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Plasma lipoproteins and the incidence of abnormal excretion of albumin in diabetic American Indians: The Strong Heart Study
Abstract
Animal studies suggest that lipids are risk factors for kidney diseases. Some prospective studies and clinical trials have reported predictive effects of lipoproteins on different stages of diabetic nephropathy in humans. We examined lipoprotein abnormalities to determine if they predict abnormal urinary excretion of albumin (> or = 30 mg albumin/g creatinine), using logistic regression. We followed 671 American Indians (211 men, 460 women) with Type II diabetes for a mean of 3.9 years (range 1.7-6.2). Participants were aged 45-74 years. They had normal excretion of albumin and normal serum creatinine at baseline. 67 men and 144 women developed abnormal excretion of albumin. In models controlled for age, treatment with oral hypoglycaemic agents or insulin, HbA1c, study site, degree of Indian heritage, mean arterial blood pressure, albumin excretion at baseline and duration of diabetes, a high HDL cholesterol was a protector for abnormal excretion of albumin in women [odds ratio (OR) comparing the 90th with the 10th percentile = 0.56, 95% confidence interval (CI) = 0.32-0.98], but not in men (OR = 1.5, 95% CI = 0.66-3.4). Further adjustment for obesity, insulin concentration, alcohol consumption or physical activity did not change the results. There was a tendency for high values of VLDL and total triglyceride and small LDL size to predict abnormal excretion of albumin in women only. We conclude that low HDL cholesterol was a risk factor for abnormal excretion of albumin in women, but not in men. Sex hormones may be responsible for sex differences in the association between HDL cholesterol and abnormal excretion of albumin.
... Elevated TG levels have been associated with DN in many reports (Bonnet and Cooper 2000;Colhoun et al. 2001;Coonrod et al. 1993;Fagot-Campagna et al. 1998;Giorgino et al. 2004;Hadjadj et al. 2004;Iseki et al. 2005;Jenkins et al. 2003;Kim et al. 2004;Muntner et al. 2000;Orchard et al. 2001;Ravid et al. 1998;Wang et al. 2003). Furthermore, studies showed an association between apo A5-1131 CC genotype and elevated TG levels vs. TT genotypes. ...
... This comes in accordance with the work done in this study. Indeed, studies carried out by a number of researchers, namely, Fagot-Campagna et al. (1998), Hadjadj et al. (2004, Kim et al. (2004), Giorgino et al. (2004), and Iseki et al. (2005), have shown that elevated TG level is a predictive factor for the development of DN. This was evidenced by the results of this study with a higher mean TG values in DN+ group compared to the DN− and control groups. ...
Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Epidemiological studies suggest genetic predisposition to DN. Apolipoprotein A5 (ApoA5) plays an important role in the triglyceride (TG) metabolism, accelerating the catabolism of the TG-rich lipoproteins. Studies revealed that the ApoA5-1131 polymorphism is strongly associated with TG levels affecting DN risk. Patients with DN have increased fasting plasma TG levels, and studies report that elevated TG precedes DN. To test the effect of polymorphism ApoA5-1131T→C on the elevated TG levels contributing to the development of DN on type 2 diabetes patients, the study was conducted on 40 diabetic patients divided into two groups according to the presence or absence of diabetic nephropathy (DN+ and DN−), compared to 20 age- and sex-matched apparently healthy controls. DNA analysis was performed using polymerase chain reaction–restriction fragment length polymorphism. ApoA5-1131 CC carriers had a higher mean TG in the DN+, DN−, and control groups (TG 224, 201, and 204 mg/dl, respectively) (p = 0.001) compared to TT and TC carriers. Genotype distribution between controls and patients revealed CC carriers in the DN− and DN+ to be 55 and 45 %, respectively, compared to only 15 % in the control group (p = 0.001). Association between DN and the polymorphism (CC) that affects fasting TG is seen in this study (OR = 4.6, 95 % CI = 1.02–21, p = 0.001). ApoA5-1131 CC carriers are more susceptible to a higher fasting TG level and the development of DN.
... Identifying genetic risk factors for DN may permit screening and preventive treatment for vulnerable DM patients and help elucidate the pathogenesis to aid the design of better treatment. A high fasting triglyceride (TG) level has been implicated as a risk factor for the development of DN in many but not all studies (Bonnet & Cooper, 2000; Colhoun et al., 2001; Coonrod et al., 1993; Fagot-Campagna et al., 1998; Giorgino et al., 2004; Hadjadj et al., 2004; Iseki et al., 2005; Jenkins et al., 2003; Kim et al., 2004; Muntner et al., 2000; Orchard, Forrest, Kuller, & Becker, 2001; Ravid, Brosh, Ravid-Safran, Levy, & Rachmani, 1998; Wang et al., 2003). One way to test the hypothesis that high TG levels help induce DN is to identify a common genetic variant that raises TG level and to examine whether that variant is overrepresented in DN patients. ...
... One possible explanation for these results could be that high TG levels observed in DN patients are merely an effect, rather than a cause, of DN. However, in addition to casecontrol studies, many prospective studies (Colhoun et al., 2001; Coonrod et al., 1993; Fagot-Campagna et al., 1998; Hadjadj et al., 2004; Kim et al., 2004; Muntner et al., 2000; Orchard et al., 2001; Ravid et al., 1998), though not others (Bonnet & Cooper, 2000; Giorgino et al., 2004; Iseki et al., 2005), have identified TG level as a predictive factor for the development of DN. Another possibility is that a high TG level may not in itself cause DN but might be closely linked with another factor that causes DN, and the apoA5 À1131TYC polymorphism might affect TG level but not the DN-causing factor. ...
Patients with diabetic nephropathy (DN) have increased plasma fasting triglyceride (TG) levels, and most prospective studies report that elevated TG precedes DN. TG-rich lipoprotein particles might promote progression of DN. To test the hypothesis that elevated TG levels contribute to the development of DN, one may examine whether a polymorphism strongly associated with TG levels affects DN risk. The apolipoprotein A5 (apoA5) -1131T-->C polymorphism has a large effect on the TG level, and all three genotypes are relatively common in East Asians. Therefore, we sought to examine the association of this polymorphism with DN. We genotyped the apoA5 -1131T-->C polymorphism in a case-control study involving 367 Chinese Type 2 diabetes patients with DN and 382 without DN, as well as 198 subjects without diabetes. Mean fasting TG levels were higher in CC than in TT carriers by 41%, 54%, and 62% in each of the three subject groups, respectively. However, the genotype distributions did not differ between patients with and without nephropathy (P=.69). Therefore, these results weigh against the hypothesis that high fasting TG per se causes DN. The strong association between TG level and DN may be due to a factor that is usually closely linked to TG level but that is not affected by the apoA5 polymorphism.
... A better understanding of the pathogenesis of DN is needed to facilitate the development of more effective and early therapeutic strategies to prevent ominous pathologic changes in kidney, which if not dealt with at an early stage would have an irreversible outcome. In addition, there are several other risk factors which further contribute to the progression of DN with worsening outcome, and they include glomerular hypertension, hyperglycemia, proteinuria, hyperlipidemia and heredity [3][4][5][6][7][8]. Although, abundant research has been carried out over a period of three decades to delineate the pathogenesis of DN a well-defined underlying unifying mechanism has yet to be emerged. ...
Matrix metalloproteinases (MMPs) are proteolytic enzymes belonging to the family of zinc-dependent endopeptidases that are capable of degrading almost all the proteinaceous components of the extracellular matrix (ECM). It is known that MMPs play a role in a number of renal diseases, such as, various forms of glomerulonephritis and tubular diseases, including some of the inherited kidney diseases. In this regard, ECM accumulation is considered to be a hallmark morphologic finding of diabetic nephropathy, which not only is related to the excessive synthesis of matrix proteins, but also to their decreased degradation by the MMPs. In recent years, increasing evidence suggest that there is a good correlation between the activity or expression of MMPs and progression of renal disease in patients with diabetic nephropathy in humans and in various experimental animal models. In such a diabetic milieu, the expression of MMPs is modulated by high glucose, advanced glycation end products (AGEs), TGF-β, reactive oxygen species (ROS), transcription factors and some of the microRNAs. In this review, we focused on the structure and functions of MMPs, and their role in the pathogenesis of diabetic nephropathy.
... These results, therefore, provide evidence that HDL, apoB, and fibrinogen are per se predictors of progression to overt nephropathy, independently of the presence of microalbuminuria or hypertension. These findings are consistent with previous studies (7,23) and could at least partially explain the excess of cardiovascular morbidity and mortality of macroalbuminuric patients (24). Whether these findings reflect lipid abnormalities characterizing the earlier phases of diabetic nephropathy, or their direct involvement in its progression, is unknown. ...
The first sign of diabetic nephropathy is microalbuminuria, but its predictive role of progression to overt nephropathy in type 2 diabetes has not yet been clarified. The aims of this study were to assess during 7 years of follow-up the incidence rate of overt nephropathy and the predictive role of microalbuminuria and other baseline variables (blood pressure, lipids, fibrinogen, uric acid, smoking, and HbA(1c) cumulative average during follow-up).
A prospective population-based study was performed in Casale Monferrato, Italy, including 1,253 type 2 diabetic patients recruited at baseline (1991-1992), 765 with normoalbuminuria (albumin excretion rate [AER] <20 microg/min) and 488 with microalbuminuria (AER 20-200 microg/min). All measurements were centralized. A nested case-control study within the cohort was performed, selecting four control subjects, frequency matched for age and attained individual time of follow-up with each case. Conditional regression analysis was performed to assess variables independently associated with risk of progression to overt nephropathy.
Of 1,253 total patients, 1,103 (88.0%) were included in the follow-up examination (median 5.33 years); their age and duration of disease at baseline were 68.4 +/- 10.5 years and 10.4 +/- 6.6 years, respectively. Cases of overt nephropathy were 202, giving an incidence rate of 37.0/1,000 person-years (95% CI 32.3-42.6). In conditional logistic regression analyses, microalbuminuria provided a 42% increased risk with respect to normoalbuminuria (95% CI 0.98-2.06), independently of duration of diabetes, hypertension, and systolic blood pressure. Other variables independently associated with progression to overt nephropathy were HbA(1c) cumulative average (P = 0.002), apolipoprotein B (P = 0.013), fibrinogen (P = 0.02), and HDL cholesterol (P = 0.03).
Of type 2 diabetic patients, 3.7% progress every year to overt nephropathy. Microalbuminuria is associated with a 42% increased risk of progression to overt nephropathy. Other independent predictors are HbA(1c), HDL cholesterol, apolipoprotein B, and fibrinogen.
... 34,35 In American Indians, using analysis models controlled for age, treatment with oral hypoglycemic agents, HbA 1C concentration, blood pressure, obesity, and duration of diabetes, low concentrations of high-density lipoproteins were reported to be a risk factor for the development of albuminuria in women but not in men with type 2 DM. 36 These observations suggest that, similar to type 1 DM, different mechanisms may be responsible for the development of diabetic nephropathy in women and men. Furthermore, the mechanisms underlying the disease process are also likely to be specific for different ethnic groups and races. ...
Across all ages, the incidence and rate of progression of most nondiabetic renal diseases are markedly higher in men compared with age-matched women. These observations suggest that female sex may be renoprotective. In the setting of diabetes, however, this female protection against the development and progression of renal disease is diminished.
This review aimed to summarize our current understanding of sex differences in the development and progression of diabetic renal disease, and of the contribution of sex hormones, particularly estrogens, to the pathophysiology of this disease. We also attempted to answer why female sex does not protect the diabetic kidney.
Using terms such as gender, sex, diabetes, diabetic nephropathy, estrogens, and sex hormones, the PubMed database was searched for English-language articles; targeted searches were conducted using terms such as gender/sex differences in diabetic renal disease. No restrictions were imposed on publication dates.
Although the existing data regarding the sex differences in the incidence and progression of diabetic renal disease are inconclusive, the undisputed fact is that women with either type 1 or type 2 diabetes mellitus exhibit a much higher incidence of renal disease compared with nondiabetic women. It is conceivable that the loss of female sex as a renoprotective factor in diabetes may be related to the abnormal regulation of sex hormone concentrations. Both clinical and experimental data suggest that diabetes may be associated with an imbalance in estradiol concentrations. Supplementation with 17beta-estradiol or administration of selective estrogen receptor modulators reduces the incidence of diabetes and attenuates the progression of diabetic renal disease.
Serum concentrations of ovarian hormones may provide a new means for predicting future risk of renal complications in diabetes. Exogenous steroid hormones may be an effective treatment for attenuating the progression of diabetic nephropathy.
Background and purpose:
Image-defined sarcopenia is linked to increased mortality among patients with cancer. Nevertheless, its effect on patients with nasopharyngeal carcinoma (NPC) is incompletely established. This study's aim was to investigate the prognostic significance of MRI-defined sarcopenia on the survival of patients undergoing concurrent chemoradiotherapy (CCRT) ± inducing chemotherapy (IC) for NPC treatment.
Methods:
1,307 patients with stage II-IVa NPC were included in this retrospective study. Sarcopenia was defined using skeletal muscle index (SMI) determined through baseline MRI at the C3 level. The association of sarcopenia with overall survival (OS) and progression-free survival (PFS) was assessed by Cox regression models using 1:1 propensity score matching (PSM) analysis. We also conducted a stratification analysis using BMI and treatment strategies.
Results:
Sarcopenia was an independent risk factor for both OS and PFS (all P < 0.05). However, BMI was not substantially linked to OS and PFS (all P > 0.05). Sarcopenic patients showed lower rates of OS (HR = 2.00, 95% CI: 1.54-2.60, P < 0.001) and PFS (HR = 1.67, 95% CI: 1.35-2.07, P < 0.001) in contrast with nonsarcopenic patients. According to stratification analysis, being overweight was linked to a protective effect in nonsarcopenic patients only. Sarcopenic patients showed similar OS and PFS regardless of the treatment modality.
Conclusions:
Sarcopenia is underrecognized in NPC patients. Measurement of sarcopenia using routine MRI scans in NPC patients provided significant prognostic information, outperforming BMI. Patients with sarcopenia failed to benefit from an additional IC regimen.
Objectives: The association between platelet status and hepatocellular carcinoma (HCC) prognoses remains controversial. Herein, we aimed to clarify the prognostic value of multiple platelet-related biomarkers, including platelet count, platelet/lymphocyte ratio (PLR), aspartate aminotransferase to platelet ratio index (APRI), and alkaline phosphatase-to-platelet count ratio index (APPRI) in HCC with microvascular invasion (MVI) after curative resection or liver transplantation.
Materials and methods: A retrospective review of 169 patients with solitary HCC and MVI who underwent resection or liver transplantation between January 2015 and December 2018 was conducted. Preoperative clinical, laboratory, pathologic, and imaging data were collected and analyzed. Overall survival (OS) and disease-free survival (DFS) were defined as the clinical endpoints. Univariate and multivariate Cox proportional hazards regression analyses were conducted to investigate potential predictors of DFS and OS.
Results: Multivariate Cox regression analyses revealed that maximum tumor diameter, poor cell differentiation, and APPRI were independent predictors of DFS; while poor cell differentiation, APRI, APPRI, prothrombin time, and alpha-fetoprotein were independent prognostic factors for OS. The 1-, 3-, and 5-year DFS rates were 66.90%, 48.40%, and 37.40% for patients with APPRI ≤0.74 and 40.40%, 24.20%,and 24.20% for patients with APPRI>0.74. The corresponding rates of OS over 1, 3, and 5 years were 92.40%, 88.10% and 77.70%, and 72.30%, 38.20%, and 19.10%, respectively. The DFS and OS rates of patients whose APPRI was more than 0.74 were substantially lower than those of patients whose APPRI was less than or equal to 0.74 (p = 0.002 and p < 0.001, respectively).
Conclusion: Elevated preoperative APPRI is a noninvasive, simple, and easily assessable parameter linked to poor prognosis in individuals with single HCC and MVI after resection or liver transplantation.
Background:
No investigations have thoroughly explored the feasibility of combining magnetic resonance (MR) images and deep-learning methods for predicting the progression of knee osteoarthritis (KOA). We thus aimed to develop a potential deep-learning model for predicting OA progression based on MR images for the clinical setting.
Methods:
A longitudinal case-control study was performed using data from the Foundation for the National Institutes of Health (FNIH), composed of progressive cases [182 osteoarthritis (OA) knees with both radiographic and pain progression for 24-48 months] and matched controls (182 OA knees not meeting the case definition). DeepKOA was developed through 3-dimensional (3D) DenseNet169 to predict KOA progression over 24-48 months based on sagittal intermediate-weighted turbo-spin echo sequences with fat-suppression (SAG-IW-TSE-FS), sagittal 3D dual-echo steady-state water excitation (SAG-3D-DESS-WE) and its axial and coronal multiplanar reformation, and their combined MR images with patient-level labels at baseline, 12, and 24 months to eventually determine the probability of progression. The classification performance of the DeepKOA was evaluated using 5-fold cross-validation. An X-ray-based model and traditional models that used clinical variables via multilayer perceptron were built. Combined models were also constructed, which integrated clinical variables with DeepKOA. The area under the curve (AUC) was used as the evaluation metric.
Results:
The performance of SAG-IW-TSE-FS in predicting OA progression was similar or higher to that of other single and combined sequences. The DeepKOA based on SAG-IW-TSE-FS achieved an AUC of 0.664 (95% CI: 0.585-0.743) at baseline, 0.739 (95% CI: 0.703-0.775) at 12 months, and 0.775 (95% CI: 0.686-0.865) at 24 months. The X-ray-based model achieved an AUC ranging from 0.573 to 0.613 at 3 time points. However, adding clinical variables to DeepKOA did not improve performance (P>0.05). Initial visualizations from gradient-weighted class activation mapping (Grad-CAM) indicated that the frequency with which the patellofemoral joint was highlighted increased as time progressed, which contrasted the trend observed in the tibiofemoral joint. The meniscus, the infrapatellar fat pad, and muscles posterior to the knee were highlighted to varying degrees.
Conclusions:
This study initially demonstrated the feasibility of DeepKOA in the prediction of KOA progression and identified the potential responsible structures which may enlighten the future development of more clinically practical methods.
Background
Diabetes is a complex metabolic disorder with multi factors playing complex interactive functions. A severe effect of this disorder is observed in the quality of life in the individuals. Diabetes not only alters the physiology processes but it also invites other disorder associated with it. It has been observed that various complexities arise once an individual develop diabetes, resulting different psychological conditions takes place.
Methods
Databases like Pubmed, Scopus were searched using a combination of keywords. Full text articles meeting inclusion criteria were selected.
Results
The search yield into several studies which have summarised the effect of quality of life on diabetes, its impact on the individuals and how the disease can be managed for improving it.
Conclusion
It is pertinent to evaluate the quality of life and other pathophysiological characters while determining the risk for diabetes. We hypothesise that by employing multi factorial moulding can be used in identifying and evaluating diabetes risk, as well as improving life quality through improved trait management.
Background:
Identifying patients at high risk of diabetic kidney disease (DKD) helps improve clinical outcome.
Purpose:
To establish a model for predicting DKD.
Data sources:
The derivation cohort was from a meta-analysis. The validation cohort was from a Chinese cohort.
Study selection:
Cohort studies that reported risk factors of DKD with their corresponding risk ratios (RRs) in patients with type 2 diabetes were selected. All patients had estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) <30 mg/g at baseline.
Data extraction:
Risk factors and their corresponding RRs were extracted. Only risk factors with statistical significance were included in our DKD risk prediction model.
Data synthesis:
Twenty cohorts including 41,271 patients with type 2 diabetes were included in our meta-analysis. Age, BMI, smoking, diabetic retinopathy, hemoglobin A1c, systolic blood pressure, HDL cholesterol, triglycerides, UACR, and eGFR were statistically significant. All these risk factors were included in the model except eGFR because of the significant heterogeneity among studies. All risk factors were scored according to their weightings, and the highest score was 37.0. The model was validated in an external cohort with a median follow-up of 2.9 years. A cutoff value of 16 was selected with a sensitivity of 0.847 and a specificity of 0.677.
Limitations:
There was huge heterogeneity among studies involving eGFR. More evidence is needed to power it as a risk factor of DKD.
Conclusions:
The DKD risk prediction model consisting of nine risk factors established in this study is a simple tool for detecting patients at high risk of DKD.
Diabetic nephropathy has a significant impact on the quality of life and longevity for patients with type 1 or type 2 diabetes. Declining kidney function leads to secondary metabolic effects and adverse changes in lipoprotein metabolism, but, crucially, in patients with diabetes, the lipid abnormalities often emerge before the glomerular reserve is lost. The lipid profile is strongly correlated with albuminuria and predicts adverse outcomes, especially in the presence of other risk factors, such as poor glycemic control, obesity, and hypertension. In this chapter, we discuss the diagnostic and prognostic significance of lipoproteins and their subclasses in diabetic kidney disease and evaluate the evidence from clinical trials of lipid-lowering treatment and renal outcomes.
Older reports of greater diabetes-associated increment in cardiovascular disease in women compared with men are confirmed in the recent reports of the Strong Heart Study of Native Americans. In that study, a greater apoprotein B level was seen n diabetic women, in keeping with a greater triglycende very low density lipoprotein C (VLDL-C), and lower high density lipoprotein C (HDL-C) level compared to men in previous studies. Greater total and low density lipoprotein (LDL) cholesterol levels may be seen as well. Lipoprotein abnormalities in diabetic women also predict the development of significant albuminuria in diabetic women compared with men and the development of diabetes itself which is a problem. Therapeutic interventions involving walking, triple drug therapy, and postmenopausal estrogen all offer promise. Major cardiovascular prevention trials have shown benefits in diabetic subjects but also have not differentiated response by gender. Such studies are greatly needed because of the greater degree of dyslipidemia and cardiovascular risk in diabetic women.
There is now good evidence supporting the efficacy and safety of currently available drugs for lowering low-density lipoprotein cholesterol (LDL-C) in the prevention of cardiovascular disease (CVD) in patients with diabetes, particularly with statin therapy. Almost all patients with type 2 diabetes who can tolerate the medication warrant such therapy. The extent to which lowering triglycerides and raising HDL-C with currently available drugs reduces CVD risk remains less clear. Trials of fibrates in patients with diabetes and established CVD have given conflicting results. In patients without CVD, lowering LDL-C with a statin seems more efficacious than focusing on triglycerides and HDL-C with a fibrate. The effect of sole therapy with niacin on CVD risk in diabetes is untested. Trials are under way to provide an evidence base for some important outstanding questions, in particular the role of combination therapy (statin plus fibrate, statin plus niacin, statin plus ezetimibe) in patients at goal for LDL-C and the efficacy of lipid lowering in advanced renal disease
A century ago, the incidence of both Type 1 (T1D) and Type 2 (T2D) was very low. Worldwide epidemics of both T1D and T2D have
placed tremendous burdens on both affected individuals and society. Disproportionate resources are spent on complications
of the diseases. Although multiple etiologies have been promulgated, for T1D, causative factors and the precise mechanisms
leading to the disease remain elusive. In contrast, the rising incidence of T2D in children is closely associated with the
obesity explosion which is strongly linked to an increased food supply and decreased physical activity. The rising incidence
of obesity has reached pandemic proportions with more than a billion people affected worldwide. Focus needs to be directed
to understanding the complex interaction between genes, the environment, and the immune system culminating in T1D and tackling
the obesity epidemic. This chapter will discuss the emergence of the diabetes explosion, the proposed pathogenic mechanisms,
and potential interventions.
Type 2 diabetes is highly prevalent and is the major cause of progressive chronic kidney disease in American Indians. Genome-wide association studies identified several loci associated with diabetes but their impact on susceptibility to diabetic complications is unknown. We studied the association of 18 type 2 diabetes genome-wide association single-nucleotide polymorphisms (SNPs) with estimated glomerular filtration rate (eGFR; MDRD equation) and urine albumin-to-creatinine ratio in 6958 Strong Heart Study family and cohort participants. Center-specific residuals of eGFR and log urine albumin-to-creatinine ratio, obtained from linear regression models adjusted for age, sex, and body mass index, were regressed onto SNP dosage using variance component models in family data and linear regression in unrelated individuals. Estimates were then combined across centers. Four diabetic loci were associated with eGFR and one locus with urine albumin-to-creatinine ratio. A SNP in the WFS1 gene (rs10010131) was associated with higher eGFR in younger individuals and with increased albuminuria. SNPs in the FTO, KCNJ11, and TCF7L2 genes were associated with lower eGFR, but not albuminuria, and were not significant in prospective analyses. Our findings suggest a shared genetic risk for type 2 diabetes and its kidney complications, and a potential role for WFS1 in early-onset diabetic nephropathy in American Indian populations.
Diabetic nephropathy is a well-known complication of diabetes and is a leading cause of chronic renal failure in the Western world. It is characterized by the accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments and by the thickening and hyalinization of intrarenal vasculature. The various cellular events and signaling pathways activated during diabetic nephropathy may be similar in different cell types. Such cellular events include excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products, activation of protein kinase C, increased expression of transforming growth factor β and GTP-binding proteins, and generation of reactive oxygen species. In addition to these metabolic and biochemical derangements, changes in the intraglomerular hemodynamics, modulated in part by local activation of the renin-angiotensin system, compound the hyperglycemia-induced injury. Events involving various intersecting pathways occur in most cell types of the kidney.
American Indians have a disproportionately high rate of kidney disease likely due to a combination of environmental and genetic factors. We performed a genome wide scan of estimated glomerular filtration rate in 3665 participants of the Strong Heart Family Study to localize genes influencing kidney disease risk factors. The participants were men and women from 13 American Indian tribes recruited from 3 centers located in Arizona, the Dakotas and Oklahoma. Multipoint variance component linkage analysis was performed for each center and on the entire cohort after controlling for center effects. Modeling strategies that incorporated age, gender and interaction terms (model 1) and another that also controlled for diabetes mellitus, systolic and diastolic blood pressure, body mass index, low density and high density lipoproteins, triglycerides and smoking status (model 2) were used. Significant evidence for linkage in the Arizona group was found on chromosome 12p12.2 at 39cM (nearest marker D12S310) using model 1. Additional loci with very suggestive evidence for linkage were detected at 1p36.31 for all groups using both models and at 2q33.3 and 9q34.2 for the Dakotas group each using model 1. No significant evidence for additive interaction with diabetes, hypertension or obesity was noted. This evidence for linkage of a quantitative trait locus influencing estimated glomerular filtration rate to a region of chromosome 12p in a large cohort of American Indians will be worth studying in more detail in the future.
The associations among obesity, height, cardiovascular risk factors, and the incidence of clinical diabetes mellitus were investigated in the Norwegian population-based Finnmark Study of 11,654 men and women aged 35-52 years at baseline in 1977-1978. A total of 87 cases of diabetes among men and 75 cases among women were registered during 12 years of follow-up. The incidence of diabetes was 1.1 per 1,000 person- years in women and 1.2 per 1,000 person-years in men, but sex-related differences in risk factors were noted. Body mass index was the dominant risk factor in men and predicted diabetes in a dose-response relation in both sexes. However, in women, the association between body mass index and diabetes was greatly attenuated after muttivariable adjustment. Serum lipid concentrations were similar in prediabetic men and women; thus, prediabetic women had a relatively more adverse metabolic risk profile as compared with nondiabetics of the same sex. In multivariable analysis, high density lipoprotein cholesterol was inversely related to diabetes in women (relative risk per 0.3 mmol/llter, 0.53; 95% confidence interval 0.41-0.70) but not in men (relative risk, 0.97; 95% confidence interval 0.78-1.19). Serum glucose was a highly significant predictor in both sexes, while height was inversely related to diabetes only in women (relative risk per 5 cm, 0.71; 95% confidence interval 0.58-0.87). Am J Epidemiol 1998; 147:49-58. diabetes mellitus, non-insulin-dependent; prospective studies; risk factors; sex
In summary, diabetic nephropathy is characterized by a multifactorial disease process. The present survey points to several factors that are treatable by available drugs. We must now consider prophylactic treatment of patients with poor metabolic control not only to lower blood glucose levels, but also to protect against the harmful effects of glucose. ACE inhibitors and several other available drugs have such effects.
The progression of nephropathy from diagnosis of type 2 diabetes has not been well described from a single population. This study sought to describe the development and progression through the stages of microalbuminuria, macroalbuminuria, persistently elevated plasma creatinine or renal replacement therapy (RRT), and death.
Using observed and modeled data from 5097 subjects in the UK Prospective Diabetes Study, we measured the annual probability of transition from stage to stage (incidence), prevalence, cumulative incidence, ten-year survival, median duration per stage, and risk of death from all-causes or cardiovascular disease.
From diagnosis of diabetes, progression to microalbuminuria occurred at 2.0% per year, from microalbuminuria to macroalbuminuria at 2.8% per year, and from macroalbuminuria to elevated plasma creatinine (>or=175 micromol/L) or renal replacement therapy at 2.3% per year. Ten years following diagnosis of diabetes, the prevalence of microalbuminuria was 24.9%, of macroalbuminuria was 5.3%, and of elevated plasma creatinine or RRT was 0.8%. Patients with elevated plasma creatinine or RRT had an annual death rate of 19.2% (95% confidence interval, CI, 14.0 to 24.4%). There was a trend for increasing risk of cardiovascular death with increasing nephropathy (P < 0.0001), with an annual rate of 0.7% for subjects in the stage of no nephropathy, 2.0% for those with microalbuminuria, 3.5% for those with macroalbuminuria, and 12.1% with elevated plasma creatinine or RRT. Individuals with macroalbuminuria were more likely to die in any year than to develop renal failure.
The proportion of patients with type 2 diabetes who develop microalbuminuria is substantial with one quarter affected by 10 years from diagnosis. Relatively fewer patients develop macroalbuminuria, but in those who do, the death rate exceeds the rate of progression to worse nephropathy.
Type 2 diabetes is becoming an increasingly prevalent disorder among young persons who are driven, as is the case in adults, by lifestyle factors leading to increased body weight. Genetic and familial factors, fetal environmental factors, particularly maternal gestational diabetes and intrauterine growth retardation, and lack of physical activity during childhood and adolescence lead to increasing levels of insulin resistance that appear to be crucial in the pathogenesis of type 2 diabetes in the young. The disorder is associated with microvascular disease, with a suggestion of greater risk of nephropathy than of retinopathy, and may also lead to early macrovascular disease. Treatment includes lifestyle modification and the pharmacotherapeutic approaches utilized in adults with type 2 diabetes, with studies to date supporting the roles of insulin and metformin, suggesting the importance of studying insulin secretagogues and thiazolidinediones as approaches in the treatment of type 2 diabetes in the young. The development of effective approaches to disease prevention will be of great importance.
This study estimated hypertension incidence and explored hypertension risk factors and their association with cardiovascular disease. Data collected from 4549 American Indian participants in the 3 exams of the Strong Heart Study were used. Hypertension was defined as systolic blood pressure > or =140 mm Hg, diastolic blood pressure > or =90 mm Hg, or current use of antihypertensive medication. Generalized linear models were used to identify the risk factors for hypertension and the correlates of blood pressures. Cox proportional models with time-dependent covariates and the mixed models were used to explore the association of hypertension with cardiovascular disease. There was no sex difference in hypertension. After adjustment for other risk factors, the risks of developing hypertension among subgroups in each characterized group were as follows: prehypertensive versus normotensive, 3.21 times; macroalbuminuria and microalbuminuria versus normal, 3.47 and 1.72; diabetic versus nondiabetic, 1.56; overweight and obese versus normal weight, 1.30 and 1.51; and current alcohol drinking versus not, 1.22. Moreover, systolic blood pressure was significantly and positively associated with age, obesity, and albuminuria and negatively with smoking. After adjusting all other risk factors, those pretreated, untreated, controlled, and uncontrolled hypertensive participants had &1.74, 1.81, 2.19, and 2.77 times higher risks of developing cardiovascular disease compared with normotensive participants, respectively. In 45- to 74-year-old American Indians, the risk of developing hypertension was rising. Prehypertensive participants had 3.2/1.74 times higher risk of developing hypertension/cardiovascular disease than normotensive participants. Age, diabetes, and macro/microalbuminuria were independently significant risk factors of both hypertension and cardiovascular disease.
This study was conducted to investigate the relationship of glomerular and tubular dysfunctions with glycaemic control, lipid, lipoprotein, apolipoproteins and antioxidant status in 72 patients with type 2 diabetes mellitus.
Urine albumin concentration was measured by immunoturbidimetric and urine N-acetyl-beta-D-glucosaminidase (NAG) and alanine aminopeptidase (AAP) activities with colorimetric methods. Glycated haemoglobin was measured using affinity chromatography. Erythrocyte glutathione reductase and glutathione peroxidase activities and serum levels of malondialdehyde, lipids, lipoproteins and apolipoproteins were determined in patients with type 2 diabetes mellitus.
In univariate regression, urinary albumin excretion, and activities of NAG and AAP were associated with glycaemic control. These glycaemic factors included serum glucose concentrations and glycated haemoglobin. Urinary albumin excretion was also inversely correlated with erythrocyte glutathione peroxidase activity, and positively correlated with erythrocyte glutathione reductase activity. No significant associations were found with serum levels of insulin, lipids, lipoproteins, apolipoproteins, malondialdehyde or blood pressure. In multivariate regression, glycated haemoglobin was the most significant predictor of urinary albumin concentration and with erythrocyte glutathione reductase, whereas only glycated haemoglobin was the independent predictor of tubular dysfunctions. Erythrocyte glutathione peroxidase was not an independent predictor of urinary albumin excretion, after adjusting for glycated haemoglobin, glutathione reductase, systolic blood pressure, diastolic blood pressure and apolipoprotein B.
In type 2 diabetes mellitus, both glomerular and tubular dysfunctions are dependent on glycaemic control. Glomerular, but not tubular, dysfunction is also significantly associated with increased glutathione reductase activity.
To examine the relationships between microalbuminuria and the development of overt diabetic nephrology, elevated blood pressure, and a more atherogenic lipid profile; and to identify risk factors for the development of microalbuminuria in individuals with IDDM. Microalbuminuria has been associated with the subsequent development of overt diabetic nephropathy in individuals with IDDM. It is associated with elevated blood pressure and a more atherogenic lipid profile, but the temporal relationship between the development of microalbuminuria and the changes in these factors is unclear.
Baseline characteristics were examined in 256 individuals with IDDM who had normal albumin excretion (urinary AER < or = 20 micrograms/min in > or = 2 timed urine collections) and were re-examined 2 yr later.
At follow-up, 24 had developed microalbuminuria (AER 20-200 micrograms/min in > or = 2 timed urine collections) and 1 had developed overt nephropathy (AER > 200 micrograms/min). Overall, the significant independent predictors of microalbuminuria were HbA1 (P < 0.001), low-density lipoprotein (P < 0.01), duration of IDDM (P < 0.05), and systolic blood pressure (P = 0.05). Sex-specific analyses showed HbA1, age, and baseline AER were particularly important for men; whereas, for women, the main predictors were duration of IDDM and triglycerides. Duration-specific analyses showed that HbA1 was an important predictor both for individuals with < and > 20-yr duration. Low-density lipoprotein cholesterol was more important for subjects with shorter durations; whereas triglycerides were important for those with longer durations.
These results suggest that glycemic control, age or duration of IDDM, disturbed lipids, and possibly elevated blood pressure all may contribute to the development of microalbuminuria; and, further, that the adverse cardiovascular risk profile seen in individuals with overt nephropathy may begin to develop even before the detection of microalbuminuria.
To study the cumulative incidence of albuminuria and its determinants in NIDDM patients and nondiabetic subjects from the diagnosis and impact of albuminuria on cardiovascular mortality.
We performed a 10-year prospective observational study of 133 well-characterized middle-aged patients with newly diagnosed NIDDM and 144 control subjects. Both groups were examined at baseline and after 5 and 10 years. Urinary albumin excretion was determined from timed 24-h (baseline and 5-year examinations) or overnight samples (10-year examination). Microalbuminuria was defined as urinary albumin excretion of 30-300 mg/24 hr or 20-200 micrograms/min, with the higher values considered as macroalbuminuria.
The cumulative incidence of micro- and macroalbuminuria increased sharply after 5 years in NIDDM patients (baseline: 18.2 and 3.0%; 5 years: 18.9 and 1.8%; and 10 years: 33.0 and 10.2%) but markedly less in control subjects (baseline: 1.4 and 0%, P < 0.001 for diabetic patients vs. control subjects for any albuminuria; 5 years: 6.0 and 0.8%, P < 0.01; 10 years: 11.9 and 0.8%, P < 0.001). The most important determinant of the development of albuminuria was the metabolic control of diabetes in NIDDM patients during the follow-up, whereas in nondiabetic subjects, the development of albuminuria was related to elevated blood pressure and fasting insulin levels. Baseline and 5-year albuminuria predicted subsequent cardiovascular mortality in diabetic patients, even when adjusted for multiple risk factors. The risk of cardiovascular death in NIDDM patients increased by simultaneous occurrence of hyperinsulinemia and albuminuria.
The frequency of microalbuminuria in patients with NIDDM increases sharply with the duration of diabetes. Chronic hyperglycemia is the main risk factor for microalbuminuria in diabetic patients. Microalbuminuria accompanied by hyperinsulinemia is a powerful predictor of cardiovascular death in NIDDM patients.
A progressive decline in glomerular function occurs in diabetic nephropathy. The predictive effects of progression promoters were examined in 182 non-insulin-dependent diabetic patients from a baseline serum creatinine concentration of 133 mumol/l. During a total of 605 person-years follow-up, 107 patients developed end-stage renal failure requiring dialysis. The rate of decline of renal function was highly variable. Urinary protein excretion was the strongest predictor correlated to the rate of decline, followed by diastolic and systolic blood pressure, total cholesterol and platelet count, while the protective effects were seen in serum albumin and haematocrit. Adjustment for urinary protein excretion revealed that diastolic blood pressure, familial predisposition to hypertension, serum albumin, and smoking were independent significant predictors. Angiotensin converting enzyme inhibitors (ACE-I) significantly retarded the development of end-stage renal failure compared to antihypertensives other than ACE-I (mostly nifedipine), and the effect was evident particularly in patients with proteinuria below the median (2.5 g/24 h) (presumably those who responded to ACE-I). A complex effect of proteinuria in association with blood pressure elevation, familial predisposition to hypertension, hypoalbuminaemia, and smoking may play an important role in the progression of nephropathy.
Hyperlipidemia is associated with accelerated glomerular sclerosis in experimental renal insufficiency. To investigate whether the dyslipoproteinemia seen in human renal failure also influences the future course of renal insufficiency, we have correlated plasma levels of lipids and apolipoproteins at start of follow-up with the subsequent change in renal function in 34 adult patients with chronic renal disease. Nineteen patients had primary renal disease, and 15 patients had diabetic nephropathy. Except for antihypertensive therapy no specific treatment to modify the progression of the disease was given during the follow-up. The rate of progression was determined by repeated measurements of the glomerular filtration rate (GFR). The time of follow-up ranged from 12 to 91 months with an average of 39.7 +/- 16.7 months. The mean initial GFR was 34.7 +/- 13.9 ml/min x 1.73 m2 body surface area and the average decline in renal function was -0.27 +/- 0.26 ml/min/month. The entry levels of triglycerides (TG; p = 0.04), very-low-density lipoprotein cholesterol (p = 0.03), apolipoprotein-B (ApoB; p = 0.008) and systolic blood pressure (SBP; p = 0.04) were significantly correlated with the rate of progression. Among lipoprotein variables, ApoB showed the strongest correlation with the decline in GFR. Patients with a progressive course of their disease also tended to have initially higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (NS), whereas the initial plasma concentration of high-density lipoprotein cholesterol did not show an association with the progression of renal insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
BackgroundRenal disease in people with insulin-dependent diabetes (IDDM) continues to pose a major health threat. Inhibitors of angiotensin-converting enzyme (ACE) slow the decline of renal function in advanced renal disease, but their effects at earlier stages are unclear, and the degree of albuminuria at which treatment should start is not known.MethodsWe carried out a randomised, double-blind, placebo-controlled trial of the ACE inhibitor lisinopril in 530 men and women with IDDM aged 20–59 years with normoalbuminuria or microalbuminuria. Patients were recruited from 18 European centres, and were not on medication for hypertension. Resting blood pressure at entry was at least 75 and no more than 90 mm hg diastolic, and no more than 155 mm hg systolic. Urinary albumin excretion rate (AER) was centrally assessed by means of two overnight urine collections at baseline, 6, 12, 18, and 24 months.FindingsThere were no differences in baseline characteristics by treatment group; mean AER was 8.0 μg/min in both groups; and prevalence of microalbuminuria was 13% and 17% in the placebo and lisinopril groups, respectively. On intention-to-treat analysis at 2 years, AER was 2.2 μg/min lower in the lisinopril than in the placebo group, a percentage difference of 18.8% (95% CI 2·0–32·7, p=0·03), adjusted for baseline AER and centre, absolute difference 2.2 μg/min. In people with normoalbuminuria, the treatment difference was 1·0 μg/min (12·7% [−2·9 to 26·0], p=0·1). In those with microalbuminuria, however, the treatment difference was 34.2 μg/min (49·7% [−14·5 to 77·9], p=0·1; for interaction, p=0·04). For patients who completed 24 months on the trial, the final treatment difference in AER was 38·5 μg/min in those with microalbuminuria at baseline (p=0·001), and 0·23 μg/min in those with normoalbuminuria at baseline (p=0·6). There was no treatment difference in hypoglycaemic events or in metabolic control as assessed by glycated haemoglobin.InterpretationLisinopril slows the progression of renal disease in normotensive IDDM patients with little or no albuminuria, though greatest effect was in those with microalbuminuria (AER ≥20 μg/min). Our results show that lisinopril does not increase the risk of hypoglycaemic events in IDDM.
Diabetic nephropathy (DN) as manifested by persistent and clinically evident proteinuria, has long been considered an irreversible process that predicts a rapid decline in renal function. The observation of reversal of DN in several individuals enrolled in a prospective study of the natural course of diabetes complications challenged this view and led to the current investigation into the correlates of such regression of proteinuria. DN was defined as a median albumin excretion rate (AER) over 200 μg/min in two or three urine collections obtained at baseline, and again at 2 and 4 years of follow-up. Among 658 individuals with childhood-onset insulin-dependent diabetes mellitus (IDDM), 146 had DN at baseline. Nine subsequently died without renal failure, and 13 were lost to follow-up. Of the 124 subjects with at least survey follow-up data, 32 (24%) developed renal failure, and 78 of the remaining 92 provided full quantitative data. AER decreased by ≥10-fold into the microalbuminuric (20 to 200 μg/min) or normal range (<20 μg/min) in 7 of these individuals and are called “regressors of proteinuria.” Compared with the remaining 71 subjects, the strongest correlate of regression of proteinuria was an improvement in fasting plasma low-density lipoprotein cholesterol (LDL-C) in the 7 regressors (P < 0.008). Improved glycemic control was not a significant predictor of improved AER. Five of the 7 individuals with improved AER had a baseline median AER below 500 μg/min. When the 7 regressors of proteinuria were combined with an additional 38 individuals who also experienced smaller decreases in median AER, such improvement was associated with a more favorable systolic (or diastolic) blood pressure (BP) change (P < 0.01), and a decrease in plasma LDL-C level (P = 0.01). These data suggest that proteinuria in DN may substantially regress in approximately 6% and improve in at least 34% of individuals with IDDM over a 4-year period, often in association with a decrease in plasma LDL-C concentration or stabilization or improvement in BP. Furthermore, the data suggest that the nonreversibility threshold for diabetic nephropathy may be higher (500 μg/min) than previously reported (200 μg/min).
This chapter focuses on the bias in analytic research. Case-control studies are attractive. They can be executed quickly and at low cost, even when the disorders of interest are rare. The execution of pilot case-control studies is becoming automated; strategies have been devised for the “computer scanning” of large files of hospital admission diagnoses and prior drug exposures, with detailed analyses carried out in the same data set on an ad hoc basis. As evidence of their growing popularity, when one original article was randomly selected from each issue of The New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association for the years 1956, 1966, and 1976, the proportion that reported case-control analytic studies increased fourfold over these two decades; however, the proportion reporting cohort analytic studies fell by half; a general trend toward fewer study subjects but more study authors was also noted.
Raised urinary albumin excretion (UAE) is associated with an increased risk of cardiovascular disease in non-insulin-dependent diabetes mellitus (NIDDM). We have examined the role of endothelial dysfunction as a possible explanation for this association in 94 NIDDM patients by investigating UAE, new cardiovascular events, and plasma concentration of von Willebrand factor (vWF), an indicator of endothelial dysfunction. At baseline, 66 patients had normal UAE (less than 15 micrograms/min), which remained normal in 33 (group 1) and increased in 33 (to median 31.5 micrograms/min, group 2). In 28 patients, baseline UAE was abnormal (67.1 micrograms/min, group 3). Follow-up ranged between 9 and 53 months. vWF did not change in group 1 (median 128% at baseline and 123% at follow-up), but increased in group 2 (from 116 to 219%, p less than 0.0001) and group 3 (from 157 to 207%, p = 0.0005). Baseline level of and change in vWF were strongly related to the development of microalbuminuria (R2 = 0.60, p less than 0.0001), but cardiovascular risk factors were not (R2 = 0.14). Raised baseline UAE was associated with an increased risk of new cardiovascular events only in patients with vWF concentrations above the median (relative risk 3.66, 95% CI 1.3-11.9) and not in patients with lower vWF (0.19, 0.01-1.33). In addition, the cardiovascular risk associated with increased UAE was modified by low compared with high concentrations of serum high density lipoprotein cholesterol (2.86 [1.03-8.48] vs 0.15 [0.01-1.43]). Dysfunction of vascular endothelium may be a link between albuminuria and atherosclerotic cardiovascular disease in NIDDM.
The aim of this study was to assess the effect of simvastatin on plasma lipoproteins and renal function in hypercholesterolaemic Type 1 (insulin-dependent) diabetic patients with diabetic nephropathy. Twenty-six hypercholesterolaemic (total cholesterol greater than or equal to 5.5 mmol/l) Type 1 diabetic patients with nephropathy were enrolled in a double-blind randomized placebo-controlled study for 12 weeks. The active treatment group (n = 14) received simvastatin (10-20 mg/day) for 12 weeks while the remaining 12 patients received treatment with placebo. The results during simvastatin treatment (baseline vs 12 weeks): total cholesterol 6.6 vs 4.8 mmol/l (p less than 0.01), LDL-cholesterol 4.25 vs 2.57 mmol/l (p less than 0.01) and apolipoprotein B 1.37 vs 1.06 mmol/l (p less than 0.01). HDL-cholesterol, and apolipoprotein A-I remained unchanged. Total cholesterol, LDL-cholesterol, HDL-cholesterol, apolipoprotein A-I, apolipoprotein B remained unchanged during placebo treatment. Albuminuria measured during the simvastatin and the placebo treatment (baseline vs 12 weeks) (the data are logarithmically transformed before analysis because of their positively skewed transformation; geometric mean (x/divided by antilog SE) is indicated) was 458 (x/divided by 1.58) vs 393 (x/divided by 1.61) and 481 (x/divided by 1.62) vs 368 (x/divided by 1.78 micrograms/min (NS). Glomerular filtration rate during simvastatin and placebo treatment (baseline vs 12 weeks) was 64 vs 63 and 72 vs 74 ml.min-1.1.73 m-2, respectively. Two patients receiving simvastatin treatment were withdrawn, one due to gastrointestinal side effects and one due to myalgia.(ABSTRACT TRUNCATED AT 250 WORDS)
Experimental studies have suggested an important role for abnormal lipid metabolism as an integral factor in modulating progressive renal damage. Dietary induced hypercholesterolemia induced relatively modest glomerular injury. However, in the presence of reduced nephron population or in the presence of underlying renal diseases, such as diabetes, nephrotic syndrome, and hypertension, nephron injury can be markedly exaggerated. These experimental results suggest that an important interaction may occur between renal disease and the occurrence of abnormalities of lipid metabolism. Additional support for the role of lipids in progressive renal injury can be obtained from studies in which pharmacological interventions reduced circulating lipids and this led to decreased glomerular damage. The mechanisms whereby lipids may amplify glomerular injury are not completely understood but may include an interaction with macrophages, alteration in vascular and mesangial functions, changes in production of mediator substances or alterations in membrane fluidity. Local glomerular modification of lipoproteins could also occur and contribute to the development of glomerular pathologic changes. Clinically, few data are available that provide insights into the potential role of renal-related lipid abnormalities in the progression of human renal disease.
The nephrotic syndrome comprises proteinuria, oedema, albuminuria, hypoalbuminaemia, and hyperlipidaemia. Some of its manifestations are present throughout the course of progressive renal disease. Hyperlipidaemia is one of the most dramatic of the clinical manifestations of the syndrome, but has not been seen as relevant to the progression of renal disease. Recently, however, increasing interest has been shown in the lipid abnormalities of patients with persistent proteinuria, largely as a result of experimental data which have emphasised the connection between progressive disease and hyperlipidaemia in animal models. This review considers some aspects of the metabolic background against which the pathological changes in animal models of nephrotic syndrome take place. Attention is drawn to analogies between glomerular disease and atherosclerosis. Lack of information on the value of long-term lipid lowering therapy in patients with proteinuria, hyperlipidaemia, and progressive renal disease emphasises the need for long-term studies of lipid-lowering therapy in these individuals. A conceptual framework for understanding the role of lipids is discussed in relation to the underlying disease processes and possible therapeutic approaches in man.
Available data indicate that cardiovascular disease has become the leading cause of death in American Indians. However, limited information is available on cardiovascular disease incidence, prevalence, and risk factors in this population. Reported cardiovascular disease rates vary greatly among groups in different geographic areas. These rates have been obtained from studies of varying sizes and different methodologies. The Strong Heart Study, which uses standardized methodology, is designed to estimate cardiovascular disease mortality and morbidity rates and the prevalence of known and suspected cardiovascular disease risk factors in American Indians. The study population consists of 12 tribes in three geographic areas: an area near Phoenix, Arizona, the southwestern area of Oklahoma, and the Aberdeen area of North and South Dakota. The study includes three components. The first is a mortality survey to estimate cardiovascular disease mortality rates for 1984-1988 among tribal members aged 35-74 years, and the second is a morbidity survey to estimate incidence of both first and first or recurrent hospitalized myocardial infarction and stroke (cerebrovascular disease) among tribal members aged 45-74 years in 1984-1988, and the third is a clinical examination of 4,500 tribal members aged 45-74 years in order to estimate the prevalence of cardiovascular disease and its associations with risk factors. Family history, diet, alcohol and tobacco consumption, physical activity, degree of acculturation, and socioeconomic status are assessed in personal interviews. The physical examination includes measurements of body fat, body circumferences, and blood pressure, an examination of the heart and lungs, an evaluation of peripheral vascular disease, and a 12-lead electrocardiogram. Laboratory measurements include fasting and postload glucose, insulin, fasting lipids, apoproteins, fibrinogen, and glycated hemoglobin. Also measured are serum and urine creatinine and urinary albumin. DNA from lymphocytes is isolated and stored for future genetic studies.
There was a need to design a questionnaire that could accurately assess the activity patterns of Native Americans to evaluate the relationship between physical activity and diabetes. Such a questionnaire was developed and implemented into the data collection scheme of the prospective Pima Indian Study of Arizona. The questionnaire, which assesses historical, past-year, and past-week leisure and occupational activity, was examined in 29 Pima individuals aged 21-36 yr and was shown to be reliable with test-retest correlations (rank-order correlations ranged from 0.62 to 0.96 for leisure and occupational activity). Reproducibility of the past-year leisure physical-activity estimate was determined in 69 participants aged 10-59 yr and was found to be reliable in all age-groups with the exception of the 10- to 14-yr-old age-group (rank-order correlations were 0.31 in the 10- to 14-yr-old age-group compared to 0.88 to 0.92 in those greater than 20 yr of age). Validity of the current-activity section of the questionnaire was demonstrated indirectly through comparisons with activity monitors. The past-week leisure-activity estimate was related to the Caltrac activity monitor counts per hour (rho = 0.62, P less than 0.05, n = 17). In summary, a physical-activity questionnaire has been developed that is both reliable and feasible to use in the Pima Indian population to evaluate the relationship of physical activity to non-insulin-dependent diabetes mellitus.
Sex hormones play a major role in determining the risk of cardiovascular disease. While earlier studies have shown that reduced sex hormone binding globulin (SHBG) is associated with increased glucose and insulin concentrations in premenopausal women, few data exist on the relationship of SHBG to other cardiovascular risk factors in women. We hypothesized that decreased SHBG would be associated with an atherogenic pattern of cardiovascular risk factors. We measured total testosterone, total estradiol and SHBG, lipids and lipoproteins, glucose and insulin, and systolic and diastolic blood pressure in 96 premenopausal women. Although total testosterone and total estradiol were not related to cardiovascular risk factors, SHBG was negatively associated with triglyceride concentration (r = -0.37) and positively associated with high density lipoprotein cholesterol (HDLC) (r = 0.42). After adjustment for overall adiposity (body mass index) and upper body adiposity (as measured by the ratio of waist-to-hip circumferences), SHBG was still positively related to HDLC, but not to triglyceride. Adjustment for insulin abolished the relationship between SHBG and triglyceride levels, but did not alter the relationship between SHBG and HDLC. Sex hormones were not related to either systolic or diastolic blood pressure.
There is experimental evidence to suggest that hypercholesterolaemia may play a pathogenetic role in progressive glomerular injury. We investigated the effect of cholesterol-lowering therapy on the progression of diabetic nephropathy in 34 patients with non-insulin-dependent diabetes mellitus. Patients were randomly assigned in a single-blind fashion to treatment with either lovastatin, an HMG CoA reductase inhibitor (n = 16; mean dose 30.0 +/- 12.6 mg/day) or placebo (n = 18) for 2 years. Renal function was assessed by serially measuring the serum creatinine, glomerular filtration rate (using Cr51-EDTA), and 24-h urinary protein excretion. Lovastatin treatment was associated with significant reductions in total cholesterol (p < 0.001), LDL-cholesterol (p < 0.001) and apo B (p < 0.01), the reductions at 24 months being 26, 30 and 18%, respectively. Beneficial effects on serum triglyceride, HDL-cholesterol and apo A1 levels were also observed. Lp(a) showed no significant change in both groups. Glomerular filtration rate deteriorated significantly in the placebo group after 24 months (p < 0.025) but showed no significant change in the lovastatin-treated patients. The increase in serum creatinine was statistically significant (p < 0.02) in placebo-treated patients at 12 and 24 months, and in the lovastatin group after 24 months. Twenty-four hour urinary protein excretion increased in both groups (p < 0.05). Lovastatin treatment was not associated with significant elevations in liver or muscle enzymes. We conclude that effective normalisation of hypercholesterolaemia may retard the progression of diabetic nephropathy.
To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications, we performed a prospective study of Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) treated with multiple insulin injection treatment. A total of 110 patients with NIDDM was randomly assigned to multiple insulin injection treatment group (MIT group) or to conventional insulin injection treatment group (CIT group). Fifty-five NIDDM patients who showed no retinopathy and urinary albumin excretions < 30 mg/24 h at the baseline were evaluated in the primary-prevention cohort, and the other 55 NIDDM patients who showed simple retinopathy and urinary albumin excretions < 300 mg/24 h were evaluated in the secondary-intervention cohort. The appearance and the progression of retinopathy, nephropathy and neuropathy were evaluated every 6 months over a 6-year period. The worsening of complications in this study was defined as an increase of 2 or more steps in the 19 stages of the modified ETDRS interim scale for retinopathy and an increase of one or more steps in 3 stages (normoalbuminuria, microalbuminuria and albuminuria) for nephropathy. The cumulative percentages of the development and the progression in retinopathy after 6 years were 7.7% for the MIT group and 32.0% for the CIT group in the primary-prevention cohort (P = 0.039), and 19.2% for MIT group and 44.0% for CIT group in the secondary-intervention cohort (P = 0.049). The cumulative percentages of the development and the progression in nephropathy after 6 years were 7.7% for the MIT group and 28.0% for the CIT group in the primary-prevention cohort (P = 0.032), and 11.5% and 32.0%, respectively, for the MIT and CIT groups in the secondary-intervention cohort (P = 0.044). In neurological tests after 6 years, MIT group showed significant improvement in the nerve conduction velocities, while the CIT group showed significant deterioration in the median nerve conduction velocities and vibration threshold. Although both postural hypotension and the coefficient of variation of R-R interval tended to improve in the MIT group, they deteriorated in the CIT group. In conclusion, intensive glycemic control by multiple insulin injection therapy can delay the onset and the progression of diabetic retinopathy, nephropathy and neuropathy in Japanese patients with NIDDM. From this study, the glycemic threshold to prevent the onset and the progression of diabetic microangiopathy is indicated as follows; HbA1c < 6.5%, FBG < 110 mg/dl, and 2-h post-prandial blood glucose concentration < 180 mg/dl.
Although coronary heart disease (CHD) is currently the leading cause of death among American Indians, information on the prevalence of CHD and its association with known cardiovascular risk factors is limited. The Strong Heart Study was initiated in 1988 to quantify cardiovascular disease and its risk factors among three geographically diverse groups of American Indians. Members of 13 Indian communities in Arizona, Oklahoma, and South and North Dakota between 45 and 74 years of age underwent a physical examination that included medical history; an electrocardiogram; anthropometric and blood pressure measurements; an oral glucose tolerance test; and measurements of fasting plasma lipoproteins, fibrinogen, insulin, hemoglobin A1c, and urinary albumin. Prevalence rates of definite myocardial infarction and definite CHD were higher in men than in women at all three centers (p < 0.0001) and higher in those with diabetes mellitus (p = 0.002 in men and p = 0.0003 in women). Diabetes was associated with relatively higher prevalence rates of myocardial infarction (diabetic:nondiabetic prevalence ratio = 3.8 vs. 1.9) and CHD (prevalence ratio = 4.6 vs. 1.8) in women than in men. Prevalence rates of heart disease were lowest in the communities in Arizona; prevalence rates were similar in Oklahoma and South Dakota/North Dakota and were two- to threefold higher than those in Arizona. By logistic regression, prevalent CHD among American Indians was significantly and independently related to age, diabetes, hypertension, albuminuria, percentage of body fat, smoking, high concentrations of plasma insulin, and low concentrations of high density lipoprotein cholesterol. In contrast to reports from other non-Indian populations, diabetes was the strongest risk factor. The lower prevalence of CHD among Indians in Arizona is distinctive in view of their higher rates of diabetes, obesity, hypertension, and albuminuria, but it may be partly related to their low frequency of smoking and their low concentrations of total and low density lipoprotein cholesterol. These findings from the initial Strong Heart Study examination emphasize the importance of diabetes and its associated variables as risk factors for CHD in Native American populations.
To examine the incidence and determinants of elevated urinary albumin excretion in Pima Indians with non-insulin-dependent diabetes mellitus (NIDDM).
The incidence of elevated urinary albumin excretion (> or = 30 mg albumin/g creatinine) and its relationship with baseline characteristics was determined in 456 Pima Indians > or = 15 years old with NIDDM who were followed for up to 11.6 years (median 4.7 years).
Of these 456 subjects, 192 (42%; 58 men, 134 women) developed elevated urinary albumin excretion, 172 of whom (90%) were within the microalbuminuric range (30-299 mg/g). The incidence of elevated urinary albumin excretion was related to retinopathy, type, of diabetes treatment, longer duration of diabetes, lower body mass index, and higher values of mean arterial pressure, HbA1, and fasting and 2-h postload plasma glucose concentration at the baseline examination, but not to sex. A relationship with cholesterol was found in durations of diabetes of > or = 10 years. The cumulative incidence of elevated albumin excretion was 17% after 5 years of NIDDM.
The incidence of elevated urinary albumin excretion in Pima Indians with NIDDM is at least as high as that reported previously in insulin-dependent diabetes mellitus, and its major determinants are the same as those shown previously to predict the development of more advanced renal disease in this population.
Ninety-four normotensive type II diabetics with normal renal function and microalbuminuria were randomized to receive enalapril 10 mg/day or placebo and were followed for five years. In the patients treated by enalapril plasma creatinine values and albuminuria remained stable throughout the observation period. Their plasma total cholesterol decreased from an initial value of 245 +/- 27 mg/dl to mean study value of 236 +/- 29 mg/dl, and to a fifth year value of 232 +/- 27 mg/dl (P < 0.001). The changes in HDL cholesterol and triglyceride values were nonsignificant. In the placebo group there was a significant increase in albuminuria and a mean decline of 13% in reciprocal creatinine values during the five years. Plasma total cholesterol increased from an initial mean value of 246 +/- 24 to a mean study value of 252 +/- 25 mg/dl, and to a fifth year mean value of 259 +/- 32 mg/dl (P < 0.001). There was a significant correlation between both initial and mean plasma total cholesterol values, and the decline in renal function and the rise in albuminuria in the placebo treated patients. This correlation persisted after stratification for blood pressure. Treatment with enalapril did not eliminate these correlations. Cholesterol may be an additional risk factor for diabetic nephropathy. ACE inhibitors may have a modest cholesterol lowering effect in diabetic patients mediated, in part, through the decline in albuminuria.
Estrogen use has been reported to decrease triglyceride and low-density lipoprotein cholesterol (LDL-C) and increase high-density lipoprotein cholesterol (HDL-C). Estrogen use increases the secretion of large, very low-density lipoprotein cholesterol (VLDL-C) and also stimulates the uptake of VLDL-C by the liver and increases the catabolism of LDL-C in the liver. Sex hormones may affect several enzymes involved in the metabolism of HDL-C and triglyceride and may also affect lipolysis. In both pre- and postmenopausal women, several studies have shown that increased glucose and insulin concentrations are associated with increased free testosterone and decreased sex hormone binding globulin. The temporal direction of this relationship in premenopausal women is not clear, however. In contrast to women, increased androgen concentrations in men do not seem to be associated with increased cardiovascular risk factors, although testosterone concentrations are associated with increased HDL-C and decreased insulin concentrations. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) appear to be associated with improved cardiovascular risk factors in men, but this connection in women is less clear.
This paper reviews the much discussed association between alcohol intake, lipoproteins and coronary heart disease (CHD). Epidemiological studies have consistently shown an inverse trend between low to moderate alcohol consumption and CHD. Such a protective effect of alcohol against atherosclerosis has been associated with the elevated concentration of HDL-cholesterol induced by alcohol. However, the underlying mechanisms whereby alcohol drinking enhances HDL-cholesterol levels are not yet fully clear. Various lifestyle variables, namely diet, smoking, hypertension, body mass index and exercise, can affect the lipoprotein status in both users and non-users of alcohol.
The development of kidney disease in diabetes mellitus can be viewed as a two-stage process: (1) the development of proteinuria, and (2) its progression to chronic renal failure. Determinants of the latter were examined in 439 IDDM patients who had nephropathy and participated in the Diabetic Retinopathy Study. Using serum creatinine levels obtained during the follow-up period to assess the rate of loss of renal function, we found that only one-third of these patients experienced a rapid loss of function, while the others had slowly declining or unchanging renal function despite the presence of proteinuria and severe diabetic retinopathy. Among the many baseline variables examined, only elevated cholesterol and elevated systemic blood pressure were predictors of a rapid loss of renal function. Patients with this rapid loss of renal function also had the highest risk of death due to cardiovascular causes, as well as all causes. Once again, hypercholesterolemia was the major predictor of these deaths. In conclusion, efforts should be undertaken early to identify patients who are rapidly losing renal function so that interventions to modify systemic blood pressure and hypercholesterolemia may prevent or postpone the development of renal failure and death in patients with IDDM.
The effect of simvastatin (10-20 mg/day) on kidney function, urinary albumin excretion rate and insulin sensitivity was evaluated in 18 Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria and moderate hypercholesterolaemia (total cholesterol > or = 5.5 mmol.l-1). In a double-blind, randomized and placebo-controlled design treatment with simvastatin (n = 8) for 36 weeks significantly reduced total cholesterol (6.7 +/- 0.3 vs 5.1 mmol.l-1 (p < 0.01)), LDL-cholesterol (4.4 +/- 0.3 vs 2.9 +/- 0.2 mmol.l-1 (p < 0.01)) and apolipoprotein B (1.05 +/- 0.04 vs 0.77 +/- 0.02 mmol.l-1 (p < 0.01)) levels as compared to placebo (n = 10). Both glomerular filtration rate (mean +/- SEM) (simvastatin: 96.6 +/- 8.0 vs 96.0 +/- 5.7 ml.min-1 x 1.73 m-2, placebo: 97.1 +/- 6.7 vs 88.8 +/- 6.0 ml.min-1 x 1.73 m-2)(NS) and urinary albumin excretion rate (geometric mean x/divided by antilog SEM) (simvastatin: 18.4 x/divided by 1.3 vs 16.2 x/divided by 1.2 microgram.min-1, placebo 33.1 x/divided by 1.3 vs 42.7 x/divided by 1.3 micrograms.min-1)(NS) were unchanged during the study. A euglycaemic hyperinsulinaemic clamp was performed at baseline and after 18 weeks in seven simvastatin- and nine placebo-treated patients. Isotopically determined basal and insulin-stimulated glucose disposal was similarly reduced before and during therapy in both the simvastatin (2.0 +/- 0.1 vs 1.9 +/- 0.1 (NS) and 3.1 +/- 0.6 vs 3.1 +/- 0.7 mg.kg-1 x min-1 (NS)) and the placebo group (1.9 +/- 0.1 vs 1.8 +/- 0.1 (NS) and 4.1 +/- 0.6 vs 3.8 +/- 0.2 mg.kg-1 x min-1 (NS)).(ABSTRACT TRUNCATED AT 250 WORDS)
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.
Although many studies show that increased androgenicity is associated with increased triglyceride (TG) and decreased high density lipoprotein cholesterol in both pre- and postmenopausal women, relatively few data are available on the association of sex hormones to lipids and lipoproteins in men. We examined the association of sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol with lipids and lipoproteins in 178 nondiabetic men from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. The TG concentration was significantly inversely related to SHBG (r = -0.22), free testosterone (r = -0.15), total testosterone (r = -0.22), and DHEA-SO4 (r = -0.16). High density lipoprotein (HDL) cholesterol was significantly positively correlated to SHBG (r = 0.21), free testosterone (r = 0.15), total testosterone (r = 0.17), and DHEA-SO4 (r = 0.16). Total testosterone was significantly related to total cholesterol (r = -0.17) and low density lipoprotein cholesterol (r = -0.15). After adjustment for age, body mass index, waist to hip ratio, and glucose and insulin concentrations, TG concentrations remained significantly related to SHBG (r = -0.20), free testosterone (r = -0.15), and DHEA-SO4 (r = -0.18), and HDL cholesterol remained significantly associated with SHBG (r = 0.17), free testosterone (r = 0.15), total testosterone (r = 0.14), and DHEA-SO4 (r = 0.16). In conclusion, we observed a less atherogenic lipid and lipoprotein profile with increased testosterone concentrations. This was not explained by differences in glucose or insulin concentrations. However, sex hormones explained only a small percentage of the variation in total TG and HDL cholesterol concentrations. These findings are in striking contrast to data from women, in whom increased androgenicity is strongly associated with increased TG and decreased HDL cholesterol levels.
Epidemiologic studies have correlated fasting and postload insulin levels with the risk of coronary heart disease, assuming that insulin levels are reliable markers of insulin resistance. However, this assumption has not been systematically studied. The author measured insulin response to an oral glucose load and quantitated insulin resistance using the euglycemic hyperinsulinemic clamp technique to evaluate the correlation between insulin level and the degree of insulin resistance in individuals with varying degrees of glucose tolerance. Subjects were randomly selected from previous population studies done in 1987-1989 at the Department of Medicine of the University of Kuopio in east Finland. Altogether, 50 subjects with normal glucose tolerance, 28 with impaired glucose tolerance, and 54 with non-insulin-dependent diabetes mellitus were studied. Correlations of insulin resistance (whole-body glucose uptake in clamp studies) with fasting or postload insulin levels were remarkably consistent, ranging from -0.58 to -0.74 (p < 0.01) in subjects with normoglycemia. In contrast, corresponding correlations were substantially weaker in subjects with impaired glucose tolerance and non-insulin-dependent diabetes. Among these subjects, only the fasting insulin level correlated significantly with insulin resistance (-0.47, p < 0.05 and -0.48, p < 0.01, respectively). The authors conclude that in population studies, only the fasting insulin level should be used as a marker of insulin resistance, particularly in subjects with abnormal glucose tolerance.
To examine the potential associations of lipoprotein(a) and the complications of IDDM and their risk factors.
This report focuses on 186 individuals with IDDM (mean age = 34 yr) participating in a 10-yr prospective study examining various complications. Lp(a) concentrations were evaluated for those with and without complications.
A weak correlation was seen between Lp(a) and HbA1 (r = 0.16, P < 0.05). Lp(a) concentrations were not significantly different for those with or without proliferative retinopathy, overt nephropathy, peripheral vascular disease, or definite myocardial infarction or angina. However, an inverse association (P < 0.05) was seen with distal symmetric polyneuropathy. These results were also confirmed by categorical analyses (i.e., Lp(a) levels < or = 30 vs. > 30 mg/dl).
These results suggest that any association of Lp(a) concentration with IDDM complications is likely to be weak or nonexistent. However, prospective studies are needed before its full role can be determined.
Fifty-four patients with noninsulin-dependent diabetes mellitus, who had established nephropathy, were examined to evaluate the risk factors for the progression of diabetic nephropathy. Time-averaged values of blood pressure, serum total cholesterol and fasting plasma glucose concentrations, and the degree of proteinuria during their follow-up period (4.2 +/- 0.5 years) were calculated. The correlation between these values and the slope of the regression line for the reciprocal of serum creatinine concentration over time, as an index of the speed of the progression of nephropathy, was examined. Age (61 +/- 1 years), mean arterial pressure (109 +/- 1 mm Hg), and the degree of the proteinureia (2.1 +/- 0.1 in dipstick test) were correlated with the slope. Effects of hypercholesterolemia and smoking on the slope were also examined. Mean arterial pressure was correlated with the slope significantly in patients without hypercholesterolemia (p < 0.05) and there was a tendency between these two in smokers (p < 0.06), while was no correlation found in patients with hypercholesterolemia or in nonsmokers. In addition, the relation between the slope and mean arterial pressure was relatively stronger in smokers without hypercholesterolemia than in nonsmokers with hypercholesterolemia. Our data suggest that blood pressure control as well as smoking avoidance may be important in preventing the progression of noninsulin-dependent diabetic nephropathy.
This article reviews flexible statistical methods that are useful for characterizing the effect of potential prognostic factors on disease endpoints. Applications to survival models and binary outcome models are illustrated.
To estimate prevalence rates of diabetes and impaired glucose tolerance (IGT) in three American Indian populations, using standardized diagnostic criteria, and to assess the association of diabetes with the following selected possible risk factors: age, obesity, family history of diabetes, and amount of Indian ancestry.
This cross-sectional study involved enrolled members, men and women aged 45-74 years, of 13 American Indian tribes or communities in Arizona, Oklahoma, and South and North Dakota. Eligible participants were invited to the clinic for a personal interview and a physical examination. Diabetes and IGT status were defined by the World Health Organization criteria and were based on fasting plasma glucose and oral glucose tolerance test results. Data on age, family history of diabetes, and amount of Indian ancestry were obtained from the personal interview, and measures of obesity included body mass index, percentage body fat, and waist-to-hip ratio.
A total of 4,549 eligible participants were examined, and diabetes status was determined for 4,304 (1,446 in Arizona, 1,449 in Oklahoma, and 1,409 in the Dakotas). In all three centers, diabetes was more prevalent in women than in men. Arizona had the highest age-adjusted rates of diabetes: 65% in men and 72% in women. Diabetes rates in Oklahoma (38% in men and 42% in women) and South and North Dakota (33% in men and 40% in women), although considerably lower than in Arizona, were several times higher than those reported for the U.S. population. Rates of IGT among the three populations (14-17%) were similar to those in the U.S. population. Diabetes rates were positively associated with age, level of obesity, amount of Indian ancestry, and parental diabetes status.
Diabetes is found in epidemic proportions in Native American populations. Prevention programs and periodic screening should be implemented among American Indians. Standards of care and intervention have been developed by the Indian Health Service for individuals in whom diabetes is diagnosed. These programs should be expanded to include those with IGT to improve glycemic control or to reduce the risk of development of diabetes as well as to reduce the risk of diabetic complications.
The objective of the present study was to estimate how glomerular filtration rate and kidney size change after six years of diabetes in subjects with non-insulin-dependent disease. It is a population-based prospective study of a cohort of non-insulin diabetic patients (n = 150) diagnosed 1985-1988. The baseline studies utilized a non-diabetic control group, whose basic characteristics were equal to the study group. The setting was a primary health care center in an urban area. Main outcome measures were the glomerular filtration rate and its relation to renal area, mean blood pressure, hemoglobin A1c, serum insulin and cholesterol. Seventeen patients had died and 109 were eligible for evaluation at follow-up. The mean (standard deviation) of the glomerular filtration rate (ml/min/1.73 m2) remained elevated at follow-up, 118 (28), just as it was at baseline, 118 (28) in the diabetic subjects compared to matched non-diabetic subjects, 103 (24) (p = 0.0000). Kidney size (cm2) was larger in diabetic subjects at follow-up, 114 (19) than at baseline, 109 (18) (p = 0.0000) and in non-diabetic subjects 98 (14) (p < 0.0000). This resulted in a decline in glomerular filtration rate per unit renal area in the diabetic subjects at follow-up, 1.0 (0.23) compared to at baseline, 1.09 (0.23) (p = 0.002) and to non-diabetic subjects, 1.07 (0.23). The renal area at baseline was directly and significantly related to the glomerular filtration rate at follow-up (p < 0.001). The relation of baseline serum cholesterol, hemoglobin A 1c and mean arterial blood pressure to the glomerular filtration rate at follow-up was inverse and reached significance in those diabetic subjects having had high filtration rates at baseline but displaying a faster decline than on average i.e. in those patients who were at increased risk of renal insufficiency. We conclude that after the first six years of non-insulin-dependent diabetes the glomerular filtration rate remains high. Kidney size increases further from the attained increase at diagnosis and is an important determinant of continuing hyperfiltration. The deleterious effect of serum cholesterol and high blood glucose on the glomerular filtration rate at this early stage of diabetic kidney disease is suggestive.
The present study was undertaken to clarify the progression of urinary albumin excretion rate (UAER) in non-insulin-dependent diabetic (NIDD) patients 6 years after diagnosis, and to elucidate the risk factors of nephropathy.
This is a population-based controlled (baseline) cohort study. The prospective evaluation utilized the diabetic patients as internal controls. The setting was an urban primary health care centre. Main outcome measures were the UAER-24 h and fractional urinary albumin excretion rate (FAC) and their relation to mean blood pressure, haemoglobin Alc, fasting serum insulin and cholesterol and renal size.
UAER (mg/24 h) was increased (geometric mean, quartile 1 and 3) in the diabetic patients at baseline, compared to the non-diabetic control subjects; 21 (10 and 33) versus 12 (8 and 15), P = 0.0001 (Wilcoxon's rank test). The UAER-24 h was not increased in diabetic subjects at follow-up; 24 (7 and 49) P = 0.3791 versus diabetic subjects at baseline. Eighteen per cent of normoalbuminuric (UAER < 30mg/24 h) patients developed microalbuminuria (UAER = 30-300 mg/24 h) and 3% clinical nephropathy (UAER > 300 mg/24 h). Of the microalbuminuric subjects 19% progressed to clinical nephropathy, 46% remained microalbuminuric and 35% remitted to normoalbuminuria. Serum insulin concentration, after assessment of confounding factors, measured at the baseline predicted the UAER for all diabetic subjects at follow-up in multiple linear regression analysis in an independent and significant way (P = 0.01). Serum insulin concentration (P = 0.034) and diuretic therapy (P = 0.050) at baseline independently predicted the outcome of the categorical variable progressor/nonprogressor (n = 22/86) based on the UAER-24 h at baseline and at follow-up.
Progression of the UAER during the first 6 years is found among approximately every fifth NIDD subject who develops either microalbuminuria (from normoalbuminuria) or clinical nephropathy (from microalbuminuria). The role of serum insulin (insulin resistance) or some factor associated with it, is suggestive in the genesis of kidney disease.
Elevated concentrations of serum sialic acid, a potent cardiovascular risk factor in the general population, have been found in patients with IDDM and microalbuminuria. We investigated whether a coincidence exists between the increase of sialic acid concentrations and albuminuria in the transition from normoalbuminuria to microalbuminuria. Furthermore, the predictability of increased sialic acid as well as von Willebrand factor (vWF) and total and HDL cholesterol concentrations in development of persistent microalbuminuria in IDDM was investigated.
This 10-year prospective study was carried out in a cohort of 209 IDDM patients with normoalbuminuria at baseline.
Of the cohort, 198 patients completed the follow-up period and 27 developed persistent microalbuminuria (urinary albumin excretion rate [UAER] > or = 30 mg/24 h). A coincident increase of UAER and serum sialic acid concentration was seen before persistent microalbuminuria was diagnosed. Elevation of serum sialic acid concentrations in those who later developed microalbuminuria occurred 3 years before the diagnosis of persistent microalbuminuria. Baseline serum sialic acid concentrations were significantly higher in the group of patients who later developed microalbuminuria than in the group who remained normoalbuminuric (2.02 +/- 0.41 vs. 1.85 +/- 0.31 mmol/l [means +/- SD], P < 0.05). Baseline serum sialic acid concentration correlated significantly with HbA1c, UAER, blood pressure, total cholesterol, HDL cholesterol, and vWF and was significantly predictive for development of microalbuminuria (hazards ratio [95% CI], 3.1 [1.2-8.1]; P = 0.02) after adjustments for sex, duration of diabetes, smoking, blood pressure, vWF, total cholesterol, and HDL cholesterol. Adjustment for the effects of HbA1c and UAER, however, canceled out the predictive effect of serum sialic acid.
UAER and serum sialic acid concentration increase coincidentally before the onset of persistent microalbuminuria. An increased serum sialic acid concentration is predictive for the onset of microalbuminuria independent of age, sex, diabetes duration, smoking, blood pressure, vWF, and total HDL cholesterol.
Albuminuria is a risk factor for renal and cardiovascular disease. We conducted a cross sectional survey of 4549 older American Indians in Arizona, Oklahoma and North and South Dakota of (micro)albuminuria. A range of 20.1 to 48.3% of all participants had either micro- (> or = 30 to < 300 mg albumin/g creatinine) or macroalbuminuria (> or = 300 mg albumin/g creatinine). A total of 53% of the participants were diabetic, and the prevalence in Arizona (65 to 70%) was significantly greater than the other two sites. Prevalence of micro- and macroalbuminuria were significantly higher among those who were older, diabetic or hypertensive, and participants from Arizona. Even normotensive, nondiabetic Arizona Indians had higher prevalence rates than similar participants elsewhere. Higher prevalence rates of micro- and macroalbuminuria were also found among Arizona participants than participants with similar degrees of glucose intolerance from the other two sites. Indians reporting the greatest degree of Indian blood were more likely to have abnormal albuminuria (P < 0.0001). The duration of diabetes, fasting plasma glucose, systolic blood pressure, fibrinogen and Indian heritage were independently associated with micro- or macroalbuminuria. The association of albuminuria with subsequent ESRD, cardiovascular morbidity and overall mortality suggests that these American Indians will face a large disease burden. The correlation with reported Indian blood implies a strong component of genetic susceptibility, possibly independent of diabetes.
The objective of this study is to examine the influence of lipid profiles and blood pressure on the development of microvascular complications in adolescents with insulin-dependent diabetes mellitus (IDDM) in a matched pairs study. Patients with early background retinopathy (n = 21) or microalbuminuria (n = 15) and their respective statistical twins participated in the study. Serum total cholesterol, high-density lipoprotein (HDL) cholesterol, fasting triglycerides, glycosylated haemoglobin A1c (HbA1c), and systolic and diastolic blood pressure during 3 years prior to the development of early background retinopathy or incipient nephropathy were examined. The multivariate discriminant analysis demonstrated glycaemic control and HDL cholesterol to be the most important variables related to the development of retinal lesions (84% correctness), and diastolic blood pressure to be associated with microalbuminuria (57% correctness). In addition to poor glycaemic control, different factors seem to be important for the early retinal or renal lesions of juvenile IDDM.
The role of plasma lipoproteins in the development of non-insulin-dependent diabetes mellitus (NIDDM) was studied in 787 non-diabetic (2-h glucose < 11.1 mmol/l) Pima Indians (265 men and 522 women). Subjects were followed for a mean of 9.8 (range: 1.8-16.4) years, during which 261 (76 men and 185 women) developed NIDDM. In men and women, very-low-density lipoprotein (VLDL) cholesterol, VLDL triglyceride, low-density lipoprotein triglyceride and total triglyceride, controlled for age, predicted NIDDM (P < 0.01 for each). These effects diminished when controlled for age, sex, body mass index, systolic blood pressure and 2-h glucose. However, high-density lipoprotein (HDL) cholesterol, controlled for age, body mass index, systolic blood pressure and 2-h glucose, was a significant protective factor for NIDDM in women (hazard rate ratio (HRR) = 0.35, 95% CI (0.23-0.54), P < 0.001, 90th compared with 10th percentile) but not in men (HRR = 1.04, 95% CI (0.53-2.05), P = 0.915). This association remained significant in women when controlled for fasting or 2-h plasma insulin concentrations, other estimates of insulin resistance or alcohol consumption. The protective effect of HDL cholesterol was similar among women with normal (2-h glucose < 7.8 mmol/1) or impaired (7.8 mmol/l < or = 2-h glucose < 11.1 mmol/l) glucose tolerance at baseline. These results indicate that lipoprotein disorders are an early accompaniment of the abnormalities that lead to NIDDM.
Low serum cholesterol concentrations are associated with high death rates from cancer, trauma, and infectious diseases, but the meaning of these associations remains controversial. The present report evaluates whether low cholesterol is likely to be a causal factor for mortality from all causes or from specific causes.
Among 4553 Pima Indians > or =20 years old, a population with low serum cholesterol (median, 4.50 mmol/L), 1077 deaths occurred during a mean follow-up of 12.8 years. Trauma was the most common cause. The relationship between serum cholesterol measured at 2-year intervals and age- and sex-standardized mortality rates was U-shaped. Cholesterol was related positively to mortality from cardiovascular diseases and diabetes (including nephropathy) and negatively to mortality from cancer and alcohol-related diseases. The relationship was U-shaped for mortality from infectious diseases, and cholesterol was not related to mortality from trauma. Change in cholesterol from one examination to the next was positively related to mortality from diabetes. In proportional-hazards models adjusted for potential confounders, the relationship between baseline cholesterol and mortality was U-shaped for all causes and diabetes and positive for cardiovascular diseases. Other relationships were nonsignificant. Among 3358 subjects followed > or =5 years, the relationship was significant and positive only for mortality from cardiovascular diseases.
Despite a high exposure risk for Pima Indians, if low cholesterol level is a causal factor, the relationships between low serum cholesterol and high mortality rates probably result from diseases lowering cholesterol rather than from a low cholesterol causing the diseases.
The objective of this study was to investigate whether reduction in hypertriglyceridaemia is associated with a slower rate of progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus (NIDDM). Fifteen normotensive NIDDM patients with hypertriglyceridaemia (> 2.5 mmol L-1) and microalbuminuria were randomly selected to receive either placebo (eight patients) or gemfibrozil 600 mg b.i.d. (seven patients). Progression of microalbuminuria was assessed during a 12-month follow-up period with measurements, consisting of blood tests and triplicate 24-h urine collections, at 1, 3, 6, 9 and 12 months. All but one patient in the treatment group showed a favourable response (> or = 20% reduction) of hypertriglyceridaemia to gemfibrozil. One patient in the placebo group showed a spontaneous reduction in triglyceride levels. Progression of microalbuminuria was lower, although not statistically significantly so, in the treatment group (36%) than in the placebo group (65%). In the group with > or = 20% reduction in triglyceride levels, progression of MA was significantly lower than in the group with stable or increasing triglyceride levels (+1%, range -56% to +49% vs. +97%, range -35% to +202% respectively) (P = 0.03). Continued follow-up data of patients switching from placebo to gemfibrozil after the trial further support the role of serum triglyceride reduction in stabilizing albumin excretion. In conclusion, the results indicate that, in microalbuminuric NIDDM patients, effective treatment of dyslipidaemia could be associated with stabilization of urinary albumin excretion.
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