Background Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. Objectives To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies. Search strategy A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Selection criteria Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. Data collection and analysis The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data. Main results Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies. Authors' conclusions There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.

/pdf/risk-of-fatal-and-nonfatal-lactic-acidosis-with-metformin-4ujte07kg8.pdf

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus

Thiazolidinediones(TDs)是一类新型的胰岛素抵抗治疗药物。动物及临床实验证实TDs通过激活核受体过氧化物酶体增殖物激活受体-γ(PPAR-γ)显著增加胰岛素敏感性，改善胰岛β-细胞功能，降低血糖和胰岛素水平，缓解高血压及脂代谢紊乱，对2型糖尿病大血管和微血管病变亦具有保护作用。临床使用耐受性好，低血糖发生率低。但其中的Troglitazone具有明显的肝脏毒性。

胰岛素增敏剂一Thiazolidinediones研究现状

This evidence-based guideline from the American College of Physicians addresses oral pharmacologic treatment of type 2 diabetes in adults.

Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians.

Growing evidence supports the role of gut microbiota in the development of obesity, type 2 diabetes, and low-grade inflammation. The endocrine activity of adipose tissue has been found to contribute to the regulation of glucose homeostasis and low-grade inflammation. Among the key hormones produced by this tissue, apelin has been shown to regulate glucose homeostasis. Recently, it has been proposed that gut microbiota participate in adipose tissue metabolism via the endocannabinoid system (eCB) and gut microbiota-derived compounds, namely lipopolysaccharide (LPS). We have investigated gut microbiota composition in obese and diabetic leptin-resistant mice (db/db) by combining pyrosequencing and phylogenetic microarray analysis of 16S ribosomal RNA gene sequences. We observed a significant higher abundance of Firmicutes, Proteobacteria, and Fibrobacteres phyla in db/db mice compared to lean mice. The abundance of 10 genera was significantly affected by the genotype. We identified the roles of the eCB and LPS in the regulation of apelinergic system tone (apelin and APJ mRNA expression) in genetic obese and diabetic mice. By using in vivo and in vitro models, we have demonstrated that both the eCB and low-grade inflammation differentially regulate apelin and APJ mRNA expression in adipose tissue. Finally, deep-gut microbiota profiling revealed that the gut microbial community of type 2 diabetic mice is significantly different from that of their lean counterparts. This indicates specific relationships between the gut microbiota and the regulation of the apelinergic system. However, the exact roles of specific bacteria in shaping the phenotype of db/db mice remain to be determined.

/pdf/altered-gut-microbiota-and-endocannabinoid-system-tone-in-4xgx4hmbp0.pdf

Altered Gut Microbiota and Endocannabinoid System Tone in Obese and Diabetic Leptin-Resistant Mice: Impact on Apelin Regulation in Adipose Tissue

The apelin receptor (APJ; gene symbol APLNR) is a member of the G protein-coupled receptor gene family. Neural gene expression patterns of APJ, and its cognate ligand apelin, in the brain implicate the apelinergic system in the regulation of a number of physiological processes. APJ and apelin are highly expressed in the hypothalamo-neurohypophysial system, which regulates fluid homeostasis, in the hypothalamic-pituitary-adrenal axis, which controls the neuroendocrine response to stress, and in the forebrain and lower brainstem regions, which are involved in cardiovascular function. Recently, apelin, synthesised and secreted by adipocytes, has been described as a beneficial adipokine related to obesity, and there is growing awareness of a potential role for apelin and APJ in glucose and energy metabolism. In this review we provide a comprehensive overview of the structure, expression pattern and regulation of apelin and its receptor, as well as the main second messengers and signalling proteins activated by apelin. We also highlight the physiological and pathological roles that support this system as a novel therapeutic target for pharmacological intervention in treating conditions related to altered water balance, stress-induced disorders such as anxiety and depression, and cardiovascular and metabolic disorders.

/pdf/the-apelin-receptor-apj-journey-from-an-orphan-to-a-5ctnx3fcdr.pdf

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis.

Objective: To investigate blood apelin concentrations in patients with newly diagnosed and untreated type 2 diabetes mellitus (T2DM) who had no additional disorder and to investigate the association of apelin with adiponectin, body mass indexes (BMI) and insulin sensitivity. Methods: Forty patients with T2DM and 40 healthy controls were enrolled. Apelin levels were measured along with BMI, lipids, glucose, insulin and adiponectin levels, and HOMA-IR indexes. Age, sex and BMI were similar in the two groups. Results: Plasma apelin and adiponectin levels were significantly lower in the diabetic group compared to controls (p<0.001, for both). Insulin levels and HOMA indexes were significantly higher in patients with T2DM (p<0.001 and p=0.001, respectively). Apelin levels were negatively correlated with age (r= -0.315, p=0.006), fasting blood glucose (r=-0.556, p<0.001) and HOMA indexes (r=-0.411, p=0.001), and positively correlated with plasma adiponectin levels (r=0.593, p<0.001). Plasma adiponectin was negatively correlated to plasma insulin (r= -0.379, p=0.001), fasting glucose (r= -0.604, p<0.001), HOMA-IR (r=-0.559, p<0.001) and BMI (=-0.229, p=0.04). Conclusions: Plasma apelin is reduced in newly diagnosed and untreated patients with T2DM having no confounders. Regulation of circulating apelin and adiponectin seems to be in the same manner in patients with T2DM. Dysregulation of apelin might be involved in the mechanism of establishment of overt diabetes mellitus as well as associated atherosclerotic complications.

Low plasma apelin levels in newly diagnosed type 2 diabetes mellitus.

Vaspin and its correlation with insulin sensitivity indices in obese children.

The effects of pioglitazone and metformin on plasma visfatin levels in patients with treatment naive type 2 diabetes mellitus.

BACKGROUND Apelin is a recently defined peptide relevant to the mechanism of obesity-related disorders There has been no report so far about the levels of plasma apelin in obese children METHODS In this study plasma apelin, adiponectin, and high sensitivity C reactive protein levels were investigated in obese (n=32) and nonobese (n=40) children The effects of pubertal status on the apelin and adiponectin levels were evaluated as well RESULTS When compared to nonobese controls, the obese children had significantly lower plasma apelin (p = 0004), adiponectin and HDL cholesterol levels (p = 0001 for both), and higher hs-CRP, triglycerides, insulin and Homeostasis Model Assessment (HOMA-IR) indexes (p < 0001 for all) The difference between the apelin levels was present only in the pubertal period (p = 0002) CONCLUSIONS The results of the present study indicate that plasma apelin levels are lower in child obesity and pubertal state is an important determinant of plasma apelin levels

Decreased plasma apelin levels in pubertal obese children.

± 1.02 vs. 12.5 ± 6.2, p<0.001) were significantly lower in the obese group. Comparisons of the clinical and metabolic characteristics between insulinresistant and noninsulin-resistant groups in obese children are summarized. The insulin-resistant group had higher visfatin levels (36 ± 9.7 vs. 22.9 ± 7.6, p<0.001) and lower adiponectin levels (1.7 ± 1.05 vs. 2.5 ± 0.77, p: 0.016). Visfatin was correlated positively and adiponectin was correlated negatively with body mass index standard deviation score (BMI-SDS) and HOMA-IR. The role of various adipokines as connectors between obesity and diabetes mellitus has been better elucidated in recent years. Based on the findings of this study, visfatin and adiponectin levels can be used as specific markers for insulin sensitivity.

Serkan Tapan

Papers

Low plasma apelin levels in newly diagnosed type 2 diabetes mellitus.

Vaspin and its correlation with insulin sensitivity indices in obese children.

The effects of pioglitazone and metformin on plasma visfatin levels in patients with treatment naive type 2 diabetes mellitus.

Decreased plasma apelin levels in pubertal obese children.

Evaluation of adipocytokines in obese children with insulin resistance.