[Magnesium supplementation to patients with type II diabetes]. / Magnesium-tilskud til patienter med type II diabetes mellitus.

The purpose of this study was to evaluate Mg status by nuclear magnetic resonance spectroscopy in a group of well-regulated non-insulin-dependent diabetic (NIDDM) patients without angiopathy. Furthermore, to investigate the effect of Mg supplementation on markers of diabetic control, hemostatic function, platelet reactivity and endothelial function in the same patient population. A double-blinded, placebo-controlled and randomized crossover study was carried out, with two 8-weeks treatment periods (360 mg Mg/day) separated by a 4-weeks wash-out period. 11 well-regulated NIDDM patients participated in the study. Eight weeks of Mg supplementation significantly raised the level of free intracellular Mg in the diabetic patients (157.35 +/- 16.53 vs. 197.49 +/- 27.60 microM; p < 0.01). No changes were observed neither in plasma level of von Willebrand factor antigen, fibrinogen and fibronectin nor in platelet release of thromboxane B2 (TxB2). Similarly, markers of diabetic regulation, HbA1c and fructosamine, showed no significant changes. These results suggest that even well regulated NIDDM patients have marked Mg deficiency. Restoring this deficiency had no effect on diabetic control, markers of platelet reactivity, hemostatic function and endothelial function.

Increased left ventricular systolic function in insulin dependent diabetic patients with normal albumin excretion.

Alterations in cardiovascular function may be an aetiological factor for the development of microalbuminuria in patients with insulin-dependent diabetes mellitus. We studied cardiac function with echocardiography in relation to the degree of albuminuria in 27 insulin-dependent diabetes mellitus patients and 13 healthy subjects. Patients were grouped according to urinary albumin excretion: <20 microg x min(-1) (normoalbuminuric), and 20 to 200 microg x min(-1) (microalbuminuric). None were or had been treated with cardiovascular drugs. The normoalbuminuric patients had a higher heart rate, mean velocity of circumferential shortening, stroke velocity index (a measure of contractility), and aortic peak velocity than controls. No difference in diastolic function was present. In the microalbuminuric group, the stroke velocity index was comparable to values observed in healthy subjects. The increased systolic performance (heart rate and contractility) may contribute to the renal hyperperfusion and glomerular hyperfiltration observed in insulin-dependent diabetes mellitus patients before the development of micro- and in turn macroalbuminuria. The possible cause effect mechanisms should be further studied, as preventive medical treatment of the hypercontractile heart is possible. In conclusion, cardiac contractility is increased in insulin-dependent diabetes mellitus patients with normoalbuminuria and returns to levels observed in healthy subjects when microalbuminuria develops.

Proximal tubular function in essential hypertensives on beta-blocker therapy with atenolol.

Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured during waterloading and constant infusion of [131I]hippuran and [125I]iothalamate in 24 mild to moderate essential hypertensive patients before and after 3.5 months treatment with atenolol. Clearances of sodium and potassium were measured 2-3 hours post-dosing and renal vascular resistance (RVR) and filtration fraction (FF) were calculated. Measurement of clearance of lithium (CLi) and uric acid (Curic acid) was employed to investigate specifically proximal tubular function. Beta-blockade with atenolol produced a borderline significant decrement in RPF but no change in GFR, RVR and FF. There was a significant reduction in CLi, fractional proximal escape of sodium and water, Curic acid and an increase in absolute proximal reabsorption of sodium, indicating an inhibition of proximal tubular function. The distal tubular parameters exhibited changes tending to normalize excretion of sodium, but not water. Changes in RVR were inversely related to changes in CLi and Curic acid, suggesting unopposed alfa-adrenergic stimulation to be implicated in the renal counterregulation at a proximal tubular site following long-term administration of atenolol in essential hypertension.

Early recognition of autonomic dysfunction in microalbuminuria: significance for cardiovascular mortality in diabetes mellitus?

The appearance of microalbuminuria in diabetic patients predicts development of macroalbuminuria and coronary heart disease. Autonomic dysfunction in ischaemic heart disease is related to an increased incidence of arrhythmic deaths. To assess sympathovagal balance in relation to microalbuminuria we performed 24-h spectral analysis of RR interval oscillations in 37 insulin-dependent diabetic patients. Patients were divided according to urinary albumin excretion as normo-(< 20 micrograms/min) (n = 12), micro-(> 20 and < 200 micrograms/min) (n = 14) and macro-albuminuria (> 200 micrograms/min) (n = 11). None had symptoms or signs of ischaemic heart disease at clinical examination or during stress testing. Fourteen matched healthy subjects served as controls. Overall RR interval variability was calculated as the 24-h standard deviation. The square root of power of the low-frequency (0.04-0.15 Hz) and high-frequency (0.15-0.40 Hz) component were considered indices of the sympathovagal interaction and vagal function, respectively. Patients with micro and macroalbuminuria had, compared to control subjects, significantly reduced 24-h standard deviation, a much smaller day/night difference in mean RR level and a significantly reduced amplitude of the low frequency and high frequency oscillations, which were even more reduced in macroalbuminuria. The differences in vagal function were also present after correction for mean RR level, and differences in physical training level and smoking. Insulin-dependent diabetic patients who develop microalbuminuria have significantly impaired vagal function and abnormal sympathovagal interaction, which is further deranged in macroalbuminuria. This early autonomic dysfunction may later contribute to a increased risk for sudden cardiac death.

Alpha-adrenoceptor blockade in patients with mild to moderate hypertension: long-term renal effects of doxazosin.

Using constant infusion technique and a water-loading procedure, we investigated renal hemodynamic and excretional variables in 15 essential hypertensive patients [diastolic blood pressure (DBP) 102 +/- 10 mm Hg] after 3 weeks of placebo and after 16 weeks of treatment with a postjunctional alpha 1-adrenoceptor-antagonist, doxazosin (1-16 mg) once daily. A minor decrease in supine DBP (p less than 0.05) but no significant changes in systolic BP (SBP) and heart rate (HR) were observed. No significant changes were noted in glomerular filtration rate (GFR), renal plasma flow (RPF), and renal vascular resistance (RVR). The mean renal excretion rate of sodium, potassium, uric acid, and albumin for the entire group was unaffected by the treatment, but the individual changes in sodium clearance correlated significantly with changes in mean BP (r = 0.64, n = 15, p less than 0.05). Six patients showed an increase in sodium excretion after treatment, whereas nine showed a decrease. No decrease in mean body weight was noted, but the BP reduction after 5 months of treatment correlated significantly with the changes in body weight (r = 0.62, n = 15, p less than 0.01). The results indicate that long-term treatment with doxazosin had no deleterious effect on renal function, but the effects on BP were rather modest. The individual BP response is probably determined by the degree of fluid retention even if an intact pressure-natriuresis relationship could still be demonstrated during chronic therapy.

Normoalbuminuria ensures no reduction of renal function in type 1 (insulin-dependent) diabetic patients.

Recent reports have suggested that impaired renal function in type 1 diabetic patients may be present despite normal urinary albumin excretion (UAE). We have studied kidney function by means of a constant-infusion technique in normoalbuminuric type 1 diabetic patients without antihypertensive medication (UAE less than 20 micrograms min-1, n = 134), in microalbuminuric patients (20 greater than or equal to UAE less than 200 micrograms min-1, n = 50) and in 27 non-diabetic control subjects. Mean UAE was 4.5 micrograms min-1 (range 1.0-19.3 micrograms min-1) in normoalbuminuric patients, 53.1 micrograms min-1 (range 20.8-147.5 micrograms min-1) in microalbuminuric patients, and 4.0 micrograms min-1 (range 2.1-17.9 micrograms min-1) in controls. Glycosylated haemoglobin A1c was significantly higher in microalbuminuric patients (8.9%, range 5.9-12.6%) than in normoalbuminuric patients (7.9%, range 5.5-11.5%) (P less than 0.0001). Glomerular filtration rate in normoalbuminuric patients (135 ml min-1, range 97-198 ml min-1) was significantly higher than in controls (118 ml min-1, range 94-139 ml min-1) (P less than 1 x 10(-6), and significantly lower than in microalbuminuric patients (142 ml min-1, range 100-186 ml min-1) (P less than 0.05). Mean arterial blood pressure was lower in normoalbuminuric patients (91 mmHg, range 78-108 mmHg) than in microalbuminuric patients (98 mmHg, range 82-131 mmHg) (P less than 1 x 10(-6), but not significantly different from that of controls (89 mmHg, range 73-103 mmHg). We conclude that normal UAE is a reliable indicator of well-preserved renal function. Glomerular hyperfiltration, elevated blood pressure and poor metabolic control are characteristic features of microalbuminuric patients.

Association of 24-h cardiac parasympathetic activity and degree of nephropathy in IDDM patients.

In insulin-dependent diabetic patients, nephropathy is a predictor of mortality and coronary heart disease. Impaired cardiac vagal function is an important factor in the pathophysiology of sudden cardiac death in coronary heart disease. Autonomic neuropathy in diabetes in particular involves vagal function. Bedside tests and 24-h measurements of cardiac parasympathetic activity were compared in 37 insulin-dependent diabetic patients, and the relationship between 24-h vagal activity and degree of nephropathy was investigated. Nephropathy was classified according to urinary albumin excretion as normoalbuminuria, incipient, and overt nephropathy. Mean age (approximately 30 yr) was not different among groups. The 24-h measurements of parasympathetic activity appeared more sensitive than bedside tests, as 33% of patients without cardiac autonomic neuropathy in bedside tests had 24-h vagal activity values below the 95% confidence limits of 14 healthy control subjects. Patients with incipient or overt nephropathy had significantly lower mean values for vagal activity during both wake and sleep time than healthy control subjects. Increasing degree of nephropathy was associated significantly with increasing attenuation of 24-h vagal activity (P less than 0.001). The covariation of degree of neuropathy and nephropathy may suggest common pathogenetic mechanisms. The reduced 24-h vagal activity, even in the early stages of nephropathy, could be an important risk factor for cardiac death in insulin-dependent diabetic patients.

Ambulatory blood pressure in microalbuminuric type 1 diabetic patients.

Twenty-four-hour ambulatory blood pressure (AMBP) was performed in microalbuminuric (micro.) type 1 diabetic patients, with the aim of comparison with a matched group of normoalbuminuric patients (normo.) and healthy controls. Thirty-four patients without antihypertensive medication were investigated in each group. Urinary albumin excretion (UAE) for micro. was (geometric mean, tolerance factor microgram/min) 51.7 x/divided by 1.94, 5.1 x/divided by 1.88 for normo. and 5.2 x/divided by 1.75 for controls. Twenty-four-hour AMBP (mean systolic/diastolic mm Hg +/- SD) was significantly higher in micro. (131 +/- 10/78 +/- 7) than in normo. (122 +/- 8/73 +/- 6; P less than 0.001/P less than 0.01). No 24-hour AMBP difference between normo. and controls (120 +/- 9/71 +/- 7) was found. No difference in the night/day ratio of blood pressure was found between the diabetic groups. Coefficient of variation for day time systolic measurements did not show any intergroup difference. Systolic day time blood pressure for the pooled diabetic group correlated significantly with UAE (r = 0.45, P less than 0.001), whereas no significant correlation with auscultatory systolic values in the clinic was found (r = 0.21; P = 0.09). In conclusion, blood pressure in micro. as compared to normo. is not more labile but is elevated day and night without significant alteration of the diurnal rhythm. AMBP reflects the association between UAE and blood pressure more precisely than clinical measurements and may be preferable for identifying candidates for antihypertensive treatment.

Effects of ACE inhibition supplementary to beta blockers and diuretics in early diabetic nephropathy.

Angiotensin converting enzyme (ACE) inhibition has shown promising results in diabetic nephropathy, but long-term results on survival are not available. In a cohort of patients receiving antihypertensive treatment predominantly consisting of beta blockers in combination with diuretics, support for an improved survival has been presented. Addition of ACE inhibition to such a combination treatment may be favorable both due to the suggested renoprotective effects of ACE inhibitors and because diuretics activate the renin-angiotensin system. In 10 insulin-dependent diabetic patients with early diabetic nephropathy [urinary albumin excretion rate (UAE) less than 100o micrograms/min], who were receiving continuous therapy with metoprolol and bendroflumethiazide, a double-blind crossover study with four months addition of ramipril 5 mg (Ramace) and placebo was conducted. UAE (radioimmunoassay) and fractional albumin excretion were significantly reduced after the four months of ramipril administration [UAE: 114.1 x/divided by 1.3 (geometric mean x/divided by confidence factor] versus 174.6 x/divided by 1.2 micrograms/min, 2P less than 0.005). Renal plasma flow (clearance of 131I-hippuran) tended to increase [497 +/- 25 (mean +/- SE) vs. 464 +/- 28 ml/min/1.73 m2, 2P = 0.08], while GFR (125I-iothalamate) stayed unchanged (121 +/- 8 vs. 120 +/- 9 ml/min/1.73 m2). Mean arterial pressure during clearance studies fell moderately (95 +/- 3 vs. 101 +/- 1 mm Hg, 2P less than 0.05) and renal resistance was decreased (2P less than 0.03). ACE activity was suppressed in all patients. Twenty-four-hour ambulatory blood pressure measurements were not significantly different after the two periods (daytime averages: 91 +/- 2 vs. 93 +/- 2, nighttime 80 +/- 2 vs. 84 +/- 3 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Micro-albuminuria and the organ-damage concept in antihypertensive therapy for patients with insulin-dependent diabetes mellitus.

OBJECT OF TREATMENT: Antihypertensive treatment in hypertensive patients with insulin-dependent diabetes mellitus is intended to prevent long-term complications, particularly diabetic nephropathy. DIABETIC HYPERTENSIVES WITH ABNORMAL ALBUMINURIA: Antihypertensive therapy, particularly with angiotensin converting enzyme (ACE) inhibitors, typically produces a permanent reduction in the decline of the glomerular filtration rate (GFR) in diabetic patients with abnormal albuminuria. The rate of decline in the GFR during antihypertensive treatment is a well accepted end-point in diabetic renal disease. DIABETIC HYPERTENSIVES WITHOUT ABNORMAL ALBUMINURIA: In insulin-dependent diabetic patients with essential hypertension but with normal urinary albumin excretion there is no reduction in the GFR. Longitudinal studies have shown a fall in the GFR only in the presence of significantly increased urinary albumin excretion. ABNORMAL ALBUMINURIA AS A MARKER OF INCIPIENT NEPHROPATHY: Micro-albuminuria and proteinuria may be pathogenetic factors in the development of nephropathy, leading eventually to end-stage renal failure in diabetic patients. Measurements of micro-albuminuria and proteinuria, in addition to blood pressure recordings, might therefore be used as indications for initiating antihypertensive treatment. NEED TO MONITOR PATIENTS FOR ABNORMAL ALBUMINURIA: Transglomerular macromolecular traffic may produce mesangial damage, with subsequent glomerulopathy and diabetic nephropathy. Thus, close monitoring for micro-albuminuria and proteinuria is desirable in the management of diabetic hypertensive patients.

ACE-inhibition and renoprotection in early diabetic nephropathy. Response to enalapril acutely and in long-term combination with conventional antihypertensive treatment.

Early antihypertensive treatment with beta1 blockers and diuretics has proved to delay progression in diabetic nephropathy. Application of angiotensin converting enzyme inhibitors (ACE-I) may also be relevant. To elucidate possible differences in acute renal response to ACE-I and beta-blockers, kidney function was investigated before and after enalaprilat (10 mg) and metoprolol (10 mg) i.v. in 8 microalbuminuric insulin-dependent diabetic patients on no antihypertensive therapy (Study A). Glomerular filtration rate (clearance of 125I-iothalamate) was unchanged with both agents. ACE-I gave rise to efferent renal vasodilation: renal resistance and filtration fraction fell, renal plasma flow (RPF; 131I-hippuran) tended to rise (2p = 0.07) and blood pressure and urinary albumin excretion rate (UAE; radioimmunoassay) were reduced. In contrast, metoprolol caused a decline in RPF, an increase in renal resistance and filtration fraction, and no change in blood pressure or UAE. In 10 diabetic, nephropathic patients undergoing treatment with metoprolol and thiazide (Study B), the acute response to enalaprilat corresponded closely to that observed in Study A, including a decrease in UAE and blood pressure. Over 6 months the addition of enalapril (20 mg/d) to metoprolol and thiazide produced a more pronounced UAE-reduction, although no significant decrease in blood pressure was observed. The present findings support that ACE-I may process specific renoprotective effects. A combination therapy with beta1 blockers, ACE-I, and diuretics is suggested.

Renal factors influencing blood pressure threshold and choice of treatment for hypertension in IDDM.

In this article, we analyze the blood pressure (BP) threshold for the start of antihypertensive treatment in insulin-dependent diabetes mellitus (IDDM) patients, with particular emphasis on those with persistent microalbuminuria or proteinuria (incipient and overt nephropathy, respectively). In such individuals, there is a clear increase in the prevalence of hypertension and in actual measured BP values that is not observed in normoalbuminuric patients. In 94 young healthy adults (less than 45 yr of age), average mean +/- SD arterial pressure (MAP; diastolic + 1/3 pulse pressure) was approximately 90.0 +/- 8.1 mmHg, closely corresponding to large population studies. In microalbuminuric IDDM patients, MAP values between approximately 105 and approximately 95 mmHg have been found in different studies, and the level has progressively decreased in various studies between 1984 and 1990 with similar BP-measuring techniques. Somewhat higher values are seen in patients with proteinuria, who are also consistently characterized by reduced glomerular filtration rate (GFR). A clear correlation is found between MAP plotted against the increased rate of microalbuminuria (%/yr) in incipient nephropathy and against fall rate of GFR (ml.min-1.mo-1) in proteinuric patients. In the natural history of renal disease, different cutoff points in MAP for start of progression are observed: greater than 95 mmHg for the start of progression of microalbuminuria and greater than 105 mmHg for the decrease in GFR. During antihypertensive treatment, there is reduction or no progression in microalbuminuria with MAP of approximately 90-95 mmHg and only a limited fall in GFR with MAP of approximately 100 mmHg. However, certain antihypertensive drugs (angiotensin-converting enzyme inhibitors) may have specific renoprotective actions, reducing microalbuminuria at rather low BP levels or even independent of BP reduction. The optimal way of monitoring BP may be by 24-h ambulatory recording.

Fatty acid binding to serum albumin in type I insulin-dependent diabetes mellitus.

Equilibria of binding of long-chain fatty acids to albumin in sera from type I diabetic patients and healthy adults were studied by dialysis exchange rate determinations and described by, p*, the reserve albumin concentration for binding of fatty acid, C*/p*, the total availability of fatty acids, where C* is the total concentration of non-esterified fatty acid, and L*, the fatty acid binding property of albumin, which is L* = p*/P + 0.05 C*/P, where P is the albumin concentration. Studies in samples from 81 diabetic patients and 99 healthy adults showed that availability of fatty acids increased with increasing fatty acid concentrations, equally in the two groups. Some diabetics had higher fatty acid concentrations, and thus higher fatty acid availabilities, than the normals. It is shown that the fatty acid binding property of serum albumin is individually variable, ranging about the same mean value in normal and diabetic persons but with a larger variation in the latter. The fatty acid binding property of albumin in serum, L*, and sixteen clinical parameters were measured in 42 of the 81 diabetic patients. Regression analysis indicated that L* was correlated to serum cholesterol concentration (probability of 0-hypothesis, p = 0.01) and to serum triglyceride concentration (p = 0.05). Values of L* were slightly correlated to age, age on diagnosis, duration, Body Mass Index (BMI), diastolic blood pressure, albumin excretion rate, serum creatinine concentration, and serum non-esterified fatty acid concentration with p-values varying from 0.10 to 0.50. For sex, retinopathy, hemoglobin A1c, systolic blood pressure, daily insulin dose, and blood glucose concentration no correlation to L* was found, p-values ranging from 0.56 to 0.96. Non-enzymatic glycosylation of serum albumin did not decrease binding affinity for fatty acid in vitro.

Renal and glycemic determinants of glomerular hyperfiltration in normoalbuminuric diabetics.

Glomerular hyperfiltration is a characteristic feature of insulin-dependent diabetes. We examined the relative roles of renal size, as well as glycemic parameters (HbA1c, glycosylated albumin, plasma glucose) in addition to growth hormone, somatomedin C, beta-hydroxybutyrate, alanine, and glycerol in determining the glomerular filtration rate (GFR). Sixty-two insulin-dependent patients with normal urinary albumin excretion rates (AER less than 15 micrograms/min), who were less than 50 years of age, were included in the study. Data were subjected to multiple regression analysis with GFR as a dependent variable. Renal volume was the primary statistical determinant of hyperfiltration, but HbA1c also significantly correlated with GFR. No correlation was found with glycosylated albumin or blood glucose, but RPF correlated strongly with GFR, and borderline correlation was found between renal volume and HbA1c. Renal hyperfiltration, defined as a GFR greater than 150 ml/min, was found in approximately 50% of patients with HbA1c values greater than 9.5%. Other studies suggest that such patients have a much higher risk of developing clinically evident diabetic nephropathy over the ensuing years. Renal volume appears to be the major determinant of GFR, but long-term metabolic control, as evidenced by the level of HbA1c, also contributes, partly independent of renal volume. Short-term metabolic control, as evaluated by blood glucose and serum-fructosamine, did not correlate with GFR. We suggest that exact determination of GFR and renal volume should be included in long-term prospective controlled intervention trials in patients with insulin-dependent diabetes mellitus (IDDM).

Effect of pump versus pen treatment on glycaemic control and kidney function in long-term uncomplicated insulin-dependent diabetes mellitus (IDDM).

Glycaemic control on pump versus pen treatment was evaluated and the effects of optimised metabolic control on kidney function was studied in very long-term uncomplicated insulin-dependent diabetes mellitus (IDDM). Ten otherwise healthy patients participated, age: 36.5 yr +/- 7.9, diabetes duration: 23.7 yr +/- 2.9, urinary albumin excretion (UAE): 5.8 micrograms/min x/ divided by 2.2, se-creatinine and blood pressure were normal and only background retinopathy was present. A 2 x 6 months randomised cross-over study was performed using continuous subcutaneous insulin infusion (CSII) and multiple injection technique (MIT). Glycaemic control was evaluated by a six point profile every two weeks and by measuring HbA1c monthly. At 0, 6 and 12 months, glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion technique, and UAE by radioimmunoassay. Glycaemic control was significantly better on CSII as compared to MIT (p = 0.01) or pre-study conventional treatment (CT), p = 0.03, whereas there was no difference between MIT and CT. There was no change in kidney function during either treatment. Thus, in these very long-term uncomplicated patients, glycaemic control was significantly improved during CSII. In spite of this, no change was found in GFR, which might suggest that in long-standing diabetes, kidney function is unaltered by changes in metabolic control.

No microalbuminuria or other adverse effects of long-standing hyperfiltration in humans with one kidney.

Hypertrophy and hyperfiltration are characteristic features of single kidneys and kidneys of patients with insulin-dependent diabetes mellitus (IDDM). In both cases the hyperfiltration has been suggested to be involved in the pathogenesis of renal functional deterioration. We studied the effect of long-standing hyperfiltration on kidney function in 29 subjects with one kidney, three of whom were insulin-dependent diabetics. Four groups were studied: (1) uninephrectomized less than 10 years since uninephrectomy (UN) (n = 7; age, 30 +/- 6 years); (2) uninephrectomized greater than or equal to 10 years since UN (19 +/- 11 years, 10 to 52); n = 14; age, 38 +/- 15 years; (3) congenital unilateral renal agenesis (n = 5, age, 39 +/- 16 years); and (4) IDDM patients with one kidney (n = 3; age, 28 to 52 years; diabetes duration, 8 to 31 years; years with one kidney, 18 to 30). Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion technique, kidney volume (KV) by ultrasonic scanning, and urinary albumin excretion rate (UAE) by radioimmunoassay. In all subjects GFR, RPF, and KV were within the normal range, representing a single kidney hyperfiltration of approximately 70% and hypertrophy of approximately 100%. Only one of the subjects with renal agenesis had an elevated UAE (117 micrograms/min); the remainder had a normal UAE, ie, less than 10 micrograms/min, and the diabetics were below the risk level of 20 micrograms/min. Serum creatinine was normal and BP was slightly elevated in only three subjects.(ABSTRACT TRUNCATED AT 250 WORDS)