DNA polymorphism of Pvu II site in the lipoprotein lipase gene in patients with non-insulin dependent diabetes mellitus

We studied the effect of variation at the lipoprotein lipase (LPL) gene locus on the susceptibility of individuals with non-insulin dependent diabetes mellitus (NIDDM) in a population of 110 NIDDM patients and 91 controls. Our objective was to study the relationship between the LPL-Pvu II polymorphism and NIDDM and lipid metabolism. PCR-RFLP was used to determine the DNA polymorphism of the sixth intron of the LPL gene. The frequencies of the genotypes in case and control groups were 29.1 and 30.8% for P+/P+; 45.5 and 36.3% for P+/P-; 25.5 and 33% for P-/P- respectively. There was no significant difference in frequencies of genotypes between the two groups. Logistic regression analysis revealed that triacylglycerol (TAG) and apolipoprotein E levels were associated with NIDDM, whereas Pvu II genotypes were not found as independent risk factors for the disease. Overall this study demonstrates the role of the Pvu II polymorphism in the LPL gene in modulating plasma lipid/lipoprotein levels in patients with NIDDM.     

糖尿病的复合超声心动图研究

现用于检测非胰岛素依赖性糖尿素（ＮＩＤＤＭ）的彩色,脉冲多普勒及二维,Ｍ型超声心动图几种方法,各有优点与不足,本文利用其各自的优点,运用复合超声心动图法检测３０例无高血压的ＮＩＤＤＭ及３２例正常人,进行了对比。发现病变组心脏的收缩,舒张功能均有下降,认为,用此方法检测早期ＮＩＤＤＭ心脏改变是实用,可行的。     

Genetic Analysis of a New Mouse Model for Non-Insulin-Dependent Diabetes

The TallyHo (TH) mouse strain is a newly established model for non-insulin-dependent diabetes mellitus (NIDDM). TH mice show obesity, hyperinsulinemia, hyperlipidemia, and male-limited hyperglycemia. A genetic dissection of the diabetes syndrome has been carried out using male backcross 1 progeny obtained from crosses between (C57BL/6J x TH)F1 and TH mice or (CAST/Ei x TH)F1 and TH mice. A genome-wide scan reveals three quantitative trait loci (QTLs), Tanidd1-3 (TH-associated NIDDM) linked to hyperglycemia. The major QTL (common in both crosses), Tanidd1, maps to chromosome (Chr) 19. Additionally, gene-gene interactions contributing to hyperglycemia have been observed between Tanidd1 and a locus on Chr 18 as well as between Tanidd2 and a locus on Chr 16. The overt hyperglycemia in TH mice is, therefore, likely due to a mutation in a major diabetes susceptibility locus on Chr 19, which interacts with additional genes to lead to an observable phenotype.     

Improvement of glucose tolerance with immunomodulators in type 2 diabetic animals

Cytokine-inducers prevent insulin-dependent diabetes mellitus (IDDM) in animal models. We extended this therapy to non-insulin-dependent diabetes mellitus (NIDDM), because it was reported that diabetes of KK-Ay mice, a model for NIDDM, was recovered by allogenic bone-marrow transplantation that also prevented IDDM in animal models. An i.p. or i.v. injection of streptococcal preparation (OK 432) lowered fasting blood glucose (FBG) levels and markedly improved glucose tolerance test (GTT) in KK-Ay mice for more than 32 h regardless of the glucose loading routes (oral, i.v. or i.p.), while an i.v. injection of BCG improved FBG and GTT for more than 4 wks without body weight loss. The improvement of FBG and GTT with OK-432 was brought about in other NIDDM animals, GK rats and Wistar fatty rats. Among various cytokines possibly induced by OK-432 and BCG, IL-1α, TNFα and lymphotoxin significantly improved FBG and GTT in KK-Ay mice, whereas IL-2 and IFN_γ did not. There were no differences between the OK-432-treated KK-Ay mice and control in histology of the pancreas, degree of insulin-induced decrease in blood glucose levels, and muscle glycogen synthase activities. As to insulin secretion, there is a tendency that the OK-432-treatment less than 1 week did not affect insulin levels during GTT, whereas the treatment more than 2 weeks increased the insulin levels. Thus, cytokine-inducers improved FBG and glucose tolerance of NIDDM animals probably via cytokines. The results imply a role of the cytokines in glucose tolerance of NIDDM, although precise immune and metabolic mechanisms remain to be elucidated.     

Selected metals status in patients with noninsulin-dependent diabetes mellitus

In order to investigate the relationships between metals zinc [Zn], copper [Cu], magnesium [Mg], or Calcium [Ca] and noninsulin-dependent diabetes mellitus, 65 patients of newly diagnosed noninsulin-dependent diabetes mellitus and 54 nondiabetic healthy controls were studied. The concentrations of selected metals in fasting blood samples and 24-h urine collections were determined. Hyperzincuria and hypermagnesuria were detected in diabetic patients (p<0.01). The diabetics also had lower Zn and Mg, and higher Cu, and Ca levels in their plasma than those of the controls, but the statistical differences in Ca and Mg were not significant.Significantly lower Zn and higher Ca levels in erythrocytes were found in diabetic patients (p<0.01). There is evidence of a significant difference in metals status between diabetic patients with or without the specific complications. This study further indicates that patients with NIDDM on Taiwan also have distinct changes in their metals status, and these perturbations are associated with some diabetic complications.     

线粒体基因突变与NIDDM发生的关系

采用PCR-SSCP、PCR-RFLP及PCR产物直接测序等技术对90例NIDDM(即非胰岛素依赖型糖尿病)及80例正常对照个体的血细胞线粒体DNA进行了突变分析。结果在2例患者中发现线粒体DNA(mitochondrial DNA,mtDNA) ND1 (NaDH Dehydrogenase subunitⅠ)基因上3316位点存在G→A的点突变,导致丙氨酸错义突变成苏氨酸,而在80例正常对照个体中均不存在此位点突变。国内外已证实的和1.5%NIDDM发生有关的mtDNA tRNA Leu^(UUR)|基因上3243位点A→G的突变在本实验中并未发现。由此推断,3316位点G→A的突变可能与NIDDM的发生在关,3243位点A→G的突变率确实很低,可见糖尿病的发生在线粒体遗传上具有广泛的异质性。 Abstract:Using PCR-SSCP,PCR-RFLP and PCR product direct sequencing techniques,we analysed the mitochondrial DNAs(mtDNAs)of 90 patients with NIDDM (Non Insulin-Dependent Diabetes Mellitus)and those of 80 normal controls.The results showed that a G to A mutation which leads alanine’s missence mutaton to threonine in the mitochondrial ND1(NaDH Dehydrogenase subunit I) gene at nucleotide pair 3316 occurred in the blood cells of 2 patients.We have not however,indentified with the A to G mutation at nucleotide pair 3243 of the mitochondrial tRNA Leu(UUR) gene,which has been reported to associate with NIDDM in about 1.5% of the diabetic population.We infer that the mutation at position 3316 is perhaps associated with the development of NIDDM,the occurance of the mutation at position 3243 is actually rare,and NIDDM has an intensive mitochondrial genetic heterogenous background.     

Insulin Sensitivity as a Predictor of Weight Regain

A recent study found that increases in insulin sensitivity following weight loss and stabilization were strongly related to subsequent weight regain. The present paper analyzed this relationship in two behavioral weight-loss programs. In the first study, 125 nondiabetic subjects were followed over 30 months; weight losses averaged 10 kg at six months, and subjects had regained 8 kg of their weight loss by their 30-month follow-up. Neither fasting insulin levels at six months nor changes in fasting insulin from zero to six months were related to subsequent weight regain. Similarly, insulin levels measured two hours after a 75 g glucose load were unrelated to subsequent weight regain. The second study followed 33 individuals with Type II diabetes, treated with behavior modification, and either a low calorie diet or a very low calorie diet. Weight losses averaged 18 kg at six months, and subjects had regained 10 kg by their 24-month follow-up. The Bergman minimal model was used to assess insulin sensitivity at 6-month intervals. Initial analyses suggested that changes in insulin sensitivity from zero to six months were related to subsequent weight regain, but this effect was strongly influenced by an outlier. After removing this individual, there were no significant relationships between the changes in insulin sensitivity that accompanied weight loss and future weight regain. Likewise, insulin sensitivity at 12 months did not predict weight regain from 12 to 24 months. These data do not support the hypothesis that increases in insulin sensitivity with weight loss are associated with subsequent weight regain.     

Identification,partial purification,and localization of a neutral sphingomyelinase in rabbit skeletal muscle: Neutral sphingomyelinase in skeletal muscle

Transgenic and gene targeting approaches have now been applied to a number of genes in order to investigate the metabolic disorders that would result by manipulating insulin action or pancreatic -cell function in the mouse. The availability of such mutant mice will allow in the future to develop animal models in which the pathophysiologies resulting from polygenic defects might be reconstituted and studied in detail. Such animal models hopefully will lead to better understanding of complex polygenic diseases such as non-insulin-dependent diabetes mellitus (NIDDM).     

Genetic distances among the diabetic “Punjabis” and comparative populations from North India

Non-insulin dependent diabetes mellitus (NIDDM) is emerging as a major non-communicable disease in developing countries. Using principal component and Mahalanobis' generalized distance analyses, we examined gene frequency data at 3 polymorphic loci in sedentee urban controls, urban diabetics of the “Punjabi” population along with other comparative populations from North India. Mahalanobis generalized distance analysis suggests relative dissimilarity in the “Punjabi” disease subgroups indicating possible genetic heterogeneity. The genetic distance analysis also identified clinal variation along a north-west to south-east axis in North India.     

The tandem of free radicals and methylglyoxal

Methylglyoxal is an alpha-oxoaldehyde inevitably produced from triose-phosphate intermediates of phosphorylating glycolysis, and also from amino acids and acetone. Recently, the attention has been focused on the involvement of free radicals in methylglyoxal toxicity. In this review, a summary of the relationship between methylglyoxal metabolism and free radical production is presented, extending discussion from the possible metabolic routes to the toxicological events by reviewing the role of free radicals in both generation and degradation of this 1,2-dicarbonyl as well as in the modification of biological macromolecules, and focusing on the action of methylglyoxal upon cellular glutathione content. Methylglyoxal-provoked free radical generation involving reactive oxygen species (ROS), reactive nitrogen species (RNS) as well as organic radicals like methylglyoxal radial or crosslinked protein radical as potential risk factors to tissue damage propagation, is thoroughly discussed. Special attention is paid to the potential therapeutic interventions. The paper arrives at the conclusion that a tight junction exists between methylglyoxal toxicity and free radical (particularly ROS) generation, though the toxicity of 1,2-dicarbonyl evolves even under anaerobic conditions, too. The events follow a sequence beginning with carbonyl stress essential for the toxicity, leading to free radical formation and finally ending in either apoptosis or necrosis. Both oxidative and nitrosative stress play important but not indispensable role in the development of methylglyoxal toxicity.