J. Y. Xu

Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice

Angiopoietin-like protein 4 (ANGPTL4) is a circulating protein predominantly expressed in adipose tissue and liver. Several recent studies demonstrated that ANGPTL4 is the target gene of peroxisome proliferation activators, the agonists of which are widely used as the antidiabetic and lipid-lowering drugs. Here we provide evidence that ANGPTL4 is a blood-borne hormone directly involved in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity. Adenovirus-mediated expression of ANGPTL4 potently decreased blood glucose and improved glucose tolerance, whereas it induced hyperlipidemia, fatty liver, and hepatomegaly in C57 mice. In db/db diabetic mice, ANGPTL4 treatment reduced hyperglycemia to a normal level, and markedly alleviated glucose intolerance and hyperinsulinemia. Ex vivo studies on primary rat hepatocytes revealed that ANGPTL4 significantly decreased hepatic glucose production and enhanced insulin-mediated inhibition of gluconeogenesis. Serum levels of ANGPTL4 in human subjects inversely correlated with plasma glucose concentrations and HOMA IR, the homeostasis model assessment of insulin resistance. In patients with type 2 diabetes, serum levels of ANGPTL4 were significantly lower than those in healthy subjects, suggesting that the decreased ANGPTL4 could be a causative factor of this disease. These results collectively indicate that ANGPTL4 exerts distinct effects on glucose and lipid metabolism, and that its beneficial effect on glucose homeostasis might be useful for the treatment of diabetes.

Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients

In Caucasians, maturity-onset diabetes of the young (MODY) is mostly caused by mutations in the hepatocyte nuclear factor (HNF)-1α (MODY3) and glucokinase (MODY2) genes. Most Japanese MODY patients, however, are not linked to known MODY genes. In this study, we examined the genetic and clinical characteristics of Chinese subjects with MODY. The study included 146 unrelated families fulfilling the minimum criteria for MODY: two consecutive generations of type II diabetes with at least one member diagnosed under the age of 25. We screened for mutations in the HNF-4α (MODY1), MODY2 and MODY3 genes by direct sequencing. Antibody to glutamic acid decarboxylase (GAD-Ab) was measured in subjects with MODY of unknown cause (MODYX). Insulin resistance index and other clinical data were compared in sex-, age- and duration-matched MODY3 and MODYX patients. In all, 13 families had MODY3 mutations and two had MODY2 mutations. No MODY1 mutation was found. Four of the 12 different MODY3 mutations were newly identified novel mutations (Q243E, A311D, P379R and P488fsdelC). In subjects with MODYX, 3% were GAD-Ab positive and 60% were overweight. Compared to MODY3 patients, MODYX patients had higher body mass index (P<0.02), higher insulin resistance index (P=0.001) and triglyceride level (P<0.02), lower HDL level (P=0.001) and more hypertension (P<0.05), but no significant difference in the prevalence of diabetic complications. In conclusion, MODY3 and MODY2 account for only 9 and 1%, respectively, of Chinese MODY. A majority of Chinese MODY patients are due to defects in unknown genes and appear to be characterized by insulin resistance.

Resistin gene polymorphisms and progression of glycaemia in southern Chinese: a 5-year prospective study

Objective  Human resistin gene (RETN) polymorphisms have been found to be associated with type 2 diabetes (T2DM), insulin resistance and/or obesity. We evaluated, in a 5‐year prospective study, whether RETN polymorphisms could predict the progression of glycaemia in southern Chinese.

Chronic treatment with growth hormone stimulates adiponectin gene expression in 3T3-L1 adipocytes.

Growth hormone (GH) is an important regulator of adiposity and systemic energy metabolism. Here, we have investigated the effects of GH on production of adiponectin, an anti‐diabetic and anti‐atherogenic hormone secreted exclusively from adipocytes. Analysis using real time quantitative PCR revealed that GH significantly increased adiponectin gene expression in a dose‐dependent manner. Time course study showed that the expression of adiponectin gene started to increase only after 30 h of GH treatment (10−8 M), suggesting it to be a chronic effect. GH‐mediated induction of adiponectin gene expression was completely blocked by treatment with the Janus kinase2 (JAK2) inhibitor AG490 and the P38 mitogen activated protein (MAP) kinase inhibitor SB203580, while the specific inhibitors of phosphatidylinositol‐3‐kinase (LY294002) and p70S6 kinase (rapamycin) moderately enhanced GHs effect. Co‐incubation of adipocytes with GH and the PPARγ agonist rosiglitazone produced additive effects on induction of adiponectin gene expression. These results collectively suggest that GH increases adiponectin gene expression through the JAK2‐P38 MAP kinase pathway, and that elevation of adiponectin production might represent a novel mechanism by which GH regulates systemic energy metabolism and insulin sensitivity.

Multiple endocrine neoplasia type 1 (MEN1): genetic and clinical analysis in the Southern Chinese

objective Multiple endocrine neoplasia type 1 (MEN1) is characterized by a triad of neoplasia affecting the parathyroid glands, enteropancreatic endocrine tissue and the anterior pituitary gland.

Effects of a promoter variation in the hepatic glucokinase gene on promoter activity and glucose tolerance in Southern Chinese subjects.

To the Editor: Glucokinase plays an important role in glucose homeostasis. In the pancreatic b-cell, it functions as the glucose sensor, whereas in the liver it facilitates glucose uptake during hyperglycaemia. A 258 G-to-A substitution in the liver promoter of the glucokinase gene was associated with diabetes and insulin resistance in African Americans and Asian Indians (1–3), but not in Danish Caucasians (4). In vitro transfection experiments showed that the G-to-A variant decreased the promoter activity to 42% of the wild-type promoter activity (2). We therefore investigated whether this promoter variation was associated with impaired glucose tolerance (IGT) in a Southern Chinese population. We studied 325 subjects with IGT and 351 subjects of similar age with normal glucose tolerance (NGT), as determined by using World Health Organization (WHO) diagnostic criteria (5), identified in the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study (6). All subjects underwent a 75-g oral glucose tolerance test with measurement of fasting and 2-h plasma glucose and insulin levels. Homeostasis model assessment (HOMA) index [(fasting glucose fasting insulin) 22.5] was calculated to estimate insulin resistance. The 258 G-to-A polymorphism was determined by AccI restriction fragment length polymorphism analysis and its effect on glucokinase promoter activity by transfection experiments. Different lengths (0.5 kb, 1.2 kb and 1.7 kb) of wild-type (G/G) and mutated (A/A) glucokinase promoter subcloned into luciferase reporter plasmid vector pGL2enhance (Promega Corp., Madison, WI) were transfected into HepG2 cells. After 72 h of incubation, the cells were harvested for protein, luciferase and b-galactosidase assay. Each experiment was repeated at least three times. All data were presented as mean SD. The differences in genotype frequency were tested using the -test and comparisons between different genotypes by analysis of covariance (ANCOVA) with confounding variables (including age, gender and body mass index) as covariates. The allele frequency of the A variant was 25.5% in IGT subjects and 23.5% in NGT subjects, and there were no differences in the distribution of genotypes between the two groups (p1⁄4 0.5). There were no significant differences in the fasting or 2-h glucose and insulin levels between the different genotypes, regardless of the glucose tolerance status, and even after adjusting for potential confounding variables (Table 1). In transient transfection experiments, the mutant promoter (A/A) activity was only 73% of the wild-type promoter (p1⁄4 0.008) when the length of the cloned glucokinase promoter was 0.5 kb from the transcription start site (Fig. 1). However, when the cloned glucokinase promoter length was increased to 1.2 kb or to 1.7 kb, the wildtype and variant glucokinase promoters exhibited similar activities. In agreement with findings reported in Caucasian subjects (4), we did not find any differences in the allelic frequency of the variant between Chinese subjects with IGT andNGT, nor in the insulin levels and HOMA index amongst subjects with different genotypes. Hence, this polymorphism is unlikely to contribute significantly to glucose intolerance in Chinese people. We have also shown that the size of the glucokinase gene promoter used in transfection experiments affects the promoter activity. The mutant promoter (A/A) activity is reduced when the Clin Genet 2003: 63: 232–234 Copyright # Blackwell Munksgaard 2003 Printed in Denmark. All rights reserved CLINICAL GENETICS