Nephropathy In Non-insulin-dependent Diabetes Mellitus Research Articles

Paraoxonase 1 gene polymorphisms concerning non-insulin-dependent diabetes mellitus nephropathy in hemodialysis patients

AimsData on involvement of paraoxonase 1 gene (PON1) in non-insulin-dependent diabetes mellitus (NIDDM) nephropathy are scarce. We investigated PON1 polymorphisms concerning end-stage NIDDM nephropathy and atherosclerotic complications in NIDDM nephropathy patients treated with hemodialysis (HD). MethodsIn NIDDM nephropathy (n = 402) and non-diabetic (n = 998) HD subjects, we obtained PON1 polymorphisms by HRM analysis (rs662) or predesigned TaqMan SNV Genotyping Assay (rs854560, rs705379). ResultsOnly PON1 rs705379 was associated with end-stage NIDDM nephropathy in the recessive (OR 1.451, 95% CI 1.104–1.906, P = 0.009) and additive (OR 1.398, 95%CI 1.009–1.936, P = 0.046) inheritance modes. NIDDM nephropathy patients bearing the rs854560 T allele were at higher risk for ischemic cerebral stroke (OR 2.087, 95%CI 1.145–3.801, P = 0.016). In non-diabetic patients but not NIDDM nephropathy subjects, atherogenic dyslipidemia corresponded with PON1 rs662 A allele and PON1 rs854560 TT homozygosity. ConclusionsIn HD patients, NIDDM nephropathy correlates with the TT genotype of PON1 rs705379. The rs854560 T allele indicates a higher risk for atherosclerotic diseases in NIDDM nephropathy subjects. The T alleles of both PON1 SNVs are known as low expression variants downregulated serum PON1 activity. An increase of diminished PON1 activity may be a target in the prevention of NIDDM nephropathy and NIDDM atherosclerotic complications.

Role of Renin Angiotensin System Inhibitors in Cardiovascular and Renal Protection: A Lesson from Clinical Trials

Beneficial effects of angiotensin converting enzyme inhibitors (ACEI) and angiotensin type 1 receptor (AT1) blockers in patients with cardiovascular and renal diseases have been clearly demonstrated in numerous large outcomes studies. In patients with heart failure (HF), ACEI have been shown to reduce overall mortality, mortality from cardiovascular causes, to increase life expectancy, as well as to preserve the renal function (CONSENSUS, SAVE, TRACE, AIRE, AIREX, CATS trials). In addition, in the PROGRESS study ACEI substantially decreased the risk of stroke and transient ischemic attacks in patients with cerebrovascular disorders. The HOPE and EUROPA studies confirmed that long term therapy with ACEI provides significant survival benefit in patients with broad range of atherosclerotic cardiovascular diseases. After these large and well designed clinical studies, ACEI have become standard therapy for routine secondary prevention in all patients with cardiovascular diseases, unless contraindicated. AT1 receptor blockers have been recently added to the cardiovascular therapeutic armamentarium. They are believed to provide additional protection by inhibition of locally synthesized angiotensin II on the level of AT1 receptor. The ELITE II, ValHeFT and CHARM studies have shown that AT1 receptor blockers are equally effective as ACEI in reduction of mortality and morbidity in patients with HF. Importantly, they may be used together with ACEI, or as alternative treatment in ACEI intolerant patients. Renal protection is another important effect of both ACEI and AT1 blockers that has been confirmed in several large clinical trials. The North American Microalbuminemia Study group and EUCLID group demonstrated significant reduction in progression of diabetic nephropathy in patients with insulin dependent diabetes mellitus (IDDM) treated with ACEI. AT1 receptor blockers are mainly studied in the non-insulin dependent diabetes mellitus (NIDDM) nephropathy. Four recent clinical trials (IRMA-2, DETAIL, RENAAL and IDNT) examined the effect of AT1 receptor blockers in patients with NIDDM nephropathy. These studies confirmed the beneficial effect of AT1 receptor blockers in patients with NIDDM nephropathy that was extended beyond the blood pressure reduction. Ongoing studies (ONTARGET, TRANSCEND and PROTECTION) should provide us with additional insights about cardiovascular, renal and other end-organ protective effects of these therapeutics.

Global heterogeneity of glomerular volume distribution in early diabetic nephropathy

Morphologic characteristics in early stage of nephropathy of noninsulin-dependent diabetes mellitus (NIDDM) have not been determined despite the fact thatdiagnosis in this stage of the disease is important for the prognosis. We hypothesized that heterogeneity in glomerular volume-distribution may be a sensitive index of early stage of diabetic nephropathy in NIDDM. In spontaneous diabetic rats [Otsuka Long-Evans Tokushima Fatty (OLETF) rat (N= 5)] of 27 to 28 weeks, an experimental model of early diabetic nephropathy in human NIDDDM and age-matched control rats [Long Evans Tokushima Lean (LETO) rat (N= 5)], we completely filled the kidney with contrast medium. Glomeruli were visualized as three-dimensional images using x-ray micro-computed tomography (micro-CT). Glomerular volumes (N= 400 in each kidney) were directly measured and evaluated as absolute volume and normalized values to kidney weight and body weight. Scattering of glomerular volume-distribution was evaluated as coefficient variation (CV) (SD/mean). The CV was significantly larger in OLETF rat (0.195) comparing to LETO rat (0.146, P < 0.01). This difference was even consistent under the normalization to kidney weight and body weight. Absolute glomerular volume was larger in OLETF rat compared to LETO rat (P < 0.005); however, when glomerular volume was normalized, this variable was comparable between two groups. We visualized three-dimensional glomerular images in the early stages of diabetic nephropathy using micro-CT and quantified the heterogeneity in glomerular volume distribution throughout the cortex by direct measurement of the individual. We propose that heterogeneity in glomerular volume distribution is a sensitive parameter to ascertain early diabetic nephropathy in NIDDM.

Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and Diabetic Albuminuria in Patients with NIDDM Followed Up for 9 Years

Nephropathy is a major cause of premature morbidity and mortality in patients with non-insulin-dependent diabetes mellitus (NIDDM). The insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme (ACE) is a genetic determinant of plasma ACE levels. Recent studies have found I/D polymorphism of the ACE gene to be associated with nephropathy in NIDDM. This association has not been evaluated in prospective studies. We, therefore, studied the relationship between ACE gene I/D polymorphism and diabetic albuminuria and glomerular filtration rate (GFR) in 83 NIDDM patients followed up for 9 years. At baseline, 29% (24 of 83) of the diabetic patients had an increased (>30 mg/24 h) urinary albumin excretion rate (UAER) and the prevalence of albuminuria at the 9-year examination was 35% (29 of 83). During the follow-up period, systolic blood pressure (p = 0.044), prevalence of hypertension (p < 0.01), and fasting blood glucose levels (p < 0.01) increased, while high-density lipoprotein cholesterol (p < 0.01) decreased. The declines of GFR during the follow-up period were 8.5, 14.1, and 16.3% within genotype groups of II, ID, and DD, respectively (p values for decreases: NS for II, <0.001 for ID, and <0.001 for DD). Patients with the DD genotype tended to have a steeper decrease of GFR, but the change was not statistically significant between the genotype groups. The increases of UAER during the follow-up period were 35.1, 8.3, and 122.4% within genotype groups of II, ID, and DD, respectively, but p values for all increases were not significant. Parallel to GFR, patients with the DD genotype tended to have a steeper increase of UAER, but the change was not statistically significant between the genotype groups. There were no differences in the ACE genotype distribution and allele frequencies between the patients with or without albuminuria either at follow-up or in cross-sectional settings. In conclusion, this 9-year follow-up study does not support the hypothesis that the ACE I/D polymorphism is a major genetic marker of diabetic nephropathy in NIDDM patients.

Gender-specific association of M235T polymorphism in angiotensinogen gene and diabetic nephropathy in NIDDM.

This study examined the association between the development of nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) patients and M235T polymorphism in the angiotensinogen gene. White NIDDM patients with diabetic nephropathy (case subjects, n = 117) and patients without any evidence of nephropathy and > or = 10 years of NIDDM (control subjects, n = 125) were selected from among patients of the Joslin Diabetes Center and examined. In addition to a standardized examination, blood was drawn for DNA and determination of M235T genotypes at the angiotensinogen locus. For the angiotensinogen gene, the frequency of the genotype 235T/235T, known to be associated with essential hypertension, was higher among case subjects with nephropathy than in control subjects without this complication. This difference, expressed as the odds ratio for nephropathy among 235T/235T homozygotes in comparison with all other genotypes, was 2.2 (95% confidence interval, 1.1 to 4.4). The difference, however, was confined to men (odds ratio, 4.8; 95% confidence interval, 1.5 to 14.9), with the distribution of genotypes in case and control subjects being equal among women (odds ratio, 1.1). DNA polymorphism M235T in the angiotensinogen gene, which is associated with higher expression of this gene, contributes to the risk of diabetic nephropathy in NIDDM men but not in women.

ApoE polymorphism and albuminuria in diabetes mellitus: a role for LDL in the development of nephropathy in NIDDM?

Chronic hyperglycaemia stands with diabetes duration as the main predicting factor for the development of nephropathy in insulin dependent diabetes mellitus (IDDM). In contrast, nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) presents with a different natural history and, as well as atherosclerosis, can precede diabetes diagnosis and even the onset of patent hyperglycaemia. The role of lipid abnormalities in this matter remains debated. We studied the prevalence of nephropathy (N+ = urinary albumin excretion rate (UAE) > 20 mg/d) in 134 Caucasian NIDDM patients ranked according to alipoprotein E (apoE) genotype (same distribution in 132 controls). Age, diabetes duration and sex ratio did not differ between N+ and N-. A patient with E2E4 (n = 1) was excluded from the analysis. The prevalence of nephropathy was significantly reduced in E2 allele carriers (36%, 8/22) vs 69% (77/111) in E2 non-carriers (P < 0.01). Relative risk (RR) of E2 carriers developing nephropathy was 0.52 (95% CI = 0.35-0.80). Both groups were comparable in terms of age (55 +/- 11 vs 57 +/- 11 years), diabetes duration (15 +/- 9 vs 14 +/- 10 years) and prevalence of retinopathy (59 vs 48%). Similar results were observed when patients with diabetes duration longer than 8 years were studied (n = 94). It has been largely established that low-density lipoprotein (LDL)-cholesterol level in E2 allele carriers (whether diabetic or not) was lower than in E2 non-carriers. The 2-fold increase of nephropathy in E2 non-carriers with NIDDM argues for a role for LDL in the development of human nephropathy in NIDDM patients. This result is in agreement with previous data established both in vitro and in vivo in animal models. These findings support evidence for the pathogenic and morphologic similarities between kidney disease and atherosclerosis in NIDDM patients.

THE SIGNIFICANCE OF URINARY N‐ACETYL‐ß‐D‐GLUCOSAMINIDASE FOR PREDICTING EARLY STAGE DIABETIC NEPHROPATHY

SUMMARYWe studied urinary N‐acetyl‐ß‐D‐glucosaminidase (NAG) in the early stage of diabetic nephropathy in 27 non‐insulin‐dependent diabetes mellitus (NIDDM) patients with a microalbumin level below 20 mg on 24‐hour urine sample. Microalbumin and NAG excretion were measured in 24‐hour urine samples collected on three separate occasions within seven days of admission. Creatinine clearance was determined simultaneously. There was a significant negative correlation between the creatinine clearance and 24‐hour urinary NAG (r=‐0.38, p&lt;0.05). Elevation of urinary NAG may indicate decreased renal function during early stage NIDDM nephropathy.

Relationships among glomerular filtration rate, albuminuria, and autonomic nerve function in insulin-dependent and non-insulin-dependent diabetes mellitus

The associations among autonomic neuropathy, urinary albumin excretion, and glomerular filtration rate (GFR) measured with 51Cr-EDTA and iohexol clearance were studied in 41 patients with insulin-dependent diabetes mellitus (IDDM) and 15 patients with non-insulin-dependent diabetes mellitus (NIDDM). The study showed that increased urinary albumin excretion was more common in NIDDM than in IDDM. In contrast with IDDM, albuminuria in NIDDM was not related to GFR. Autonomic neuropathy was common in IDDM as well as in NIDDM, and also in patients without nephropathy, but was not connected with hyperfiltration. Low brake index, an ortostatic autonomic index, was associated with nephropathy in NIDDM. Iohexol, a non-ionic contrast medium, was found to be a useful alternative to 51Cr-EDTA for determination of GFR. Moreover, comparison between conventional four-sample plasma clearance and single-sample clearance showed a close correlation. Accordingly, assessment of GFR using a single plasma sample provides reliable results even at high GFR values.

Retardation of renal function impairment in patients with advanced nephropathy due to non-insulin dependent diabetes mellitus (NIDDM)—A RCT of enalapril (E) & metoprolol (M)

Objective: To estimate the comparative rate of changes in creatinine clearance (CC) ml/min/year and macro proteinuria in patients with NIDDM nephropathy treated with (E) and (M) for 2 years. Design: A randomized controlled trial. Setting: Patients attending Outpatient Diabetic Clinics of G.M. a M 190 f 128 & 189 ? 134) (p < 0.01) Conclusion: Patients on E had a 38% (95% CL 33,43) lesser fall in CC/year at 2 years than those on M. Implication: If these relative differences persist in subsequent years, end stage renal disease would occur 4 years later in patients with advanced NIDDM nephropathy on E than those on M.

Age as a determinant of glomerular filtration rate in non-insulin-dependent diabetes mellitus

The level of glomerular filtration rate (GFR) and its determinants in non-insulin-dependent diabetes mellitus (NIDDM) are currently controversial. We measured GFR and effective renal plasma flow (ERPF) in 121 consecutive NIDDM without evidence of overt diabetic nephropathy. Age varied from 28 to 70 years, 61.2% were women and known duration of NIDDM was 0-37 years. Hypertension was detected in 36.4% of patients and 47.8% had microalbuminuria. An inverse correlation was found between GFR and age, but not with known duration of NIDDM: It was a weak correlation (r = -0.41) but statistically significant (P < 0.001). The other variables considered were not significant by multiple stepwise regression analysis, but patients with lower GFR tended to have diabetic retinopathy more frequently. GFR was lower in hypertensive compared to normotensive patients (123 +/- 28.4 versus 136 +/- 32.5 ml/min/1.73 m2; P < 0.05), but was not different between patients with normal and elevated albumin excretion rate. ERPF also had an inverse correlation with age (r = -0.45, P < 0.001). We conclude that (i) age should be considered as a confounding variable when evaluating GFR in patients with NIDDM, and (ii) the age-dependent decline in GFR may mask hyperfiltration in the early stages of diabetic nephropathy in NIDDM:

Erythrocyte sodium-lithium countertransport activity as a marker of predisposition to hypertension and diabetic nephropathy in NIDDM.

To evaluate the potentiality of erythrocyte sodium-lithium countertransport activity (SLC) as a marker of predisposition to hypertension and diabetic nephropathy in non-insulin-dependent diabetes mellitus (NIDDM). We examined 96 patients with NIDDM and 26 healthy control subjects. SLC and other data were compared among subgroups of the patients classified on the basis of hypertension, family history of hypertension, and stages of nephropathy. Data were also analyzed by stepwise multiple regression analyses. SLC was significantly higher in patients with hypertension than in those with normotension and significantly higher in patients with a positive family history of hypertension than in the negative group. Further analysis revealed that a family history of hypertension has independent influence on SLC, but hypertension itself does not. SLC was significantly higher in patients with macroalbuminuria than with microalbuminuria and higher in patients with microalbuminuria than with normalbuminuria. In stepwise multiple regression analyses, a family history of hypertension was the most important determinant of SLC, and SLC was the most important determinant of nephropathy. These data suggest that SLC strongly reflects a predisposition to hypertension and that it can be a useful marker of diabetic nephropathy in NIDDM.

The relationship between early diabetic nephropathy and control of plasma glucose in non-insulin-dependent diabetes mellitus: The effect of glycemic control on the development and progression of diabetic nephropathy in an 8-year follow-up study

To clarify the relationship between early diabetic nephropathy and the glycemic control in non-insulin-dependent diabetes mellitus (NIDDM) without hypertension, excretion of urinary albumin was studied retrospectively for 8 years. The patients with early diabetic nephropathy were divided into two groups according to the initial urinary albumin index (UAI: mg/g · creatinine), namely, a normoalbuminuric (less than 15 mg/g · creatinine) and a microalbuminuric group (15 ≤ UAI < 200 mg/g · creatinine). Comparisons of changes in UAI were made between good (HbA 1 < 9.0% and fasting plasma glucose (FPG) < 140 mg/100 mL throughout the observation period) and poor glycemic control groups after 4 and 8 years. In the patients with normoalbuminuria at the initial determination, five of 11 patients (45.5%) with good glycemic control and 14 of 22 patients (63.6%) with poor glycemic control became microalbuminuric after 8 years, respectively ( p < 0.05). In the microalbuminuric patients, five of ten patients (50%) with poor glycemic control became macroalbu minuric (UAI ≥ 200 mg/g · creatinine), although only one case worsened of five patients with good glycemic control ( p < 0.05). In conclusion, the development or progression of early diabetic nephropathy in NIDDM was significantly inhibited by good glycemic control (FPG < 140 mg/100 mL and HbA 1 < 9.0%), independent of hypertension, and probably irrespective of the mode of therapeutic intervention.

Nephropathy in noninsulin-dependent diabetes mellitus: Comparative study with normoproteinuric and microproteinuric subjects

The role of specific risk factors in the development of diabetic nephropathy was examined among noninsulin-dependent diabetic subjects attending the Diabetes clinic of Christian Medical College Hospital, Vellore during 1986–1987. Seventy-three subjects with normal protein excretion ( <150 mg 24 hr ) were compared with 66 microproteinuric ( 150–500 mg 24 hr ) and 61 macroproteinuric subjects ( 500 mg 24 hr ). The risk factors included family history of diabetes, tobacco use, dietary habits and metabolic control; the latter was assessed from an average of 5 clinic blood sugar determinations done annually per patient. Patients who had developed proteinuria were characterized as mostly men, with increased tobacco consumption and early onset of proteinuria in relation to duration of diabetes. The mean blood sugar value was significantly high in both the proteinuric groups compared to the group with no proteinuria ( p < 0.01). There was a striking increase in the prevalence of ischemic heart disease, hypertension and retinopathy in the macroproteinuric group compared to the other two groups ( p < 0.01). It is concluded that the risk of developing nephropathy was significantly higher in men, in smokers and in those with poor metabolic control (mean postprandial blood sugar more than 200 mg/dL). Furthermore, it was clearly evident from our study that the diabetic subjects with nephropathy had a higher incidence of hypertension, retinopathy, hyperlipidemia and ischemic heart diseases.

Eye Disease and Nephropathy in NIDDM

Diabetic eye disease and diabetic nephropathy are major causes of morbidity among the elderly. Herein, I focus on the epidemiology, prevention, and treatment of diabetic eye and kidney disease in people with noninsulin-dependent diabetes mellitus (NIDDM) and identify some of the major gaps in our knowledge about these conditions.

Diabetic Hypouricemia as an Indicator of Clinical Nephropathy

We studied the possible association of the low serum uric acid level with incipient diabetic nephropathy in non-insulin-dependent diabetes mellitus (NIDDM). Of 201 NIDDM patients without a diminished glomerular filtration rate, 66 patients (32.8%) showed moderate hypouricemia of less than the mean-1 SD of 201 nondiabetic controls. Thirteen (6.5%) showed marked hypouricemia of less than the mean-2 SD. Hypouricemic patients showed normal daily urinary urate excretion with a markedly elevated urate clearance/creatinine clearance ratio. Most were under poor glycemic control, and presented either negative or intermittent clinical proteinuria. However, neither poor glycemic control, nor the presence of proteinuria or retinopathy alone significantly affected the serum uric acid level of the whole diabetic population. The glomerular filtration rate was determined in comparable groups of diabetic patients with hypouricemia and nonhypouricemic diabetic controls. The hypouricemic group showed a significantly higher endogenous creatinine clearance and lower serum beta-2-microglobulin levels than the nonhypouricemic group. These findings suggest that the hypouricemic group had a higher glomerular filtration rate. Long-term observation of up to 12 years of the above patients revealed that, in most patients, persistent hypouricemia was observed prior to the initial appearance of intermittent proteinuria. We hypothesize that glomerular hyperfiltration also occurs in NIDDM and that it lowers the serum uric acid by increasing the renal clearance of urate. Hypouricemia may also predict the future progression of incipient nephropathy in NIDDM.

Nephropathy in non-insulin-dependent diabetes mellitus

End-stage renal disease develops in about 5 percent of patients with non-insulin-dependent diabetes mellitus (NIDDM). The large majority of diabetic patients have this form of the disease. Thus, end-stage renal disease is an important clinical problem in patients with NIDDM. Moreover, hypertension and its macrovascular sequelae are significant problems in patients with NIDDM and may be linked with renal disease. A review of the problem of nephropathy in NIDDM is attempted, pointing out, where data are available, the clinical and pathophysiologic differences from its presentation in insulin-dependent diabetes. The need for further studies of the impact of renal disease in this maturity onset form of diabetes is emphasized.