Normotensive Non-insulin-dependent Diabetes Mellitus Research Articles

Cerebrovascular reactivity is impaired in patients with non-insulin-dependent diabetes mellitus and microangiopathy

Cerebrovascular reactivity (CVR) is a hemodynamic parameter representing the increase in normal cerebral artery blood flow in response to a vasodilatory stimulus such as hypercapnia. The aim of the study was to assess CVR using transcranial Doppler ultrasound and the breath-holding test (BHT) in normotensive patients with non-insulin-dependent diabetes mellitus (NIDDM). The cerebrovascular response to hypercapnia was evaluated in relation to risk factors for cerebral microangiopathy. The study was carried out in a group of 34 normotensive NIDDM patients and a group of 31 sex- and age-matched normal controls. The NIDDM group was subdivided into 21 patients with microangiopathic complications (Group A, 12 men, 9 women; mean age 58.77 +/- 8.91 years) and 13 patients with no such complications (Group B, 8 men, 5 women; mean age 56.34 +/- 9.83 years). The control group comprised 17 men and 14 women (Group C, mean age 58.43 +/- 6.31 years). Exclusion criteria were hypertension and past or present symptomatic cerebrovascular disease. The BHT consisted of spontaneous hypercapnia induced by holding the breath for 20 seconds. CVR was estimated in relation to the increase in the mean flow velocity (MFV) compared with the basal velocity in both middle cerebral arteries during hypercapnia. In Group A, the CVR was significantly decreased in 71.42% of patients, whereas in Group B only 30.76% of patients presented with mildly to moderately impaired CVR. Predictors for impaired % increase in the MFV during the BHT demonstrated by univariate regression analysis were: duration of diabetes (r = 0.802; P < 0.0001), fibrinogen (r = 0.574; P < 0.0001), C-reactive protein (r = 0.525; P < 0.001), proteinuria (r = 0.924; P < 0.0001) and serum creatinine (r = 0.969; P < 0.0001). Multivariate regression analysis showed as predictors: duration of diabetes (P < 0.0001), proteinuria (P < 0.0001) and serum creatinine (P < 0.0001). CVR is impaired in normotensive NIDDM patients. These cerebral hemodynamic changes correlate significantly with the duration of DM, parameters of inflammation, proteinuria and serum creatinine.

Effects of aging on serum ionized and cytosolic free calcium: relation to hypertension and diabetes.

Elevated cytosolic free calcium (Ca(i)) and reciprocally reduced, extracellular ionized calcium (Ca-ion) levels are observed in both hypertension and non-insulin-dependent diabetes mellitus (NIDDM). Because the changes of vascular function and insulin sensitivity in these conditions resemble the changes associated with "normal" aging, we wondered to what extent similar alterations in calcium metabolism occur with aging per se in the absence of overt hypertension or diabetes. We therefore measured platelet Ca(i) levels by spectrofluorometry and serum Ca-ion levels in normotensive, nondiabetic, healthy, normal, elderly (>65 years old) subjects, mean age +/-SEM, 72.2+/-1.5 years old (n=11); in healthy, normal, young (<65 years old) adults, 46.1+/-2.3 years old (n=12); in 10 young adult hypertensives, 48.6+/-1.9 years old; and in 10 normotensive NIDDM subjects, 49.2+/-1.6 years old. Platelet Ca(i) levels were higher (104.5+/-4.9 versus 80.2+/-1.8 nmol/L, P<0.01) and Ca-ion levels lower (1.212+/-0.010 versus 1.236+/-0.011 mmol/L, P<0.05) in normal elderly compared with young control subjects, but normal elderly Ca(i) and Ca-ion levels were indistinguishable from those in hypertensive (Ca(i) 107.5+/-3.6 nmol/L, Ca-ion 1.210+/-0.009 mmol/L) and NIDDM (Ca(i) 110.7+/-4.7 nmol/L, Ca-ion 1.204+/-0.014 mmol/L) subjects. In normal subjects, significant correlations were found between platelet Ca(i) levels and age (r=0.655, P<0.01) and between Ca(i) levels and systolic blood pressure (r=0.733, P<0.001). We conclude that aging is associated with alterations of Ca(i) and Ca-ion levels resembling those changes present at any age in hypertension and type 2 diabetes. We hypothesize that these alterations of calcium metabolism underlie the predisposition to the alterations of blood pressure and insulin sensitivity characteristic of "normal" aging. The data also suggest that studies of the aging process should be limited to subjects with normal blood pressure and glucose tolerance.

Effect of nifedipine retard on glucose-induced insulin response in patients with and without non—insulin-dependent diabetes mellitus and hypertension

To study the long-term effects of nifedipine retard on insulin response to oral loading of 75-g glucose, insulin responses to oral glucose were assessed using the insulin area under the concentration—time curve (AUC) and the insulin secretion ratio (30-minute increments of plasma insulin to 30-minute increments of plasma glucose) during oral glucose tolerance tests (OGTTs). The tests were repeated before and after a nifedipine treatment period of 49 ± 3 months (mean ± SE) in 8 non—insulin-dependent diabetes mellitus (NIDDM) hypertensive and 12 nondiabetic hypertensive patients. We recruited 32 consecutive normotensive individuals (19 NIDDM patients and 13 nondiabetic individuals) as a control group, who received OGTTs twice at a mean interval of 43 ± months. They were matched for age; sex disribution; glycated hemoglobin A 1c (Hb A 1c) levels; fasting and 2-hour postglucose levels of plasma glucose during OGTTs; and, for diabetic patients, the type of diabetic medication. No statistically significant differences were noted between diabetic hypertensive and diabetic normotensive patients in changes over time in the insulin secretion ratio. The two diabetic groups of patients showed the same improvement in Hb A 1C and glucose AUC. Insulin AUC, however, increased by 156 ± 108 pmol × h/L in the hypertensive diabetic patients, whereas it decreased by 84 ± 42 pmol × h/L in normotensive NIDDM patients ( P = 0.02). In nondiabetic patients, Hb A 1c and glucose AUC increased to a similar extent in both hypertensive and normotensive individuals. Despite this, maximum insulin concentrations and insulin AUC increased by 90 ± 66 pmol/L and 168 ± 120 pmol × h/L, respectively, in hypertensive patients whereas they did not change in normotensive controls, although the differences between the two groups were not significant. At baseline, no statistically significant differences were noted in fasting and maximum concentrations of insulin, and insulin AUC between NIDDM hypertensive and NIDDM normotensive patients. In conclusion, the study indicated that long-term treatment with nifedipine retard was not associated with an adverse effect on insulin response to oral glucose loading in either diabetic or nondiabetic patients with hypertension.

A long-term comparison between enalapril and captopril on insulin sensitivity in normotensive non-insulin dependent diabetic volunteers

There are conflicting reports about the effects of angiotensin converting enzyme inhibitors on insulin sensitivity and glycaemic control. In addition, the chronic effects of ACEI on insulin sensitivity in normotensive but insulin resistant individuals have been controversial. To determine the long-term effects of low-dose captopril or enalapril on insulin sensitivity and lipid parameters in normotensive non-insulin dependent diabetic volunteers. Twenty-eight normotensive non-insulin dependent diabetes mellitus subjects on diet alone or diet plus oral hypoglycaemic agents were randomized in a single-blind cross-over study to receive either captopril (12.5 mg daily) or enalapril (5 mg daily). Initially, captopril was compared with enalapril for 28 days with a 28-day washout period between drug regimens. For the long-term study, the subjects then remained on the second ACEI for a further 11 months. Insulin sensitivity was measured using the isoglycaemic hyperinsulinaemic clamp (insulin infusion rate 20 mIU/kg/min) at the start and completion of each part of the cross-over study and then at 3, 6 and 12 months of drug therapy. Fasting glucose, insulin, HbA1, lipids and lipoproteins were measured at the start of each clamp. No first or second order carry-over effects were demonstrated between the ACEIs. No differences were detected between enalapril and captopril on insulin sensitivity at any of the time points. Statistically significant hypotension was avoided, and at doses used the ACEIs did not modify any parameters of glycaemic control over the 12-month study period. There were no significant alterations in plasma cholesterol, triglycerides, HDL cholesterol or Apo A1 levels during the study. Long-term low-dose ACEIs (captopril/enalapril) do not modify insulin sensitivity, glycaemic control or lipids in normotensive non-insulin dependent diabetic subjects.

The renal response to exogenous insulin in non-insulin-dependent diabetes mellitus in relation to blood pressure and cardiovascular hormonal status.

Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by insulin resistance hyperinsulinaemia and a high frequency of hypertension. It has recently been shown that insulin exerts a sodium-retaining effect, which is preserved in NIDDM: We sought to determine whether insulin affected renal sodium handling differently in hypertensive and normotensive NIDDM patients. After a baseline period of 2 h, eight normotensive (N-) NIDDM patients and eight NIDDM patients with hypertension (H-) underwent a euglycaemic clamp with infusion of two sequential doses of insulin (50 and 500 mU/kg/h) or vehicle (time control) during 2-h periods each. Fractional clearances of sodium and lithium were determined according to standard methods. Fractional lithium clearance was used to assess segmental tubular sodium handling. Insulin induced similar decrements in fractional sodium excretion (N-NIDDM: 43+/-5.9 and 57+/-9.1%,H-N IDDM: 48+/-16.4 and 62+/-12.5%, low and high insulin dose respectively). Distal tubular sodium absorption increased simultaneously. A fall in fractional proximal sodium reabsorption was observed in N-NIDDM (4.4+/-2.7 and 29.8+/-5.1%, low and high insulin dose respectively), which was attenuated in H-NIDDM (-5.0+/-7.3 and -2.1+/-13.9% respectively). The latter appeared to be related to a defective atrial natriuretic factor (ANF) and renal cyclic GMP response. A modest decrease in blood pressure occurred during insulin infusion that was not related to changes in ANF or FeLi. The findings suggest that insulin-induced sodium retention may contribute to hypertension in NIDDM if the homeostatic response to offset this effect fails.

The use of antihypertensive agents in prevention and treatment of diabetic nephropathy

Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (> 300 mg/24 h), a relentless decline in glomerular filtration rate, and elevated systemic blood pressure. The prevalence of an abnormally elevated albumin excretion rate (> 30 mg/24 h) is approximately 40% in patients with both insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). Diabetes has become the leading cause of end-stage renal failure in the United States and Japan and it is still the second leading cause in Europe. Identification of patients at high risk of developing diabetic nephropathy is possible by screening for microalbuminuria (30 to 300 mg/24 h). Randomized controlled trials in normotensive IDDM and NIDDM patients with persistent microalbuminuria indicate that angiotensin-converting enzyme (ACE) inhibitors diminish urinary albumin excretion rate and postpone or may even prevent progression to clinically overt diabetic nephropathy. These findings suggest that screening and intervention programs are likely to have life-saving effects and lead to considerable economic savings. High blood pressure is an early and frequent phenomenon that can accelerate the course of diabetic nephropathy. Besides ACE inhibitors, conventional antihypertensive treatment (mainly beta-blockers and diuretics) reportedly reduce albuminuria and diminish the loss of kidney function in IDDM patients with diabetic nephropathy. The same beneficial effect has been demonstrated using ACE inhibition combined with diuretics in hypertensive IDDM patients with overt nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

糖尿病早期腎症に対する抗脂血剤ベザフィブラートの効果

The effect of Bezafibrate on early-stage diabetic nephropathy was examined. Twenty-four normotensive non-insulin-dependent diabetes mellitus (NIDDM) patients with persistent microalbuminuria, nineteen of them revealed either hypertriglyceridemia or hypercholesterolemia, were treated with Bezafibrate 400mg/day for six months. Urinary albumin/creatinine ratio (ACR) decreased significantly (P<0.05) from the basal value (73.1±12.2mg/g·Cr; mean±SE) to levels of 79.9±9.3% (1M), 74.8±11.8% (2M) and 64.6±10.5% (6M) during Bezafibrate treatment. In eighteen patients, ACR dropped 25% or more from the basal value. Although a significantly lower serum triglyceride levels, fasting plasma glucose levels and diastolic blood pressure were also observed, a significant association was found only between a reduction of ACR and alterations in serum triglyceride levels; not for the other clinical data.These results suggest that treatment with Bezafibrate reduces microalbuminuria in diabetic patients by a mechanism probably linked to changes in lipid metabolism, and could alleviate incipient diabetic nephropathy. Further studies will be needed to assess the anti-proteinuric effect of Bezafibrate.

Circadian Rhythm of Blood Pressure in Normotensive NIDDM Subjects: Its Relationship to Microvascular Complications

To investigate the relationship between circadian rhythm of mean blood pressure (MBP) and microvascular complications in non-insulin-dependent diabetes mellitus (NIDDM) subjects. Seventy-six normotensive NIDDM subjects without azotemia were studied under ordinary hospital conditions with a noninvasive ambulatory blood pressure monitoring device. Time series data were analyzed by the cosinor method. Fifty-four subjects had a circadian MBP rhythm similar to that of 34 age-matched nondiabetic control subjects, with a peak value in the afternoon (group 1). In contrast, 22 had a reversed circadian MBP rhythm, with a peak value during the night (group 2). Obvious complications were found in 65% of group 1 and in all of group 2. The prevalence of retinopathy and somatic neuropathy and the degree of retinopathy were similar in the two groups. The prevalence and degree of autonomic neuropathy (postural hypotension and reduced beat-to-beat heart-rate variation) and nephropathy were greater in group 2 than group 1. Linear discriminant analysis revealed a correlation between the reversed circadian MBP rhythm and postural hypotension (F = 32.2, P less than 0.001) and overt nephropathy (F = 5.1, P less than 0.05) but not with beat-to-beat heart-rate variation (F = 0.17, NS). These results suggest that in the hospitalized normotensive NIDDM subjects, there are normal and reversed circadian MBP rhythms and that the reversal of normal circadian MBP rhythm may be related to the degree of postural hypotension and/or nephropathy.

Cellular ions in hypertension, diabetes, and obesity. A nuclear magnetic resonance spectroscopic study.

To investigate the cellular basis linking hypertension, non-insulin-dependent diabetes mellitus (NIDDM), and obesity, we used 31P and 19F nuclear magnetic resonance spectroscopy to measure intracellular pH (pHi), free magnesium (Mgi), and cytosolic free calcium (Cai) in erythrocytes of obese and NIDDM subjects with and without hypertension. Compared with normotensive, nondiabetic controls (Cai, 25.2 +/- 1.4 nM; Mgi, 232 +/- 8 microM), Cai was elevated in both normotensive (36.8 +/- 2.7 nM, sig = 0.005) and hypertensive (43.4 +/- 2.9 nM, sig = 0.001) NIDDM subjects, and Mgi was concomitantly suppressed (normotensive: 206 +/- 11 microM, sig = 0.05; hypertensive: 196 +/- 8 microM, sig = 0.001). Similar but less striking changes were noted in obese subjects. Values of pHi were significantly lower (sig = 0.05) in all hypertensive groups compared with their normotensive controls. Continuous relations were observed for all subjects between Cai and diastolic blood pressure (r = 0.649, p less than 0.001) and body mass index (r = 0.565, p less than 0.001), between Mgi and diastolic blood pressure (r = -0.563, p less than 0.001) and fasting blood glucose (r = -0.580, p less than 0.001), and in diabetics, between pHi and diastolic blood pressure (r = -0.680, p less than 0.001). Thus, the constellation of elevated Cai and suppressed Mgi and pHi levels is characteristic of the hypertensive state. These abnormalities of cellular ion handling in whole or in part common to hypertension, diabetes, and obesity may contribute to the pathophysiology of these syndromes and may help to explain their frequent clinical coexistence.