Normoalbuminuric Type Research Articles

Albumin and Fibrinogen Synthesis and Insulin Effect in Type 2 Diabetic Patients With Normoalbuminuria

Insulin stimulates albumin synthesis but inhibits that of fibrinogen in both type 1 diabetic and healthy subjects. In type 2 diabetes, fibrinogen production is increased both in the postabsorptive state and in response to hyperinsulinemia. No data exist on the rate of albumin synthesis and its response to insulin in type 2 diabetes. We measured fractional synthesis rates (FSRs) and absolute synthesis rates (ASRs) of both albumin and fibrinogen in postabsorptive normoalbuminuric type 2 diabetic patients at their spontaneous glucose levels (study A), as well as albumin FSR and ASR before and after a hyperinsulinemic-euglycemic euaminoacidemic clamp (study B), using leucine isotope methods. In postabsorptive type 2 diabetes (study A), albumin FSR (11.2 +/- 0.9%/day) and albumin ASR (15.4 +/- 1.2 g/day) were not different from control values (albumin FSR: 9.4 +/- 0.7%/day; albumin ASR: 13.8 +/- 1.2 g/day, P > 0.1 for both). In contrast, in the type 2 diabetic subjects, both fibrinogen FSR (24.9 +/- 2.1%/day) and ASR (2.4 +/- 0.2 g/day) were greater (P < 0.025 and P < 0.007, respectively) compared with the control subjects (FSR: 18.6 +/- 1.51%/day; ASR: 1.6 +/- 0.2 g/day). Worse metabolic control in the type 2 diabetic patients was associated with hyperfibrinogenemia and increased leucine rate of appearance, whereas neither the (increased) fibrinogen ASR nor the (normal) albumin production was affected. In study B, after hyperinsulinemia (raised to approximately 860 nmol/l), albumin FSR and ASR increased by approximately 25% versus basal (P < 0.04) and to the same extent in both type 2 diabetic and control subjects. In normoalbuminuric type 2 diabetic patients, postabsorptive albumin synthesis and its response to insulin were normal, whereas fibrinogen synthesis was increased, irrespective of metabolic control. Furthermore, in normoalbuminuric type 2 diabetic patients, a normal insulin sensitivity with respect to albumin production but a selective hepatic dysregulation of fibrinogen metabolism were present.

A longitudinal evaluation of urinary glycosaminoglycan excretion in normoalbuminuric type 1 diabetic patients

Previously, we found high urinary glycosaminoglycan (GAG) concentration, together with an altered electrophoretic pattern, in normoalbuminuric type 1 diabetic subjects with hemoglobin A(1c) (HbA(1c)) > or =8.0%. The purpose of this study was long-term evaluation of GAG excretion variations in these patients compared to those with HbA(1c) < 8.0% at baseline who maintained better metabolic control over time. We enrolled 26 normotensive, normoalbuminuric type 1 diabetic patients and divided them into two groups according to mean HbA(1c) levels during the follow-up period. GAGs were isolated from 24-h urine samples on two separate occasions, at baseline and after a mean (+/-SD) follow-up of 6.8+/-1.1 years. All patients remained normoalbuminuric at follow-up, and had normal urinary alpha(1)-microglobulin levels. In patients with HbA(1c) <8.0%, total GAG levels and low sulfated chondroitin sulfate-proteoglycan/chondroitin sulfate ratio were almost unchanged during the follow-up period. In contrast, these increased in patients with HbA(1c) > or =8.0% and were significantly related to both HbA(1c) levels and the duration of poor glycemic control. Our results show a strong influence of hyperglycemic environment on GAG metabolism in diabetes and indicate that the distribution pattern of urinary GAGs, besides their total concentration, may be predictive of altered GAG metabolism in type 1 diabetes.

Left ventricular hypertrophy in normoalbuminuric type 2 diabetic patients not taking antihypertensive treatment

Left ventricular hypertrophy (LVH) is an independent risk factor for myocardial ischaemia, cardiac arrhythmia, sudden death, and heart failure, all common findings in patients with type 2 diabetes. To determine the prevalence of, and risk factors for, LVH in normoalbuminuric type 2 diabetic patients not taking antihypertensive treatment. Cross-sectional study. From 1994 to 1998, M-mode echocardiography was performed by one experienced examiner in 262 consecutive, normoalbuminuric Caucasian type 2 diabetic patients, all with blood pressure <160/95 mmHg and not taking antihypertensive medication. Mean +/- SD age was 54 +/- 10 years, 109 were women, and median known duration of diabetes was 4 (range 1-28) years. Body mass index (BMI) was 28 +/- 5 kg/m(2), and blood pressure 134 +/- 13/79 +/- 8 mmHg, all means +/- SD. Median urinary albumin excretion rate was 9 (range 2-30) mg/24 h. The prevalence of LVH indexed to height(2.7) was 43% (95%CI 38-50%), and was similar in men and women. BMI, HbA(1c) and log urinary albumin excretion were significantly associated with left ventricular hypertrophy in a logistic regression model, whereas sex, age, known duration of diabetes and blood pressure were not. Similar results were obtained for left ventricular mass index. LVH was frequent in our normoalbuminuric type 2 diabetic patients not taking antihypertensive treatment. Several potentially modifiable risk factors, such as raised BMI, poor glycaemic control and elevated urinary albumin excretion rate, were associated with LVH.

Modulation of the Renal Response to ACE Inhibition by ACE Insertion/Deletion Polymorphism During Hyperglycemia in Normotensive, Normoalbuminuric Type 1 Diabetic Patients

ACE inhibition protects kidney function, but ACE insertion/deletion (I/D) polymorphism affects renal prognosis in type 1 diabetic patients. ACE genotype may influence the renal benefits of ACE inhibition. We studied the impact of ACE I/D polymorphism on the renal hemodynamic changes induced by ACE inhibition in type 1 diabetes. We studied renal hemodynamics (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], filtration fraction [GFR/ERPF], mean arterial pressure [MAP], and total renal resistances [MAP/ERPF]) repeatedly during normoglycemia and then hyperglycemia in 12 normotensive, normoalbuminuric type 1 diabetes and the II genotype (associated with nephroprotection) versus 22 age- and sex-matched subjects with the ACE D allele after three randomly allocated 2- to 6-week periods on placebo, 1.25 mg/day ramipril, and 5 mg/day ramipril in a double-blind, cross-over study. During normoglycemia, the hemodynamic changes induced by ramipril were similar in both genotypes. During hyperglycemia, the changes induced by ramipril were accentuated in the II genotype group and attenuated dose dependently in the D allele group (treatment-genotype interaction P values for ERPF, 0.018; MAP, 0.018; and total renal resistances, 0.055). These results provide a basis to different renal responses to ACE inhibition according to ACE genotype in type 1 diabetes.

Angiotensin II does not affect endothelial tone in Type 1 diabetes—results of a double‐blind placebo controlled trial

Previously, we have demonstrated that patients with normoalbuminuric Type 1 diabetes are characterized by impaired nitric oxide bioavailability compensated for by increased vasodilatory prostanoid-mediated vasodilation. Experimental evidence suggests vascular responses to endogenous angiotensin II involve the nitric oxide and prostaglandin pathways. We examined whether selective blockade of angiotensin II influences endothelial tone with particular reference to the nitric oxide/prostaglandin pathways in patients with Type 1 diabetes free from vascular complications. At baseline, we studied changes in forearm blood flow in response to brachial arterial infusions of acetylcholine, l-NMMA, a combination of l-NMMA and the cyclo-oxygenase inhibitor indomethacin and nitroprusside in 30 patients with normoalbuminuric Type 1 diabetes [21 male, 9 female; age 38.5 +/- 1.9 years (mean +/- sem)]. Patients were randomized to 2 weeks' treatment with placebo or the selective angiotensin II receptor blocking agent irbesartan, 300 mg, prior to forearm vasoactive responses being re-examined. The forearm responses to nitroprusside and acetylcholine were unchanged by both placebo (P = 0.23 and P = 0.36, respectively) and irbesartan (P = 0.41 and P = 0.36). Similarily, dose-response curves to acetylcholine in the presense of l-NMMA alone (P = 0.42) and a combination of l-NMMA and indomethacin (P = 0.44) were not altered by angiotensin II blockade. This study demonstrated that physiological blockade of endogenous angiotensin II in Type 1 diabetes does not augment agonist-evoked vasodilation or the contribution of nitric oxides and prostanoids to endothelial tone.

A 100-kDa urinary protein is associated with insulin resistance in offspring of type 2 diabetic patients

One-third of normoalbuminuric type 1 diabetic patients show immunoreactive nephrin in urine. Offspring of type 2 diabetic patients are insulin-resistant and susceptible to the development of diabetes. We investigated whether the offspring of type 2 diabetic patients show nephrin in urine and whether possible nephrinuria is associated with insulin resistance. Urinary proteins from timed overnight urine collections from 128 offspring of type 2 diabetic patients and 9 control subjects were analysed by western blotting using an antibody against nephrin. Glucose metabolism was assessed by OGTT and IVGTT and the euglycaemic-hyperinsulinaemic clamp technique. Of the offspring, 12.5% were strongly and 14.1% weakly positive for a 100-kDa urinary protein. All controls were negative. During the first 10 min of an IVGTT, the offspring strongly positive for the urinary protein had a higher insulin response than the offspring without the protein (3,700 vs 2,306 pmol l(-1)min(-1), p=0.007). Insulin sensitivity (the rate of whole-body glucose uptake divided by the steady-state insulin level x 100) was lower among the offspring strongly positive for the urinary protein than among the offspring negative for the protein (11.3 vs 15.8 micromol kg(-1)min(-1)pmol(-1)l(-1), p=0.008). A 100-kDa urinary protein detectable with a nephrin antibody is associated with insulin resistance in offspring of type 2 diabetic patients.

The Early Natural History of Nephropathy in Type 1 Diabetes

Predictors of albumin excretion rate (AER) abnormalities could provide earlier indicators of diabetic nephropathy risk. Data from the Natural History Study, a prospective 5-year observation of renal structure and function in young type 1 diabetic patients, were examined for predictors of AER patterns in normoalbuminuric type 1 diabetic patients. Included were 170 patients (96 females) (aged 16.7 +/- 5.9 years, duration of diabetes 8.0 +/- 4.3 years) with normal blood pressure, normoalbuminuria (AER <20 microg/min), and eight or more follow-up visits over 5 years. AER, blood pressure, and HbA1c (A1C) were determined quarterly and glomerular filtration rate (GFR) annually. Persistent microalbuminuria (PMA) was defined as 20-200 microg/min in two of three consecutive values within 6-12 months. Four different AER patterns were identified. Group 1 (n = 99): all values <20 microg/min. Group 2 (n = 49): intermittent levels >20 microg/min but not meeting microalbuminuria criteria. Group 3 (n = 14): PMA during follow-up but normoalbuminuria at study exit. Group 4 (n = 8): microalbuminuria at study exit. Group 4 (497 +/- 95 nm, P < 0.01) and group 3 (464 +/- 113 nm, P = 0.03) patients had greater baseline glomerular basement membrane (GBM) width versus group 1 (418 +/- 67 nm). Baseline GFR in group 4 (163 +/- 37 ml.min(-1). 1.73 m(-2)) was higher than group 1 (143 +/- 28 ml.min(-1) . 1.73 m(-2), P = 0.04). A1C was higher in group 2 (9.0 +/- 1.2%) than group 1 (8.4 +/- 1.1%, P = 0.008). Thus, greater increases in GBM width and GFR were predictors of PMA. Since 64% of the patients that developed microalbuminuria reverted to normoalbuminuria, the risk of diabetic nephropathy as defined by current microalbuminuria criteria is unclear.

Urinary Albumin Excretion Rate Is Associated With Increased Ambulatory Blood Pressure in Normoalbuminuric Type 2 Diabetic Patients

To evaluate the 24-h blood pressure profile in normoalbuminuric type 2 diabetic patients. A cross-sectional study was conducted in 90 type 2 diabetic patients with a urinary albumin excretion rate (UAER) <20 microg/min on two occasions, 6 months apart (immunoturbidimetry). Patients underwent clinical and laboratory evaluations. Ambulatory blood pressure monitoring and echocardiograms were also performed. UAER was found to correlate positively with systolic doctor's office blood pressure measurements (r = 0.243, P = 0.021) and ambulatory blood pressure (24 h: r = 0.280, P = 0.008) and left ventricular posterior wall thickness (r = 0.359, P = 0.010). Patients were divided into four groups according to UAER (<5, > or =5-10, > or =10-15, and > or =15-20 microg/min). Systolic blood pressure parameters for the 1st, 2nd, 3rd, and 4th groups, respectively, were 123.0 +/- 10.6, 132.5 +/- 15.0, 139.0 +/- 23.4, and 130.7 +/- 8.0 mmHg for 24-h blood pressure (ANOVA P = 0.004) and 48.4 +/- 6.0, 54.5 +/- 11.2, 58.8 +/- 15.6, and 57.6 +/- 8.0 mmHg for 24-h pulse pressure (ANOVA P = 0.003). A progressive increase in the prevalence of diabetic retinopathy was observed from the 1st to the 4th UAER group: 27.3, 43.8, 45.5, and 66.7% (P = 0.029 for trend). In type 2 diabetic patients, UAER in the normoalbuminuric range is positively associated with systolic ambulatory blood pressure indexes, left ventricular posterior wall thickness, and diabetic retinopathy, suggesting that intensive blood pressure treatment may prevent diabetes complications in these patients.

The contribution of nitric oxide and vasodilatory prostanoids to bradykinin‐mediated vasodilation in Type 1 diabetes

To investigate the effect of bradykinin on endothelial tone in normoalbuminuric Type 1 diabetic patients and specifically whether any changes are mediated through nitric oxide or prostaglandins. Forearm blood flow was measured using venous occlusion plethysmography at baseline and after brachial artery infusions of incremental doses of bradykinin (50, 100 and 200 ng/min) in 15 patients with Type 1 diabetes and 13 non-diabetic controls. Forearm blood flow at baseline and following bradykinin was then re-examined after local infusion of L-NMMA, a nitric oxide synthase inhibitor, and L-NMMA with indomethacin, a cyclo-oxygenase inhibitor. Baseline blood flow in the diabetic and control groups were similar (4.46 +/- 1.11 vs. 3.41 +/- 1.23 ml/min/100 ml, respectively; P = 0.07). After infusion of L-NMMA and L-NMMA with indomethacin, there was a similar reduction in blood flow responses to bradykinin in both groups. There was no significant difference between the diabetic patients and control subjects in the percentage reduction in forearm blood flow following L-NMMA (16.55 vs. 18.12%, respectively, P = 0.94) and L-NMMA with indomethacin (47.1 vs. 37.3%, respectively, P = 0.14). This study demonstrates that bradykinin-stimulated vasodilation is mediated by both nitric oxide and prostaglandin release from the endothelium in patients with Type 1 diabetes and normoalbuminuria, and in healthy control subjects. We have also shown that the relative contributions of nitric oxide and prostaglandin to bradykinin-mediated vasodilation are similar in these diabetic patients compared with non-diabetic subjects.

Glomerular hyperfiltration in type 1 diabetes mellitus results from primary changes in proximal tubular sodium handling without changes in volume expansion

Glomerular hyperfiltration plays a role in the pathophysiology of diabetic nephropathy. An increase in the glomerular filtration rate (GFR) could result from primary actions at the glomerular/vascular level or could be the consequence of a primary increase in proximal tubular sodium reabsorption resulting in systemic volume expansion. Recently it was hypothesized that an increase in sodium reabsorption may lead to glomerular hyperfiltration through the tubulo-glomerular feedback mechanism (tubular-hypothesis) without volume expansion. We have studied 54 normoalbuminuric patients with type 1 diabetes. The GFR was measured by inulin clearance. Proximal and distal sodium reabsorption were calculated according to standard formulas using the free water clearance technique. Plasma volume, measured by the (125)I-albumin method, atrial natriuretic peptide (ANP) and the second messenger cyclic guanosine-3,5-monophosphate (c-GMP) were used as markers of extracellular volume expansion. Glomerular hyperfiltration (GFR >or= 130 mL min(-1) 1.73 m(-2)) was present in 14 out of 55 patients with diabetes (25%). There were no differences in plasma volume between normo-(NF) and hyper-filtrating (HF) patients (2933 +/- 423 in NF vs. 3026 +/- 562 mL in HF, NS). Also plasma ANP and c-GMP levels were not significantly different between the groups. The fractional proximal reabsorption of sodium was significantly increased in HF [fPRNa(+) (%) 90.1 +/- 2.0 vs. 91.5 +/- 1.6, P = 0.02]. There were no differences in distal sodium reabsorption or distal sodium load (approximately macula densa concentration of NaCl) in both groups. Our data suggest that the primary event in diabetic glomerular hyperfiltration is an increase in proximal tubular sodium reabsorption. They do not support the hypothesis that systemic volume expansion or ANP mediate glomerular hyperfiltration in patients with normoalbuminuric type 1 diabetes. As such, changes in tubular sodium handling most probably influence tubulo-glomerular feedback.

Increased levels of mannan-binding lectin in type 1 diabetic patients with incipient and overt nephropathy

Diabetic nephropathy is associated with insulin resistance, and low-grade inflammation and activation of the complement system may contribute to this cascade. Mannan-binding lectin (MBL) activates the complement system, and elevated MBL concentrations have been observed in normoalbuminuric type 1 diabetic patients. The aim of this study was to assess whether MBL is associated with diabetic nephropathy in type 1 diabetes, and whether there is an association between MBL and low-grade inflammatory markers or insulin resistance. A total of 191 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based upon their AER. Patients with normal AER (n=67) did not take antihypertensive medication, while patients with microalbuminuria (n=62) or macroalbuminuria (n=62) were all treated with an ACE inhibitor. As a measure of insulin sensitivity we used estimated glucose disposal rate. MBL was measured by an immunofluorometric assay, C-reactive protein by a radioimmunoassay and IL-6 by high-sensitivity enzyme immunoassay. Patients with normal AER (median [interquartile range]: 1,154 microg/l [180-2,202 microg/l]) had lower levels of MBL than patients with microalbuminuria (1,713 microg/l [724-2,760 microg/l]; p=0.029) or macroalbuminuria (1,648 microg/l [568-3,394 microg/l]; p=0.019). There was a significant correlation between MBL and estimated glucose disposal rate, but not between MBL and C-reactive protein or IL-6 levels in univariate analysis. However, in a multiple regression analysis, HbA1c was the single variable independently associated with MBL (beta+/-SEM: 0.26+/-0.08; p=0.003). MBL concentrations are increased in type 1 diabetic patients with diabetic nephropathy. MBL was not associated with low-grade inflammatory markers.

Functional variant in the (alpha)2B adrenoceptor gene, a positional candidate on chromosome 2, associates with hypertension.

In a genome-wide scan in Scandinavians, we found suggestive linkage between early-onset primary hypertension and a region on chromosome 2. The alpha(2B)-adrenoceptor gene, a candidate gene within this region, harbors a functional insertion/deletion (I/D) polymorphism of three glutamate residues. The aim of this study was to investigate if the DD genotype is associated with hypertension in Swedes. We performed an association study between the I/D polymorphism of the alpha(2B)-adrenoceptor and hypertension in the Skaraborg population. The material consists of all known patients with primary hypertension in Skara (n=772 nondiabetic subjects; n=171 normoalbuminuric type 2 diabetic subjects) and 817 population control subjects. We first compared genotype frequencies between patients with early-onset hypertension (aged 50 years or younger at onset) and subjects with normotension (blood pressure <120/80 mm Hg). Thereafter, the polymorphism was tested for association with hypertension at the population level. When comparing patients with early-onset hypertension and normotensive subjects, the DD versus II genotype was associated with early-onset hypertension when diabetic subjects were excluded from the analysis (OR=2.0; 95% CI=1.2 to 3.5) or when they were not excluded (OR=1.8; 95% CI=1.0 to 3.1). At the population level, the DD versus II genotype was weakly associated with nondiabetic hypertension (OR=1.4; 95% CI=1.0 to 1.8). Our data suggest that carriers of the DD versus II genotype of the alpha(2B)-adrenoceptor are at increased risk for hypertension. The genotypic effect is most evident when comparing groups corresponding to the upper and lower tails of the blood pressure distribution in the population; however, in nondiabetic hypertensive subjects it is weakly detectable even at the population level.

Altered Renal Function in Normoalbuminuric Type 2 Diabetes

Altered renal function namely enhanced FE Mg and impaired hemodynamics is observed in normoalbuminuric type 2 diabetes. Since FE Mg correlates directly with tubulointerstitial fibrosis, enhanced FE Mg reflects tubulointerstitial disease even in normoalbuminuric type 2 diabetes. This implies that microalbuminuria is not sensitive to early detect diabetic nephropathy.

Increased leptin concentrations and lack of gender difference in Type 2 diabetic patients with nephropathy

Leptin plays an important role in the regulation of body weight and energy balance. Women have higher circulating leptin level than men. In this study, we examined serum leptin concentrations in Type 2 diabetic men and women with or without nephropathy. Fasting plasma glucose (FPG), lipid profile, and serum leptin concentrations were measured in 34 Type 2 diabetic patients with nephropathy (DMN), 12 normoalbuminuric Type 2 diabetic subjects (DM) and 34 non-diabetic control subjects, all matched for age and body mass index (BMI). Result: Patients with diabetic nephropathy had lower high-density lipoprotein cholesterol and higher triglyceride, FPG, urinary albumin/creatinine ratio (ACR) and serum creatinine than the other two groups. There was a significant trend in serum leptin concentrations ( P<0.001, analysis of variance ANOVA) across the three groups with the main difference being detected between DMN and control subjects (DMN: 17.5±16.8 ng/ml, DM: 14.6±10.5 ng/ml and control: 9.1±7.1 ng/ml). Women had higher serum leptin concentration than men in the control group (12.5±7.3 ng/ml versus 4.2±2.0 ng/ml, P=0.001) and in the DM group (18.9±11 ng/ml versus 8.6±5.9 ng/ml, P=0.07) whereas this gender difference was not observed in the DMN group (18.6±17.0 ng/ml versus 16.8±17.0 ng/ml, P=0.754). On multivariate analysis, ACR ( β=0.411, P<0.001) and BMI ( β=0.240, P=0.002) were independently associated with serum leptin concentrations ( R 2=0.194, F=22.1, P<0.001) in the whole group. In the DMN group, ACR ( β=0.370, P=0.016) was the only independent determinant of serum leptin concentrations ( R 2=0.159, F=11.4, P=0.016). Serum leptin concentrations were higher in Type 2 diabetic patients with nephropathy than normoalbuminuric diabetic patients and controls. Diabetic men with nephropathy had proportionally higher serum leptin such that the gender difference in leptin observed in non-nephropathic individuals was abolished.

Serum and urinary nitric oxide in Type 2 diabetes with or without microalbuminuria: Relation to glomerular hyperfiltration

Background Glomerular hyperfiltration is considered as one of the pathophysiological mechanisms for the development of diabetic nephropathy. Oxidative stress is enhanced in patients with diabetes mellitus. Reportedly, nitric oxide (NO) might be involved in the pathogenesis of hyperfiltration. We investigated the relationship between hyperfiltration and NO system, and malondialdehyde (MDA) levels in Type 2 diabetics with/without microalbuminuria. Methods In 39 microalbuminuric, 29 normoalbuminuric Type 2 diabetic patients and 32 healthy controls, serum creatinine, nitrite, nitrate, urinary microalbumin, nitrite, nitrate, plasma MDA and estimated glomerular filtration rate (EGFR) values, calculated according to the Cockcroft and Gault formula, were recorded. Results Serum and urine NO levels were higher in both microalbuminurics and normoalbuminurics than controls. There were no significant differences in EGFR between groups. However, hyperfiltration was determined in 31% of normoalbuminurics and 20% of microalbuminurics. Serum and urine NO levels were higher in patients with hyperfiltration. Plasma MDA levels were significantly elevated in both microalbuminurics and normoalbuminurics when compared with controls. Serum glucose and microalbuminuria were positively correlated in microalbuminuric diabetics. Serum NO levels were also positively correlated with EGFR in both normoalbuminurics and microalbuminurics. HbA1c levels were positively correlated with both urinary albumin excretion and plasma MDA levels in normoalbuminuric diabetics. Conclusion Hyperglycemia is associated with an increased NO biosynthesis and lipid peroxidation. Increased oxidative stress may contribute to the high NO levels in Type 2 diabetes. Furthermore, the high NO levels may lead to hyperfiltration and hyperperfusion, which in turn leads to an increase in urinary albumin excretion and thus causes progression of nephropathy in early Type 2 diabetes.

Elevated levels of mannan-binding lectin in patients with type 1 diabetes.

The hepatic protein mannan-binding lectin (MBL) activates the complement system on binding to carbohydrate patterns and is involved in first-line defense against invading microorganisms. Emerging evidence indicates that in some situations MBL may cause inexpedient complement activation and tissue injury through binding to endothelial glycosylations. MBL levels are suppressed by insulin treatment in critically ill patients, and, hypothetically, hepatic portal hypoinsulinemia could lead to increased levels of MBL in patients with type 1 diabetes. We measured MBL and C-reactive protein (CRP) levels in 132 normoalbuminuric type 1 diabetic patients and 66 healthy age- and sex-matched controls. The median MBL concentration was higher in diabetic patients than in healthy controls [1290 micro g/liter (interquartile range, IQR 354-2961 micro g/liter) vs. 970 micro g/liter (IQR 277-1607 micro g/liter), P = 0.025], whereas CRP concentrations were similar among patients and controls [1.42 mg/liter (IQR 0.95-2.21) vs. 1.21 mg/l (IQR 0.74-2.13), NS]. In diabetic subjects, CRP levels correlated with poor glycemic control as indicated by hemoglobin A(1c) and daily insulin dose, which was not the case with MBL. MBL concentrations were positively correlated with urinary albumin excretion (r = 0.22; P = 0.013) and increased with increasing urinary albumin excretion tertile (P = 0.036). In conclusion, our data demonstrate that circulating MBL concentrations are significantly elevated in patients with type 1 diabetes and suggest a possible role of MBL in the pathogenesis of renovascular complications in diabetes.

Diurnal blood pressure pattern may predict the increase of urinary albumin excretion in normotensive normoalbuminuric type 1 diabetes mellitus patients

To characterise the relationship between diurnal blood pressure and the subsequent increase of urinary albumin excretion (UAE) in normotensive normoalbuminuric type 1 diabetic patients, ambulatory blood pressure monitoring (ABPM) was performed in 53 patients, who were then followed for 5 years. Albumin excretion rate changed from 12.4 (8.9–17.2) to 29.3 (15.2–47.0) mg/day. Macroalbuminuria developed in 2 (3.8%), microalbuminuria in 22 (41.5%) patients, 29 (54.7%) remained normoalbuminuric. Night-time diastolic blood pressure was significantly higher (64.3±6.5 vs. 60.9±5.5 mmHg, P<0.05), diastolic diurnal index significantly lower (15.5±9.7 vs. 22.3±6.2%, P<0.01) in patients who later progressed to micro- or macroalbuminuria. Diastolic diurnal index (r=−0.40; P<0.01) and nocturnal diastolic pressure (r=0.35; P<0.01) were correlated to the change in albumin excretion. In a multivariate analysis model with the change of albumin excretion as dependent, and means and diurnal indices of systolic and diastolic blood pressure, baseline UAE, cholesterol, triglycerides, HbA 1c and retinopathy as independent parameters (r=0.68; P=0.001), diurnal index for diastolic blood pressure (β=−0.30; r=0.013), baseline HbA 1c (β=0.32; P=0.010) and retinopathy (β=0.44; P=0.001) were significant independent correlates. We conclude that the relative increase of nocturnal blood pressure is associated with the subsequent increase of albuminuria, which in turn is predictive of overt diabetic nephropathy.

Low Glomerular Filtration Rate in Normoalbuminuric Type 1 Diabetic Patients

Increased urinary albumin excretion rate is widely accepted as the first clinical sign of diabetic nephropathy. However, it is possible that some diabetic patients could first manifest reduced glomerular filtration rate (GFR) or hypertension. Relatively advanced diabetic renal lesions can be present in some diabetic patients with long-standing normoalbuminuria, and this might indicate increased risk of progression to microalbuminuria and then to overt diabetic nephropathy. The aim of this study was to identify a group of normoalbuminuric type 1 diabetic patients with low GFR and compare them with normoalbuminuric patients with normal GFR. Altogether, 105 normoalbuminuric type 1 diabetic patients with at least 10 years of diabetes duration that had a renal biopsy performed for research purposes were studied. Patients were divided according to GFR into groups with normal (>/=90 ml x min(-1) x 1.73 m(-2)) or reduced (<90 ml x min(-1) x 1.73 m(-2)) GFR. Clinical and renal structural parameters were compared between these two groups. Glomerular structural parameters were estimated by electron microscopic morphometry. The 23 patients with reduced GFR had more advanced diabetic glomerular lesions. The finding of reduced GFR was much more common among female patients, particularly if retinopathy and/or hypertension were also present. This report confirms that reduced GFR occurs among long-standing normoalbuminuric type 1 diabetic patients and is associated with more advanced diabetic glomerular lesions and, probably, with increased risk of progression. For these reasons, we suggest that regular measurements of GFR be performed in long-standing normoalbuminuric type 1 diabetic female diabetic patients, especially in those with retinopathy or hypertension.

Single photon emission tomography (SPECT) study of regional cerebral blood flow in normoalbuminuric children and adolescents with type 1 diabetes.

Cerebral damage in diabetes can be related to chronic hyperglycemia and recurrent severe hypoglycemia as well as due to the associated vasculopathy. The pattern of regional cerebral blood flow using cerebral single photon emission tomography (SPECT) was evaluated in normoalbuminuric type 1 diabetic children and adolescents and its relation to the metabolic control and cognitive functions. Thirty-one type 1 diabetics aged 10-18 yr (mean 14.7 +/- 3.4) were included, 16 males and 15 females, divided into four groups: group I (n = 8) with history of recurrent severe hypoglycemia (> or = 3); group II (n = 8) with history of severe diabetic ketoacidosis (> or = 3); group III (n = 7) with recurrent minor hypoglycemia (> or = 3/week); and group IV (n = 8) with controlled diabetes. The control group (V) comprised seven healthy children, aged 10-18 yr (mean 14.2 +/- 3.1). SPECT was done using technetium-99m hexamethyl propylene amine oxime. There was significant brain hypoperfusion in diabetics compared with controls, mainly in the basal ganglia (p < 0.01) and frontal regions (p < 0.01), with less changes in parietal and temporal regions. These changes were not related to the age, sex, diabetes duration, mean blood glucose or HbA1C. Basal ganglia hypoperfusion was significant in groups I (p < 0.01) and II (p < 0.01) compared with controlled diabetics. There was no correlation between cerebral SPECT changes and cognitive scores in type 1 diabetics. Subclinical alterations in cerebral blood flow (hypoperfusion) are present in children and adolescents with type 1 diabetes mainly affecting the basal ganglia and frontal regions, usually not associated with measurable alterations of the cognitive functions

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 (51Cr-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 (R2=.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 μg/min/month, P=.002) and was associated with baseline UAER levels only (R2=.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.