A. C. Nieuwenhuijzen Kruseman

Health-related quality of life of diabetic foot ulcer patients and their caregivers.

Aims/hypothesisThe effect of a foot ulcer on health-related quality of life (HRQoL) of patients with diabetes mellitus and their caregivers is unclear, and was therefore evaluated prospectively in this multicentre study.MethodsHRQoL according to the 36-item health-related quality of life questionnaire (SF-36) of 294 patients (ulcer duration ≥4 weeks) and 153 caregivers was analysed at baseline (time-point zero [T0]), once the ulcer was healed or after 20 weeks (time-point 1 [T1]), and 3 months later (time-point 2 [T2]). Patients with severe ischaemia were excluded.ResultsThe mean age of the patients was 60 years, 72% were male, and time since diagnosis of diabetes was 17 years. Patients reported a low HRQoL on all SF-36 subscales. At T1, HRQoL scores in physical and social functioning were higher in patients with a healed vs a non-healed ulcer (p<0.05). At T2, these differences were larger, with higher scores for physical and social functioning, role physical and the physical summary score (all p<0.05). Within-group analysis revealed that HRQoL improved in different subscales in patients with a healed ulcer and worsened in patients with a persistent ulcer from T0 to T2 (all p<0.05). The caregivers of patients with a persisting ulcer had more emotional difficulties at T2.Conclusions/interpretationDiabetic patients with a healed foot ulcer had a higher HRQoL than patients with a persisting ulcer. Healing of a foot ulcer resulted in a marked improvement of several SF-36 subscales 3 months after healing (from T0 to T2). HRQoL declined progressively when the ulcer did not heal. A diabetic foot ulcer appeared to be a large emotional burden on the patients’ caregivers, as well.

Correlation of Serum Osteocalcin Fractions with Bone Mineral Density in Women During the First 10 Years after Menopause

Abstract. Serum immunoreactive osteocalcin (irOC) consists of two fractions that differ from each other by their affinity for hydroxyapatite. The high and low affinity fractions are referred to as irOCbound and irOCfree, respectively. To evaluate whether these fractions are determinants for different characteristics of bone or bone metabolism, we have performed a cross-sectional study among 212 apparently healthy women between 20 and 90 years of age. Bone mineral density (BMD) was determined at the lumbar spine, and the right femur neck, trochanter, and Wards triangle using dual-energy X-ray absorptiometry (DXA). Biochemical markers for bone formation and resorption were determined in serum and in urine. After classification according to menopausal age, an inverse correlation was found in the 1–10 years postmenopausal women between irOCfree and BMD, notably of the Wards triangle and femur neck. It is concluded that in 1–10 years postmenopausal women, irOCfree is an independent marker for BMD, but that in other age groups the association is less clear or is absent.

Effects of a new oral hypoglycaemic agent, repaglinide, on metabolic control in sulphonylurea-treated patients with NIDDM

SummaryWe have evaluated the effects of repaglinide, a new non-sulphonylurea oral hypoglycaemic agent that has a stimulatory effect on insulin secretion. Forty-four patients with NIDDM, already treated with a sulphonylurea, took part in an open, randomised, group comparison study of 12 weeks duration, during which they received either repaglinide or glibenclamide twice daily.While glibenclamide had a greater effect on fasting blood glucose (10.4 to 8.6 mmol·l−1), repaglinide significantly lowered postprandial blood glucose (13.8 to 12.2 mmol· l−1). Glycosylated haemoglobin remained unchanged in both groups, and serum fructosamine showed a tendency to fall. With both treatments total cholesterol was significantly decreased after 12 weeks, while HDL-cholesterol and triglycerides did not change. Fasting plasma insulin in the repaglinide group decreased from 80 (median value) to 67 pmol·l−1; it did not change in the glibenclamide group. Two patients in the repaglinide group did not complete the study, one for personal reasons, and one because of a rise in blood glucose.No abnormal findings attributable to repaglinide were observed in clinical and laboratory examinations, and no hypoglycaemic symptoms caused by it were observed.

Lipoprotein(a) levels in relation to diabetic complications in patients with non-insulin-dependent diabetes

Abstract. The relationship between serum levels of lipoprotein(a) (Lp(a)) and the presence of chronic diabetic complications was studied in 194 patients with non‐insulin‐dependent diabetes mellitus (NIDDM; 75 males, 119 females; age 66±11 years; duration of diabetes, 11 (range 1–35) years). They were taking various treatments (diet alone, oral hypoglycaemic agents and/or insulin). Metabolic status and prevalence of diabetic complications were assessed by detailed history, physical examination, laboratory analysis and ECG. Average metabolic control was moderate (HbAle, 8.2±1.7%). Median serum Lp(a) level was 183 U 1‐‐1 (range 8–2600 U I‐1), which was significantly higher than in control subjects of comparable age (median 101; range 8–1747 U I‐1; P<0.05), while HDL‐cholesterol levels were lower (1.14 ± 0.38 vs. 1.35 ± 0.35 mmol l‐1; P=0.001), and total cholesterol levels were comparable. No significant relation ships between diabetes treatment or metabolic control and Lp(a) levels were observed. In the quartile of patients with the highest Lp(a) levels. total cholesterol and triglycerides were slightly higher (P < 0.05), where as HDL‐cholesterol was not different. With increasing Lp(a) levels, higher prevalences of preproliferative retinopathy and of coronary artery disease (CAD) were observed, but not of the other complications. No relationship was found between the degree of albuminuria and Lp(a) levels. We conclude that in NIDDM patients, Lp(a) levels are elevated compared with non‐diabetic subjects, and that higher Lp(a) levels are associated with higher prevalences of CAD and of retinopathy.

Skin blood cell flux in insulin‐dependent diabetic subjects in relation to retinopathy or incipient nephropathy

Abstract. We studied the relationship of retinal and/or renal microvascular complications and duration of disease with altered finger skin microcirculation in insulin‐dependent diabetic (IDDM) subjects. Short‐term and long‐term IDDM subjects without complications or with proliferative retinopathy or incipient nephropathy were investigated with laser‐Doppler fluxmetry. An increased resting flux in skin microcirculation was found in short‐term (median: 34 perfusion units, PU) and uncomplicated long‐term IDDM subjects (25 PU) as compared with age‐matched healthy controls (18 PU), which suggests a generalized dilatation of the microcirculation throughout the body. In long‐term IDDM subjects with retinopathy we also observed an increased resting flux (37 PU), but in subjects with incipient nephropathy resting flux was decreased (17 PU) relative to the other diabetic subjects, to a level not different from the healthy control group. Post‐occlusive hyperaemic peak flux was decreased in patients with incipient nephropathy relative to the other diabetic patients, which suggests a defect in maximal arteriolar vasodilatation. No differences were found between the groups in the veno‐arteriolar reflex during venous occlusion. In conclusion, IDDM patients demonstrated increased red blood cell flux. However, with the occurrence of incipient nephropathy the resting flux and the maximal post‐occlusive vasodilatation decreased, which suggests that development of nephropathic changes in diabetes is representative of a more generalized alteration of microvascular flow regulation. Local neuro‐genic microvascular control appears to be unaffected in these patients.

Aminoguanidine reduces regional albumin clearance but not urinary albumin excretion in streptozotocin-diabetic rats

SummaryAdvanced glycation end-product-formation is thought to play a role in the development of diabetic angiopathy. By altering the structure of different extracellular matrix components advanced glycation end-products might affect vascular and glomerular permeability. In this study we investigated the effect of treatment with an inhibitor of advanced glycation end-product-formation, aminoguanidine, on vascular permeability and the development of albuminuria in streptozotocin-induced diabetic rats. Male Wistar Rp rats were randomized into a control group, a diabetic group, and an aminoguanidine-treated diabetic group. After 8 weeks, 24-h urine collections were taken and rats were implanted with an arterial and a venous catheter. Mean arterial blood pressure was determined by intra-arterial measurement. Regional albumin clearances were assessed in the eye, ileum, lung, skeletal muscle and skin using an isotope technique. Mean arterial pressure in the diabetic group was significantly lower in the control and aminoguanidine-treated groups (p<0.02). Regional albumin clearances were significantly increased in all tissues of diabetic rats compared to control rats (p<0.05). Aminoguanidine treatment of diabetic rats resulted in a significant decrease of regional albumin clearance in all tissues except the lung (p<0.05, lung p=0.07). The development of albuminuria in diabetic rats however, was not affected by aminoguanidine.

Diurnal variations in total forearm and skin microcirculatory blood flow in man

The aim of the present study was to determine diurnal variations in total forearm and skin microcirculatory blood flow in healthy man. At six time points between 08.00 and 18.00 hours was measured: blood pressure, forearm blood flow (FBF; strain gauge plethysmography), skin thermoregulatory blood flow (LDF; laser-Doppler fluxmetry), and skin nutritive blood flow (CBV: Capillary Blood Cell Velocity; intravital capillary microscopy) in 15 healthy, fasting, and resting men. FBF increased gradually from 2.8 in the morning to 4.3 ml 100 ml min-1 in the afternoon (p < 0.001). In contrast, LDF decreased, predominantly in the morning, from 18.3 at 09.00 hours to 13.1 at 12.00 hours and to 12.1 perfusion units at 17.30 hours (p < 0.001). However, performing the same protocol starting in the afternoon resulted in a similar initial decrease in LDF, suggesting an acclimatization phenomenon. Although not statistically significant, the decrease in CBV showed a similar pattern as compared to LDF. Blood pressure did not change. In conclusion, forearm blood flow increased during the day, probably due to diurnal variation in muscle flow. The initial decrease we observed in skin thermoregulatory blood flow is probably not related to diurnal variation but due to long-term acclimatization to the experimental conditions. These data suggest different regulatory mechanisms for the different vascular beds studied. Measurements of forearm blood flow should preferably be performed at the same time of day, and skin microcirculatory haemodynamic measurements should be performed after a standard period of acclimatization.

Improved Blood Glucose Control by Insulin Therapy in Type 2 Diabetic Patients Has No Effect on Lipoprotein(a) Levels

The effects of improved blood glucose control by insulin therapy on lipoprotein(a) and other lipoproteins were studied in 54 patients with Type 2 diabetes (mean ± SD: age 67 ± 9 years, body mass index 26.1 ± 4.4 kg m−2, median duration of diabetes 10 (range 1–37) years, 23 males, 31 females), who were poorly controlled despite diet and maximal doses of oral hypoglycaemic agents. After 6 months of insulin treatment, mean fasting blood glucose concentrations had decreased from 14.1 ± 2.2 mmol l−1 to 8.4 ± 1.8 mmol l−1 (p < 0.001), and HbA1c had fallen from 11.1 ± 1.4 % to 8.2 ± 1.1 % (p < 0.001). Significant decreases of total and LDL cholesterol, triglycerides, apolipoprotein B, and free fatty acids were observed, while HDL‐cholesterol and apoA1 increased by 10 %. Baseline serum Lp(a) levels were elevated compared to non‐diabetic subjects of similar age (median 283, range 8–3050 mg I−1, vs 101, range 8–1747 mg I−1, p < 0.05), but did not change with insulin, and there was no correlation with the degree of metabolic improvement and changes in Lp(a) levels. It is concluded that improved blood glucose control by insulin therapy does not alter elevated Lp(a) levels in Type 2 diabetic patients, but has favourable effects on the other lipoproteins.

The effects of 7-hour local hyperglycaemia on forearm macro and microcirculatory blood flow and vascular reactivity in healthy man

SummaryAnimal studies suggest that hyperglycaemia directly affects local blood flow and vascular reactivity. We studied the effects of 7 h of local forearm hyperglycaemia, on forearm (muscle) and skin microcirculatory blood flow in 12 healthy men. Furthermore, the effects of this local hyperglycaemia on forearm vasoreactivity to noradrenaline were studied. Using the perfused forearm technique, a local hyperglycaemia of approximately 16 mmol/l was induced by continuous intraarterial infusion of 5% glucose. All subjects received both glucose and placebo (0.9% NaCl) infusions on two different occasions, in random order and blinded for the subjects. Forearm (muscle) blood flow and vascular reactivity to noradrenaline were measured using venous occlusion plethysmography. Skin microcirculatory blood flow was evaluated using intravital capillary microscopy (nutritive blood flow) and laser-Doppler fluxmetry (thermoregulatory blood flow). Measurements were performed at baseline, after 4 h, and after 7 h of intraarterial glucose or placebo infusion. During local glucose infusion there was a slight increase in the levels of insulin, C-peptide, systemic glucose, and blood pressure, compared to the placebo experiments. No differences were observed in forearm blood flow and laser-Doppler flux ratio (infused: contralateral arm), as well as in capillary blood cell velocity between glucose and placebo experiments. Noradrenaline produced similar reductions in forearm blood flow ratio during glucose and placebo experiments. We conclude that in contrast to animal studies, local hyperglycaemia (≈ 16 mmol/1) for 7 h does not affect forearm macro and microcirculatory blood flow or vascular reactivity to noradrenaline in man.

Venous compliance and the venodilatory effect of nitroglycerin in insulin-dependent diabetic patients with and without (incipient) nephropathy

Abstract. The venous system plays a pivotal role in volume and blood pressure homeostasis. We tested the hypothesis that the visco‐elastic properties of the peripheral venous system are reduced in patients with (incipient) diabetic nephropathy. Twenty‐two normotensive patients with long‐term insulin‐dependent diabetes mellitus (IDDM), 11 without and 11 with (incipient) nephropathy (eight microalbuminuria and three proteinuria, serum creatinine below 100 μmol l‐1), and 14 healthy age/sex matched controls were studied. Forearm venous compliance (VENCOMP) was determined using strain gauge plethysmography and direct intravenous pressure measurements. Furthermore, the venodilatory effect of 0·4 mg sublingual nitroglycerin (NTG) was studied. In comparison with healthy controls, VENCOMP was decreased in patients without and with (incipient) nephropathy, without any differences between the two diabetic groups: 0·059 (0·052–0·066), 0·044 (0·038–0·059) and 0·049 (0·046–0·058) ml 100 ml‐1 mmHg‐1, respectively (medians and interquartile ranges) (P<0·05). No differences in the increase of forearm volume after NTG were observed: 0·34 (0·11–0·51), 0·37 (0·19–0·50) and 0·39 (0·20–0·55) ml 100 ml‐1, respectively. In conclusion, the visco‐elastic properties of the peripheral venous system are reduced in patients with long‐term IDDM. This reduction is not related to the presence of nephropathy. No major differences were observed in NTG‐induced venodilation between diabetic patients and healthy subjects.