Glucose-induced changes in renal haemodynamics in proteinuric Type 1 (insulin-dependent) diabetic patients: inhibition by acetylsalicilic acid infusion

Summary The effect of hyperglycaemia on renal function in diabetic nephropathy remains poorly understood. We investigated the renal haemodynamic response to an acute plasma glucose rise from sustained euglycaemia to sustained hyperglycaemia in eight persistently proteinuric Type 1 (insulin-dependent) diabetic patients. Studies were performed in a double-blind cross-over manner after i.v. injection of 450 mg lysine acetylsalicilate (equivalent to 250 mg acetylsalicilic acid) or equal volume of 0.9% NaCl (isotonic saline). In the isotonic saline experiments hyperglycaemia produced a significant rise, by approximately 35%, in glomerular filtration rate in all patients from 41.5±5.2 to 55±6 ml·min^–1·1.73 m^–2 (p<0.005) and an increase in sodium paraminohippurate clearance from 178±22.7 to 220±20.0 ml·min^–1·1.73 m^–2 (p<0.05). These changes took place within the first 30 min of glucose infusion and were maintained for a 90 min hyperglycaemic period. Filtration fraction did not change significantly. Infusion of lysine acetylsalicilate lowered baseline glomerular filtration rate (isotonic saline vs lysine acetylsalicilate 41.5±5.2 vs 30.0±5.7 ml·min^–1·1.73 m^–2; p<0.05) and significantly blunted the rise in glomerular filtration rate during hyperglycaemia (glomerular filtration rate increment: saline vs lysine acetylsalicilate: 13.6±2.8 vs 5.3±1.8 ml·min^–1 ·1.73 m^–2; p<0.005). The effects on renal plasma flow were similarly blunted. In five additional patients, time- and volume-controlled isotonic saline experiments during sustained euglycaemia showed no significant changes in glomerular filtration rate and sodium paraminohippurate clearance. In Type 1 diabetic patients with advanced renal failure, acute hyperglycaemia induces a significant elevation in glomerular filtration rate and renal plasma flow which is likely to be mediated by renal prostaglandin production.     

Kidney function in newly diagnosed Type 2 (non-insulin-dependent) diabetic patients, before and during treatment

Summary Glomerular filtration rate, kidney volume, and urinary albumin excretion rate were studied in otherwise healthy newly diagnosed Type 2 (non-insulin-dependent) diabetic patients, untreated at diagnosis, after short-term treatment and after 3 months treatment. In 10 patients (Group A) glomerular filtration rate (measured by the plasma clearance of 51-Cr-EDTA) decreased from the time of diagnosis 106.2±14.6 ml·min^–1·1.73m^2–1 (mean±SD) to 95.9±13.7 ml·min^–1·1.73m^2–1 after 3 months treatment (p=0.049). At the same time, mean plasma glucose was reduced from 13.3±3.2 mmol/l to 6.5±1.1 mmol/l. The fall in mean plasma glucose was correlated to the reduction in glomerular filtration rate, r=0.76, p=0.011. Kidney volume as measured by ultrasonic scanning was reduced from 264.0±33.7 ml/l.73m² to 210.8±23.8 ml/l.73 m² (p<0.005). The relative decline in urinary albumin excretion rate was correlated to the fall in glomerular filtration rate, r=0.69, p=0.026. In 15 patients (Group B) 24-h urine collections were made during 9.5±3.2 days, urinary albumin excretion rate fell from the first to the last day in hospital from 14.0×/÷3.0 g/min (geometric mean ×/÷ tolerance factor) to 7.0×/÷2.7 g/min p=0.015. The relative decline was correlated to the change in mean plasma glucose, r=0.65, p=0.032.Thus, kidney function in Type 2 diabetic patients is influenced by metabolic control, although to a lesser extent than is seen in Type 1 (insulin-dependent) diabetic patients with comparable glycaemic control. Urinary albumin excretion is reduced by improvement in glycaemic control, to which it is significantly correlated. Long-term consequences of reduction in urinary albumin excretion on the development of diabetic nephropathy and on survival remains to be elucidated.     

Ketone bodies increase glomerular filtration rate in normal man and in patients with Type 1 (insulin-dependent) diabetes mellitus

Summary The purpose of this study was to investigate whether the administration of acetoacetic and hydrochloric acids in a group of control and Type 1 (insulin-dependent) diabetic patients influenced renal haemodynamics. Renal plasma flow increased from 657±88 to 762±81 ml·min^–1. 1.73 m^–2 in diabetic patients (p<0.01) and from 590±71 to 691±135 in control subjects (p<0.01). Glomerular filtration rate increased from 135±9 to 180±8 ml·min^–1·1.73 m^–2 in diabetic patients (p< 0.001) and from 117±8 to 145±7 in control subjects (p<0.01). Similar effects on renal haemodynamics, even if less pronounced, were observed with low dose acetoacetic but not with hydrochloric acid infusion. Total protein, 2-microglobulin but not albumin excretion rates were increased by acetoacetic acid. We conclude that an acute increase in blood concentration of ketone bodies within the range found in diabetic patients with poor metabolic control (1) increases renal plasma flow and glomerular filtration rate both in control subjects and diabetic patients and (2) causes a tubular proteinuria.     

Enalapril does not alter renal function in normotensive,normoalbuminuric, hyperfiltering Type 1 (insulin-dependent) diabetic children

Summary Using a prospective randomised double-blind crossover design, the effect of the angiotensin converting enzyme inhibitor enalapril compared to a placebo was studied in 18 normotensive, normoalbuminuric Type 1 (insulin-dependent) diabetic children. Each patient had a high normal or clearly elevated glomerular filtration rate (145 ml· min^–1· 1.73 m² or higher) in the 6 months prior to the study. Enalapril, 0.5 mg·kg^–1· day^–1, was given for 4 weeks followed by placebo for 4 weeks, or vice versa. At the end of each period, glomerular filtration rate, renal plasma flow, blood pressure, plasma renin activity, and converting enzyme activity were determined. Enalapril caused significant reduction (p=<0.001) in blood pressure and converting enzyme activity and a rise in plasma renin activity. A slight but not significant rise in glomerular filtration rate and renal plasma flow without change in filtration fraction was observed. These data suggest that the renin angiotensin system is not involved in the glomerular hyperfiltration of Type 1 diabetes, and can be interpreted as showing no evidence for the presence of intraglomerular hypertension in these patients.Recipient of the Schering Award of the Canadian Society of Clinical Investigation during the period of this research     

Effect of insulin on renal sodium handling in hyperinsulinaemic Type 2 (non-insulin-dependent) diabetic patients with peripheral insulin resistance

Summary The sodium retaining effect of insulin was studied in ten Type 2 (non-insulin-dependent) diabetic patients (mean age 56 (43–73) years, mean body mass index 29.5 (24.2–33.7) kg/m²) and eight age-matched control subjects (mean age 57 (43–68) years, mean body mass index 23.4 (20.8–26.6) kg/m²). The renal clearances of ^99mTc-DTPA, lithium, sodium and potassium were measured over a basal period of 90 min. Then insulin was infused at a rate of 40 mU·mirr^–1·m^–2. After an equilibration period of 90 min, the clearance measurements were repeated during a new 90 min period. Blood glucose was clamped at the basal level (diabetic patients: 9.9±3.5, control subjects: 5.3±0.5 mmol/l) by a variable glucose infusion. Basal plasma insulin concentration was elevated in the diabetic patients (0.12±0.05 vs 0.05±0.02 pmol/ml, p<0.01). Insulin infusion resulted in comparable absolute increments in plasma insulin concentrations in the diabetic group and in the control group (0.44±0.13 vs 0.36±0.07 pmol/ml, NS). The metabolic clearance rate of glucose during the last 30 min of insulin infusion was lower in the diabetic patients (155±62 vs 320±69 ml·min^–1·m², p<0.01), reflecting peripheral insulin resistance. The decline in sodium clearance during insulin infusion was similar in diabetic subjects (1.8±1.1 vs 0.7±0.4 ml·min^–1·1.73 m^–2, p< 0.01) and in control subjects (1.7±0.3 vs 0.8±0.3 ml · min^–1 · 1.73 m^–2, p<0.01). The glomerular filtration rate and lithium clearance was unchanged, consequently calculated distal tubular fractional sodium reabsorption increased (diabetic patients: 92.9±4.1 vs 97.1±1.5, p<0.01, control subjects: 93.1±1.1 vs 96.5±0.6%, p< 0.01). Estimated extracellular fluid volume was 10% higher in the diabetic subjects (16.3±2.1 vs 14.8±2.01·1.73 m^–2, NS). In conclusion, the sodium retaining effect of insulin is preserved in Type 2 diabetic patients with peripheral insulin resistance. Insulin may contribute to sodium and fluid retention and thus to the increased frequency of hypertension in hyperinsulinaemic Type 2 diabetic patients.     

Factors associated with basal metabolic rate in patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary To examine determinants of basal metabolic rate we studied 66 Type 2 (non-insulin-dependent) diabetic and 24 healthy age- and weight-matched control subjects with indirect calorimetry and infusion of [³H-3-] glucose. Eight Type 2 diabetic patients were re-studied after a period of insulin therapy. Basal metabolic rate was higher in Type 2 diabetic patients than in control subjects (102.8 ± 1.9 J · kg LBM^–1-min^–1 vs 90.7 ± 2.8 J · kg LBM^–1;min^–1; p<0.01) and decreased significantly with insulin therapy (p <0.01). The basal rate of hepatic glucose production was higher in Type 2 diabetic patients than in control subjects (1044.0 ± 29.9 vs 789.3 ± 41.7 mol/min; p <0.001) and decreased after insulin therapy (p <0.01). Hepatic glucose production correlated positively with basal metabolic rate both in Type 2 diabetic patients (r = 0.49; p <0.001) and in control subjects (r = 0.50; p<0.05). Lipid oxidation was increased in Type 2 diabetic patients compared with control subjects (1.68 ± 0.05 vs 1.37 ± 0.08 mol · kg LBM^–1 · min^–1'; p <0.01) and decreased significantly after insulin therapy (p <0.05). The rate of lipid oxidation correlated positively with basal metabolic rate both in Type 2 diabetic patients (r = 0.36; p <0.01) and in control subjects (r = 0.51; p <0.01). These data demonstrate that basal metabolic rate, rates of hepatic glucose production and lipid oxidation are interrelated in Type 2 diabetic patients. A reduction of the hepatic glucose production, however, is associated with a reduction in lipid oxidation, which in turn, may result in a reduction in basal metabolic rate.     

Reduction of protein intake decreases glomerular filtration rate in young Type 1 (insulin-dependent) diabetic patients mainly in hyperfiltering patients

Summary The influence of different protein intake on renal function was studied in 16 Type 1 (insulin-dependent) diabetic patients, aged 15–23 years, with onset of diabetes before puberty and with a duration of diabetes between 5 and 20 years. The glomerular filtration rate, renal plasma flow, albumin excretion rate, and blood pressure were examined in a cross-over randomised order after 10 days on isocaloric diets with either 10% (i.e. 0.9±0.06 g·kg^–1·day^–1) or 20% (1.9±0.1 g·kg^–1·day^–1) of the calories as protein, the latter being equal to the recommended diet. Dietary compliance was evaluated using fractional phosphate excretion and overnight urea excretion. Glomerular filtration rate was lower after the low-protein diet compared to the usual protein diet (p<0.001). Patients with glomerular filtration rate above +2 SD of the normal mean on the usual protein diet (n=6) exhibited the steepest fall in glomerular filtration rate with a mean decrease of 20ml/min compared to 7 ml/min in those with initially normal glomerular filtration (p=0.01). Filtration fraction tended to decrease on low protein diet, more so in initially hyperfiltering patients (p=0.09). Renal plasma flow remained unchanged. In patients with elevated glomerular filtration rate on usual protein diet, albumin excretion rate and systolic, but not diastolic blood pressure, were decreased on low protein diet (p=0.03 and p=0.01, respectively) but not in initially normal-filtering patients. Mean blood glucose and serum fructosamine were unchanged on both diets. In conclusion, low protein diet decreases glomerular filtration rate independently of glycaemic control in young Type 1 diabetic patients and more so in hyperfiltering patients. This decline in glomerular filtration rate is accompanied by a decrease in albumin excretion rate and systolic blood pressure in hyper-filtering patients.     

Effect of sodium intake on blood pressure and albuminuria in Type 2 diabetic patients: the role of insulin resistance

Aims/hypothesis This study was done to measure the effect of Na⁺ intake on blood pressure and albuminuria, in relation with insulin sensitivity and kidney haemodynamics, in Type 2 diabetic patients with and without microalbuminuria.Methods Type 2 diabetic patients, 20 with microalbuminuria, 21 without, spent two consecutive 7-day periods, one on a high (250 mmol), the other on a low-Na⁺ (20 mmol) diet. Body weight, 24-h blood pressure and albuminuria were measured at the end of each period. At the end of high-Na⁺ diet insulin sensitivity (euglycaemic insulin clamp; 2 mU·kg^–1·min^–1) and kidney haemodynamics were measured in nine patients from each group.Results Switching from low to high-Na⁺ diet resulted in an increase in blood pressure (7.4±4.7 mmHg; p<0.001), body weight (1.9±0.4 kg; p<0.05) and albuminuria [from 80 (31–183) µg/min to 101 (27–965) µg/min; p<0.01) in patients with microalbuminuria. No changes occurred in patients without microalbuminuria. Patients with microalbuminuria also had greater intraglomerular pressure (44±1 mmHg vs 36±1; p<0.001), calculated from glomerular filtration rate, renal plasma flow, plasma protein concentration and the relationship between pressure and natriuresis. In these patients insulin sensitivity was lower (5.16±49 vs 7.36±0.63 mg·kg^–1·min^–1; p=0.007). Urinary albumin excretion (r=0.40; p=0.009) and insulin sensitivity (r=–0.59; p=0.01) were correlated with intraglomerular pressure.Conclusion/interpretation High salt intake increases blood pressure and albuminuria in Type 2 diabetic patients with microalbuminuria. These responses are associated with insulin resistance and increased glomerular pressure. Insulin resistance could contribute to greater salt sensitivity, increased glomerular pressure and albuminuria.Abbreviations GFR Glomerular filtration rate - PGC intraglomerular pressure - AER albumin excretion rate     

The influence of human C-peptide on renal function and glucose utilization in Type 1 (insulin-dependent) diabetic patients

Summary The possible influence of C-peptide administration on renal function and whole body glucose utilization was examined in 11 patients (Group 1) with Type 1 (insulin-dependent) diabetes mellitus. They were given an i. v. insulin infusion during the night before the study and were euglycaemic at the time of examination. The glomerular filtration rate and effective renal plasma flow were measured by clearance techniques using constant-rate infusions of inulin and sodium para-aminohippurate. After baseline measurements C-peptide was infused during two periods of 60 min at rates of 5 and 30 pmol·kg^–1·min^–1. In a control study 0.9% NaCl was infused during two 60 min periods in ten Type 1 diabetic patients (Group 2), Glomerular filtration rate decreased by 7%(p<0.001), effective renal plasma flow increased by 3%, (p<0.05) and whole-body glucose utilization rose by approximately 25%(p<0.05) above basal during low-dose C-peptide infusion. Group 2 showed an unaltered glomerular filtration rate, effective renal plasma flow and glucose utilization during 60 min of NaCl infusion. The differences between Group 1 and Group 2 in glomerular filtration rate and glucose utilization were statistically significant. It is concluded that short-term administration of C-peptide in physiological amounts to patients with Type 1 diabetes may reduce the glomerular filtration rate and increase whole-body glucose utilization. The results suggest the possibility that short-term C-peptide administration may exert a regulatory influence on renal function and stimulate glucose utilization in Type 1 diabetic patients.     

A strong correlation between glomerular filtration rate and filtration surface in diabetic nephropathy

Summary Quantitative structural studies were performed in kidney biopsy specimens from 24 long-term Type 1 (insulin-dependent) diabetic patients with persistent albuminuria due to diabetic glomerulopathy. Ten patients were receiving antihypertensive treatment, and among the remaining patients the mean blood pressure was 142/91 mmHg (SD = 11/9). The urinary albumin excretion rate showed a range from 100 to 5494 g/min (geometric mean 688 g/min.) Glomerular filtration rate also showed a wide range, from supranormal to markedly decreased values (128 to 28 ml·min^–1· (1.73 m²)^–1, mean 75). The filtration surface (interface between capillary and urinary space) per total number of nephrons (open+occluded) was estimated by combined light- and electron microscopy. The percentage occluded glomeruli as well as structural quantities in the open glomeruli were taken into account in this estimate. A highly significant correlation was seen between glomerular filtration rate and filtration surface per nephron (r=0.77, p<10^–4). The percentage occluded glomeruli contributed significantly to the variation in glomerular filtration rate (for this relationship tested separately r=-0.78, p<10^–5). The volume of open glomeruli was even larger than that seen in early diabetic glomerular hypertrophy and tended to increase with the percentage of glomerular closure, indicating that a compensatory hypertrophy might have taken place. In the open glomeruli the filtration surface constituted a smaller percent of total capillary surface (the remaining part facing the mesangial regions) than in early diabetic patients and control subjects.Our study has demonstrated that reduced glomerular filtration surface is closely associated with reduced glomerular filtration rate in Type 1 diabetic patients with diabetic nephropathy.     

Diabetic background retinopathy is associated with impaired coronary vasoreactivity in people with Type 1 diabetes

Aims/hypothesis We examined whether diabetic background retinopathy is associated with reduced coronary vasoreactivity in people with Type 1 diabetes.Methods A total of 21 men with Type 1 diabetes were investigated, including 9 men with background retinopathy and 12 men without retinopathy. In addition, 12 non-diabetic, age-matched subjects were studied. All subjects were non-smokers, otherwise healthy and had no other diabetic complications. Resting myocardial blood flow and hyperaemic dipyridamole-stimulated flow (dipyridamole, 0.56 mg/kg during a 4-min period), a measure of coronary vasoreactivity, were measured during euglycaemic hyperinsulinaemic clamp (1 mU·kg^–1·min^–1) using positron emission tomography and oxygen-15-labelled water.Results Resting myocardial blood flow (0.82±0.13 vs 0.96±0.23 vs 0.88±0.25 ml·g^–1·min^–1, with vs without retinopathy vs non-diabetic subjects) and coronary vascular resistance (111.2±23.4 vs 95.5±15.8 vs 101.9±31.5 mmHg·min·g·ml^–1 respectively) were not significantly different between the groups. Dipyridamole infusion induced an increase in blood flow and a decrease in coronary vascular resistance in all study subjects (p<0.001). However, dipyridamole-stimulated flow and coronary vascular resistance were blunted in diabetic patients with retinopathy (2.9±0.9 ml·g^–1·min^–1 and 34.1±11.3 mmHg·min·g·ml^–1) when compared to diabetic patients without retinopathy (4.0±1.3 ml·g^–1·min^–1, p=0.04 and 24.6±7.5 mmHg·min·g·ml^–1, p=0.03) or non-diabetic subjects (4.5±1.4 ml·g^–1·min^–1, p=0.008 and 22.2±8.7 mmHg·min·g·ml^–1, p=0.01). Myocardial flow reserve was impaired in diabetic patients with retinopathy (3.6±1.0) when compared to non-diabetic subjects (5.3±1.9, p=0.02) but not significantly reduced when compared to diabetic patients without retinopathy (4.2±1.4, p=0.2).Conclusions/interpretation Diabetic background retinopathy appears to be associated with impaired coronary vasoreactivity in young people with Type 1 diabetes.Abbreviations PET positron emission tomography - [¹⁵O]H₂O oxygen-15-labelled waterJ. Sundell and T. Janatuinen contributed equally to this work     

Effect of antihypertensive treatment on blood-retinal barrier permeability to fluorescein in hypertensive Type 1 (insulin-dependent) diabetic patients with background retinopathy

Summary The effect of antihypertensive treatment on blood-retinal barrier leakage of fluorescein in background retinopathy was studied in nine hypertensive Type 1 (insulin-dependent) diabetic patients suffering from nephropathy. The patients were investigated before and after 7 (3 to 13) months of treatment with captopril (n=8; 25 to 100 mg daily) and a diuretic, either frusemide (n=4; 80 to 200 mg daily) or bendrofluazide (n=2; 2.5 mg daily). Retinal function was assessed by fundus photography, fluorescein angiography, vitreous fluorometry, and renal function by glomerular filtration rate, and albuminuria. The antihypertensive treatment induced a significant reduction (p<0.05) in: blood pressure from 152/97±14/8 mmHg to 134/82±11/6 mmHg; blood-retinal barrier leakage of fluorescein from 2.4 ±1.1 to 1.4±0.5·10^–7 cm/second; albuminuria from 1391 (range: 168–4852) g/min to 793 (range: 35–2081) ug/min. Glomerular filtration rate declined from 88±15 to 78±23 ml·min^–1·1.73 m² (0.05<p<0.10). The metabolic control of the patients as reflected by their blood glucose and HbA_1c levels remained stable during the study. Our study suggests that systemic blood pressure elevation contributes to the abnormal blood-retinal barrier permeability to fluorescein characteristically found in diabetic background retinopathy and that this abnormality can be reversed during antihypertensive treatment.     

Effects of insulin on kidney function and sodium excretion in healthy subjects

Summary Insulin action on kidney function was evaluated in 8 healthy subjects, (mean age 27 years) using the euglycaemic clamp technique. Insulin was infused at rates of 0, 20 and 40 mU·min^–1·m^–2 over consecutive periods of 120 min resulting in plasma insulin concentrations of 8±2, 29±7 and 66±14 mU/l. The renal clearance of ⁵¹Cr-EDTA, lithium, sodium and potassium was determined during the last 90 min of each period. Sodium clearance declined with increasing plasma insulin concentrations (1.3±0.4, 1.0±0.3 and 0.5±0.2 ml·min^–1·1.73 m^–2, p<0.001), while glomerular filtration rate (108±21, 104±21 and 108±20ml·min^–1·1.73 m^–2) and lithium clearance (a marker of fluid flow rate from the proximal tubules) 29±5, 29±4 and 30±4 ml·min^–1·1.73 m^–2) remained unchanged. Calculated proximal tubular reabsorption of sodium and water was unchanged, while calculated distal fractional sodium reabsorption increased (95.5±1.5, 96.4±1.2 and 98.1±0.7%, p<0.001). Potassium clearance and plasma potassium concentration declined, whereas plasma aldosterone and plasma renin concentrations were unchanged. In conclusion, elevation of plasma insulin concentration within the physiological range has a marked antinatriuretic action. This effect is located distally to the proximal renal tubules.     

Aldosterone escape during blockade of the renin–angiotensin–aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate

Aims/hypothesis It has been suggested that aldosterone plays a role in the initiation and progression of renal disease independently of arterial blood pressure and plasma angiotensin II levels. We evaluated the influence of plasma aldosterone levels on progression of diabetic nephropathy during long-term blockade of the renin–angiotensin–aldosterone system.Methods A total of 63 hypertensive patients with type 1 diabetes and diabetic nephropathy were treated with losartan, 100 mg once daily, for a mean follow-up period of 35 months. Plasma aldosterone, GFR, albuminuria and 24-h blood pressure were determined at baseline and at regular intervals during the study.Results Patients were divided according to their increasing or decreasing levels of plasma aldosterone during long-term losartan treatment in an escape group (n=26) and a non-escape group (n=37). In the escape group, aldosterone levels increased from (geometric mean [95% CI]) 57 pg/ml (43–76 pg/ml) at 2 months, to 102 pg/ml (78–134 pg/ml) at the end of the study (p<0.01). The corresponding levels in the non-escape group were 83 pg/ml (69–102 pg/ml) and 49 pg/ml (40–60 pg/ml; p<0.01). The median rate of decline in GFR was 5.0 ml·min^–1·year^–1 (range 0.4–15.9 ml·min^–1·year^–1) in the escape group, compared with 2.4 ml·min^–1·year^–1 (–1.6 to 11.0 ml·min^–1·year^–1) in the non-escape group (p<0.005). The increase in plasma aldosterone correlated with the rate of decline in GFR (r²=0.19, p<0.001), corresponding to a decline in GFR of 1.5 ml·min^–1·year^–1 for every two-fold increase in plasma aldosterone. Pre-treatment and treatment values of plasma aldosterone were not related to albuminuria or to changes in albuminuria during the study.Conclusions/interpretation Our data suggest that aldosterone escape during long-term blockade of the renin–angiotensin–aldosterone system is associated with an enhanced decline in GFR in patients with type 1 diabetes and diabetic nephropathy.Conflict of interest. Hans-Henrik Parving received honoraria or consulting fees from Merck, AstraZeneca, BMS, Sanofi-Synthelabo and Pfizer, and grant/research support from Merck and Sanofi-Synthelabo.     

High-sensitivity C-reactive protein and impaired coronary vasoreactivity in young men with uncomplicated type 1 diabetes

Aims/hypothesis Elevated high-sensitivity C-reactive protein (hsCRP) concentrations indicate increased risk of future coronary events. The association between hsCRP and coronary vasoreactivity has not yet been examined in type 1 diabetic subjects.Methods We studied 18 young men who were non-smokers and who had uncomplicated type 1 diabetes. The diabetic subjects were divided into two groups, according to their median hsCRP concentration, as follows: (i) subjects with slightly elevated hsCRP (median 0.76 mg/l, range 0.47–4.73 mg/l, n=8); and (ii) subjects with low hsCRP (median 0.32 mg/l, range 0.11–0.35 mg/l, n=10). In addition we investigated 22 non-diabetic age-matched subjects (hsCRP: median 0.42 mg/l, range 0.11–1.31 mg/l). Resting myocardial blood flow and hyperaemic adenosine-stimulated flow during euglycaemic–hyperinsulinaemic clamp were determined using positron emission tomography and oxygen-¹⁵-labelled water.Results Diabetic subjects with slightly elevated hsCRP had significantly higher hsCRP concentrations than non-diabetic subjects (p=0.008). Resting myocardial blood flow was similar (NS) in diabetic subjects with slightly elevated hsCRP (0.79±0.19 ml·g^–1·min^–1) or low hsCRP (0.81±0.15 ml·g^–1·min^–1) and non-diabetic subjects (0.80±0.19 ml·g^–1·min^–1). Adenosine infusion induced a significant increase in blood flow in all study subjects (p<0.001) but was blunted in diabetic subjects with slightly elevated hsCRP (3.42±0.61 ml·g^–1·min^–1) when compared with diabetic subjects with low hsCRP (5.08±1.65 ml·g^–1·min^–1, p=0.02) or non-diabetic subjects (4.51±1.36 ml·g^–1·min^–1, p=0.04). Adenosine-stimulated flow was inversely correlated with hsCRP concentrations in all diabetic subjects (r=–0.70, p=0.001).Conclusions/interpretation In young subjects with uncomplicated type 1 diabetes, even slightly elevated hsCRP concentrations are associated with reduced coronary vasoreactivity.     

Insulin resistance,hypertension and microalbuminuria in patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary We examined the impact of hypertension and microalbuminuria on insulin sensitivity in patients with Type 2 (non-insulin-dependent) diabetes mellitus using the euglycaemic insulin clamp technique in 52 Type 2 diabetic patients and in 19 healthy control subjects. Twenty-five diabetic patients had hypertension and 19 had microalbuminuria. Hypertension per se was associated with a 27% reduction in the rate of total glucose metabolism and a 40% reduction in the rate of non-oxidative glucose metabolism compared with normotensive Type 2 diabetic patients (both p<0.001). Glucose metabolism was also impaired in normotensive microalbuminuric patients compared with normotensive normoalbuminuric patients (29.4±2.2 vs 40.5±2.8 mol · kg lean body mass^–1 · min^–1; p=0.012), primarily due to a reduction in non-oxidative glucose metabolism (12.7±2.9 vs 21.1±2.6 mol · kg lean body mass^–1 ·min^–1; p=0.06). In a factorial ANOVA design, however, only hypertension (p=0.008) and the combination of hypertension and microalbuminuria (p=0.030) were significantly associated with the rate of glucose metabolism. The highest triglyceride and lowest HDL cholesterol concentrations were observed in Type 2 diabetic patients with both hypertension and microalbuminuria. Of note, glucose metabolism was indistinguishable from that in control subjects in Type 2 diabetic patients without hypertension and microalbuminuria (40.5±2.8 vs 44.4±2.8 mol · kg lean body mass^–1 · min^–1). We conclude that insulin resistance in Type 2 diabetes is predominantly associated with either hypertension or microalbuminuria or with both.     

Monitoring kidney function in diabetic nephropathy

Summary Progression in diabetic nephropathy is usually determined by repeated measurements of glomerular filtration rate and expressed as rate of decline in glomerular filtration rate. Our aim was to evaluate the agreement between rate of decline in glomerular filtration rate estimated from the Cockroft-Gault formula: (140-age)^*K^*body weight^* (1/S-creatinine) and measured by the plasma clearance of ⁵¹CrEDTA. All insulin-dependent diabetic patients with diabetic nephropathy followed-up for at least 5 years with at least 5 simultaneous measurements of glomerular filtration rate, s-creatinine, and weight were included in the study. Forty-three patients (32 male/11 female), age 31 (18–61) years were enrolled. Observation period: 6.6 (5.1–9.9) years and number of investigations per patient 6 (5–16) (median(range)). Baseline glomerular filtration rate (ml/min) was 97 (30) measured and 107 (37) estimated (mean(SD))(p<0.001) and the 95% limits of agreement were –42.0 to 20.8 ml/min. Measured and estimated glomerular filtration rate correlated significantly (r = 0.91, p<0.00001). Rate of decline in kidney function ml · min^–1 · year^–1 was 4.7 (3.3) measured and 4.8 (3.5) estimated (mean(SD)) (NS), but the 95% limits of agreement showed a wide range –3.9 to 3.5 ml · min^–1 · year^–1. A significant correlation between rate of decline in measured and estimated glomerular filtration rate was present (r = 0.84, p<0.00001). In conclusion, glomerular filtration rate is overestimated by the Cockroft-Gault formula. The mean rates of decline in glomerular filtration rate are comparable, but the limits of agreement are wide, which make the Cockroft-Gault method unacceptable for clinical purposes, i.e. monitoring progression in kidney function in the individual patient. However, the estimated glomerular filtration rate may be used for comparison of groups in observational studies and in clinical trials with a long observation period.Abbreviations GFR Glomerular filtration rate - ⁵¹Cr-ED-TA ⁵¹Chromium ethylene diamine tetra-acetic acid - IDDM insulin-dependent diabetes mellitus     

Impaired response to angiotensin II in Type 1 (insulin-dependent) diabetes mellitus. Role of prostaglandins and sodium-lithium countertransport activity

Summary The pathogenesis of diabetic nephropathy remains elusive. A role for renal prostaglandins in antagonizing the hormonal effects of renin-angiotensin II has been postulated as a putative factor leading to hyperfiltration in patients with Type 1 (insulin-dependent) diabetes mellitus. Our aim was to elucidate the effects of angiotensin II on kidney haemodynamics and on blood pressure in eight normal subjects, in nine normotensive, in nine hypertensive with normal sodium-lithium countertransport activity in erythrocytes, in seven hypertensive without and in eight hypertensive Type 1 diabetic patients with microalbuminuria and with high sodium-lithium countertransport activity in erythrocytes. Angiotensin II infusion 4ng·kg^–1·min^–1 for 60 min) decreased the glomerular filtration rate to a greater extent in normal subjects (–20%), than in normotensive patients (–5% p<0.01), in hypertensive patients with normal sodium-lithium countertransport activity in erythrocytes (–8% p<0.01) in hypertensive patients with high sodium-lithium countertransport (–6% p<0.01) and in hypertensive microalbuminuric patients (–5% p<0.01) with Type 1 diabetes. The urinary excretion rate of vasodilatory prostaglandins was two-three fold higher in all patients than in normal subjects. Acute indomethacin treatment restored a normal response to angiotensin II infusion in normotensive patients, but did not change the renal haemodynamic response in normal subjects. With regard to hypertensive patients with and without microalbuminuria indomethacin treatment restored a normal response to angiotensin II in some but not all patients. An inverse relation was found between angiotensin II-induced decrease in the glomerular filtration rate and the sodium-lithium countertransport activity in erythrocytes during indomethacin treatment. Hypertensive and microalbuminuric patients with a sodium-lithium countertransport activity higher than 0.41 mmol·l erythrocyte^–1·h^–1 (the upper limit in normal subjects) also had a greater intimal plus medial thickness of the carotid artery using an ultrasonic imaging technique. Chronic indomethacin administration (30 days) significantly decreased the baseline overnight fasting glomerular filtration rate in normotensive and in hypertensive patients with normal but not in hypertensive and microalbuminuric patients with high sodium-lithium countertransport activity.In conclusion these results demonstrate that: (1) excessive synthesis of vasodilatory prostaglandins antagonizes the regulation of renal haemodynamics by angiotensin II, at least partially accounting for hyperfiltration in Type 1 diabetes, (2) elevated sodium-lithium countertransport activity in erythrocytes identifies a subgroup of patients with Type 1 diabetes and hypertension, with and without microalbuminuria, in whom the normalization of urinary excretion rate of prostaglandins does not restore a normal response to angiotensin II.     

Effect of improved metabolic control on loss of kidney function in Type 1 (insulin-dependent) diabetic patients: an update of the Steno studies

Summary We re-examined 69 of the 70 patients entering the two independent Steno Studies of effects of improved metabolic control on progression of late diabetic complications. They were analysed according to an intent to treat after follow-up for 8 years (Steno Study 1) and 5 years (Steno Study 2). The glycaemic control had improved in the insulin infusion group compared with the conventional treatment group (mean HbA_1c) by 2.0±0.6% vs 0.7±1.2 in Steno Study 1 and by 1.8±1.2% vs 0.4±1.3 (p<0.01) in Steno Study 2. In the insulin infusion groups three patients had died during episodes of ketoacidosis. These were not caused by malfunction of the insulin infusion pumps. In the conventional treatment groups, three patients suffered five cardiovascular events causing two deaths. From the sixth month of Steno Study 1 the annual change of the glomerular filtration rate was –3.7 (–5.4 to –2.0) ml·min^–1·1.73 m^–2 vs –1.0 (–2.1 to –0.1) (conventional vs insulin infusion group, mean (95% confidence interval, p<0.01)). The change in urinary albumin excretion was associated with the glycaemic control (n=69, r=0.49, p<0.0002). No progression was observed among 32 patients with low range microalbuminuria (30 to 99 mg/24 h). Among the 19 patients with an initial albumin excretion between 100 and 300 mg/24 h, progression of complications was more frequent during conventional treatment (n=10) vs insulin infusion (n=9): Clinical nephropathy (10 of 10 vs 2 of 9, p<0.01) and arterial hypertension (7 of 10 vs 1 of 9, p<0.01). The glomerular filtration rate declined during conventional treatment by –23 (–42 to –4) ml·mm^–1·1.73 m^–2 (p<0.05) but not during insulin infusion (–13 (–31 to 5) NS). These results suggest that patients at risk of nephropathy should be offered near normal glycaemic control in order to preserve their kidney function.     

Insulin resistance and hyperinsulinaemia in mild to moderate progressive chronic renal failure and its association with aerobic work capacity

Summary Tissue sensitivity to insulin and aerobic work capacity was measured in patients with mild to moderate progressive chronic renal failure. Twenty-nine non-diabetic patients with a glomerular filtration rate of 25 ml·min^–1·1.73 m^–2 (11–43) (median, range) and 15 sex, age, and body mass index matched control subjects with normal renal function were studied. Fasting blood glucose was comparable and in the non-diabetic range in the two groups as was the oral glucose tolerance test. Patients demonstrated hyperinsulinaemia both during fasting (p<0.01) and during the test (p<0.02). The tissue sensitivity to insulin, expressed by the amount of glucose infused during the last 60 min of a 120-min hyperinsulinaemia euglycaemic clamp (M-value) and the M/I ratio, was significantly lower in the patients than in the control subjects (M-value 404±118 vs 494±85 mg glucose/kg body weight, p<0.02) (M/I ratio 1.77±0.71 vs 2.57±0.70 (mg/(kgBW·min) per pmol/l·100, p<0.001). The maximal aerobic work capacity was significantly lower in the patients than in the control subjects (24±8 vs 32±11 ml O₂/(kg body weight·min), p<0.02) and positively correlated to the M-value and the M/I ratio in both groups. In conclusion, not only patients with end-stage chronic renal failure but also those with mild to moderate progressive chronic renal failure are insulin resistant and hyperinsulinaemic. The tissue sensitivity to insulin is correlated to the maximal aerobic work capacity suggesting that these patients might benefit from physical training programmes.Abbreviations CRF Chronic renal failure - GFR glomerular filtration rate - NEFA non-esterified fatty acids - CO cardiac output - GH growth hormone - OGTT oral glucose tolerance test