C.K. Christensen

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

SummaryThe 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 Μg/min) (n=12), micro-(>20 and <200 Μg/min) (n=14) and macro-albuminuria (>200 Μg/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.

Increased myocardial contractility in short-term Type 1 diabetic patients: an echocardiographic study

SummaryCardiac function was investigated by echocardiography in 24 short-term Type 1 diabetic patients with a mean diabetes duration of 7 years (range 4–14 years) during conditions of ordinary metabolic control. Compared to 24 age and sex matched normal control subjects, measurements of myocardial contractility as left ventricular fractional shortening and mean circumferential shortening velocity were increased by 12% and 20% respectively. Another 8 Type 1 diabetic patients were examined during conditions of poor (hyperglycaemia and ketosis) and good metabolic control. Following improved glycaemic control, left ventricular fractional shortening and mean circumferential shortening velocity decreased by 16% and 24% respectively. Our findings show that short-term Type 1 diabetes is associated with increased myocardial contractility. Furthermore, this condition is related to the state of metabolic control.

Effect of continuous subcutaneous insulin infusion on kidney function and size in IDDM patients: A 2 year controlled study

Glomerular filtration rate (GFR), renal plasma flow (RPF), kidney volume, and urinary albumin excretion rate were measured in 24 insulin-dependent diabetics, aged 29 +/- 7 years (mean +/- SD) with diabetes duration of 8 +/- 4 years who were randomly allocated to either continuous subcutaneous insulin infusion (CSII) (n = 12) or unchanged conventional insulin treatment (CIT) (n = 12). GFR, RPF, and kidney volume were identical but significantly increased above normal values in the two groups at the start of the study. After 24 months of CSII treatment, significant reduction in GFR was seen compared to pretreatment values (145 +/- 21 ml/min vs 139 +/- 21 ml/min, 2p less than 5.0%). However, RPF was not reduced after 24 months of CSII treatment (608 +/- 104 ml/min vs 601 +/- 106 ml/min). In the CIT group no changes in GFR or RPF was seen, and kidney volume remained unchanged in both groups; urinary albumin excretion was normal or near normal in both groups and remained unchanged. Thus, improved glycemic control in long-term IDDM patients is associated with normalization (reduction) of renal hyperfunction, but despite this, no reduction was seen in the associated nephromegaly.

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 < 20 μg min−1, n = 134), in microalbuminuric patients (20 ≥ UAE < 200 μg min−1, n = 50) and in 27 non‐diabetic control subjects. Mean UAE was 4.5 μg min−1 (range 1.0–19.3 μg min−1) in normoalbuminuric patients, 53.1 μg min−1 (range 20.8–147.5 μg min−1) in microalbuminuric patients, and 4.0 μg min−1 (range 2.1–17.9 μg 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 < 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 < 1 times 10−6), and significantly lower than in microalbuminuric patients (142 ml min−1, range 100–186 ml min−1) (P < 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 < 1 times 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.

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).

Enhancement of glomerular filtration rate and renal plasma flow by oral glucose load in well controlled insulin-dependent diabetics

Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured in 27 patients with uncomplicated insulin-dependent diabetes (IDDM) before and after an oral glucose load of 1.1 g glucose/kg body wt. In the 18 patients showing near-normoglycaemia (blood glucose less than or equal to 8 mmol/l) before the glucose challenge the increase in blood glucose from 4.2 +/- 1.7 to 15.2 +/- 2.3 mmol/l was accompanied by an enhancement of GFR from 128 +/- 15 to 132 +/- 14 ml/min X 1.73 m2 (2p = 0.030) and of RPF from 534 +/- 116 to 562 +/- 105 ml/min X 1.73 m2 (2p = 0.023). By contrast oral glucose load to the nine patients with hyperglycaemia (greater than 8 mmol/l) during baseline conditions raising blood glucose from 11.9 +/- 2.0 to 19.6 +/- 1.5 mmol/l was accompanied by a reduction in GFR from 149 +/- 15 to 139 +/- 9 ml/min X 1.73 m2 (2p less than 0.001) while RPF was unchanged. No changes in blood pressure or urinary albumin excretion rates took place in either group. The reduction in plasma protein and in plasma growth hormone concentration were similar in the two groups. No change was seen in plasma arginine vasopressin concentration. There was no difference in the qualitative GFR response in patients with high initial GFR values (greater than or equal to 130 ml/min X 1.73 m2) as compared to patients with initial values below 130 ml/min X 1.73 m2. It is concluded that the induction of moderate hyperglycaemia in IDDM patients is followed by an enhancement of GFR and RPF-provided near-normoglycaemia before the glucose challenge.

Near normoglycemia for 1 year has no effect on platelet reactivity, factor VIII, and von willebrand factor in insulin-dependent diabetes mellitus: A controlled trial

The impact of prolonged near-normoglycemia on platelet reactivity (spontaneous and induced platelet aggregation), factor VIII, and von Willebrand factor in patients with insulin-dependent diabetes mellitus (IDDM) was evaluated in a prospective, randomized, controlled clinical trial. Twenty IDDM patients with no or only minor clinical signs of microvascular disease were randomly assigned to 1 year of continuous subcutaneous insulin infusion (CSII) or unchanged conventional insulin treatment (CIT). Hemoglobin A1c declined during the 12 month observation period from 7.3 +/- 1.2% to 6.4 +/- 0.9% (2p less than 0.01) in the CSII group, while this measure of glycemic control was unchanged in the CIT group: 7.2 +/- 1.1% vs 8.0 +/- 1.6% (NS). Platelet reactivity, factor VIII, and von Willebrand factor concentrations were identical in the two groups at entry into the study, and no significant changes in these variables were seen in either group. Thus, the present results do not support the concept of increased platelet reactivity following CSII treatment.

Combining antihypertensive agents in early diabetic nephropathy

80 Antihypertensive treatment induces a fall in urinary protein and albumin excretion in insulin-dependent diabetic (IDDM) patients with both incipient,‘s2 and overt nephropathy. 3r4 These observations indicate that protein excretion in some way reflects the level of the systemic blood pressure, probably via parallel changes in intraglomerular pressure. Accordingly, antihypertensive agents may reduce high intraglomerular pressure during exercise in patients with diabetic nephropathy. 5,6 More importantly, clinical studies have shown that antihypertensive treatment can reduce the rate of fall in GFR considerably in the overt stage of diabetic nephropathy,3s4 and even more optimistic results have been published in diabetics with incipient nephropathy.‘v2 ACE inhibitors have been shown to have a beneficial effect on kidney function both in the early2s6 and more advanced stages of diabetic nephropathy. 7-9 However, studies using ACE inhibitors in combination with selective beta-blockers and diuretics in the early phase of diabetic nephropathy has not been performed, but may be rational, since both early cardiac hyperfunction1° and increased extracellular volume” may be present in these patients with abnormal renal hemodynamics.12 We have, therefore, undertaken a triple treatment study adding an ACE inhibitor to a conventional antihypertensive program consisting of a selective beta-blocker and a thiazide diuretic.

Low-dose dopamine infusion, renal haemodynamics and urinary albumin excretion rate in insulin-dependent diabetics and in normal man

The effect of experimental renal vasodilatation by means of low-dose (2.0 micrograms/kg/min) intravenous dopamine infusion was investigated in 28 insulin-dependent diabetes mellitus (IDDM) patients with normal basal urinary albumin excretion rate (UAE) (less than 15 micrograms/min), 9 IDDM patients with UAE between 15-200 micrograms/min (microalbuminuria), and 7 normal subjects. Glomerular filtration rate (GFR) (thalamate clearance) showed a small increase with dopamine infusion, in the normoalbuminuric IDDM patients from 140 +/- 20 to 146 +/- 20 ml/min (2p less than 0.01), in the microalbuminuric IDDM patients from 146 to 151 ml/min (NS), and in normal subjects from 115 +/- 16 to 122 +/- 15 (2p less than 0.05). A marked increase in renal plasma flow (RPF) (hippuran clearance) was seen in all three groups--533 +/- 82 to 724 +/- 120 ml/min (2p less than 0.01), 574 +/- 69 to 777 +/- 140 ml/min (2p less than 0.01) and 523 +/- 87 to 749 +/- 145 ml/min (2p less than 0.05), respectively. Urinary albumin excretion rate (radioimmunoassay) increased from 5.3 x/divide 1.5 (tolerance factor) to 6.5 x/divide 1.8 micrograms/min (2p less than 0.05) in the normoalbuminuric IDDM patients and from 6.1 x/divide 2.1 to 7.8 x/divide 2.3 micrograms/min (2p less than 0.05) in the normal subjects, while no significant change was seen in the microalbuminuric group of diabetics. Kidney volume (ultrasonic scanning) was significantly enhanced in IDDM patients (294 +/- 73 ml vs. 196 +/- 49 ml). There was no significant correlation between kidney volume and the renal haemodynamic response to dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)