Metabolic effects of darglitazone,an insulin sensitizer,in NIDDM subjects

Summary Insulin resistance is a significant pathogenetic factor in the development of non-insulin-dependent diabetes mellitus (NIDDM). A new class of drugs, the thiazolidinediones, have been shown to lower blood glucose levels without stimulating insulin secretion. We report the metabolic effect of the thiazolidinedione, darglitazone, in obese NIDDM subjects. Nineteen subjects were enrolled in a doubleblind placebo-controlled study in which 25 mg of darglitazone was given once a day for 14 days. Nine subjects received the active drug and ten subjects received placebo. Darglitazone-treated subjects showed; 1) a decrease in 24-h plasma glucose area under the curve from 292.8±31.2 to 235.2±21.6 mmol · h^–1 · l^–1 p=0.002; 2) a decrease in 24-h serum insulin area under the curve from 1027.2±254.4 to 765.6±170.4 U · h^–1 · l^–1 p=0.045; 3) a decrease in 24-h non-esterified fatty acid area under the curve from 1900±236 to 947±63 g · h^–1 · l^–1 p=0.002; 4) a decrease in mean 24-h serum triglyceride by 25.9±6.2% as compared to – 3.9±4.8% for the placebo-treated group, p=0.012. Placebo-treated subjects showed no change in their metabolic parameters after treatment. Thus, darglitazone is effective in increasing insulin effectiveness in obese NIDDM subjects. The potential for this and similar drugs to treat or prevent NIDDM as well as the insulin-resistance syndrome needs to be explored.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - NEFA non-esterified fatty acids - IVGTT intravenous glucose tolerance test - AUC area under the curve     

NIDDM患者左心室功能与高胰岛素血症的关系探讨

观察９８例ＮＩＤＤＭ患者彩色多普勒超声心动图、血清胰岛素和Ｃ肽释放试验的检测结果，显示在左心室功能障碍的患者血清胰岛素水平，胰岛素／Ｃ肽比值均较左心室功能正常的患者增高，而胰岛素敏感性指数则降低，提示高胰岛素血症可能参与ＮＩＤＤＭ患者左心室功能异常的发生机制。     

Systolic blood pressure relates to the rate of progression of albuminuria in NIDDM

Summary We prospectively followed a cohort of 278 non-insulin-dependent (NIDDM) patients for a 6-year period, intending to estimate the rate of increase of albuminuria and to identify clinical variables that influence this increase. At baseline, normo-albuminuria (N) was seen in 74%, microalbuminuria (M) in 19% and 7% presented with proteinuria (P). A total of 80 patients died; they were older (p<0.001) and had higher albumin excretion both at baseline and as an average during follow-up (p<0.01). At baseline, patients with proteinuria had higher blood pressures (systolic and diastolic), whereas there was no difference between patients with normo- and microalbuminuria. Glycaemic control was increasingly poor throughout the three groups. At follow-up, an average relative rate of increase of albuminuria (slope) of 17% per year was seen both for patients with complete 6 years, follow-up (n=135) and patients with at least 4 years follow-up (n=178). Slope correlated significantly with systolic blood pressure (r=0.26 and 0.29) in both groups, diastolic blood pressure only in the 4-year group (r=0.22) and average albuminuria in both (r=0.31 and 0.24). By multiple regression analyses systolic blood pressure and average albuminuria remained with significant influence on slope. Progression was defined as an increase in the category (e. g. normoto microalbuminuria) as well as an increase of more than 20% in albumin excretion, and was seen in 46 patients with at least 4 years' follow-up. Progressors (patients demonstrating progression) had higher systolic blood pressure (165 mm Hg±20 vs 156±17) and poorer glycaemic control (HbA_1C: 8.2%±1.5 vs 7.7±1.3) p<0.05, as well as a higher level of albuminuria at baseline. The present study points to systolic blood pressure and general level of albuminuria as factors determining the rate of progression of albuminuria. However, only a modest fraction of the variation between subjects was explained by these variables.Abbreviations IDDM insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus - N normal urinary albumin excretion - M microalbuminuria - P proteinuria - Slope relative rate of increase - UAC urinary albumin concentration - UAE urinary albumin excretion rate     

Heterogeneous nature of microalbuminuria in NIDDM: studies of endothelial function and renal structure

Summary Microalbuminuria (MA) is associated with microangiopathy (renal and retinal lesions) in insulin-dependent diabetic (IDDM) patients. In contrast MA does not reflect microvascular damage in a substantial number of non-insulin-dependent diabetic (NIDDM) patients. MA predicts cardiovascular disease in NIDDM patients with increased von Willebrand factor (vWF) plasma levels which are hypothesized to reflect endothelial dysfunction. However, it is not known whether MA is consequent to generalised endothelial dysfunction or to renal injury. Thus, this study evaluated vWF plasma levels in relation to renal and retinal structural abnormalities in NIDDM patients with MA. Kidney biopsies, fundoscopy and measures of vWF plasma levels were performed in 32 NIDDM patients with MA. These patients were allocated to two renal structural categories: A) Without renal structural abnormalities (C I, n = 10): normal or near-normal renal structure, and B) With renal structural abnormalities (n = 22), further divided into: C II (n = 12) with typical diabetic nephropathology, predominantly glomerulopathy, and C III (n = 10) with atypical patterns of renal injury (more advanced tubulo-interstitial and arteriolar than glomerular changes). vWF plasma levels were significantly higher in category B (C II: 195 ± 49 % and C III: 161 ± 46 %) than in category A (C I: 119 ± 42 %), (chi-square, p < 0.05). Diabetic retinopathy was also related to vWF plasma levels (ANOVA, p < 0.05). These data suggest that there are two types of MA in NIDDM: one associated with increased vWF levels, established renal injury and frequently retinopathy, and the other characterized by normal vWF levels, normal renal structure and absent or mild diabetic retinopathy. We propose that vWF plasma levels in NIDDM patients with MA may help to identify patients with important renal structural changes, increased retinopathy risk and, perhaps, generalised endothelial dysfunction. Whether vWF plasma levels predict end-stage renal disease and cardiovascular events deserves longitudinal studies. [Diabetologia (1998) 41: 233–236] Received: 2 October 1997 and in revised form: 4 November 1997     

Segregation analysis of NIDDM in Caucasian families

Summary Non-insulin-dependent diabetes mellitus (NIDDM) has a substantial genetic component, but the mode of inheritance and the molecular basis are unknown. We have undertaken segregation analysis of NIDDM after studying 247 subjects in 59 Caucasian nuclear pedigrees ascertained without regard to family history of the disorder. The analyses were performed using POINTER and COMDS, which are computer programs which apply statistical models to the data. POINTER analysis was performed defining the phenotype as a presence or absence of hyperglycaemia. Among single locus hypotheses, the analyses rejected a recessive model and favoured a dominant model, but could not statistically show that this fitted better than a mixed model (a single locus against a polygenic background) or a polygenic model. COMDS analysis assumed a continuum of hyperglycaemia from normality to NIDDM, classified family members into a series of diathesis classes with increasing plasma glucose levels and compared the distribution with that found by screening the normal population. This analysis improved the likelihood of a dominant single locus model and suggested a gene frequency of 7.4%. It raised the possibility of a second locus, but cannot identify or exclude a polygenic model. In conclusion, two types of segregation analyses rejected a recessive model and favoured a dominant model of inheritance, although they could not statistically show that this fitted better than the polygenic model. The results raised the possibility of a common dominant gene with incomplete penetrance, but genetic analysis of NIDDM needs to take into account the likelihood of polygenic inheritance with genetic heterogeneity.Abbreviations MODY Maturity onset diabetes of the young - IDDM insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus - FPG fasting plasma glucose - AIC Akaike Information criterion     

常见型非胰岛素依赖型糖尿病患者的葡萄糖激酶基因分子扫查

对３０例起病于４５岁或以前及／或伴糖尿病家族史的中国人常见型非胰岛素依赖型糖尿病（ＮＩＤＤＭ）患者，进行葡萄糖激酶基因（ＧＣＫ）编码区及拼接区分子扫查。就扫查中发现的突变／变异，进一步在５６例ＮＩＤＤＭ者及１３４例非糖尿病患者中筛查，确认其频率。结果表明：①分子扫查未见ＧＣＫ编码区及拼接区突变，提示此类突变不是中国人常见型ＮＩＤＤＭ主要病因。②中国人常见型ＮＩＤＤＭ中，尤其是起病早及伴有明显糖尿病家族史者，可伴ＧＣＫ内含子１ｂ变异，此种变异未见于非糖尿病患者（４．７％比０％，Ｆｉｓｈｅｒ确切Ｐ值＝０．０２２）。此变异是否影响ＧＣＫ表达尚待阐明。     

Albumin excretion rate levels in non-diabetic offspring of NIDDM patients with and without nephropathy

Summary Familial clustering of diabetic nephropathy points to genetic susceptibility. The observation that in non-diabetic subjects microalbuminuria occurs more frequently in the presence of a parental history of diabetes supports this hypothesis. However, the role of inherited factors is poorly understood in non-insulin dependent diabetes mellitus (NIDDM). This study investigated the albumin excretion rate in non-diabetic offspring of NIDDM patients with increased albumin excretion rate (>20 g/min) or normal albumin excretion rate (<20 g/min). We recruited 20 offspring of NIDDM patients with increased albumin excretion rate (A-off) and 20 offspring of NIDDM patients with normal albumin excretion rate (N-off), matched for age, sex, body mass index, blood pressure and estimated protein intake. All offspring were normotensive, had normal creatinine clearance, normal glucose tolerance and sterile urine collection. Albumin excretion rate was measured on three sterile overnight urine collections and median values were used for calculations. Albumin excretion rate was significantly higher in A-off than in N-off (7.7±1.2 vs 3.4±0.6 g/min p<0.01) and significantly related to parents' albumin excretion rate (p<0.01, r=0.53). These results suggest that an increased glomerular permeability is present in non-diabetic offspring of NIDDM patients with increased albumin excretion rate.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - AER albumin excretion rate - OGTT oral glucose tolerance test - A-off offspring of NIDDM patients with increased albumin excretion rate - N-off offspring of NIDDM patients without increased albumin excretion rate     

Low birth weight – is it associated with few and small glomeruli in normal subjects and NIDDM patients?

Summary These studies were undertaken to ascertain if there is any association between low birth weight, and low kidney weight, few and/or small glomeruli, in kidneys from a control group and a group of non-insulin-dependent diabetic (NIDDM) patients. The background for this study comes from findings suggesting a correlation between low birth weight and the development of NIDDM and high blood pressure. Furthermore, Brenner has postulated that humans born with a low number of glomeruli, thereby having a low glomerular filtration surface area, have a greater tendency to develop high blood pressure. We examined 79 autopsy kidneys, with known weight from normal and NIDDM patients, which had previously been used for studies of glomerular number and volume. In the archives of the Danish midwives we were able to find birth weight for 26 NIDDM patients and an age- and sex-matched sample of 19 control persons. The kidney weight (g) (Control: 137 ± 36; NIDDM: 150 ± 38; 2p = 0.26), glomerular number (10³) (Control: 670 ± 176; NIDDM: 673 ± 200; 2p = 0.95), glomerular volume (10⁶μm³) (Control: 6.25 ± 1.48; NIDDM: 5.71 ± 1.74; 2p = 0.28) or birth weight (g) (Control: 3577 ± 400; NIDDM: 3489 ± 429; 2p = 0.49) were not different between the groups. There was no significant correlation between birth weight and glomerular number (Control: 2p = 0.80; r = 0.06 and NIDDM: 2p = 0.10; r = –0.33), glomerular volume (Control: 2p = 0.43; r = 0.19 and NIDDM: 2p = 0.78; r = 0.06) or kidney weight (Control: 2p = 0.56; r = 0.14 and NIDDM: 2p = 0.81; r = 0.05). Our results on a limited number of subjects in Denmark do not support the hypothesis that there is any association between low birth weight and low kidney weight or low birth weight and few and/or small glomeruli in NIDDM patients. [Diabetologia (1996) 39: 1634–1637]     

How often is NIDDM complicated with non-diabetic renal disease? An analysis of renal biopsies and the literature

Summary According to extensive autopsy studies, non-diabetic renal disease seems to be rare in diabetes mellitus, but recent publications suggest a significant prevalence of non-diabetic renal disease in non-insulin-dependent diabetic (NIDDM) patients, especially in the absence of retinopathy. The purpose of this study was to evaluate the prevalence of non-diabetic renal disease in NIDDM patients in renal biopsies from clinical practice, in patients suspected of having non-diabetic renal disease. In addition we systematically reviewed the literature. Biopsies were evaluated at the University Department of Pathology, Aarhus, Denmark, but had been collected at several departments of nephrology. In total 33 consecutive biopsies were available from 1988–1995 (mean age of patients: 62 years (range 39–75) (mean known diabetes duration 8 years (range 1–25); the main clinical reason for a biopsy was proteinuria. Renal function changes ranged from slight elevation of serum creatinine to uraemia. In addition 9 original papers, including our own material 580 patients were examined. On the basis of careful morphological evaluation according to international criteria, no patient exhibited an unequivocal sign of non-diabetic glomerular disease. Two patients had strongly but not completely convincing evidence of glomerulonephritis. One patient had some evidence of glomerulonephritis. These 3 patients also exhibited diabetic lesions. One patient with end-stage renal disease showed evidence of interstitial nephropathy without glomerular lesions. Thus, in 4 patients evidence of non-diabetic lesions was found. In the remaining 29 patients typical diffuse (n = 9) or nodular (n = 20) diabetic lesions were found. Twenty patients showed evidence of diabetic retinopathy. One of the patients with evidence of non-diabetic renal disease had simplex retinopathy. In the literature a considerable bias exists towards including patients with non-diabetic renal disease. In non-biased materials with proteinuria the prevalence of non-diabetic renal disease is very similar to our series. In microalbuminuric patients non-diabetic renal disease seems to be very rare. It can be concluded that in our material non-diabetic renal disease is uncommon in NIDDM patients, even if a clinician has suggested renal disease of other origin. A considerable bias towards including non-diabetic renal disease in NIDDM patients exists in the literature. The indication for biopsy should be evaluated carefully, and biopsy should by no means be routinely performed in NIDDM patients with proteinuria. [Diabetologia (1996) 39: 1638–1645]     

The Onset of NIDDM and its Relationship to Clinical Diagnosis in Egyptian Adults

The onset of diabetes relative to clinical diagnosis was estimated in Egyptians with non-insulin-dependent diabetes mellitus (NIDDM) based on the relationship between retinopathy and duration of diabetes. Between July 1992 and October 1993 the Diabetes in Egypt (DIE) Project performed a cross-sectional, population-based survey with clinical and laboratory follow-up to describe the prevalence of microvascular, neuropathic, and macrovascular complications among Egyptians ⩾ 20 years of age with diagnosed diabetes, previously undiagnosed diabetes, impaired glucose tolerance, and normal glucose tolerance. The sample of persons with diabetes diagnosed prior to the survey had medical examinations which included a dilated eye examination and retinal photographs. Generalized linear models were used to relate the probability of retinopathy to duration of diabetes. Among 218 persons with diabetes diagnosed prior to the DIE project, 87 (40 %) had diabetic retinopathy. The onset of retinopathy was estimated to occur 2.6 years (p = 0.04) prior to clinical diagnosis. The estimated annual incidence of retinopathy was 5 % and the estimated prevalence at the time of clinical diagnosis of diabetes was 12 %. On the basis of reports that retinopathy does not occur until approximately 5 years after the development of diabetes, the onset of NIDDM was estimated to occur 7.6 years prior to its clinical diagnosis. This estimate of the onset of NIDDM in Egyptians is comparable to other estimates reported for US and Australian populations.     

Clustering of albumin excretion rate abnormalities in Caucasian patients with NIDDM

Summary Proteinuria and nephropathy have been found to cluster in families of non-insulin-dependent diabetic (NIDDM) Pima Indian, and in Caucasian insulin-dependent diabetic (IDDM) patients. No information is at present available for Caucasian NIDDM patients. The aim of the present study was to determine whether micro-macroalbuminuria (AER + ) is associated with albumin excretion rate abnormalities in diabetic and non-diabetic siblings of probands with NIDDM and AER + . We identified 169 Caucasian families with one NIDDM proband (the patient with longest known NIDDM duration) (101 families with only NIDDM siblings, 33 families with both NIDDM and non-NIDDM siblings and 35 families with only non-NIDDM siblings). Of the probands 56 had AER + [Prob-NIDDM-(AER + )], 78 had AER– [Prob-NIDDM-(AER–)], 74 siblings of Prob-NIDDM-(AER + ), and 113 siblings of Prob-NIDDM-(AER–) also had NIDDM. Data on albuminuria and retinopathy from multiple sibling pairs when the size of the sibship was more than two was adjusted according to a weighting factor. The odds ratio for AER + , in siblings of Prob-NIDDM-(AER + ) adjusted for age, hypertension, glycated haemoglobin A_{1 c} and other confounding variables was 3.94 (95 % confidence intervals: 1.93–9.01) as compared to siblings of Prob-NIDDM-(AER–). The 74 siblings of Prob-NIDDM-(AER + ) had higher prevalence of proliferative retinopathy than siblings of Prob-NIDDM-(AER–) (14 vs 2 %; p < 0.01). We also identified 66 non-diabetic siblings of 41 NIDDM probands with AER + and 36 non-diabetic siblings of 27 NIDDM probands with AER–. Albumin excretion was two times higher, although still within the normal range, in the non-diabetic siblings of Prob-NIDDM-(AER + ) than in siblings of Prob-NIDDM-(AER–) [median = 13.5 (range 0.5–148) vs 6.6 (range 1–17) μg/min (p < 0.05)]. In conclusion higher rates of albumin excretion aggregate in Caucasian families with NIDDM. Proliferative retinopathy is more frequently observed in families showing a clustering of AER + and NIDDM. These findings suggest that familial factors play a role in the pathogenesis of renal and retinal complications in NIDDM. [Diabetologia (1997) 40: 816–823] Received: 6 November 1996 and in revised form: 17 February 1997     

Albumin excretion and vascular deaths in NIDDM

Summary Non-insulin-dependent diabetes mellitus (NIDDM) is associated with premature mortality, generally thought to be exaggerated in patients with microalbuminuria. This prospective 8-year follow-up study aimed to determine outcome, mortality and cause of death in NIDDM patients with abnormal urinary albumin excretion compared to those with normal albumin excretion. We recruited 153 NIDDM patients with abnormal urinary albumin excretion and 153 control subjects with albumin excretion within the normal non-diabetic range, matched for age, sex and duration of diabetes, from three University hospital diabetic clinics in Newcastle upon Tyne. The outcome measures were status at follow-up, mortality and cause of death. Subjects with abnormal albumin excretion had a significantly higher 8-year mortality than matched control subjects (Odds Ratio 1.47, p=0.02; 108 vs 66 per 1000 person years follow-up, p<0.001). This difference was seen at all levels of abnormal albumin excretion, from just outside the normal range (10.6–29.9 g/min: 104 vs 61 per 1000 person years follow-up, p<0.001) to more conventional definitions of microalbuminuria (30 g/min: 111 vs 71 per 1000 person years follow-up, p<0.01). Those with abnormal albumin excretion had an excess of vascular deaths compared to matched control subjects (Odds Ratio 1.70, p = 0.009), again at different levels of albumin excretion (10.6–29.9 g/min p<0.01, 30–150 g/min p<0.05). On multivariate analysis, age, initial ischaemic heart disease and initial albumin excretion rates were independent predictors of death from all causes. Even a minor elevation of albumin excretion above the normal non-diabetic range is associated with excess mortality from vascular causes in NIDDM.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - AER albumin excretion rate - SBP systolic blood pressure - DBP diastolic blood pressure - CI confidence interval - MAP mean arterial pressure     

HepG2/erythrocyte glucose transporter (GLUT1) gene in NIDDM: a population association study and molecular scanning in Japanese subjects

Summary To evaluate the role of mutations in the glucose transporter (GLUT1) gene in Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM), we first conducted a population association study using the XbaI polymorphism of the gene. A polymerase chain reaction (PCR)-based assay was developed and used for the analysis. When analysed in 91 diabetic patients and 87 non-diabetic control subjects, the distribution of the genotype frequency was significantly different between the two groups (p=0.0025). The (–) allele was significantly associated with NIDDM (odds ratio 2.317, 95% confidence interval 1.425–3.768). To identify possible mutation(s) in the GLUT1 gene, which was in linkage disequilibrium with the (–) allele, all ten exons of the gene were analysed by PCR single-strand conformation polymorphism (SSCP) analysis in 53 diabetic patients with at least one (–) allele. Variant SSCP patterns were detected in exons 2, 4, 5, 7, 9 and 10. Sequence analysis revealed that all the variants represented silent mutations. One of the variants in exon 2, GCT (Ala¹⁵)GCC(Ala), created a HaeIII restriction site. This polymorphism was common in Japanese subjects with heterozygosity of 0.36 and polymorphism information content 0.29. We conclude that the structural mutation of GLUT1 is rare and not likely to be a major genetic determinant of NIDDM in Japanese subjects. The Xbal (–) allele of the GLUT1 gene appeared to be a genetic marker of NIDDM in Japanese subjects. The possibility of the presence of mutation(s) in the regulatory region of the gene or in another locus nearby could not be excluded.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - PCR polymerase chain reaction - SSCP single strand conformation polymorphism - BMI body mass index - RFLP restriction fragment length polymorphism - TRE TPA-responsive elements - GLUT1 glucose transporter 1     

Incidence of NIDDM and the effects of gender, obesity and hyperinsulinaemia in Taiwan

Summary Our aim is to determine non-insulin-dependent diabetes mellitus (NIDDM) incidence in Taiwan and examine its relation to obesity and hyperinsulinaemia in Chinese men and women. A total of 995 men and 1195 women aged 35–74 years free from diabetes in two townships in Taiwan were followed up with a second examination. At baseline general and metabolic data were recorded, and detailed anthropometric parameters and plasma glucose and insulin were assessed. World Health Organisation (WHO) criteria of fasting glucose 7.8 mmol/l or greater was utilized for defining diabetes. The age-standardized incidence rate based on the United States population in 1970 was 9.3/1000 (CI 5.8–12.8) in men and 9.3/1000 (CI 6.2–12.4) in women and the based on the WHO population in 1976 was 8.9/1000 (CI .5–12.3) in men and 8.9/1000 (CI 5.9–11.9) in women for the Chinese who had a mean BMI slightly greater than 24 (kg/m²). The predictability of the plasma glucose level was greater than that of the insulin level and the obesity indices. NIDDM incidence increased approximately threefold with each 0.67 mmol/l increase in plasma glucose level in men and women. The present study demonstrated the essential relationship of not only BMI but also central obesity indices (such as subscapular and waist circumference) to the incidence of NIDDM among men and women and a stronger relationship between NIDDM incidence and obesity in women than in men. The predictive effects of obesity indices and fasting plasma insulin values on NIDDM risk were independent of each other in men. Obesity and hyperinsulinaemia each without the presence of the other can lead to an increased risk of NIDDM. In women the NIDDM incidence increased more than additively in those with both obesity and hyperinsulinaemia compared to those with single obesity or hyperinsulinaemia. A slightly higher incidence of NIDDM in Taiwan than in western countries was found. The importance of obesity is indicated for predicting NIDDM in the community. Hyperinsulinaemia was found to play a significant role in predicting NIDDM incidence independent of obesity in men and synergistically with obesity in women. [Diabetologia (1997) 40: 1431–1438] Received: 20 January 1997 and in final revised form: 11 June 1997     

Relationship Between Insulin Sensitivity and Insulin Receptor Substrate-1 Mutations in Non-diabetic Relatives of NIDDM Families

Insulin receptor substrate-1 (IRS-1) occupies a key position in the insulin-signalling pathway. Two mutations of the IRS-1 gene (Gly₉₇₂Arg and Ala₅₁₃Pro) have been described, although their roles in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) remain controversial. Insulin resistance has been described in non-diabetic relatives of NIDDM families, suggesting that it may be due to an inherited defect of insulin action. We therefore examined the relationships between the two mutations and insulin senstivity in 93 non-diabetic first degree relatives from North European families with 2 or more living NIDDM subjects. Anthropometric measurements, an oral glucose tolerance test, and an insulin tolerance test to assess insulin sensitivity (K_ITT) were performed. Basal insulin sensitivity was assessed by homeostasis model assessment (HOMA). Comparisons were made between the following relative subgroups: with (n = 9) and without (n = 84) the 972 mutation; with (n = 5) and without (n = 88) the 513 mutation; and with either one or both mutations (n = 13) or without either (n = 80). General linear model analysis was used to compare K_ITT and HOMA between the subgroups with the anthropometric variables known to influence insulin sensitivity as covariates. There were no significant differences between the subgroups for K_ITT and HOMA. In conclusion, the 513 and 972 mutations, alone and in combination, are not associated with decreased insulin sensitivity in non-diabetic relatives of NIDDM families.     

Changes in insulin receptor functions of the erythrocyte by treatment of non-insulin-dependent diabetes mellitus (NIDDM) patients with glibenclamide and diet control

Summary The insulin binding of erythrocytes from: (i) fifteen age-matched normal subjects, (ii) ten untreated NIDDM patients and (iii) fifteen treated (glibenclamide + hypocaloric diet) NIDDM patients (all males) has been studied. A significant decrease in specific insulin binding was observed in group (ii) which improved in cases controlled after treatment (group iii). Scatchard analysis of the results suggested that changes in insulin binding were due to alteration in the number of insulin receptors on erythrocytes. The number of insulin receptors/cell was 471 in normals, 160 in diabetics and 282 in treated diabetic subjects. No significant change in the binding affinity was observed in the three groups (1.0×10⁸, 1.2 × 10⁸ and 1.1×10⁸ M⁻¹ in normal subjects, untreated diabetics and treated diabetics, respectively). CDRI Communication No. 3807.     

Macro-microangiopathy and endothelial dysfunction in NIDDM patients with and without diabetic nephropathy

Summary The Steno hypothesis suggests that albuminuria reflects widespread vascular damage (proliferative retinopathy and severe macroangiopathy) due to a generalized vascular (endothelial) dysfunction. We assessed this concept in NIDDM (non-insulin-dependent diabetic) patients with (13 female/39 male, age 60 ± 7 years, group 1) and without (12 female/41 male, age 61 ± 7 years, group 2) diabetic nephropathy compared to matched non-diabetic subjects (7 female/15 male, age 58 ± 8 years, group 3). A 12-lead ECG was recorded and coded blindly using the Minnesota Rating Scale; the World Health Organization cardiovascular questionnaire was used to assess past and present evidence of myocardial infarction, angina pectoris, stroke, and peripheral vascular disease (digital systolic blood pressure determination). The degree of diabetic retinopathy was scored from fundus photography. The following variables were measured: transcapillary escape rate of albumin (initial disappearance of intravenously injected ¹²⁵I-labelled human serum albumin), plasma concentrations of prorenin (radioimmunoassay) and serum concentrations of von Willebrand factor (enzyme-linked immunoadsorbent assay). Prevalence of ischaemic heart disease (ECG reading) (49/20/5)% and peripheral vascular disease as indicated by reduced systolic blood pressure on big toe (69/30/14)% was significantly higher in group 1 vs group 2 (p < 0.01) and in group 2 vs group 3 (p < 0.01), respectively. The prevalence and severity of retinopathy was higher in group 1 vs 2 (p < 0.01). Transcapillary escape rate of albumin (%/h) was elevated in group 1 and 2 as compared to control subjects: 7.9 (4.3–13.7); 7.4 (3.7–16.4) vs 6.0 (3.4–8.7), (p < 0.005), respectively. Plasma prorenin activity (IU/ml) was raised in group 1 and group 2 as compared to group 3: 272 (59–2405); 192 (18–813), and 85 (28–246), p < 0.001, respectively. Serum von Willebrand factor (IU/ml)was elevated in group 1 as compared to group 2 and 3: 2.07 (0.83–4.34); 1.60 (0.30–2.99) and 1.50 (1.00–2.38), p < 0.001, respectively. Our study demonstrated that NIDDM patients with and without albuminuria had increased transcapillary escape of albumin and raised prorenin activity, whereas only those with albuminuria had increased von Willebrand factor. Patients with NIDDM may have abnormal endothelial function in the absence of albuminuria. [Diabetologia (1996) 39: 1590–1597]     

Long-term instability of fasting plasma glucose predicts mortality in elderly NIDDM patients: the Verona Diabetes Study

Summary The aim of this study was to evaluate whether long-term glucose control, as assessed by fasting plasma glucose determinations during 3 years, is a predictor of all-cause mortality in elderly NIDDM patients. Five hundred and sixty-six NIDDM patients attending the Verona Diabetes Clinic, aged 75 years and over, were followed-up from 1 January 1987 to 31 December 1991 to assess all-cause mortality. From their clinical records all fasting plasma glucose determinations available for the years 1984 to 1986 were collected and analysed. Patients were grouped in tertiles according to mean (M-FPG), coefficient of variation (CV-FPG) and trend over time (slope, S-FPG) of fasting plasma glucose during the period of retrospective evaluation. Mortality was assessed by observed/expected ratios, univariate Kaplan-Meier survival analysis and multivariate Poisson regression model. By 31 December 1991, 61 men and 127 women had died. Increased observed/expected ratios were found in women from the top M-FPG tertile, in patients (men and women) from the top CV-FPG tertile and in patients with a S-FPG less than –0.30 mmol/l per year (lowest tertile). Patients in the lowest tertile of CV-FPG and in the middle tertile of S-FPG had a reduced mortality risk. Kaplan-Meier survival analysis indicated that patients with high CV-FPG as well as those in tertiles I and III of S-FPG (i.e., those with a definitely negative or definitely positive slope) had an increased probability of dying, without any significant differences between the three tertiles of M-FPG. Poisson regression model showed that CV-FPG, but not M-FPG or S-FPG, was an independent significant predictor of mortality. These results suggest that glucose stability needs to be considered along with the absolute level of metabolic control when treating elderly NIDDM patients.Abbreviations SHU Social Health Unit - M-FPG mean fasting plasma glucose - CV-FPG coefficient of variation of fasting plasma glucose - S-FPG slope of fasting plasma glucose over time     

核素肾动态显像对老年非胰岛素依赖型糖尿病患者肾功能的研究

目的旨在评价非胰岛素依赖型糖尿病（ＮＩＤＤＭ）老年患者糖尿病肾病（ＤＮ）的进程，为临床治疗和判断预后提供依据。方法以９９ｍＴｃ－ＤＴＰＡ为示踪剂进行肾动态显像，同时获得肾小球滤过率（ＧＦＲ）、肾功能曲线和肾动态显像。结果本组患者ＧＦＲ均降低，病程≤１０年（６５．３±１３．１ｍｌ／ｍｉｎ）和病程＞１０年（５４．２±１５．７ｍｌ／ｍｉｎ）较对照组（９０．４±１６．６ｍｌ／ｍｉｎ）明显降低（Ｐ＜０．０１）；肾功能曲线峰时，病程≤１０年（左右肾分别为４．４±１．５及４．４±１．４分）和病程＞１０年（４．５±１．８及４．６±１．７分）较对照组（均为３．６±０．９分）明显后延（Ｐ＜０．０１），１０和２０分钟残存率均增高，后者仅病程＞１０年（左右肾分别为５４．２％±１４．１％及５３．９％±１４．２％）者较对照组（４８．６％±８．３％及４８．２％±９．３％）明显增高（Ｐ＜０．０５）。结论本组糖尿病患者的肾脏滤过和排泌功能均受损，其程度随ＮＩＤＤＭ病程的延长而加重，提示病程已进入ＤＮⅡ～Ⅳ期。