Effect of insulin analogs on the decline of hemoglobin in diabetic patients with nephropathy.

AIM: Decrease of hemoglobin occurs in diabetic patients with nephropathy earlier than in nondiabetic patients, probably due to impaired synthesis of erythropoietin (EPO). Apart from EPO, insulin also stimulates erythropoiesis. We investigate whether there are differences between human insulin and insulin analogs in respect of their erythropoiesis stimulating effect. PATIENTS AND METHODS: Hemoglobin concentration and other factors which may influence hemoglobin levels were analyzed retrospectively in 203 type 1 diabetic patients with various degrees of kidney function. Eighty-six patients were treated with human insulin and 117 patients received an insulin analog. RESULTS: Hemoglobin concentration did not differ in patients with normal renal function (creatinine clearance (CCL) >90 ml/min) treated with human insulin or insulin analogs. In patients with impaired renal function (CCL<90 ml/min) there was a significant decrease of hemoglobin with declining kidney function in patients treated with human insulin (r=0.463; p<0.003) but not in patients treated with insulin analog (r=-0.12; p=0.4). This result remained significant after adjustment of multiple potential confounders such as age, gender, diabetes duration, BMI, metabolic control, kidney function, chronic inflammation or use of ACE-inhibitors or AT1-blockers. CONCLUSION: Insulin analogs mitigate the decline of hemoglobin in diabetic patients with impaired renal function. This might be due to a stimulating effect of insulin analogs on erythropoiesis via IGF receptor or a sustained activation of the insulin receptor.

[Insulin requirement in patients with type 1 diabetes with reduced renal function: human insulin versus analogue insulin]. / Insulinbedarf bei Typ-1-Diabetikern mit nachlassender Nierenfunktion: Human-Insulin versus Analog-Insulin.

INTRODUCTION: Insulin clearance and the degree of insulin resistance change in type 1 diabetes in patients with reduced kidney function and make it more difficult to achieve good metabolic control. For some years different analogue insulins have become available. Their pharmacological characteristics in renal failure have not as yet been investigated in detail. The aim of the present retrospective study was to determine the insulin dosage in relation to kidney function in patients with type 1 diabetes treated with human or analogue insulin. METHODS: Insulin dosage of 68 patients treated with human insulin and 74 patients treated with analogue insulin was related to the creatinine clearance (calculated with the Cockcroft-Gault formula). In addition, diabetes-related laboratory parameters, the prevalence of hypertension and the kind of antihypertensive therapy were analysed in both groups. RESULTS: Patients with type 1 diabetes treated with human or analogue insulin have different insulin demands if their renal function is decreased. In analogue-treated patients, insulin dosage significantly decreased with reduced creatinine clearance (r = 0,257; p = 0,026) in contrast to human insulin treated patients who did not show such a decrease (r = 0,159; p = 0,165). There were no significant differences between treatment groups with respect to demographic data, metabolic control or antihypertensive therapy. Linear regression analysis revealed kidney function as a significant factor influencing insulin dosage in the analogue group, while the corresponding factors in the human insulin group were metabolic control and age. CONCLUSION: The results indicate that insulin clearance and/or the metabolic activity of human and analogue insulin differ if renal function is reduced. This may be due to different pharmacokinetic or pharmacodynamic characteristics of these insulins in renal failure, a finding which needs further investigation.

[Protection of renal function in diabetics]. / Protektion der Nierenfunktion bei Diabetikern.

The course of diabetic nephropathy is affected by several factors that can be manipulated. In primary prevention, near normal metabolic control beginning at the time of the diagnosis of diabetes diminishes the risk of microalbuminuria to an extent depending on the HbA1c level attained. Hypertensive diabetics should be consistently treated with renin-angiotensin system (RAS)-blocking agents. In secondary prevention, a multifactorial therapy is able to stop or retard further progression. Its components are a sustained decrease of blood pressure in the normotensive range using RAS-blocking agents (normotensive patients should also be treated) as well as near normal metabolic control that takes into account the changing pharmacokinetic and pharmacodynamic properties of blood glucose-lowering drugs in renal insufficiency. Consideration of further factors (smoking, protein intake, anemia) and several general nephroprotective measures complete the treatment spectrum. Therapy for dyslipidemia and the administration of aspirin are important in view of the high cardiovascular morbidity. It is essential to monitor kidney function and the therapeutic components at short intervals.

[Severe hypoglycemia in diabetics with impaired renal function]. / Schwere Hypoglykämien bei Diabetikern mit eingeschränkter Nierenfunktion.

BACKGROUND AND OBJECTIVE: Reduction of renal function in patients with type 1 or type 2 diabetes is associated with a clearly increased risk of hypoglycemia. Main causes are an altered pharmacokinetics of insulin and oral antidiabetics and/or impaired renal glucose production. A knowledge of renal function is, therefore, essential for preventing hypoglycemia caused by antidiabetic treatment. But serum creatinine, most commonly used in general practice, is an imprecise indication of renal function. This investigation assessed the significance of a false estimation of renal function as a partial cause of severe hypoglycemia. PATIENTS AND METHODS: The study group consisted of 35 diabetics (21 females, 14 males; average age 61 years) who had been hospitalized because of an episode of severe hypoglycemia accompanied by loss of consciousness. Renal function was measured by serum creatinine and by creatinine clearance as calculated by the formula of Cockcroft and Gault. Also taken into account were HBA1c the antidiabetic treatment before and after discharge, and any additional medication. RESULTS: Impaired renal function was established by the serum creatinine level in 9 patients and by calculated creatine clearance in 24. Compared with patients with normal renal function, those with renal failure were older (74.3 vs. 32.8 years), had more rarely undergone intensive insulin treatment (5 of 24 vs. 9 of 11) and had more commonly received ACE inhibitors (10/24 vs. 1/11). The insulin dosage at discharge had been reduced in 16 off 22 insulin-dependent patients in renal failure, and long-acting sulfonylurea preparation were discontinued or changed to gliquidone in the others. CONCLUSION: This investigation indicates that false estimation of renal function from the level of serum creatinine is an important partial cause of hypoglycemia requiring treatment, especially in elderly persons with reduced muscle mass in whom renal function should be determined by calculating or measuring creatinine clearance.

Single- and multiple-dose pharmacokinetics of repaglinide in patients with type 2 diabetes and renal impairment.

OBJECTIVE: The primary objective of this single-centre, open-label, parallel-group study was to evaluate the pharmacokinetics and safety profile of the prandial glucose regulator repaglinide, following single and multiple dosing, in patients with type 2 diabetes with and without varying degrees of renal impairment. METHODS: The study comprised three screening visits, followed by a 7-day inpatient period. Thirty-four patients, with normal renal function (n = 12), mild-to-moderate renal dysfunction (n = 12) or severe renal dysfunction (n = 10), received a single 2-mg dose of repaglinide on day 1, followed by preprandial 2-mg doses with main meals (breakfast, lunch and dinner) on each of days 2-4. A final 2-mg dose of repaglinide was administered on day 5. RESULTS: Patients with mild-to-moderate renal impairment showed no significant differences in the pharmacokinetics of repaglinide, compared with patients with normal renal function. In the group of patients with severe renal dysfunction, the main pharmacokinetic finding was a longer half-life after multiple dosing. Rates of minor hypoglycaemia were similar in patients with severe, mild-to-moderate and no renal dysfunction. No major hypoglycaemic episodes occurred. CONCLUSION: Patients with type 2 diabetes and mild or moderate impairment of renal function may be treated with repaglinide without special precautions. If repaglinide is used in patients with severely impaired renal function, dose adjustment may be necessary if indicated by blood glucose measurements.

The influence of the ACE inhibitor lisinopril on the glomerular metabolism of proteolytic enzymes in diabetic rats.

Clinical studies indicate a nephro-protective effect in conjunction with the use of ACE inhibitors. This study's aim was to determine whether ACE inhibitors influence the metabolism of glomerular cells in addition to their known hemodynamic effects. Streptozotocin diabetic rats were treated with lisinopril (DLis 1.5 mg/l water), or hydralazine (Dhyd, 50 mg/l water) over 4 weeks. Untreated diabetic rats (DC) and non-diabetic rats (C) served as controls. After four weeks of treatment, urinary excretion of albumin, blood pressure and metabolic control (Glyc-Hb) were measured. After treatment glomeruli were isolated and homogenized, and beta-NAG and total proteolytic activity against azocasein were measured. Glycated hemoglobin levels were similar in all diabetic groups (DC, 12%, Dhyd, 10%; DLis 11%). Blood pressure of DLis rats (79 +/- 3 mmHg) and DHyd rats (46 +/- 2 mmHg) was lower than that of DC rats (111 +/- 3 mmHg). Urinary albumin excretion of diabetic groups was lowest in DLis. Diabetic rats showed a decrease in glomerular beta-NAG (10 vs. 60.5 U/g protein) and total proteolytic activity against azocasein (148 vs. 170 U/mg protein hour) compared to non-diabetic rats. Lisinopril increased beta-NAG (30 vs. 14 U/g protein) and total proteolytic activity (160.5 vs. 141.5 U/mg protein hour) compared with hydralazine. Our study confirms that the nephro-protective effect of ACE inhibitors is partially due to modulatory effects on the metabolism of basement membrane proteins.

[Von Recklinghausen type I neurofibromatosis and neuroendocrine tumor (somatostatinoma) in a 50-year-old woman]. / Neurofibromatose von Recklinghausen Typ I und neuroendokriner Tumor (Somatostatinom) bei einer 50jährigen Frau.

HISTORY AND CLINICAL FINDINGS: A 50-year-old woman has had diffuse abdominal symptoms for approximately 2 weeks. For 30 years a von Recklinghausen's neurofibromatosis has been known. INVESTIGATIONS: Clinically and chemically there was a cholestasis (alkaline phosphatase 244 U/l, gamma GT 83 U/l) with uneventful values for transaminases and bilirubin. The hepatitis serology (A, B, C) as well as the AMA were negative. Somatostatin with 73 ng/l was slightly increased. Ultrasonography revealed a low-grade intrahepatic cholestasis, the ductus pancreaticus was extended to 9 mm, while endoscopic retrograde cholangiopancreatography showed an extended pancreatic duct without inflamed changes as well as an extended intra- and extrahepatic gall duct system without detecting a stone. The oesophagogastroduodenoscopy showed a polypoid tumor 3 cm above the Papilla Vateri which is part of a neuroendocrine tumor of the carcinoid type, immunoreactive towards somatostatin. TREATMENT AND COURSE: In the framework of the surgical intervention carried out by extirpation of the polypoid tumor above the Papilla Vateri by segment excision with a duodeno-duodenostomy. Within a period of 15 months, the patient was free from a tumor relapse or metastasis. CONCLUSION: Carcinoid tumors should always be considered in patients who have von Recklinghausen's neurofibromatosis in combination with abdominal pain in the duodenal area, especially if cholestasis parameters and bilirubin are high or if gastrointestinal bleeding occurs.

Apolipoprotein E polymorphism and renal function in German type 1 and type 2 diabetic patients.

OBJECTIVE: To examine the association of renal function in diabetic patients with apolipoprotein (apo) E polymorphism. RESEARCH DESIGN AND METHODS: Apo E genotypes, lipid and lipoprotein serum levels, creatinine clearance (CCr), and excretion of marker proteins were determined in German type 1 (IDDM; n = 162) and type 2 (NIDDM; n = 124) diabetic patients. Albumin and immunoglobulin (Ig) G are considered to reflect charge-size permselectivity of the glomerular capillary basement membrane, and increased alpha 1-microglobulin (MG) excretion indicates compromised reabsorptive capacity of the renal tubules. RESULTS: Patients with NIDDM had higher lipid levels and lower CCrs than patients with IDDM. In patients with IDDM, age- and sex-adjusted analysis of variance showed an association between apo E genotypes and CCr, and the Jonckheere-Terpstra test demonstrated a decreasing glomerular filtration rate in the following order of genotypes: epsilon 4 epsilon 4/epsilon 4 epsilon 3 > epsilon 3 epsilon 3 > epsilon 2 epsilon 2/epsilon 2 epsilon 3. Multiple linear regression analyses revealed that in patients with IDDM, the epsilon 2 allele was a negative predictor of CCr and a positive predictor of urinary excretion of albumin, IgG and alpha 1-MG independent from HDL and LDL cholesterol, TG concentration, age, and sex. CONCLUSIONS: Apo E polymorphism influences serum lipoprotein levels in patients with IDDM and NIDDM. Apo E polymorphism may be a renal risk factor of clinical relevance in normolipidemic patients with IDDM.

Urinary glycosylated, free and total pyridinoline and free and total deoxypyridinoline in diabetes mellitus.

OBJECTIVE: Published data on bone metabolism in diabetes mellitus are conflicting. We have measured pyridinium crosslinks, biochemical markers of bone resorption, in order to evaluate bone resorption in diabetes mellitus. We also wished to investigate whether, as a consequence of chronic hyperglycaemia, pyridinoline is glycosylated to a greater extent in patients with diabetes mellitus. DESIGN AND PATIENTS: This cross sectional study included 142 patients (64 males, 78 females) with insulin dependent and non-insulin dependent diabetes mellitus (IDDM and NIDDM). These patients were compared to a healthy control group of 99 individuals (39 males and 60 females). MEASUREMENTS: Pyridinium crosslinks, glycosylated, free and total pyridinoline (gPYD, fPYD, tPYD) and free and total deoxypridinoline (fDPD, tDPD) were measured in a spot urine sample by high performance liquid chromatography (HPLC). Urinary creatinine, albumin and glucose were also measured. RESULTS: In the diabetic group, values of urinary gPYD and tDYD were significantly lower than in controls. gPYD excretion was lowest in patients with severe glycosuria. Free pyridinium crosslinks, both fPYD and fDPD, were excreted to a significantly lower extent. The molar ratio of tPYD to tDPD was significantly increased in diabetes mellitus. CONCLUSIONS: Decreased excretion of tDPD suggests low bone resorption in IDDM and NIDDM. Pyridinoline is not glycosylated to a greater extent in diabetes mellitus and tends to be decreased in proportion to the degree of glycosuria. Excretion of gPYD, fPYD and fDPD is depressed in severe glycosuria. Diminshed degradation to the final products, fPYD and fDPD, might represent increased resistance to enzymatic activity or diminished enzymatic activity. The increased molar ratio tPYD/tDPD in urine suggests an increased ratio in bone collagen in diabetes mellitus.

Levels and molecular size distribution of serum laminin in adult type I diabetic patients with and without microangiopathy.

The glycoprotein laminin, a cross-shaped complex of three genetically different polypeptide chains, is a structural component of the capillary basement membrane. Serum laminin concentrations of healthy controls (n = 60) and adult type I diabetic patients (n = 170) were not age-dependent. Laminin was correlated with hemoglobin A1 (HbA1) values in normoalbuminuric patients (rs = .33, P < .0005, n = 116). Type I diabetic patients without nephropathy or retinopathy in good metabolic control had normal laminin levels. However, increasing stages of microangiopathy were associated with higher laminin levels. The molecular size distribution of serum laminin of control subjects (n = 4) and type I diabetic patients (n = 15) was analyzed by molecular-sieve chromatography. Laminin was eluted in two peaks with a molecular mass of 900 and 300 kd, most likely representing intact laminin and its P1 fragment, respectively. The areas of the two peaks were determined by two-gaussian function fitting. In patients without microangiopathy in poor metabolic control, an increase in the high-molecular weight (HMW) fraction could be detected as compared with healthy subjects and patients with acceptable metabolic control. Furthermore, the HMW laminin fraction and the ratio between the areas of the first and second peak increased with the stage of nephropathy (P < .001, Jonckheere-Terpstra test). These results provide evidence that (1) laminin concentration is increased in chronic hyperglycemia, (2) laminin may be a marker of microangiopathic lesions, and (3) elevated laminin levels may reflect an increased synthesis and/or a defective incorporation of laminin into the capillary basement membrane.

Multicenter evaluation of the Micral-Test II test strip, an immunologic rapid test for the detection of microalbuminuria.

OBJECTIVE: To assess the performance of the Micral-Test II immunologic test strip for the detection of microalbuminuria, a multicenter evaluation in eight European study sites was performed. RESEARCH DESIGN AND METHODS: Using both the Micral-Test II test strip and the routine method for the determination of albumin concentration, we investigated 2,228 urine samples from diabetic patients. Additionally, interperson variability, color stability, and possible interfering factors (temperature, pH, leucocyturia, erythrocyturia, and drugs) were tested. RESULTS: For a cutoff concentration of 20 mg/l with respect to the routine methods, a sensitivity of 96.7% and a specificity of 71% were calculated for the Micral-Test II test strip. The negative predictive value was 0.95, and the positive predictive value was 0.78, with a prevalence of positive samples (laboratory method) of 52%. The interperson variability of color interpretation showed 93% concordant readings. The interference study showed an influence of oxytetracycline, leading to higher readings. There was no interference from pH. A sample temperature of < 10 degrees C led to lower readings. In the case of samples with massive leucocyturia and erythrocyturia that may delete the chromatographic process, waiting an additional 1-2 min is needed before reading. CONCLUSIONS: The results of the multicenter evaluation show that the Micral-Test II test strip permits an immediate and reliable semiquantitative determination of low albumin concentrations in urine samples with an almost user-independent color interpretation.

Western blotting of NC1 type IV collagen fragments in human plasma.

Collagen IV matrix of glomerular basement membrane may be involved in the development of various renal diseases, e.g. diabetic nephropathy. An immunoblotting method for the detection of the carboxy-terminal non-collagenous (NC1) domain of type IV collagen in plasma was developed. The high sensitivity down to the picogram range enabled characterization of NC1(IV) fragments in human blood for the first time. Both Western blotting and gel filtration chromatography coupled with an enzyme-linked immunoassay surprisingly revealed that the NC1(IV)-related components are bound to the fibrin clot forming during blood coagulation. About 40% of the NC1(IV) fragments in plasma had an apparent molecular mass higher than 340,000. Abnormal NC1(IV) immunoblot patterns were observed in about 50% of patients with insulin-dependent (n = 20) and non-insulin-dependent (n = 20) diabetes mellitus compared with less than 7% in healthy control subjects (n = 30). There were no obvious associations between abnormal immunoblots and stage of nephropathy or glycaemic control in diabetic subjects.

[Diabetic nephropathy: diagnosis and therapy]. / Diabetische Nephropathie: Diagnostik und Therapie.

Diabetic nephropathy is the most frequent cause for renal replacement therapy in many countries. This is mainly due to an increase of renal insufficiency of type II diabetic patients. The poor situation could be improved by following measures: (a) screening of microalbuminuria for early diagnosis of diabetic nephropathy, (b) consequent treatment of known factors influencing the course of nephropathy such as poor metabolic control, hypertension, increased protein ingestion or smoking, (c) improved cooperation between general practitioner and specialized centers concerning treatment of diabetic patients with nephropathy.

Circadian variation of blood pressure in normo- and hypertensive diabetic patients with and without nephropathy.

Blood pressure control over 24 h is an important influence factor for prevention of diabetic angiopathy, i.e., diabetic nephropathy. We performed 24 h-measurements of blood pressure in normotensive and hypertensive type I- and type II-diabetic patients with different stages of nephropathy and observed the variation of circadian changes of blood pressure. The patients were divided into "dippers", whose nightly decrease in mean arterial pressure was greater than 10% and non-dippers with less than 10%. Even 30% of patients without nephropathy are non-dippers. We conclude that 24 h-blood pressure measurements must be required in all diabetic patients with or without nephropathy. An early therapy may prevent or slow the development of an end-stage renal failure.

[ACE inhibitor in metabolic syndrome]. / ACE-Hemmer bei metabolischem Syndrom.

The metabolic syndrome is characterized by cluster-like occurrence of various risk-factors for vascular disease: overweight, hypertension, hyperlipidemia, hyperproteinuria. In the pathogenesis of this syndrome the peripheral resistance to insulin leading to hyperinsulinemia plays most likely a central role, as the development of individual components of the metabolic syndrome may causally be explained in this way. Various possible explanations exist for the development of insulin resistance: on the receptor level, as a result of changes in the capillary bed or in muscle fiber composition, or resulting from disturbed circulation of muscles. Clinical symptoms of hyperinsulinemia are hypertension, lipodystrophy, and type II diabetes. Patients with metabolic syndrome represent a group at high risk for arteriosclerotic vascular disease. Therapy aims primarily at reduction of hyperinsulinemia as the underlying factor. In particular non-medical intervention plays an important role (reduction of body weight, exercise). In drug therapy of hypertension only such antihypertensives which remain neutral to metabolism should be applied, i.e., ACE-inhibitors which even improve the metabolic condition.

Effect of metabolic factors and blood pressure on kidney function in proteinuric type 2 (non-insulin-dependent) diabetic patients.

Decline of kidney function with time and its influencing factors were investigated in the present longitudinal study in Type 2 (non-insulin-dependent) diabetic patients with clinical diabetic nephropathy. Compared to a control group of Type 2 diabetic patients without proteinuria, the proteinuric patients showed a higher prevalence of hypertension, higher systolic blood pressure values and serum triglyceride levels. The annual loss of glomerular kidney function was much higher in the proteinuric patients (5.3 ml.min-1 x 1.73 m2) than in the control subjects (0.9 ml.min-1 x 1.73 m2). Correlation analyses revealed a close correlation between the annual decrease of kidney function and the factors, systolic and diastolic blood pressure, triglyceride and postprandial blood glucose level as well as body mass index. Regression analyses showed for the first time that in addition to the systolic blood pressure and metabolic control, the triglyceride level is also an independent factor influencing the progression of nephropathy. Higher values of these parameters were associated with a more rapid deterioration of kidney function.