Renal autoregulation is normal in newly diagnosed, normotensive, NIDDM patients

Summary Abnormalities of renal autoregulation with glomerular hyperfiltration and raised intraglomerular pressure have been suggested as important factors in the initiation and development of diabetic nephropathy. Angiotensin converting enzyme (ACE) inhibition appears to have a specific reno-protective role in diabetic nephropathy, possibly by reducing intraglomerular pressure. The acute effects of ACE inhibition on renal haemodynamics in normotensive, non-insulin-dependent diabetes mellitus (NIDDM) have not been previously reported. We measured simultaneous glomerular filtration rate (GFR) and renal plasma flow (RPF) in 29 (4 female) subjects, mean age 52 years (range 27–70), using ⁵¹Cr EDTA and ¹²⁵I Hippuran. Clearances were corrected to 1.73 m^–2. All patients were normotensive (blood pressure < 75^th centile for age and sex), newly diagnosed ( < 30 days), taking no antihypertensive or hypoglycaemic medication. Subjects were randomly allocated (double blind) to receive the ACE inhibitor trandolapril 4 mg day^–1 (H) (hypotensive dose), trandolapril 0.5 mg day^–1 (L) (non-hypotensive dose) or placebo (P) for 10 days after which renal haemodynamics were remeasured. For all subjects baseline GFR, RPF and filtration fraction (FF) were 97 ± 21 ml min^–1 mean ± SD, 439 ± 120 ml min^–1 and 22.3 ± 2.9 % respectively. Glomerular hyperfiltration (GFR > 120 ml min^–1) was only demonstrated in 3 subjects (10.3 %). In group H mean arterial pressure (103 ± 8 vs 93 ± 9 mmHg, p < 0.001) and FF (23.8 ± 2.3 vs 20.0 ± 4.0 %, p = 0.03) fell while RPF increased (376 ± 111 vs 426 ± 60 ml min^–1, p = 0.02), there was no significant change in GFR. No significant change in mean arterial pressure, GFR, RPF or FF occurred in groups P and L. These studies suggest that in newly diagnosed normotensive NIDDM subjects normal renal autoregulation occurs and glomerular hyperfiltration is uncommon. [Diabetologia (1998) 41: 206–211] Received: 2 July 1997 and in revised form: 16 September 1997     

Addition of chlorthalidone to slow-release nifedipine in the treatment of arterial hypertension: A controlled study versus placebo

Summary The use of calcium antagonists and diuretics in combination for treatment of hypertension is controversial.In a single-blind study 16 patients (8 men, 8 women, age range 39 to 62 years) with primary hypertension of mild to moderate degree were given slow-release nifedipine 20 mg twice daily for 6 weeks, thereafter either chlorthalidone 25 mg (Group A) or placebo (group B) daily was randomly added for a further 6-week period.Blood pressure (BP), heart rate, plasma renin activity (PRA), aldosterone, and 24 hour urinary electrolytes were evaluated.Nifedipine decreased supine BP from 159/92±16/8 to 151/89±10/6 mmHg in group A and from 162/94±20/12 to 145/85±14/6 mmHg in group B. A further fall to 139/84±7/6 mmHg (p<.05) was observed after addition of chlorthalidone.PRA significantly increased with combined treatment compared to baseline (3.3±0.8 to 9.9±3.3 ng/ml/hr;p<0.05). A slight reduction of 24-hour urinary calcium was observed after the addition of chlorthalidone.These data indicate that the combination of nifedipine and chlorthalidone might be beneficial in the treatment of arterial hypertension.     

Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial

Aims/hypothesis  The purpose of this study was to evaluate the optimal renoprotective effect of ultrahigh doses of lisinopril, as reflected by short-term changes in urinary albumin excretion rate (UAER), in type 1 diabetic patients with diabetic nephropathy. Methods  At the Steno Diabetes Center, 49 type 1 diabetic patients with diabetic nephropathy completed this double-masked randomised crossover trial consisting of an initial washout period followed by three treatment periods each lasting 2 months, where all patients received lisinopril 20, 40 and 60 mg once daily in randomised order in addition to slow-release furosemide. Allocation was concealed by sequentially numbered opaque sealed envelopes. UAER, 24 h ambulatory blood pressure (ABP) and estimated GFR were determined at baseline and after each treatment period. Results  All 49 patients completed all three treatment periods. Baseline values were: UAER (geometric mean [95% CI]) 362 (240–545) mg/24 h, 24 h ABP (mean [SD]) 142 (14)/74 (8) mmHg and estimated GFR 75 (29) ml min⁻¹ 1.73 m⁻². Reductions in UAER from baseline were 63%, 71% and 70%, respectively, with the increasing doses of lisinopril (p < 0.001). Compared with lisinopril 20 mg there was a further reduction in UAER of 23% with lisinopril 40 mg and 19% with 60 mg, p < 0.05. ABP was reduced from baseline by 10/5, 13/7 and 12/7 mmHg (p < 0.001 vs baseline, p < 0.05 for diastolic ABP 20 vs 40 mg, otherwise NS between doses). The difference in UAER between 20 and 40 mg lisinopril was significant after adjustment for changes in ABP (p < 0.01). Two patients were excluded from the study because of an increase in plasma creatinine and one because of high BP; otherwise the study medication was well tolerated with few, mild, dose-independent adverse effects. Conclusions/interpretation  Lisinopril 40 mg once daily is generally safe and offers additional reductions in BP and UAER in comparison with the currently recommended dose of 20 mg. Lisinopril 60 mg offers no further beneficial effect. Trial registration: ClinicalTrials.gov NCT00118976 Funding: This study was financed out of local funds and was not supported by the medical industry. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Angiotensin AT1 receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodiliation in normotensive diabetic rats

Aims/hypothesis The renin angiotensin system is emerging as a potential therapeutic target for diabetic retinopathy. This study examines the effects of angiotensin-converting-enzyme inhibition by captopril and angiotensin AT₁ receptor antagonism using candesartan-cilexetil on retinal blood flow and acetylcholine-stimulated vasodilatation in normotensive diabetic rats.Methods Non-diabetic or streptozotocin-induced diabetic rats were treated for 2 weeks with captopril (100 mg/kg/day) or candesartan cilexetil (2 mg/kg/day). Retinal haemodynamics were measured using video fluorescein angiography. Effects of exogenous acetylcholine on retinal haemodynamics were examined following intravitreal injection. Total retinal diacylglycerol was labelled using diacylglycerol kinase, separated by thin-layer chromatography, and quantified using autoradiography.Results Diabetic rats had prolonged retinal mean circulation time and decreased retinal blood flow compared with non-diabetic rats. Treatment of diabetic rats with either captopril or candesartan blocked the development of these blood flow abnormalities. Intraviteral injection of acetylcholine (10^–5 mol/l) in non-diabetic rats increased retinal blood flow by 53.9±22.0% relative to baseline whereas this response to acetylcholine was blunted in diabetic rats (4.4±19.6%, p<0.001). Candesartan treatment of diabetic rats restored the acetylcholine-stimulated retinal blood flow response to 60.0±18.7% compared with a 56.2+20.1% response in candesartan-treated non-diabetic rats. Total retinal diacylglycerol levels were increased in diabetic rats (3.75±0.98 nmol/mg, p<0.05) compared with non-diabetic rats (2.13±0.25 nmol/mg) and candesartan-treatment of diabetic rats normalized diacylglycerol levels (2.10±0.25 nmol/mg, p<0.05).Conclusion/interpretation This report provides evidence that angiotensin-converting enzyme inhibition and AT₁ receptor antagonism ameliorates retinal haemodynamic dysfunctions in normotensive diabetic rats.Abbreviations ACh acetylcholine - AT appearance time - DAG diacylglycerol - DM diabetic - MCT mean circulation time - NDM non-diabetic - RAS renin angiotensin system - RBF retinal blood flow - STZ streptozotocin     

Serum uric acid and progression of diabetic nephropathy in type 1 diabetes

Aims

Uric acid (UA) is a risk factor for CKD. We evaluated UA in relation to change in GFR in patients with type 1 diabetes.

Glomerular hyperfiltration during the onset of diabetes mellitus in two strains of diabetic mice (C57BL/6Jdb/db and C57BL/KsJdb/db)

Summary GFR estimated by the total clearence of⁵¹Cr-EDTA increases from 41 to 60 ml/min·m² at the onset and during the development of marked hyperglycaemia and obesity in female diabetic mice (db/db) of the C57BL/6J and the C57BL/KsJ strains (blood sugar rises from 160 to 400 mg/100 ml). GFR decreases slowly in older diabetic mice (>120 days old) approaching the control values (42±7 ml/ min·m²) and then decreases still further. The total clearance of¹⁴C-hippuric acid is unaltered indb/db mice and controls between 45 and 150 days of age (96±20 ml/min·m²). This suggests no alteration of RPF during the development of the diabetic syndrome. The glomerular hyperfiltration of diabetic mice lasts until they are 120 days old and shows no correlation with the different blood glucose levels typical for diabetic mice (db/db) of the two strains.     

Ultrastructural alterations in capillaries of the diabetic hypertensive rat retina: protective effects of ACE inhibition

Aims/hypothesis The ACE inhibitor cilazapril was administered to diabetic hypertensive rats to evaluate its ability to influence the development of retinal capillary alterations.Methods Normotensive (strain: Wistar Kyoto) and genetically hypertensive (strain: spontaneously hypertensive) rats were rendered diabetic by intravenous injections of streptozotocin. Half of the diabetic animals received cilazapril with their daily food. At 20 weeks of diabetes, endothelial cells, pericytes and extracellular matrix were assessed by ultrastructural morphometry. Each experimental group consisted of seven animals.Results Cilazapril normalised systolic arterial pressure in diabetic hypertensive rats (137±2 mm Hg compared with 188±16 mm Hg in non-medicated diabetic hypertensive rats, p<0.001). The number of endothelial intercellular junctions was reduced in untreated diabetic hypertensive rats (0.15±0.05, p<0.02, vs 0.47±0.20 in non-diabetic normotensive rats). In diabetic hypertensive animals treated with cilazapril, this loss was attenuated (0.32±0.16, p<0.05). The significant thickening of the basement membrane observed in the diabetic normotensive (132.8±19.4 nm) and diabetic hypertensive (150.3±20.2 nm) groups was decreased by cilazapril in the diabetic hypertensive group (116.7±11.0 nm, p<0.01), but was unaffected in the normotensive (131.9±17.3 nm) group. No protective effect of the drug was observed in either group on pericytes.Conclusions/interpretation Long-term administration of an effective antihypertensive therapy normalises endothelial alterations and basement membrane thickness in diabetic hypertensive conditions, and thus may account for the well-known improvement of the blood-retinal barrier observed during antihypertensive treatment.Abbreviations ANGII angiotensin II - RAS renin-angiotensin system - SHR spontaneously hypertensive rat - STZ streptozotocin - VEGF vascular endothelial growth factor - WKY Wistar Kyoto     

Renal plasma flow: glomerular filtration rate relationships in man during direct renin inhibition with aliskiren

We examined the relation between change in renal plasma flow (RPF) and change in glomerular filtration rate (GFR) in healthy humans on a low-salt diet during direct renin inhibition with aliskiren. We measured the renal hemodynamic response to acute dosing of 300 mg aliskiren by mouth to 19 healthy normotensive subjects (age, 33 ± 3 years; baseline RPF, 575 ± 23; GFR, 138 ± 14 mL/min/1.73 m²) on a low-sodium diet (10 mmol/day). GFR and RPF were measured by the clearance of inulin and para-aminohippurate. There was a marked increase in average RPF (169 ± 24 mL/min/1.73 m²) and a small rise in average GFR (1.4 ± 5 mL/min/1.73 m²) from baseline in response to aliskiren. There was a clear correlation between the change in RPF and the change in GFR between subjects (r = 0.65; P < .003). A substantial increase in RPF was accompanied by a rise in GFR. Dependence of GFR on RPF was identified in healthy humans after RPF rose significantly with aliskiren. The responsible mechanism likely involves intravascular oncotic pressure along the glomerular capillary resulting in greater surface area available for filtration.     

Neointimal proliferation within carotid stents is more pronounced in diabetic patients with initial poor glycaemic state

Aims/hypothesis We studied the influence of initial hyperglycaemia on neointimal proliferation within carotid Wallstents.Methods A total of 112 patients were followed by duplex sonography after carotid stenting for 24 months. Patients were assigned to three groups: non-diabetic subjects (group A) and diabetic patients, who were assigned according to their baseline HbA₁c values, to group B1(HbA₁c6.5%) or group B2 (HbA₁c>6.5%).Results At baseline the groups did not differ with respect to other vascular risk factors and residual stenosis on angiograms. The maximal thickness of the layer between the stent and the perfused lumen was measured at the duplex follow-ups. At 3 months the typical ultrasonic structure of the neointima was clearly discernible. From this point on, group B2 differed significantly (p<0.001) compared with B1 and A with respect to the maximal thickness of neointima and the time course of its ingrowth: group A vs B1 vs B2 was 0.51±0.39 vs 0.52±0.33 vs 0.56±0.35 at 3 months, 0.91±0.27 vs 0.90±0.38 vs 1.14±0.48 at 6 months, 1.02±0.24 vs 0.97±0.34 vs 1.21±0.44 at 12 months and 1.09±0.23 vs 1.10±0.31 vs 1.23±0.37 at 24 months.Conclusion/interpretation Initial hyperglycaemia seems to be a predictor of more pronounced neointimal proliferation after carotid stenting independent of diabetes. As intimal hyperplasia is known to be responsible for stent restenosis, strict optimisation of the hyperglycaemic state should be aimed at before elective carotid artery stenting.Abbreviations CCDS Colour coded duplex sonography - CHD coronary heart disease - PAOD peripheral arterial occlusive disease - CCA common carotid artery - ICA internal carotid artery - IMT intima-media thickness - UKPDS United Kingdom Prospective Diabetes Study Group     

Elevated serum angiotensin I converting enzyme activity in type I,insulin-dependent diabetic subjects with persistent microalbuminuria

Angiotensin I-converting enzyme (ACE), which is synthesized by vascular endothelial cells, is sometimes elevated in diabetic subjects. To determine whether serum ACE is elevated in subjects at high risk of malignant microangiopathy, serum ACE activity in 34 normotensive, type 1 insulin-dependent diabetic subjects with persistent microalbuminuria (30–300 mg/24 h) was compared with that in 30 normotensive, normoalbuminuric type 1 diabetic subjects of the same age [37±15 (mean ±SD) vs 38±14 years], sex (21 M/13 F vs 15 M/15 F), stage of retinopathy (14 vs 16 nil/11 vs 7 background/6 vs 4 preproliferative/3 vs 3 proliferative) and HbA_1c (7.7±1.9 vs 8.2±1.0%). Serum ACE activity of diabetic subjects was also compared with 120 age and sex related healthy controls. Serum ACE activity was higher in subjects with microalbuminuria than in those with normoalbuminuria (406±114 vs 359±97 IU/l;P=0.03), or in controls (307±95 IU/l;P=0.0001). Normoalbuminuric subjects also had higher ACE activity than controls (P=0.02). Serum ACE activity was not related to diabetes duration (r=0.01; NS), HbA_1c (r=0.05; NS), or stage of retinopathy in diabetic subjects (r=0.06; NS), while stage of retinopathy was related to age (r=0.42;P=0.003) and to diabetes duration (r=0.74;P=0.0001) in these subjects. Elevated ACE activity occurs in type 1 diabetic subjects, especially in those with microalbuminuria. This may give early indication of lesions in vascular endothelial cells.This work was presented at the 27th meeting of the European Association for the Study of Diabetes in Dublin, Ireland, 10–14 September 1991, and published in an abstract form: Diabetologia (1991) 34: A17     

ACE and PC-1 gene polymorphisms in normoalbuminuric Type 1 diabetic patients: a 10-year prospective study

The aim of this study was to analyze the role of ACE gene insertion/deletion (I/D) and PC-1 gene K121Q polymorphisms in the changes of glomerular filtration rate (GFR), urinary albumin excretion rate (UAER), and blood pressure (BP) levels in a cohort of normoalbuminuric Type 1 diabetic patients. This is a 10.2+/-2.0-year prospective study of 30 normotensive normoalbuminuric Type 1 diabetic patients. UAER (immunoturbidimetry), GFR ((51)Cr-EDTA single injection technique), GHb (ion exchange chromatography), and BP levels were measured at baseline and at 1.7+/-0.6-year intervals. The presence of ACE gene I/D and PC-1 gene K121Q polymorphisms was determined by polymerase chain reaction (PCR) and restriction enzyme techniques. Three patients developed diabetic nephropathy (DN), all carriers of allele D. The presence of allele D was the only predictor (R(2)=.15, F=4.92, P=.035) of the observed GFR decline (-0.29+/-0.34 ml/min/month, P<.05). UAER increased during the study (log UAER=0.0275+/-0.042 microg/min/month, P=.002) and was associated with baseline UAER levels only (R(2)=.17, F=5.72, P=.024). A significant increase (P<.05) in cases of hypertension and retinopathy were observed in ID/DD (n=19) and not in II patients (n=11). Patients with the KQ/QQ genotype (n=8) presented a significant increase (P=.045) in new cases of retinopathy. In conclusion, the presence of the ACE gene D allele in this sample of normoalbuminuric normotensive Type 1 diabetic patients was associated with a higher proportion of microvascular complications and hypertension.     

Contrasting effects of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy

Microalbuminuria is a reliable predictor of the eventual development of overt diabetic nephropathy and blood pressure is known to accelerate the course of this nephropathy. In the present studies, the effect of a 6-week treatment by placebo (n = 7), nifedipine (n = 7) and captopril (n = 8) on renal function and urinary excretion of albumin (UAE) was investigated in normotensive, insulin-dependent, diabetic patients with incipient nephropathy (UAE greater than 15 micrograms/min). No change in arterial pressure, renal function or UAE was observed in the placebo group. In response to captopril and nifedipine, mean arterial pressure decreased slightly and similarly in both groups. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) increased to a similar extent in the nifedipine group, thus resulting in no change in filtration fraction (FF). In response to captopril, GFR was unchanged whilst ERPF increased; as a consequence FF decreased. Opposite changes in UAE were observed in response to the two treatments; UAE decreased by 40% in the captopril group and by 40% in nifedipine-treated patients. These results indicate that intrarenal changes may be crucial with respect to the effect of therapy on UAE. It is suggested that only agents which reduce FF and probably intraglomerular capillary pressure, such as converting enzyme inhibitors, alter UAE and may possibly interfere with the course of incipient diabetic nephropathy in normotensive patients.     

Renal functional reserve in IDDM patients

Summary The aim of this study was to determine whether renal functional reserve (RFR) is altered in insulin-dependent diabetic (IDDM) patients according to the stage of diabetic nephropathy. RFR was examined in 33 IDDM patients in similar glycaemic and metabolic control and compared to 12 healthy control subjects, during eight 1 h clearance periods prior to, during and after a 3-h stimulation by amino acid infusion (4.5 mg · kg⁻¹· min⁻¹). RFR was calculated as the difference between stimulated and baseline glomerular filtration rates (GFR). In 14 early normotensive diabetic patients with normal urinary albumin excretion, mean baseline GFR (133 ± 3 ml · min⁻¹· 1.73 m⁻²) was higher whereas RFR (10 ± 4 ml · min⁻¹· 1.73 m⁻²) was lower (p < 0.05) than in control subjects (113 ± 4 and 28 ± 2 ml · min⁻¹· 1.73 m⁻², respectively). In 10 normotensive patients who had lived with IDDM for 16 years and who had microalbuminuria, baseline GFR and RFR (109 ± 7 and 24 ± 6 ml · min⁻¹· 1.73 m⁻², respectively) were similar to those in control subjects. In 9 patients who had suffered IDDM for 23 years and had developed macroalbuminuria and hypertension, baseline GFR (78 ± 8 ml · min⁻¹· 1.73 m⁻²) was lower than in control subjects (p < 0.05) and RFR (8 ± 4 ml · min⁻¹· 1.73 m⁻²) was not significant. In addition, renal vascular resistance decreased significantly during infusion (p < 0.05) in microalbuminuric normotensive patients as well as in control subjects (by 9 ± 4 and 11 ± 4 mm Hg · l⁻¹· min⁻¹· 1.73 m⁻², respectively) but not in normoalbuminuric normotensive or macroalbuminuric hypertensive patients. These results indicate that microalbuminuric normotensive patients retain a normal RFR, whereas RFR is reduced or suppressed at two opposite stages of the disease: in normoalbuminuric normotensive patients with a high GFR and in macroalbuminuric hypertensive patients with a decreased GFR. This dissimilar impairment reveals permanent glomerular hyperfiltration in both early IDDM without nephropathy and IDDM with overt diabetic nephropathy, but not in IDDM with incipient nephropathy. [Diabetologia (1998) 41: 86–93] Received: 12 February 1997 and in final revised form: 28 August 1997     

Renal scintigraphy in insulin-dependent diabetes mellitus: Early glomerular and urologic dysfunction

Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by intravenous injection of ^99mTc-diethylenetriaminepentaacetic acid (DTPA) and ¹³¹I-Hippuran in 115 insulin-dependent diabetic patients with albumin excretion rates (AER) <200 μg/min, and in 45 normal subjects. Separate kidney function and urinary elimination were estimated by renography.GFR was increased in the diabetic patients (152 ± 24 ml/min/1.73m², vs. 128 ± 15) and correlated significantly with RPF (r = 0.5; p < 10⁻⁹). No relationship was found between GFR and the duration of diabetes, blood glucose, HbA_1c, or AER. Fifty patients were hyperfiltering with RPF and filtration fraction higher than those in the normofiltering group. Slow intrarenal or pyeloureteral elimination, either unilateral or bilateral, was observed in 3 controls and 60 diabetic subjects (24 hyperfiltering; 36 normofiltering) and did not disappear with the patient in the standing position. In these 60 patients, mean age, duration of diabetes, blood glucose, HbA_1c, 24 h albumin excretion rate, and frequency of peripheral or autonomic neuropathy did not differ from patients with normal scintigraphy; GFR was lower in the group with slow elimination, but not significantly so. ^99mTc-DTPA renal uptake was symmetric in all the controls; asymmetric renal uptake with asymmetric GFR was observed in 13 patients (7 hyperfiltering; 6 normofiltering) and often associated with slower elimination. No evidence for renal stenotic atheroma or parenchymatous disease was found on the angiopyeloureterography. The results suggest that incipient uropathy is a very common phenomenon that occurs irrespective of glomerular dysfunction.     

Effect of nifedipine on mouth-to-cecum transit of liquid meal in normal subjects

Nifedipine has been shown to inhibit small bowel motility and to increase ileal water and electrolyte absorption in animals, but few reports are available in human subjects. The drug has been reported to influence esophageal and colon motility in man, without affecting gastric emptying. We performed a double-blind, controlled, crossover, randomized study to investigate the effect of oral nifedipine 30 mg vs placebo on the orocecal transit time of a lactulose-labeled, liquid caloric meal in nine healthy volunteers, and its correlation with plasma nifedipine concentration. The transit time was measured using the breath hydrogen test. The drug study was preceded by a reproducibility study, which showed a mean variation in transit time of 8.3% (± 1%, SE). Nifedipine significantly increased orocecal transit time compared to placebo (nifedipine 131±16; placebo 104±14.5 min;P<0.05). This effect correlated well with plasma nifedipine concentration expressed as area under the curve (r=0.92,P<0.004). Nifedipine 30 mg significantly delays orocecal transit of a liquid caloric meal. The small bowel is likely to be the site of action. These findings may afford a rational basis for investigating a possible antidiarrheal role of nifedipine.     

Preservation of Renal Haemodynamic Response to an Oral Protein Load in Non-insulin-dependent Diabetes Mellitus

Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) were determined, for 2h prior to and 3h following the ingestion of a 1.2 g kg^?1 meat meal, in seven normotensive normoalbuminuric Type 2 diabetic patients exhibiting good glycaemic control (fasting plasma glucose (mean ± SD): 7.2 ± 2.0 mmol l^?1; glycosylated haemoglobin: 8.1 ± 1.7%) and in nine normal subjects selected for similar basal GFR values. Baseline GFR and ERPF (corrected to 1.73 m² surface area) were 83 ± 10 and 410 ± 76 ml min^?1 for the Type 2 diabetic patients and 86 ± 11 and 405 ± 113 ml min^?1 for the normals. GFR increased by 38 ± 8 and 32 ± 15% in the diabetic patients and normals, to 108 ± 25 and 105 ± 26 ml min^?1 (p < 0.01 vs baseline). Peak ERPF was 501 ± 127 and 476 ± 119 ml min^?1 for the two respective groups (p < 0.01 vs baseline). Filtration fractions at peak GFR and EPRF values were unchanged from baseline for either groups. Fractional clearance of albumin for the Type 2 diabetic patients was unaltered by protein ingestion. Therefore, protein ingestion in Type 2 diabetes, as in normals, results in an acute elevation of GFR. Absolute and incremental changes in GFR were identical for the two groups. These data demonstrate a preserved capacity for renal vasodilatation in Type 2 diabetic patients despite their greater chronological age.     

The effect of the calcium antagonist nifedipine on peripheral nerve function in streptozotocin-diabetic rats

Summary Recent data suggests that reduced nerve blood flow is implicated in the aetiology of experimental diabetic neuropathy, which may be prevented by manipulations that reduce receptor-mediated vasoconstrictor activity. This investigation examines the effects of nifedipine, a voltage-sensitive calcium channel antagonist which has a direct vasodilatory effect on vessels, on nerve conduction, hypoxic resistance and capillary density in streptozotocin-induced diabetic rats. Treated and non-treated non-diabetic and diabetic groups were employed. Diabetes duration was 2 months. Treatment was preventive, groups received a nifedipine dietary supplement (40 mg · kg^–1 · day^–1) for 2 months from the start of the study. Conduction was measured in sciatic motor branches supplying tibialis anterior and gastrocnemius muscles, and sensory saphenous nerve. Diabetes resulted in a 23–28 % reduction in motor conduction velocity (p<0.001), and a 15% deficit for sensory saphenous nerve (p<0.001). In the nifedipine-treated diabetic group, motor and sensory conduction deficits were minimal compared with non-treated diabetes (p<0.001). Nifedipine treatment had no significant effect on conduction velocity in nondiabetic rats. In vitro measurement of sciatic nerve hypoxic resistance revealed a 60 % increase in the time taken for compound action potential amplitude to reach half its initial value with diabetes (p<0.001). This was not significantly affected by nifedipine treatment. Experimental diabetes or nifedipine treatment did not significantly alter sciatic nerve endoneurial capillary density. We conclude that nifedipine, a vasodilator which acts directly on vascular smooth muscle, prevents nerve conduction deficits in experimental diabetes.     

Regression of microalbuminuria in type 1 diabetic patients: results of a sequential intervention with improved metabolic control and ACE inhibitors

Abstract The objective was to evaluate the effect of improved metabolic control and ACE inhibition used sequentially in the treatment of type 1 diabetic patients with microalbuminuria. We studied 44 consecutive type 1 diabetic patients with microalbuminuria not previously treated with ACE inhibitors. Improved metabolic control (optimisation period) was attempted for 6–12 months and patients with persistent microalbuminuria were subsequently treated with ACE inhibitors. Stepwise logistic regression analysis included the variables age, age at diabetes onset, duration of diabetes, HbA1c, initial albumin excretion rate (AER) and mean blood pressure as predictors of final AER. Thirty per cent of patients regressed to normoalbuminuria after the optimisation period, and 58% of them maintained normal AER 4.5±1.3 years later (3–7 years). Patients achieving normoalbuminuria had lower baseline AER (53±22 vs. 94±63 mg/24 h, p=0.012). The initial AER level was the only factor associated with final AER (r=0.58, p=0.021). Thirty patients with persistent microalbuminuria were treated with ACE inhibitors for two years, 35.5% of whom regressed to normal AER. Patients achieving normoalbuminuria after ACE inhibitor treatment had lower baseline AER (55±24 vs. 132±75 mg/24 h, p=0.03). The initial AER was the sole predictor of final AER (r=0.51, p<0.013). Overall, the sequential use of improved metabolic control and ACE inhibitor therapy resulted in long-term normalisation of AER in 47.4% of patients. The sequential implementation of improved metabolic control and ACE inhibitor therapy had a long-term beneficial effect in type 1 diabetic patients with microalbuminuria. We propose that type 1 diabetic patients with microalbuminuria could benefit from a period of metabolic improvement before the initiation of ACE inhibitor therapy.     

Decreased circulating CD34+ cells are associated with progression of diabetic nephropathy

Aims Circulating progenitor cells such as CD34+ cells play a key role in maintenance of vascular endothelial function and neovascularization, and a decrease in the number of CD34+ cells is associated with cardiovascular disease. However, the contribution of circulating progenitor cells to microvascular disease, such as diabetic nephropathy, is unclear. This study was therefore designed to clarify the association between diabetic nephropathy and circulating CD34+ cells. Methods We measured circulating CD34+ cell numbers in 85 Type 2 diabetic patients aged 40–70 years with normo‐ and microalbuminuria and determined the association with urinary albumin excretion rate (UAER). Results The number of circulating CD34+ cells significantly correlated with log UAER (r = –0.289, P = 0.008). Furthermore, in patients with low numbers of CD34+ cells (0.68 > cells/µl, lowest quartile of CD34+ cell number) UAER increased significantly after 12 months compared with baseline [from 34.3 ± 7.0 to 53.6 ± 10.8 mg/g creatinine (gCr), P < 0.05], whereas in patients with a high number of CD34+ cells (1.0 < cells/µl, highest quartile of CD34+ cell number) UAER did not change (from 16.7 ± 4.8 to 20.1 ± 3.0 mg/gCr). Conclusions These results suggest that a decreased number of circulating CD34+ cells is involved in the progression of diabetic nephropathy and may be a predictor of the disease.     

Sympathetic activation after two weeks of nifedipine treatment in primary Raynaud's patients and controls

Summary The effect of a standardized cold pressor test on circulating noradrenaline and neuropeptide-Y-like immunoreactivity was investigated in 12 women with primary Raynaud's phenomenon and 12 healthy female controls before and after 2 weeks of treatment with the calcium antagonist, nifedipine. Measurement before treatment showed significant increase during the cold pressor test on circulating noradrenaline in both the primary Raynaud's phenomenon group and in the control group (from 0.29±0.15 ng/ml to 0.33±0.16 ng/ml, p<0.05, and from 0.21±0.14 ng/ml to 0.29±0.16 ng/ml, p<0.005, respectively). However, treatment with nifedipine resulted in significantly increased levels of circulating noradrenaline during the cold pressor test only in the control group (from 0.43±0.21 ng/ml to 0.50±0.20 ng/ml, p<0.01). Plasma concentrations of neuropeptide-Y-like immunoreactivity were unchanged by the standardized cold pressor test, whether performed before or during nifedipine treatment in both groups. Nifedipine treatment per se significantly increased circulating noradrenaline in both the primary Raynaud's phenomenon patient group and in the control group (from 0.29±0.15 to 0.49±0.13 and 0.21±0.14 to 0.43±0.21 ng/ml, respectively, p<0.001). Similarly, the circulating neuropeptide-Y-like immunoreactivity significantly increased in both the primary Raynaud's phenomenon group and in the control group (from 105±21 to 137±19 pmol/l and 107±17 to 147±13 pmol/l, respectively, p<0.001). No significant differences were seen between the two groups, and the increased levels of circulating noradrenaline and neuropeptide-Y-like immunoreactivity were maintained during the entire test period in both groups. The standardized cold pressor test increased circulating noradrenaline significantly in both study groups before treatment with nifedipine. On the other hand, nifedipine moderately increased circulating noradrenaline during the cold pressor test in the primary Raynaud's phenomenon patient group. Besides these findings, this study demonstrates that treatment with nifedipine, a drug widely used in cardiovascular disease, increases circulating levels of noradrenaline and neuropeptide-Y-like immunoreactivity in normotensive women.Address for correspondence: Department of Clinical Physiology, Central Hospital Västerås, S-721 89 Västerås, Sweden.