Clustering of risk factors in hypertensive insulin-dependent diabetics with high sodium-lithium countertransport

Clustering of risk factors in hypertensive insulin-dependent diabetics with high sodium-lithium countertransport. Diabetic nephropathy is more common in patients with a positive family history of hypertension and with elevated red blood cell sodium-lithium countertransport, a marker of risk for essential hypertension. To evaluate whether there is a relationship between this cation transport system and indicators of risk of renal and cardiovascular complications in diabetic patients before the development of clinical proteinuria, we studied 31 type 1 (insulin-dependent) diabetic patients with arterial hypertension, without clinical proteinuria and 12 normotensive normoalbuminuric diabetic patients. Sodium-lithium countertransport activity was significantly higher in hypertensive patients (0.43 ± 0.03 mmol/1 RBC x hr) than in normotensive patients (0.23 ± 0.03; P < 0.001). To better explore the nature of the association between this transport system and arterial hypertension, hypertensive patients were divided in two groups, with high (>0.41 mmol/1 RBC x hr) or normal (<0.41) sodium-lithium countertransport activity. The two groups of hypertensive diabetics were similar in age, sex, body mass index and blood pressure levels. Hypertensive patients with elevated rates of sodium-lithium counter-transport compared with those with normal sodium-lithium counter-transport activity showed elevated glomerular filtration rate (130 ± 4 ml/min/1.73 m2 vs. 122 ± 3; P < 0.05), albumin excretion rate (median 26 /Lcg/min vs. 11; P < 0.001), higher fractional proximal sodium reabsorption (74 ± 1.2% vs. 71.6 ± 0.9; P < 0.01), exchangeable sodium pool (2937 ± 62 mmol/1.73 m2 vs. 2767 ± 56; P < 0.01), larger kidney volume (317 ± 7 ml/1.73 m2 vs. 270 ± 8; P < 0.05) and left ventricular mass index (122 ± 4 g/m2 vs. 107 ± 5; P < 0.05). Hypertensive patients with normal sodium-lithium countertransport activity had renal parameters similar to normotensive diabetic patients, except higher left ventricular mass index and kidney volume. Hypertensive diabetic patients with elevated sodium-lithium countertransport activity also had higher levels of plasma triglycerides, lower plasma HDL-cholesterol and impaired insulin sensitivity (assessed by euglyce-mic insulin-glucose clamp) compared with the other two groups. In conclusion, renal, cardiac and metabolic abnormalities are prominent in hypertensive type 1 (insulin-dependent) diabetic patients with higher sodium-lithium countertransport

Relationship between blood glucose control, pathogenesis and progression of diabetic nephropathy

The present review briefly discusses evidence that the risk of a rapid decline of glomerular function abruptly increases when glycated hemoglobin is steadily higher than 7.5% and postprandial blood glucose is >200 mg/dl. The capacity to accomplish and to maintain steadily tightly controlled blood glucose levels is scanty using the currently implemented hypoglycemic drugs. Moreover, it must be highlighted that most patients with type 2 diabetes, particularly when renal damage does occur, have arterial hypertension. Several studies suggested that the development of ESRD is prevented significantly better by drugs that modulate the renin angiotensin system than by other compounds in patients with type 1 and 2 diabetes with overt diabetic nephropathy. However, a recent trial, the study Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared lisinopril, chlorthalidone, and amlodipine in a large population of patients with arterial hypertension, either associated or not with diabetes, demonstrated that the development of both coronary heart diseases and renal complications was equally prevented by the three drugs. One word of caveat, however, needs to be raised concerning one of the results of the ALLHAT study: the higher risk of developing new-onset diabetes among hypertensive patients who are not treated with lisinopril. Even if it is true that this latter side effect was not accompanied by a worse outcome of macrovascular and renal complications during the 5-yr follow-up period, one cannot rule out the possibility that this might be the case during more prolonged periods of follow-up in the future. Thus, the advantage of a lower cost in the treatment of hypertension with diuretics as compared with other drugs, with similar degree of success in the prevention of vascular complications, should be weighed also taking into consideration the burden of a higher rate of occurrence of new-onset diabetes

Importance of glycemic control on the course of glomerular filtration rate in type 2 diabetes with hypertension and microalbuminuria under tight blood pressure control

Background and aims: To evaluate the role of glycemic control on the evolution of glomerular filtration rate (GFR) in type 2 diabetes (T2DM) with mild-moderate hypertension under tight blood pressure control, and to address the current controversy whether diabetic nephropathy worsens, independently of blood pressure, proportionally to HbA1c at any physiological level or only when HbA1c is above a 7.5-8% threshold. Methods and results: T2DM (N &#61; 127) during early stage diabetic nephropathy characterized by microalbuminuria were followed during a 2 year multicenter study. Individual GFR profiles were accurately obtained by 51 Cr e EDTA bolus injections and analyzed with linear statistical mixed-effects models. GFR at baseline was significantly negatively correlated with age and plasma creatinine concentration (P &#8804; 0.0001), and GFR declined, on average, by 4.0 ml/min 1.73 m2/year (P &#61; 0.001). A significant correlation was found between individual GFR decline rate and average systolic (SBP) and diastolic (DBP) blood pressures ( = 0.254 (0.736) ml/min 1.73 m2/year per mmHg increase in SBP (DBP), P &#61; 0.041 (0.014)) and % of glycated hemoglobin (HbA1c) = 1.78 ml/min 1.73 m2/year per % increase in HbA1c, P &#61; 0.048). This implies a 44% increase/reduction in GFR decline rate for 1% HbA1c increase/reduction around 7.0% (i.e. 5.79 and 2.24 ml/min 1.73 m2/year at 8% and 6% HbA1c, respectively). Conclusions: This study demonstrates that, despite tight blood pressure control, an accurate glycemic control till very low patterns of HbA1c (from 10 &#8722; 11% to 5&#8722; 6%) is needed to delay the progression of GFR decay in Mediterranean T2DM in south Europe with microalbuminuria

Is the "pool-fraction" paradigm a valid model for assessment of in vivo turnover in non-steady state?

Quantification of in vivo turnover of endogenous substances in nonsteady state is of fundamental importance for understanding a variety of physiological and clinical metabolic situations. Toward this end, a pool-fraction model has become a paradigm in the glucose and ketone body areas. We discuss the basic assumptions on which the pool-fraction model is based and the criteria on which it has been validated. Specific comments are then made on its current and potential use for quantifying the non-steady-state turnover of glucose, ketone bodies, and insulin. We conclude that the quantitative reliability of predictions provided by the pool-fraction model is quite poor and that new developments are needed for quantifying the non-steady-state situation

Intracellular calcium handling by fibroblasts from non-insulin dependent diabetic patients with and without hypertension and microalbuminuria

Intracellular calcium handling by fibroblasts from non-insulin dependent diabetic patients with and without hypertension and microalbuminuria. Intracellular calcium ([(Ca2+)i]) plays a role in many cellular functions, and is involved in the pathogenesis of some conditions observed in non-insulin dependent diabetic patients (NIDDM), such as hypertension and insulin resistance. Hyperinsulinemia and hyperglycemia are also implicated in the pathogenesis of chronic diabetes complications. It is not clear whether disturbances in [(Ca2+)i] are accounted for only by metabolic abnormalities of diabetes or by other mechanisms. The aim of this study was to investigate [(Ca2+)i] handling by skin fibroblasts in NIDDM patients with similar features regarding diabetes duration and metabolic control, but who differ concerning blood pressure levels and albumin excretion rate. Using a fluorimetric technique with the indicator Fura-2/AM, we investigated the effect of chronic exposure to insulin and glucose on [(Ca2+)i] after FGF stimulation in fibroblasts from NIDDM with hypertension alone (NIDDM H+M−) and with hypertension and microalbuminuria (NIDDM H+M+) in comparison with normotensive normoalbuminuric NIDDM (NIDDM H-M−) and control subjects (C). We studied also a group of hypertensive non-diabetic subjects (HYPER). We found that (1) FGF increases [(Ca2+)i] in all subjects; (2) insulin or high glucose per se increase [(Ca2+)i] in NIDDM H+M+ and NIDDM H+M− with respect to NIDDM H-M− and C; (3) HYPER show a [(Ca2+)i] response similar to that of NIDDM H+M− and NIDDM H+M+; (4) when stimuli are combined, all NIDDM have altered [(Ca2+)i] with respect to C, but NIDDM H+M−, NIDDM H+M+ and HYPER have higher values than NIDDM H-M−. This disorder in [(Ca2+)i] appears to be an intrinsic feature of a subgroup of hypertensive NIDDM patients, which persists in cultured cells, at least partially independent of the metabolic challenge of diabetes in vivo, and could contribute to the development of their renal and cardiovascular complications

Altered transcapillary escape of Albumin and microalbuminuria reflects two different pathogenetic mechanisms

We studied the following in normo- and microalbuminuric hypertensive type 2 diabetic patients: 1) transcapillary escape rate of albumin (TERalb) and 2) expression of mRNA slit diaphragm and podocyte proteins in renal biopsies. Normoalbuminuric subjects had renal cancer, and kidney biopsy was performed during surgery. TERalb was evaluated by clearance of 125I-albumin. Real-time PCR of mRNA slit diaphragm was measured in kidney specimens. Albumin excretion rate (AER) was by definition lower in normoalbuminuric subjects than in microalbuminuric subjects with typical diabetic glomerulopathy (group 1), in microalbuminuric subjects with normal or near-normal glomerular structure (group 2), and in microalbuminuric subjects with atypical diabetic nephropathy (group 3). This classification was based on light microscopy analysis of renal tissue. TERalb (%/h) was similar in normoalbuminuric and microalbuminuric group 1, 2, and 3 diabetic patients (medians: 14.1 vs. 14.4 vs. 15.7 vs. 14.9, respectively) (ANOVA, NS). mRNA expression of slit diaphragm proteins CD2AP, FAT, Actn 4, NPHS1, and NPHS2 was higher in normoalbuminuric patients than in microalbuminuric patients (groups 1, 2, and 3) (ANOVA, P &lt; 0.001). All diabetic patients had greater carotid artery intimal thickness than normal control subjects using ultrasound technique (ANOVA, P &lt; 0.01). In conclusion, the present study suggests that microalbuminuria identifies a subgroup of hypertensive type 2 diabetic patients who have altered mRNA expression of slit diaphragm and podocyte proteins, even before glomerular structure shows abnormalities using light microscopy analysis. On the contrary, altered TERalb and increased carotid artery intimal thickness are shown by all hypertensive type 2 diabetic patients, both with normal and altered patterns of AER

Increased renal arterial resistance predicts the course of renal function in type 2 diabetes with microalbuminuria

Type 2 diabetic patients often die because of end-stage renal failure, but no definitive reliable factor predicting long-term renal outcome has been identified. We tested whether a renal arterial resistance index (R/I) ≥80, using Doppler ultrasound technique, was predictive of worsening renal function. The primary end points of the study were 1) the course of glomerular filtration rate (GFR) and 2) the albumin excretion rate in 157 microalbuminuric, hypertensive, type 2 diabetic patients after a 7.8-year follow-up period (range 7.1–9.2). Kaplan-Meier curves for the primary end point (decrease of GFR ≥−3.0 ml/min per 1.73 m2 per year) was two to three times more frequently observed in patients with R/I ≥80. Four- to fivefold fewer patients showed a regression to normoalbuminuria during the follow-up period from baseline microalbuminuria in the cohort with R/I ≥80. Overt proteinuria did develop in 24% of patients with R/I ≥80 and in 5% of patients with R/I &lt;80 (P &lt; 0.01). In conclusion, intrarenal arterial resistance appears to play a nontrivial role in deteriorating renal function in type 2 diabetic patients. R/I is a noninvasive diagnostic procedure, which strongly predicts the outcome of renal function in type 2 diabetic patients, even when GFR patterns are still normal