Enhanced pressor responsiveness to norepinephrine in type II diabetes. Effect of ACE inhibition.

OBJECTIVE: To evaluate the effect of angiotensin-converting enzyme (ACE) inhibition on the pressor responsiveness to norepinephrine in type II diabetes. RESEARCH DESIGN AND METHODS: Eight normotensive subjects, eight mild-to-moderate hypertensive type II diabetic patients, and eight nondiabetic patients with essential hypertension were studied before and after 4 weeks of being administered enalapril. The pressor response to norepinephrine was assessed by infusing the hormone in an antecubital vein at incremental doses of 30 ng.kg-1.min-1 for periods of 5 min until reaching an increase of 20 +/- 2 mmHg in mean arterial pressure (MAP) measured by an automatic device at 1-min intervals. An effective dosage of norepinephrine that increased MAP by 20 mmHg (EDNE 20) was thereafter calculated. Before and during the last minute of norepinephrine infusion at maximum dosage, a venous blood sample was drawn to determine plasma renin activity (PRA), aldosterone, and norepinephrine levels. RESULTS: In the three groups of patients, blood pressure and aldosterone were reduced while PRA was raised following ACE inhibition. Basal and maximum postinfusion levels of norepinephrine were not modified by enalapril. The EDNE 20 was basally lower in diabetic patients and remained unchanged after ACE inhibition, contrary to that observed in nondiabetic patients with essential hypertension. CONCLUSIONS: Both normotensive and hypertensive type II diabetic patients have an increased pressor responsiveness to norepinephrine that is not modified by therapeutic doses of enalapril, contrary to what is observed in nondiabetic patients with essential hypertension.

[Diabetic nephropathy and pregnancy]. / Nefropatia diabetica e gravidanza.

During pregnancy, the kidneys of diabetic women undergo an elevated functional load which occurs to a greater extent if nephropathy coexists. Functional abnormalities, such as reduction of glomerular filtration rate, increase of creatinine and proteinuria, which can be observed in about 1/3 of the cases, regress or stabilize progressing only in a limited number of patients. Arterial hypertension and poor metabolic control seem to be the factors most closely correlated to the loss of renal function. Diabetic nephropathy determines an increased risk of maternal and fetal complications to be seen more frequently in women with more compromised renal function at conception, and with poor metabolic control during pregnancy. From here stems the importance of good metabolic control right from conception. Moderate physical exercise, a caloric intake of 25-35 kcal/kg/day and slight reduction of protein diet content are also advisable. Monitoring includes periodical evaluation of glycated haemoglobin, creatinine, uric acid, creatinine clearance and albuminuria not only during pregnancy but also after months or years following delivery. Arterial pressure must be monitored avoiding aggressive antihypertensive treatment. The most suitable drugs are considered alfa-methyldopa, clonidine, hydralazine and prazosine.

Angiographic evaluation of the anatomic pattern of arterial obstructions in diabetic patients with critical limb ischaemia.

OBJECTIVE: The present study was undertaken to evaluate, by means of angiography, the anatomic pattern of arterial obstructions in the lower extremities of diabetic patients presenting with critical limb ischaemia. We particularly examined the differences in involvement of the foot arteries between patients with and without diabetes. PATIENTS AND METHODS: A group of 150 patients with limb-threatening ischaemia, manifested by rest pain and/or non-healing ischaemic ulcers or gangrene, underwent angiologic evaluation in prevision of vascular surgery. The patients, of whom 89 were suffering from diabetes, were examined by means of digital subtraction angiography using the Seldinger technique. In each patient, details of arterial tree were obtained from the aortoiliac to the foot arteries and the site and the extent of obstructions were determined blindly with the radiologist unaware of the patient's history of diabetes. RESULTS: Diabetic patients showed significantly more obstructions in the infrapopliteal arteries when compared to the patients without diabetes who had more pronounced involvement of aortoiliac and femoropopliteal arteries. Diabetic patients, moreover, showed a higher prevalence of obstruction in posterior tibial, peroneal and plantar arteries than the non-diabetics. At the time of presentation, the age of patients did not differ between the two groups but diabetic patients had more frequent ischaemic ulcers or gangrene and less rest pain than the non-diabetics. CONCLUSIONS: Our study confirms earlier reports carried out with non-angiographic methods indicating more frequent involvement of calf arteries in diabetic patients but disagrees with those which report that patients with diabetes have less occlusive disease in foot arteries.

Low-dose angiotensin converting enzyme inhibitors: effect on renal function in normo- and hypertensive type 1 diabetic patients.

OBJECTIVES: To investigate the effect of low doses of the angiotensin converting enzyme inhibitor enalapril on renal haemodynamics and albuminuria in normotensive and hypertensive type 1 (insulin-dependent) diabetic patients with incipient or overt nephropathy. METHODS: Twenty-two type 1 (insulin-dependent) diabetic patients with persistent microalbuminuria or macroalbuminuria and normal serum creatinine were studied. Of all patients, 16 males and 6 females, age 45 +/- 13 years, diabetes duration 19 +/- 11 years, insulin dose 38 +/- 11 U/day, 10 were normotensive and 12 were hypertensive. After 3 months of run-in period the patients were assigned to treatment with 5 mg or 10 mg enalapril based on the presence of normotension or hypertension respectively. Before and after 6 months of treatment, renal function was assessed by evaluation of glomerular filtration rate (99m Tc-DTPA), renal plasma flow (131-I iodohippurate), filtration fraction and renal vascular resistance. Mean arterial pressure, albumin excretion rate, urinary urea excretion and glycated haemoglobin were also determined. RESULTS: Administration of enalapril resulted in both groups of patients in a significant fall in mean arterial pressure, albumin excretion rate, glomerular filtration rate, filtration fraction, and renal vascular resistance. Decreasing albumin excretion did not correlate with a drop in systemic blood pressure or filtration fraction. No significant variations were observed in renal plasma flow, in urinary urea excretion or in glycated haemoglobin. CONCLUSIONS: Our results suggest that low doses of enalapril are effective in influencing renal haemodynamics and reducing urinary albumin excretion in both normotensive and hypertensive type 1 (insulin-dependent) diabetic patients with incipient or overt nephropathy. The lowering effect of the angiotensin converting enzyme inhibitor on albuminuria seems to be independent of the action on systemic blood pressure and renal haemodynamic changes.

ACE inhibition in diabetic patients: effect on pressor responsiveness to noradrenaline.

The pressor responsiveness to noradrenaline was assessed before and after four weeks of treatment with enalapril (20 mg/day) in eight mild-to-moderate essential hypertensives, in eight normotensive type II diabetics and in eight mild-to-moderate hypertensive type II diabetic patients. The ACE inhibitor interfered to the same extent with the renin-angiotensin system and did not alter noradrenaline kinetics in the three groups of patients, but significantly reduced the arterial responsiveness only in non-diabetic subjects. It is suggested that factors, such as an exaggerated sodium retention, might determine the lack of effect of enalapril in diabetic patients.

Intra-arterial urokinase infusion in diabetic patients with rapidly progressive ischemic foot lesions.

OBJECTIVE: The effectiveness of local intra-arterial thrombolysis by urokinase was evaluated in eight non-insulin-dependent diabetic patients with angiographic evidence of infrapopliteal occlusive disease and rapidly progressive foot lesions. RESEARCH DESIGN AND METHODS: With an electric peristaltic pump, urokinase was infused for 96 h by a 5-6 F catheter introduced into the femoral artery and placed immediately above the occluded infrapopliteal arteries. After baseline, angiography was repeated at 24- to 48-h intervals and at conclusion of the treatment. RESULTS: Six patients showed immediate improvement of clinical symptoms. Angiography revealed the reestablishment of blood flow in collateral vessels of the leg and foot in the dorsal pedal artery in three patients and in the plantar arch in two. Recanalization of the major arteries of the trifurcation was not achieved. After 12 mo of follow-up, all limbs were salvaged, although four patients required vascular reconstruction to further improve foot perfusion and complete healing. CONCLUSIONS: Intra-arterial urokinase, which opens collateral and smaller vessels of the leg and foot in patients with diabetes, may be effective in improving blood flow in lower extremities and in making the patient a better candidate for vascular surgery.

The effect of ace inhibition on peripheral hemodynamics in normotensive and hypertensive patients with type II diabetes.

The effect of treatment with enalapril (10 days at 10 mg/d followed by 4 weeks at 20 mg/d) on forearm hemodynamics was assessed in eight normotensive patients and eight patients with hypertension affected by Type II diabetes as well as in eight patients with essential hypertension and normal glucose tolerance. The ACE inhibitor decreased regional vascular resistances and increased the maximum arteriolar-vasodilating capacity and venous distensibility in the three groups of patients. Thus, this study shows that ACE inhibition by enalapril improves regional hemodynamics in patients with Type II diabetes.

Oesophageal transit time and cardiovascular autonomic neuropathy in type 1 (insulin-dependent) diabetes mellitus.

Oesophageal computerized dynamic scintigraphy with 99 mTc was used to evaluate oesophageal motility in type 1 (insulin-dependent) diabetic patients without upper gastrointestinal symptoms. Twenty-nine patients, 10 women and 19 men, mean age 38 +/- 12 yr (range 17-55), mean duration of diabetes 15 +/- 8 yr (range 3-30) and 15 controls were studied. Background or proliferative retinopathy was found in 72.4% of patients, incipient or clinical nephropathy in 48.3% and peripheral neuropathy in 62% of them. In all, oesophagitis and/or other disorders of the upper gastrointestinal tract were excluded by barium studies and endoscopy. Oesophagus scintigraphy with 99 mTc sulphur colloid was performed in each subject after fasting for at least 3 hr in the supine position and repeated after few minutes to assess its reproductivity. The rate of passage of the fluid bolus through oesophagus was analyzed by computer and oesophageal transit time (OTT) for the whole oesophagus was measured by time-activity curves. All diabetic patients were screened for autonomic cardiovascular function by standard tests and, on the base of results, assigned to cardiovascular autonomic neuropathy positive (CVAN-positive) or to cardiovascular autonomic neuropathy negative (CVAN-negative) group. Abnormal oesophageal motility (OTT less than 14 sec as mean +/- 2 SD of controls) was found in 68.7% of CVAN-positive and in 15.4% of CVAN-negative patients (p less than 0.05). CVAN-positive patients resulted older and had significantly longer duration of diabetes than other patients. Furthermore, they showed higher frequency of severe retinopathy, nephropathy, peripheral neuropathy and prolonged OTT compared with CVAN-negative patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Possible effectiveness of plasmapheresis and immunosuppressive therapy in reversing subcutaneous insulin resistance: a case report.

Severe resistance to subcutaneous insulin with normal sensitivity to intravenous insulin developed in a 39 year old woman affected by type 1 diabetes mellitus. The patient had been treated for ten months with continuous intravenous or intraperitoneal insulin before undergoing pancreatic transplantation. After surgery repeated plasmapheresis were performed and immunosuppressive therapy was undertaken. When studied again, one month after surgery, the patient showed normal sensitivity to subcutaneous insulin. Our data suggest that plasmapheresis and/or immunosuppressive treatment could have played a role in reversing insulin resistance.

Investigation of insulin resistance associated with Werner's syndrome.

The tissue sensitivity to insulin and the metabolic clearance rate of insulin were evaluated in a new case of Werner's syndrome, by means of the euglycemic clamp technique using an artificial endocrine pancreas. The possible contribution of pancreatic insulin secretion and of reduced hepatic insulin breakdown to the peripheral hyperinsulinism was also studied by simultaneous determination of C-peptide and insulin levels and by analysis of the C-peptide/insulin molar ratio. The data obtained are consistent with the presence of marked insulin resistance and of reduced metabolic clearance rate of insulin in our patient, confirming what has been observed previously using other techniques. The finding of a reduced C-peptide to insulin ratio during the intravenous glucose tolerance test suggests that hepatic extraction of insulin could also be altered in Werner's syndrome, as found in several hyperinsulinism conditions, therefore contributing to peripheral hyperinsulinism.