Role of prostaglandin D2 and the autonomic nervous system in niacin‐induced flushing (前列腺素D2与自主神经系统在烟酸引起的脸红中的作用)

Background: Although niacin often has beneficial effects on the lipoprotein profile, flushing is an untoward effect associated with its use. Aspirin can only reduce the flushing response by 30–40%. Thus, the aim of the present study was to investigate the mechanisms of niacin‐induced flushing, with and without aspirin, in normal, healthy individuals. Methods: Niacin‐induced flushing was evaluated in 30 healthy individuals after oral administration of 1000 mg niacin alone or with 325 mg aspirin. Neurological, autonomic nervous system, and skin blood flow measurements (using laser Doppler on the glabrous and hairy skin of each participant) were made at various times after drug administration. In addition, the systemic release of 9α,11β‐prostaglandin (PG) F₂ was determined. Flushing symptoms of redness, warmth, tingling, itching, and intensity were recorded using the modified Flushing ASsessment Tool (FAST). Results: After aspirin, the mean flushing scores for all symptoms decreased significantly; however, 36–53% of participants still had some degree of symptoms, even though aspirin completely blocked 11β‐PGF₂ synthesis. Maximum skin blood flow (MaxSkBF) in both the glabrous and hairy forearm increased significantly after niacin, but decreased significantly after aspirin only in hairy skin. Regression analysis showed that, in glabrous skin, both PGF₂ and parasympathetic activity were significant predictors of MaxSkBF after niacin, contributing 26% and 14%, respectively (total R² = 40%). Conclusions: The present study indicates, for the first time, that the parasympathetic nervous system, in addition to PGD₂, may play an important role in niacin‐induced flushing. Changing the sympathetic/parasympathetic balance in favor of parasympathetic activation may be a good therapeutic target to reduce niacin‐induced flushing.     

β‐Cell failure in type 2 diabetes

Type 2 diabetic patients are insulin resistant as a result of obesity and a sedentary lifestyle. Nevertheless, it has been known for the past five decades that insulin response to nutrients is markedly diminished in type 2 diabetes. There is now a consensus that impaired glucose regulation cannot develop without insulin deficiency. First‐phase insulin response to glucose is lost very early in the development of type 2 diabetes. Several prospective studies have shown that impaired insulin response to glucose is a predictor of future impaired glucose tolerance (IGT) and type 2 diabetes. Recently discovered type 2 diabetes‐risk gene variants influence β‐cell function, and might represent the molecular basis for the low insulin secretion that predicts future type 2 diabetes. We believe type 2 diabetes develops on the basis of normal but ‘weak’β‐cells unable to cope with excessive functional demands imposed by overnutrition and insulin resistance. Several laboratories have shown a reduction in β‐cell mass in type 2 diabetes and IGT, whereas others have found modest reductions and most importantly, a large overlap between β‐cell masses of diabetic and normoglycemic subjects. Therefore, at least initially, the β‐cell dysfunction of type 2 diabetes seems more functional than structural. However, type 2 diabetes is a progressive disorder, and animal models of diabetes show β‐cell apoptosis with prolonged hyperglycemia/hyperlipemia (glucolipotoxicity). β‐Cells exposed in vitro to glucolipotoxic conditions show endoplasmic reticulum (ER) and oxidative stress. ER stress mechanisms might participate in the adaptation of β‐cells to hyperglycemia, unless excessive. β‐Cells are not deficient in anti‐oxidant defense, thioredoxin playing a major role. Its inhibitor, thioredoxin‐interacting protein (TXNIP), might be important in leading to β‐cell apoptosis and type 2 diabetes. These topics are intensively investigated and might lead to novel therapeutic approaches. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00094.x, 2011)     

Type 2 diabetes mellitus‐related genetic polymorphisms in microRNAs and microRNA target sites (MicroRNAs中与2型糖尿病相关的基因多态性及microRNA靶位)

MicroRNAs (miRNAs) are important endogenous regulators in eukaryotic gene expression and a broad range of biological processes. MiRNA‐related genetic variations have been proved to be associated with human diseases, such as type 2 diabetes mellitus (T2DM). Polymorphisms in miRNA genes (primary miRNAs, precursor miRNAs, mature miRNAs, and miRNA regulatory regions) may be involved in the development of T2DM by changing the expression and structure of miRNAs and target gene expression. Genetic polymorphisms of the 3′‐untranslated region (UTR) in miRNA target genes may destroy putative miRNA binding sites or create new miRNA binding sites, which affects the binding of UTRs with miRNAs, finally resulting in susceptibility to and development of T2DM. Therefore, focusing on studies into genetic polymorphisms in miRNAs or miRNA binding sites will help our understanding of the pathophysiology of T2DM development and lead to better health management. Herein, we review the association of genetic polymorphisms in miRNA and miRNA targets genes with T2DM development.     

β‐cell differentiation status in type 2 diabetes

Type 2 diabetes (T2D) affects 415 million people worldwide and is characterized by chronic hyperglycaemia and insulin resistance, progressing to insufficient insulin production, as a result of β‐cell failure. Over time, chronic hyperglycaemia can ultimately lead to loss of β‐cell function, leaving patients insulin‐dependent. Until recently the loss of β‐cell mass seen in T2D was considered to be the result of increased rates of apoptosis; however, it has been proposed that apoptosis alone cannot account for the extent of β‐cell mass loss seen in the disease, and that a loss of function may also occur as a result of changes in β‐cell differentiation status. In the present review, we consider current knowledge of determinants of β‐cell fate in the context of understanding its relevance to disease process in T2D, and also the impact of a diabetogenic environment (hyperglycaemia, hypoxia, inflammation and dyslipidaemia) on the expression of genes involved in maintenance of β‐cell identity. We describe current knowledge of the impact of the diabetic microenvironment on gene regulatory processes such alternative splicing, the expression of disallowed genes and epigenetic modifications. Elucidating the molecular mechanisms that underpin changes to β‐cell differentiation status and the concomitant β‐cell failure offers potential treatment targets for the future management of patients with T2D.     

Significance of valine/leucine247 polymorphism of β2‐glycoprotein I in antiphospholipid syndrome: Increased reactivity of anti–β2‐glycoprotein I autoantibodies to the valine247 β2‐glycoprotein I variant

Objective

To clarify the consequences of the valine/leucine polymorphism at position 247 of the β₂‐glycoprotein I (β₂GPI) gene in patients with antiphospholipid syndrome (APS), by investigating the correlation between genotypes and the presence of anti‐β₂GPI antibody. The reactivity of anti‐β₂GPI antibodies was characterized using recombinant Val²⁴⁷ and Leu²⁴⁷ β₂GPI.

Methods

Sixty‐five Japanese patients with APS and/or systemic lupus erythematosus who were positive for antiphospholipid antibodies and 61 controls were analyzed for the presence of the Val/Leu²⁴⁷ polymorphism of β₂GPI. Polymorphism assignment was determined by polymerase chain reaction followed by restriction enzyme digestion. Recombinant Val²⁴⁷ and Leu²⁴⁷ β₂GPI were established to compare the reactivity of anti‐β₂GPI antibodies to β₂GPI between these variants. The variants were prepared on polyoxygenated plates or cardiolipin‐coated plates, and the reactivity of a series of anti‐β₂GPI antibodies (immunized anti‐human β₂GPI monoclonal antibodies [Cof‐19–21] and autoimmune anti‐β₂GPI monoclonal antibodies [EY1C8, EY2C9, and TM1G2]) and IgGs purified from patient sera was investigated.

Results

A positive correlation between the Val²⁴⁷ allele and the presence of anti‐β₂GPI antibodies was observed in the patient group. Human monoclonal/polyclonal anti‐β₂GPI autoantibodies showed higher binding to recombinant Val²⁴⁷ β₂GPI than to Leu²⁴⁷ β₂GPI, although no difference in the reactivity of the immunized anti‐β₂GPI between these variants was observed. Conformational optimization showed that the replacement of Leu²⁴⁷ by Val²⁴⁷ led to a significant alteration in the tertiary structure of domain V and/or the domain IV–V interaction.

Conclusion

The Val²⁴⁷ β₂GPI allele was associated with both a high frequency of anti‐β₂GPI antibodies and stronger reactivity with anti‐β₂GPI antibodies compared with the Leu²⁴⁷ β₂GPI allele, suggesting that the Val²⁴⁷ β₂GPI allele may be one of the genetic risk factors for development of APS.

     

Homozygous G γλβ thalassaemia

Summary This report describes the clinical and haematological findings in three siblings homozygous for ^Gγ δβ thalassaemia in an Indian family. There was a mild to moderate anaemia and markedly abnormal red cell morphology. Haemoglobin analysis showed 100% Hb F, solely of the ^Gγ type, with a pancellular but uneven distribution. Considerable chain imbalance was detectable in globin synthesis studies. In contrast to the five previously reported cases, these children were essentially asymptomatic and have never required transfusions.     

β‐cell mass in people with type 2 diabetes

The early occurrence of β‐cell dysfunction has been broadly recognized as a critical determinant of the development and progression of type 2 diabetes. β‐cell dysfunction might be induced by insufficient β‐cell mass, by a dysfunction of the β‐cells, or both. Whether or not β‐cell dysfunction constitutes a cause of reduced β‐cells or vice‐versa currently remains unclear. The results of some studies have measured the loss of β‐cells in type 2 diabetic patients at between 22 and 63% by planimetric measurements. Because β‐cell hypertrophy has been noted in type 2 diabetic patients, the loss of β‐cell number should prove more profound than what has thus far been reported. Furthermore, β‐cell volumes are reduced even in patients with impaired fasting glucose. Such defects in β‐cell mass are associated with increased apoptosis rather than insufficient replication or neogenesis of β‐cells. With these results, although they still require clarification, the peak β‐cell mass might be determined at quite an early stage of life, and then might decline progressively over time as the result of exposure to harmful environmental influences over one’s lifetime. In this review, we have summarized the relevant studies regarding β‐cell mass in patients with type 2 diabetes, and then presented a review of the various causes of β‐cell loss in adults. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00072.x, 2010)     

Role of premixed insulin analogues in the treatment of patients with type 2 diabetes mellitus: A narrative review (预混胰岛素类似物在2型糖尿病治疗中的作用：叙述性综述)

Because of the progressive nature of type 2 diabetes mellitus (T2DM), insulin therapy will eventually become necessary in most patients. Recent evidence suggests that maintaining optimal glycemic control by early insulin therapy can reduce the risk of microvascular and macrovascular complications in patients with T2DM. The present review focuses on relevant clinical evidence supporting the use of premixed insulin analogues in T2DM when intensifying therapy, and as starter insulins in insulin‐naïve patients. Our aim is to provide relevant facts and clinical evidence useful in the decision‐making process of treatment selection and individualized treatment goal setting to obtain sustained blood glucose control.     

Glucagon‐like peptide 1‐potentiated insulin secretion and proliferation of pancreatic β‐cells GLP‐1促进胰岛素分泌和胰岛β细胞增殖的机制

Glucagon‐like peptide‐1 (GLP‐1) is the primary incretin hormone secreted from the intestine upon uptake of food to stimulate insulin secretion from pancreatic β‐cells. GLP‐1 exerts its effects by binding to its G‐protein coupled receptors and subsequently activating adenylate cyclase, leading to generation of cyclic adenosine monophosphate (cAMP). cAMP stimulates insulin secretion via activation of its effectors PKA and Epac2 in pancreatic β‐cells. In addition to its insulinotropic effects, GLP‐1 also preserves pancreatic β‐cell mass by stimulating β‐cell proliferation. Unlike the action of sulphonylureas in lowering blood glucose levels, action of GLP‐1 is affected by and interplays with glucose levels. Due to such advantages, GLP‐1‐based therapeutics have been rapidly developed and used clinically for treatment of type 2 diabetes. However, molecular mechanisms underlying how GLP‐1 potentiates diminished glucose‐stimulated insulin secretion and β‐cell proliferation under diabetic conditions are not well understood. Here, we review the actions of GLP‐1 in regulation of insulin secretion and pancreatic β‐cell proliferation.