Beta(2)-adrenergic receptor gene variation and hypertension in subjects with type 2 diabetes

The aim of this study was to investigate whether polymorphisms in the beta(2)-adrenergic receptor gene (5'LC-Arg19Cys, Arg16Gly, Gln27Glu) are associated with hypertension in patients with or without type 2 diabetes and with the blood pressure levels in normotensive sib pairs. The association study included 291 hypertensive patients without type 2 diabetes, 124 hypertensive patients with type 2 diabetes, and 265 healthy control subjects from SWEDEN: In addition, normotensive sib pairs that were discordant for the Arg16Gly (72 pairs) and Gln27Glu (40 pairs) polymorphisms were identified in type 2 diabetes families from FINLAND: Genotyping was performed using polymerase chain reaction-restriction fragment-length polymorphism analysis. Homozygous carriers of the Arg16 allele had a significantly increased odds ratio (OR) for hypertension in patients with type 2 diabetes (OR 2.14; 95% confidence interval [CI], 1.05 to 4.33), particularly among lean (body mass index<27 kg/m(2)) patients (OR 3.47; 95% CI, 1.06 to 11.33). The Gln27 allele showed a weaker association to hypertension (OR 1.55; 95% CI, 1.00 to 2.41) and was found to be in linkage disequilibrium with the Cys19 allele of the 5'LC-Arg19Cys polymorphism. In the paired-sibling analysis, siblings with at least 1 copy of the Arg16 allele had higher systolic blood pressure (P=0.049), and nondiabetic siblings had a higher body mass index (P=0.026) than siblings homozygous for the Gly16 allele. These results indicate that the Arg16 allele of the beta(2)-adrenergic receptor gene confers an increased risk for hypertension in subjects with type 2 diabetes and is associated with higher blood pressure levels and higher body mass index in sib pairs who are discordant for the polymorphism.     

Beta cell function during rapamycin monotherapy in long-term type 1 diabetes

Aims/hypothesis  

Type 1 diabetes is considered non-reversible at end-stage disease when there is no measurable insulin production. However, there are indications that insulin-producing beta cells could be present or return if autoimmunity could be controlled. We therefore sought to determine whether immunosuppression therapy can reinstate beta cell function in patients with long-term type 1 diabetes.     

Islet amyloid in type 2 (non-insulin-dependent) diabetes is related to insulin

Summary Amyloid deposition is the most typical islet alteration in Type 2 (non-insulin-dependent) diabetes. In the present study we show by immunohistochemistry that the amyloid reacts with an antiserum against insulin B chain. Islet amyloid was also purified, dissolved in guanidine-HCl and gel filtered on a Sepharose 6B column. Immunization of a guinea pig with a high molecular weight fraction from this gel filtration resulted in an antiserum with insulin-binding capacity. This binding was partially blocked with pure insulin B chain. The results indicate that islet amyloid contains insulin B chain and that the amyloid is a product of the islet B cells. Thus the study support previous morphological studies.     

Beta cells in type 2 diabetes - a crucial contribution to pathogenesis

The healthy β-cell has an enormous capacity to adapt to conditions of higher insulin demand (e.g. in obesity, pregnancy, cortisol excess) to maintain normoglycaemia with an increase in its functional β-cell mass. This compensates in 80–90% of individuals for insulin resistance. However, in 10–20% of individuals, the β-cells are unable to match the demands of insulin resistance and insulin levels are relatively insufficient to maintain normal glycaemic control. This eventually leads to glucose intolerance and type 2 diabetes (T2DM). Accordingly, preservation of functional β-cell mass has become central in the treatment of type 1 diabetes as well as T2DM. The purpose of this review is to summarize the recently described mechanisms of β-cell death in T2DM and to postulate possible new targets for treatment.     

Leukocyte-endothelial cell adhesion molecule 1 (LECAM-1) polymorphism is associated with diabetic nephropathy in type 2 diabetes mellitus

BACKGROUND/AIMS: Glomerular infiltration with monocytes/macrophages has been implicated in the pathogenesis of diabetic nephropathy. In this study, we evaluated the relationship between the genetic polymorphism in leukocyte-endothelial adhesion molecule-1 (LECAM-1) and diabetic nephropathy in patients with type 2 diabetes mellitus. METHODS: We determined the frequency of the LECAM-1 P213S genotype in 102 diabetic patients with diabetic nephropathy, 90 diabetic patients with no evidence of diabetic nephropathy, and 200 healthy control individuals. RESULTS: The frequency of the LECAM-1 213PP genotype and P allele in patients with diabetic nephropathy was significantly higher than that in patients without nephropathy (genotype 68% vs. 53%, chi(2)=6.78, P=.034; allele 83% vs. 72%, chi(2)=6.26, P=.012). The LECAM-1 P213 genotype was associated with a 1.86-fold increased risk for nephropathy independently of other risk factors. CONCLUSION: The data suggest that the LECAM-1 213PP genotype is a genetic risk factor for the development of nephropathy in type 2 diabetes mellitus.     

Autoimmunity, insulin resistance and Beta cell function in subjects with low body weight type 2 diabetes mellitus

In developing countries like India, the majority of Type 2 diabetics are non-obese, and many are "lean" with a body mass index (BMI) below 18.5. This type is referred to as "Low Body Weight Type 2 DM" (LB Type 2 DM). LB Type 2 DM are confused with Type 1 DM or late autoimmune diabetes in adults (LADA) due to their high blood glucose levels and early insulin-requiring state. We assessed pancreatic islet cell autoimmunity by using both glutamic acid decarboxylase 65 antibody (GADA) and anti-IA(2) antibody estimation in 23 patients with LB Type 2 DM and 10 age-matched normal weight (NW) Type 2 DM. Fasting blood glucose (FBG) and 2 hr postchallenge blood glucose (PGBG2) were significantly higher in LB (p < 0.05), while mean values of fasting insulin (24.47 +/- 73.15 muIU/mL vs. 13.4 +/- 16.54 muIU/mL, p > 0.7) and fasting C-peptide (180.81 +/- 357.08 pM/mL vs. 279.83 +/- 281.38 pM/mL, p > 0.5) in LB and NW respectively were not statistically different. All 23 LB and 10 NW subjects were GADA negative while IA(2) positivity was found in 1/23 and 1/10 cases, respectively. LB Type 2 DM revealed good beta cell function with homeostasis model assessment beta cells (HOMAB) values of 57.41 +/- 153.18 as compared to 44.74 +/- 56.24 (p > -0.2) in NW Type 2 DM. Insulin resistance as assessed by homeostasis model assessment insulin resistant (HOMA IR) was 13.50 +/- 42.83 and 5.68 +/- 6.90 (p > 0.6) in LB and NW Type 2 DM, respectively, suggesting that LB Type 2 DM are a phenotypic variant of Type 2 DM.     

Beta cell specific probing with fluorescent exendin-4 is progressively reduced in type 2 diabetic mouse models

Probes based on GLP-1R agonist exendin-4 have shown promise as in vivo β cell tracers. However, questions remain regarding the β cell specificity of exendin-4 probes, and it is unclear if the expression levels of the GLP-1R are affected in a type 2 diabetic state. Using in vivo probing followed by ex vivo imaging we found fluorescent exendin-4 probes to distinctly label the pancreatic islets in mice in a Glp-1r dependent manner. Furthermore, a co-localization study revealed a near 100 percent β cell specificity with less than one percent probing in other analyzed cell types. We then tested if probing was affected in models of type 2 diabetes using the Lepr^db/db (db/db) and the Diet-Induced Obese (DIO) mouse. Although nearly all β cells continued to be probed, we observed a progressive decline in probing intensity in both models with the most dramatic reduction seen in db/db mice. This was paralleled by a progressive decrease in Glp-1r protein expression levels. These data confirm β cell specificity for exendin-4 based probes in mice. Furthermore, they also suggest that GLP-1R targeting probes may provide a tool to monitor β cell function rather than mass in type 2 diabetic mouse models.     

Beta cell specific probing with fluorescent exendin-4 is progressively reduced in type 2 diabetic mouse models

Probes based on GLP-1R agonist exendin-4 have shown promise as in vivo β cell tracers. However, questions remain regarding the β cell specificity of exendin-4 probes, and it is unclear if the expression levels of the GLP-1R are affected in a type 2 diabetic state. Using in vivo probing followed by ex vivo imaging we found fluorescent exendin-4 probes to distinctly label the pancreatic islets in mice in a Glp-1r dependent manner. Furthermore, a co-localization study revealed a near 100 percent β cell specificity with less than one percent probing in other analyzed cell types. We then tested if probing was affected in models of type 2 diabetes using the Lepr^db/db (db/db) and the Diet-Induced Obese (DIO) mouse. Although nearly all β cells continued to be probed, we observed a progressive decline in probing intensity in both models with the most dramatic reduction seen in db/db mice. This was paralleled by a progressive decrease in Glp-1r protein expression levels. These data confirm β cell specificity for exendin-4 based probes in mice. Furthermore, they also suggest that GLP-1R targeting probes may provide a tool to monitor β cell function rather than mass in type 2 diabetic mouse models.     

Nateglinide is useful for nonalcoholic steatohepatitis (NASH) patients with type 2 diabetes

BACKGROUND/AIMS: In the present study we administered nateglinide to nonalcoholic steatohepatitis (NASH) patients with type 2 diabetes who had failed to respond adequately to diet and exercise therapy, and we compared the resulting changes in insulin kinetics and improvements in blood glucose levels, as well as the concomitant changes in hepatic function, diagnostic liver images and liver histology, with the results from a non-treated control group. METHODOLOGY: Subjects for this study consisted of 10 patients with NASH. They all suffered from diabetes and they were all diagnosed with fatty liver by abdominal ultrasonography (US) and computed tomography (CT). Nonalcoholic steatohepatitis was diagnosed as the result of liver biopsy. The subjects were randomly divided into two groups, the nateglinide-treated group and the non-treated control group. Each group contained five patients. The members of the nateglinide-treated group were administered nateglinide every day (270mg/day) before each meal for a period of 20 weeks. Both groups continued to receive diet and exercise therapy. Body mass index (BMI), blood chemistry, plasma glucose and HbAlc, abdominal US and CT were measured before treatment, and every four weeks thereafter. Liver biopsy was performed over again at 16 weeks af terinitiating treatment. RESULTS: The results were compared. Postprandial blood glucose, HbA1c, a 75-g oral glucose tolerance test, liver function, abdominal US and CT imaging tests and liver histological findings were all improved after treatment with nateglinide. CONCLUSIONS: From these results we concluded that nateglinide is useful in the treatment of NASH in patients with type 2 diabetes.     

The Tre2 (USP6) oncogene is a hominoid-specific gene

Gene duplication and domain accretion are thought to be the major mechanisms for the emergence of novel genes during evolution. Such events are thought to have occurred at early stages in the vertebrate lineage, but genomic sequencing has recently revealed extensive amplification events during the evolution of higher primates. We report here that the Tre2 (USP6) oncogene is derived from the chimeric fusion of two genes, USP32 (NY-REN-60), and TBC1D3. USP32 is an ancient, highly conserved gene, whereas TBC1D3 is derived from a recent segmental duplication, which is absent in most other mammals and shows rapid amplification and dispersal through the primate lineage. Remarkably, the chimeric gene Tre2 exists only in the hominoid lineage of primates. This hominoid-specific oncogene arose as recently as 21-33 million years ago, after proliferation of the TBC1D3 segmental duplication in the primate lineage. In contrast to the broad expression pattern of USP32 and TBC1D3, expression of Tre2 is testis-specific, a pattern proposed for novel genes implicated in the emergence of reproductive barriers. The sudden emergence of chimeric proteins, such as that encoded by Tre2, may have contributed to hominoid speciation.     

2型糖尿病家系肝细胞核因子1β基因1968A/G的多态性

糖尿病组中肝细胞核因子1β基因的G等位基因携带者的空腹C肽、△I10／△G30均明显低于AA基因型纯合子。一级亲属组中G等位基因携带者的空腹及餐后3h血糖，空腹、餐后2h及3h胰岛素明显高于AA基因型纯合子。     

Beta cell destruction in the development of autoimmune diabetes in the non-obese diabetic (NOD) mouse

In the non-obese diabetic (NOD) mouse model of Type 1 (insulin-dependent) diabetes, evidence suggests that pancreatic beta cells are destroyed in part by apoptotic mechanisms. The precise mechanisms of beta cell destruction leading to diabetes remain unclear. The NOD mouse has been studied to gain insight into the cellular and molecular mediators of beta cell death, which are discussed in this review. Perforin, secreted by CD8(+) T cells, remains one of the only molecules confirmed to be implicated in beta cell death in the NOD mouse. There are many other molecules, including Fas ligand and cytokines such as interferon-gamma, interleukin-1 and tumor necrosis factor-alpha, which may lead to beta cell destruction either directly or indirectly via regulation of toxic molecules such as nitric oxide. As beta cell death can occur in the absence of perforin, these other factors, in addition to other as yet unidentified factors, may be important in the development of diabetes. Effective protection of NOD mice from beta cell destruction may therefore require inhibition of multiple effector mechanisms.     

Beta 3-adrenergic receptor gene polymorphism and type 2 diabetes in a Caucasian population

Summary
Aim   The β₃-adrenergic receptor (β₃-AR) is suspected to play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. A mutation in the β₃-AR gene (Trp64Arg) has been associated with the capacity of weight gain and with early onset of noninsulin dependent diabetes mellitus (type 2 diabetes). In this study we investigated the prevalence of the two β₃-AR alleles in a Caucasian population and studied the association between the β₃-AR genotype and metabolic disorders (obesity and type 2 diabetes).
Methods   Genomic DNA extracted from peripheral blood leucocytes of 200 Caucasian subjects (137 subjects with and 63 subjects without type 2 diabetes). The Mva I polymorphism of β₃-AR, which detects the Trp64Arg mutation, was determined by polymerase chain reaction (PCR). We studied the correlation between the Trp64Arg mutation and the body mass index (b.m.i. kg/m²).
Results   There was no significant difference between the patients with type 2 diabetes and control subjects in the frequency of the Arg64 allele (5.5% and 4.8%, respectively). Within the group of type 2 diabetes patients were 14 subjects with the Trp64Arg mutation (b.m.i., mean ± s.d.: 31 ± 8.5 kg/m²) and 123 without the mutation (b.m.i. 29 ± 4.8). There was no association between the β₃-AR gene polymorphism and sex, obesity, blood pressure, glycohaemoglobin concentration, proteinuria.
Conclusion   Our results suggest that the Trp64Arg mutation is not a major determinant of metabolic disorders (type 2 diabetes, obesity) and chronic complications of type 2 diabetes in a Dutch population.