitative flow measurements were performed in 15 KP patients (mean age 39.0 +/- 1.7 years, 10 men and 5 women), in 11 KD patients (mean age 47.3 +/- 1.9 years, 7 men and 4 women), and in 8 nondiabetic kidney transplant patients (mean age 44.0 +/- 4.8 years, 7 men and 1 woman), who were used as control subjects, to measure renal blood flow and velocity and renal vascular resistance before and immediately after infusion of L-arginine. RESULTS: Renal blood flow and velocity were not different at baseline in KP, KD, and control subjects. In contrast, during L-arginine administration renal blood flow increased significantly in KP subjects (basal 8.4 +/- 0.6 vs. post 9.6 +/- 0.8 ml/s, Delta 14.3 +/- 4.4%, P < 0.05) and in control subjects (basal 9.3 +/- 0.8 vs. post 9.1 +/- 0.8 ml/s, Delta 17.3 +/- 6.2%, P < 0.01), while it remained unchanged in KD subjects (basal 10.0 +/- 0.8 vs. post 11.6 +/- 0.9 ml/s, Delta -1.36 +/- 6.9%, NS). Parallel results have been achieved for renal blood velocity (KP subjects: 20.1 +/- 4.9%, P < 0.01; control subjects: 23.0 +/- 7.99%, P < 0.01; and KD subjects: -0.3 +/- 6.5%; NS). A reduction in renal vascular resistance in response to L-arginine was evident in KP and control subjects but not in KD patients. CONCLUSIONS: L-Arginine vasodilatory response was successfully assessed with MR quantitative flow measurements. KP patients and control subjects, but not those with KD, showed a preserved L-arginine-induced vasodilation of the renal vasculature.     

Effects of cyclo-oxygenase inhibition on vasodilatory response to acetylcholine in patients with type 1 diabetes and nondiabetic subjects

OBJECTIVE: Studies examining vasodilatory responses to acetylcholine (ACh) and its derivatives have been conflicting. Enhanced activation of the cyclo-oxygenase pathway and increased availability of vasodilatory prostanoids may occur in type 1 diabetes, and this may compensate for the observed reduction in nitric oxide (NO) activity We examined the role of cyclo-oxygenase inhibition on vasodilatory responses in 12 healthy normotensive type 1 diabetic adults and 12 nondiabetic control subjects of similar age, sex, and BMI. RESEARCH DESIGN AND METHODS: Forearm blood flow was measured using a venous occlusion plethysmography technique at baseline and after brachial artery infusions of ACh (7.5, 15, and 30 microg/min). Forearm blood flow at baseline and after ACh was then reexamined after local intra-arterial infusion of indomethacin (0.3 mg/100 ml forearm volume), a cyclo-oxygenase inhibitor. RESULTS: Baseline blood flow in the diabetic and control groups were similar (2.65 +/- 0.26 vs. 2.59 +/- 0.20 ml/min per 100 ml, respectively; P = 0.4). After indomethacin infusion, the vasodilatory responses to all doses of ACh were reduced in both the diabetic (by 25.30 +/- 4.90%) and control group (by 11.23 +/- 5.45%). However, the reduction in blood flow response to ACh after indomethacin was greater in diabetic patients compared with control subjects (P = 0.03). CONCLUSIONS: Our findings suggest that vasodilatory, prostanoids are important in determining endothelial response to ACh in diabetic and nondiabetic subjects. Increased prostaglandin-mediated vasodilation may compensate for attenuated responses to NO previously reported in diabetic subjects. These findings may partly explain the conflicting reports of endothelial dysfunction in patients with type 1 diabetes.     

Vascular K(ATP) channel blockade by glibenclamide, but not by acarbose, in patients with Type II diabetes

Glibenclamide inhibits the opening of vascular ATP-sensitive potassium (K(ATP)) channels, which represents a protective mechanism during ischaemia. This effect may imply harmful cardiovascular effects of glibenclamide when used under conditions of ischaemia in patients with Type II diabetes. Acarbose is not associated with effects on the cardiovascular system, because the drug is not absorbed from the bowel. Therefore we hypothesized that treatment of Type II diabetes patients with glibenclamide will impair the vasodilator function of K(ATP) opening, unlike treatment with acarbose. A double-blind randomized cross-over study in 12 patients with Type II diabetes was performed to compare the effects of glibenclamide with those of acarbose on the vasodilator responses to K(ATP) channel opening in the forearm vascular bed. The study consisted of two periods: 8 weeks of treatment with orally administered glibenclamide (10 mg x day(-1)) followed by 8 weeks of treatment with acarbose (300 mg x day(-1)), or vice versa. At the end of each treatment period, forearm blood flow (venous occlusion plethysmography) in response to intra-arterially administered diazoxide, acetylcholine and dipyridamole and to forearm ischaemia was measured. The diazoxide-mediated increase in the forearm blood flow ratio (infused/control arm) was significantly less pronounced after glibenclamide than after acarbose (290 +/- 58% and 561 +/- 101% respectively; P<0.0005). Forearm blood flow responses to acetylcholine, dipyridamole and forearm ischaemia were similar during glibenclamide and acarbose treatment. Thus, in patients with Type II diabetes mellitus, treatment with glibenclamide is associated with an attenuated response to K(ATP) opening as compared with treatment with acarbose. This implies that glibenclamide may affect defensive mechanisms under conditions of K(ATP) channel activation.     

Interaction of sulfonylureas and exercise on glucose homeostasis in type 2 diabetic patients.

OBJECTIVE: To determine whether the plasma glucose-lowering effects of sulfonylureas and acute submaximal exercise are additive and, accordingly, to determine whether they may increase the risk of hypoglycemia when combined in fasting patients. RESEARCH DESIGN AND METHODS: Eight postabsorptive type 2 diabetic patients were examined at three occasions: after oral sulfonylurea (7 mg glibenclamide), during 60 min of ergometer cycle exercise at 57 +/- 3% of VO2max, and during exercise after glibenclamide. RESULTS: Heart rate, VO2, and lactate responses to exercise were comparable (P > 0.05) on days with and without glibenclamide. Plasma insulin concentrations were always increased by glibenclamide, and they were lowered identically by exercise with and without glibenclamide. However, throughout exercise, absolute concentrations of insulin were lower on days without glibenclamide compared with days with glibenclamide (34.5 +/- 4.7 vs. 47.4 +/- 5.5 pmol/l; P < 0.05). At the start of exercise, glucose concentrations were similar between experiments (P > 0.05). The rate of decrease in glucose during exercise was higher (P < 0.05) on days with both glibenclamide and exercise, compared with days with glibenclamide alone and days with exercise alone (-0.035 +/- 0.009 vs. -0.016 +/- 0.002 and -0.022 +/- 0.005 mmol.l-1.min-1, respectively). Consequently, the glucose nadir was lower on days with glibenclamide and exercise than on days with glibenclamide or exercise alone (6.7 +/- 1.1 vs. 8.1 +/- 0.9 and 7.6 +/- 1.0 mmol/l, respectively; P < 0.05). During exercise, the rate of appearance of plasma glucose determined by 3-[3H]glucose infusion was lower on days with glibenclamide than on days without glibenclamide (2.3 +/- 0.1 vs. 2.9 +/- 0.1 mg.min-1.kg-1; P < 0.05). In contrast, glucose clearance was identical (P > 0.05). CONCLUSIONS: In postabsorptive type 2 diabetic patients, the hypoglycemic action of glibenclamide and exercise is enhanced when the treatments are combined. The interaction reflects an increased inhibition by glibenclamide-enhanced insulin levels of hepatic glucose production when hepatic glucose production is accelerated by exercise.     

Delayed vascular reactivity to ischemia in diabetic microangiopathy

To investigate vascular responses in insulin-dependent diabetic patients both with and without retinopathy, we have assessed vasodilation by forearm transcutaneous pO2 measurement after 10 min of ischemia produced by a sphygmomanometer cuff. Diabetic patients with proliferative retinopathy had a delayed vasodilatory response at 60 s (mean +/- SD pO2 = 9 +/- 3 mm Hg) compared with those having diabetes without retinopathy (15 +/- 4 mm Hg, P less than 0.01) and matched normal subjects (14 +/- 4 mm Hg, P less than 0.01). Recently diagnosed insulin-dependent diabetic patients had a very similar response (15 +/- 5 mm Hg) to matched normal subjects (15 +/- 3 mm Hg). The diminished vascular reactivity may be a consequence of microangiopathy and neuropathy, although patients with an impaired vascular response might be particularly at risk from the development of capillary closure.     

Microvascular response in patients with cardiogenic shock

OBJECTIVE: To examine the mechanisms contributing to decreased microvascular blood flow in cardiogenic shock by comparing patients with cardiogenic shock with critically ill controls and with patients with septic shock. DESIGN: Prospective, consecutive entry of patients meeting the criteria for septic shock, cardiogenic shock, and critical illness without coexisting infection or shock. SETTING: University hospital, medical intensive care unit, coronary care unit, and respiratory care unit. PATIENTS: Eight patients with cardiogenic shock secondary to acute myocardial infarction, six critically ill controls, and six patients with septic shock. MEASUREMENTS AND MAIN RESULTS: Forearm blood flow was measured at rest and during reactive hyperemia by venous air plethysmography. Red cell deformability was determined by filtration. Leukocyte aggregation was detected by the leukergy test. Neutrophil CD11b/CD18 expression and soluble intercellular adhesion molecule-1 levels were also measured. In cardiogenic shock, forearm arterial resistance was significantly increased at rest and during reactive hyperemia compared with controls and patients with septic shock. The response to reactive hyperemia was attenuated in cardiogenic and septic shock patients, as measured by the absolute change in forearm blood flow from baseline, which was significantly less as compared with controls (p < .01). The percent change in forearm blood flow during reactive hyperemia compared with forearm blood flow at rest was significantly lower in cardiogenic shock (60+/-10) and in septic shock (50+/-11) compared with controls at baseline (145+/-20; p < .01). Red cell deformability was significantly decreased in cardiogenic shock (1.2+/-0.2 mL/min; p < .05) and septic shock (1.1+/-0.2 mL/min; p < .05), compared with controls (1.8+/-0.1 mL/min). Neutrophil CD11b/CD18 expression, leukergy, and serum intercellular adhesion molecule-1 levels in cardiogenic shock patients were not significantly different from controls. CONCLUSION: These data suggest that the response to reactive hyperemia is attenuated in cardiogenic shock. This appears to reflect increased vasoconstriction and an impaired capacity for vasodilation. Decreased erythrocyte deformability may also be important in limiting systemic microvascular flow. However, evidence supporting a role for neutrophil-endothelial cell interactions was not observed.     

Contribution of nerve-axon reflex-related vasodilation to the total skin vasodilation in diabetic patients with and without neuropathy

OBJECTIVE: To examine the contribution of nerve-axon reflex-related vasodilation to total acetylcholine-induced vasodilation in the skin of normal and diabetic subjects. RESEARCH DESIGN AND METHODS: The skin microcirculation was evaluated at the forearm level in 69 healthy subjects and 42 nonneuropathic diabetic patients and at the foot level in 27 healthy subjects and 101 diabetic patients (33 with neuropathy, 23 with Charcot arthropathy, 32 with peripheral vascular disease and neuropathy, and 13 without complications). Two single-point laser probes were used to measure total and neurovascular vasodilation response to the iontophoresis of 1% acetylcholine, 1% sodium nitroprusside, and deionized water. RESULTS: The neurovascular response to acetylcholine was significantly higher than the response to sodium nitroprusside and deionized water (P < 0.01). At the forearm level, the contribution of neurovascular response to the total response to acetylcholine was 35% in diabetic patients and 31% in control subjects. At the foot level, the contribution was 29% in diabetic patients without neuropathy and 36% in control subjects, while it was significantly diminished in the three neuropathic groups. A significantly lower nonspecific nerve-axon-related vasodilation was observed during the iontophoresis of sodium nitroprusside, which does not specifically stimulate the C nociceptive fibers. CONCLUSIONS: Neurovascular vasodilation accounts for approximately one-third of the total acetylcholine-induced vasodilation at both the forearm and foot levels. The presence of diabetic neuropathy results in reduction of both the total vasodilatory response to acetylcholine and the percentage contribution of neurovascular vasodilation to the total response. Acetylcholine and sodium nitroprusside cause vasodilation in the skin microcirculation through different pathways.     

Type 2 diabetic individuals have impaired leg blood flow responses to exercise: role of endothelium-dependent vasodilation

OBJECTIVE: Diabetic individuals have impaired endothelium-dependent forearm vasodilatory responses to ischemia, acetylcholine, and other endothelium-dependent agonists. The functional significance of impaired endothelium-dependent dilation in diabetic individuals is uncertain but is most likely to be manifest during leg muscle exercise and may have relevance to peripheral vascular disease and leg ischemia, which is prevalent in diabetic individuals. The current study aimed to determine the relationship between leg blood flow (LBF) responses to endothelium-dependent vasodilation and dynamic large muscle exercise. RESEARCH DESIGN AND METHODS: LBF responses (thermodilution) to intrafemoral arterial infusions of an endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilator and a standardized 25-min cycling bout at 60% VO(2peak) were compared in nine male type 2 diabetic subjects and nine age-, sex-, VO(2peak)-, and weight-matched control subjects. RESULTS: LBF responses to acetylcholine and exercise but not sodium nitroprusside were significantly (P < 0.05) attenuated in patients with diabetes compared with healthy control subjects. The percentage increase in LBF in response to exercise and acetylcholine were significantly correlated (r = 0.54, P = 0.02). Furthermore, resting plasma glucose was significantly related to the LBF response to exercise (r = -0.66, P = 0.003) independently of insulin, HbA(1c), lipids, BMI, and blood pressure. CONCLUSIONS: The increase in LBF during exercise is substantially attenuated in type 2 diabetic compared with matched control subjects. Impaired endothelium-dependent vasodilation secondary to elevated plasma glucose may underlie this observation. This mechanism may be of importance in determining the leg ischemic threshold in diabetic individuals with peripheral vascular disease.     

Insulin-induced decreases in aortic wave reflection and central systolic pressure are impaired in type 2 diabetes

OBJECTIVE: To determine whether large arteries are resistant to insulin. RESEARCH DESIGN AND METHODS: Insulin normally acutely decreases central systolic pressure by decreasing wave reflection in vivo. This effect occurs before any changes in peripheral vascular resistance or heart rate under normoglycemic conditions. We determined whether the ability of insulin to decrease central aortic pressure is altered in uncomplicated type 2 diabetes. The study subjects consisted of 16 type 2 diabetic patients (age 54 +/- 2 years, BMI 29 +/- 1 kg/m(2)) and 19 matched nondiabetic individuals (51 +/- 2 years, 29 +/- 1 kg/m(2)) studied under normoglycemic-hyperinsulinemic conditions. Central aortic pressure waveforms were synthesized from those recorded in the periphery using applanation tonometry and a validated reverse transfer function to construct the central aortic pressure waveform every 30 min. This method allowed determination of aortic augmentation (the pressure difference between the first and second central systolic pressure waves) and the augmentation index (augmentation divided by pulse pressure). RESULTS: Whole-body insulin sensitivity was 31% lower (P < 0.05) in the type 2 diabetic patients than in the normal subjects. Basally, before the insulin infusion, augmentation averaged 8.9 +/- 1.3 and 11.1 +/- 1.2 mmHg (NS) and the augmentation index averaged 23.1 +/- 2.1 and 27.5 +/- 2.1% (NS) in the normal subjects and diabetic patients, respectively. After 30 min of hyperinsulinemia, augmentation decreased significantly to 6.1 +/- 1.1 mmHg (P < 0.001) in the normal subjects but remained unchanged at 9.1 +/- 1.1 mmHg (NS) in type 2 diabetic patients. At 30 min, the augmentation index had decreased significantly (30 +/- 7% decrease) to 17.9 +/- 2.6% in the normal subjects but remained at 24.4 +/- 2.4% in the diabetic patients (13 +/- 4% decrease, P < 0.05 for change vs. normal subjects). Central systolic pressure decreased significantly by 30 min in the normal subjects but only after 120 min in the type 2 diabetic patients. There were no significant changes in heart rate, pulse pressure, or forearm blood flow during the first 120 min of the insulin infusion. CONCLUSIONS: Insulin resistance in type 2 diabetes involves a delay in the ability of insulin to decrease central aortic pressure. This defect could predispose these patients to develop systolic hypertension.     

Five-year follow-up study on plasma insulin levels in newly diagnosed NIDDM patients and nondiabetic subjects

A representative group of middle-aged (45- to 64-yr-old) patients with non-insulin-dependent diabetes mellitus (NIDDM) (n = 133; 70 men, 63 women) were examined at the time of diagnosis and 5 yr afterward for metabolic control and insulin response to oral glucose; 144 nondiabetic control subjects (62 men, 82 women) were similarly examined twice between 5-yr intervals. At the 5-yr examination, 56 of the diabetic patients (36 men, 20 women) were on diet therapy only, 60 (27 men, 33 women) received oral antidiabetic drugs, and 5 were treated with insulin. The metabolic control of diabetic patients was poor at the time of diagnosis and 5-yr examination. Fasting plasma insulin levels were higher in diabetic patients than in control subjects both at baseline (23 +/- 2 vs. 14 +/- 1 mU/L, P less than 0.01, for men; 26 +/- 2 vs. 15 +/- 1 mU/L, NS, for women) and 5-yr examination (19 +/- 1 vs. 16 +/- 2 mU/L, NS, for men; 29 +/- 5 vs. 15 +/- 1 mU/L, P less than 0.05, for women). The frequency of insulin deficiency in diabetic patients based on a postglucagon (1 mg i.v.) C-peptide level less than 0.60 nM was 3.3% at the 5-yr examination, indicating that true insulin deficiency was uncommon during the first years after diagnosis of diabetes in middle-aged subjects.     

Lack of cutaneous hyperemia in response to insulin-induced hypoglycemia in IDDM

Cutaneous blood flow was measured with the laser Doppler technique and by recording cutaneous O2 tension on the forearm and forehead in nine young adult patients with insulin-dependent diabetes mellitus (IDDM) and nine sex- and age-matched healthy control subjects after induction of hypoglycemia. In the healthy subjects, cutaneous blood flow measured with the laser Doppler technique was increased by 120 +/- 26% in the forehead (P less than 0.01) and 196 +/- 50% in the forearm (P less than 0.01) at the glucose nadir (blood glucose 1.8 +/- 0.2 mM) compared with basal blood flow. In contrast, in diabetic patients, cutaneous blood flow was unchanged. The corresponding changes, at the glucose nadir, with cutaneous O2 tension recordings were 286 +/- 131% (P less than 0.05) in control subjects and -22 +/- 15% (NS) in diabetic patients. An impairment of sympathetic nervous function, not detectable by simple cardiovascular tests, could be responsible for the lack of cutaneous hyperemia and sweating and could contribute to unawareness of hypoglycemia in diabetic patients.     

Comparison of the effects of three insulinotropic drugs on plasma insulin levels after a standard meal

OBJECTIVE: To compare the effects of repaglinide, glipizide, and glibenclamide on insulin secretion and postprandial glucose after a single standard 500-kcal test meal. RESEARCH DESIGN AND METHODS: A total of 12 type 2 diabetic patients with early diabetes (mean HbA(1c) of 6.1%) and 12 matched control subjects were enrolled in this randomized, double-blind, crossover trial. Subjects received placebo, 2 mg repaglinide, 5 mg glipizide, and 5 mg glibenclamide in a random fashion during the trial. Administration of each drug was followed by a single standard 500-kcal test meal. A washout period of 7-12 days existed between the four study visits. RESULTS: All three drugs were equally effective on the total prandial insulin secretion (area under the curve [AUC] -15 to 240 min). However, clear differences were noted in the early insulin secretion (AUC -15 to 30 min); both repaglinide and glipizide increased secretion in nondiabetic subjects by approximately 61 and 34%, respectively, compared with placebo. In the diabetic patients, the difference versus placebo was 37 and 47%, respectively. The difference between glipizide and glibenclamide reached significance in both groups of subjects, whereas repaglinide was more effective than glibenclamide only in the healthy nondiabetic subject group. All three drugs were effective in decreasing total glucose AUC in the nondiabetic and diabetic population. In the nondiabetic subjects, however, repaglinide was significantly more effective than glibenclamide. The differences disappeared in the diabetic subjects, probably as a result of increased prevalence of insulin resistance in this group. CONCLUSIONS: Repaglinide and glipizide but not glibenclamide significantly enhanced the early insulin secretion in both nondiabetic and diabetic subjects with preserved beta-cell function after a single standard meal.     

Angiotensin II attenuates the vasodilating effect of a nitric oxide donor,glyceryl trinitrate: roles of superoxide and angiotensin II type 1 receptors

OBJECTIVE: The development of tolerance to organic nitrates limits their usefulness in the treatment of heart disease. Activation of the renin-angiotensin system by heart failure itself and by nitrate therapy may be one possible mechanism underlying nitrate tolerance. We investigated the effect of subpressor doses of angiotensin II on the vasodilating effect of glyceryl trinitrate in human forearm resistance vessels of healthy male subjects by using venous occlusion strain-gauge plethysmography. METHODS: Glyceryl trinitrate was infused intra-arterially with angiotensin II or vehicle. The effect of blockade of angiotensin II type 1 receptors by candesartan or an antioxidant, vitamin C, on the interaction between angiotensin II and glyceryl trinitrate was also investigated. RESULTS: Angiotensin II infused at 5 pmol/min significantly attenuated the vasodilating effect of glyceryl trinitrate (mean +/- standard deviation [SD] of percentage change in forearm blood flow [FBF]: 28% +/- 20%, 79% +/- 59%, and 208% +/- 72% at 100, 250, and 1000 ng/min of glyceryl trinitrate with placebo; 8% +/- 18%, 47% +/- 41%, and 173% +/- 98% with angiotensin II at 1 pmol/min; and 2% +/- 27%, 39% +/- 40%, and 132% +/- 74% with angiotension II at 5 pmo;/min; P =.0259). Either a single dose of candesartan or coinfusion with vitamin C abolished the angiotensin II-induced attenuation of vasodilation of glyceryl trinitrate. CONCLUSION: Our results suggest that angiotensin II may attenuate the arterial vasodilating effect of glyceryl trinitrate through angiotensin type 1 receptors and presumably through receptor-mediated superoxide production, which may be relevant to the development of nitrate tolerance.     

Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus.

Endothelium-dependent vasodilation is impaired in humans with diabetes mellitus. Inactivation of endothelium-derived nitric oxide by oxygen-derived free radicals contributes to abnormal vascular reactivity in experimental models of diabetes. To determine whether this observation is relevant to humans, we tested the hypothesis that the antioxidant, vitamin C, could improve endothelium-dependent vasodilation in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus. We studied 10 diabetic subjects and 10 age-matched, nondiabetic control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intraarterial infusion of methacholine (0.3-10 micrograms/min). Endothelium-independent vasodilation was measured by intraarterial infusion of nitroprusside (0.3-10 micrograms/min) and verapamil (10-300 micrograms/min). Forearm blood flow dose-response curves were determined for each drug before and during concomitant intraarterial administration of vitamin C (24 mg/min). In diabetic subjects, endothelium-dependent vasodilation to methacholine was augmented by simultaneous infusion of vitamin C (P = 0.002); in contrast, endothelium-independent vasodilation to nitroprusside and to verapamil were not affected by concomitant infusion of vitamin C (P = 0.9 and P = 0.4, respectively). In nondiabetic subjects, vitamin C administration did not alter endothelium-dependent vasodilation (P = 0.8). We conclude that endothelial dysfunction in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus can be improved by administration of the antioxidant, vitamin C. These findings support the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes.     

Clinical Characteristics of Diabetic vs Nondiabetic Patients Who "Rule-in" for Acute Myocardial Infarction

OBJECTIVE: To compare the clinical characteristics of diabetic vs nondiabetic patients who present to the ED with acute myocardial infarction (AMI). METHODS: This was a prospective, observational study at a suburban, university hospital ED of patients presenting to the ED during study hours between December 1993 and October 1996 with typical and atypical symptoms consistent with cardiac ischemia. Diabetic and nondiabetic patients with AMI were compared. Demographic, historical, and clinical data were recorded by trained research assistants using a standardized, closed-question, data collection instrument. Final discharge diagnosis of AMI was assigned by WHO criteria. Continuous variables were analyzed by t-tests. Clinical variables were analyzed by chi-square tests. All tests were two-tailed with alpha preset at 0.05. RESULTS: There were 216 patients with AMI during the study period; 51 of these patients (24%) were diabetic. For diabetic vs nondiabetic patients with AMI, there was no significant difference in age (64.0 +/- 13 vs 60.0 +/- 14 years, p = 0.13), female gender (37% vs 26%, p = 0.13), and time to presentation from symptom onset (192 +/- 238 vs 251 +/- 456 minutes, p = 0.41). Hypertension was the only cardiac risk factor significantly more prevalent in diabetic vs nondiabetic patients with AMI (77% vs 50%, OR = 1.54, 95% CI = 1.24 to 1.91, p = 0.001), though elevated cholesterol (48% vs 33%, OR = 1.47, 95% CI = 1.02 to 2.12, p = 0.06) tended to be more prevalent in the diabetic group. There was no statistically significant difference between the two groups in terms of the frequency of chest pain (OR = 1.04, 95% CI = 0.95 to 1.14, p = 0.30), associated symptoms, and diagnostic ECGs (OR = 1.16, 95% CI = 0.76 to 1.79, p = 0.53). CONCLUSION: Diabetic patients with AMI may have similar symptoms upon presentation as do nondiabetic patients with AMI. Of the cardiac risk factors, hypertension is more prevalent in diabetic vs nondiabetic patients with AMI.     

Improvement of cardio-ankle vascular index by glimepiride in type 2 diabetic patients

Aims: Glimepiride, a third generation sulfonylurea (SU), is known to have extrapancreatic effects, but its vascular effect is unclear. We investigated the efficacy of glimepiride in improving arterial stiffness assessed by cardio‐ankle vascular index (CAVI) in type 2 diabetic patients, compared with glibenclamide, a conventional SU. Methods: Forty type 2 diabetic patients were randomly assigned to two groups. One group was administered glimepiride 1.5 mg/day, and the other group was administered glibenclamide 1.25 mg/day for 6 months. Results: No significant difference in hypoglycaemic effect was observed between two groups. CAVI significantly decreased only in glimepiride group (9.4 ± 1.4→8.9 ± 0.8, p < 0.05). Decrease in CAVI was greater in glimepiride group than in glibenclamide group (?0.50 ± 0.98 vs. ?0.04 ± 0.57, p = 0.048). Urinary 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) decreased in glimepiride group and increased in glibenclamide group, and the changes were significantly different between groups (?1.5 ± 3.5 vs. + 1.8 ± 3.6, p = 0.009); whereas serum lipoprotein lipase mass increased in glibenclamide group and decreased in glibenclamide group, and the changes tended to be different between groups (+ 2.1 ± 19.1 vs. ?7.4 ± 19.2, p = 0.096). Change in urinary 8‐OHdG was a significant independent predictor for change in CAVI in all subjects. Conclusions: These results suggest that glimepiride improves CAVI compared with glibenclamide. Reduced oxidative stress and improved insulin resistance may contribute to the improvement of CAVI by glimerpiride.     

Foot pressure measurements in diabetic and nondiabetic amputees.

OBJECTIVE--Foot problems are common in the remaining foot of diabetic amputees. Because high foot pressures are associated with foot ulceration, we studied foot pressures of the remaining foot of diabetic and nondiabetic unilateral amputees. RESEARCH DESIGN AND METHODS--Four age-matched groups of 11 subjects were studied. The groups were comprised of diabetic subjects with previous major amputation, nondiabetic nonneuropathic amputees, diabetic nonamputee patients with similar peripheral nerve involvement as the diabetic amputees, and nondiabetic control subjects. Vibration perception threshold (VPT) was assessed by biothesiometry and foot pressures with an optical pedobarograph. RESULTS--Mean +/- SE VPT in the diabetic amputees was significantly higher than the nondiabetic amputees (40.2 +/- 3.7 vs. 17.7 +/- 2.8 V, P less than 0.002) and similar to diabetic nonamputees (43.4 +/- 3.3 V, NS). VPT was abnormal in 9 (82%) diabetic amputees, 2 (18%) nondiabetic amputees, and 10 (91%) nonamputee diabetic patients. The mean peak foot pressure in the diabetic amputees was higher compared with nondiabetic amputees (18.3 +/- 2.2 vs. 11.3 +/- 1.4 kg/cm2, P less than 0.05) and control subjects (10.0 +/- 1.5 kg/m2, P less than 0.01), but no difference existed with diabetic nonamputees. Abnormally high foot pressures (greater than 12.3 kg/cm2) were present in 8 (73%) diabetic amputees, 3 (27%) nondiabetic amputees, 8 (73%) diabetic nonamputees, and 4 (36%) healthy subjects. CONCLUSIONS--We conclude that high pressures are present under the remaining foot in diabetic amputees, and that these pressures are associated with diabetic neuropathy. Prosthetic usage does not increase the pressures under the remaining foot in nondiabetic amputees.