Myostatin is a procachectic growth factor during postnatal myogenesis

PURPOSE OF REVIEW: To describe the most relevant recent observations concerning the molecular mechanisms behind myostatin-induced muscle wasting. RECENT FINDINGS: The main theme of this review is to summarize the biology and function of myostatin. Myostatin is a secreted growth factor that negatively regulates muscle growth. While inactivation of myostatin leads to muscle growth in vivo, excess levels of myostatin induces cachectic-like muscle wasting. Molecular analyses reveal that excess levels of myostatin induce Atrogin-1 expression by reducing Akt phosphorylation and thereby increasing FoxO1 activity. Recent findings have further speculated that myostatin may also play a role in cardiac cachexia. SUMMARY: As myostatin is a potent inducer of muscle wasting, antagonists to myostatin have been speculated to have great therapeutic value in alleviating muscle wasting. Indeed, myostatin peptide antagonists and antibodies have shown great promise in containing muscle loss in animal models of muscle wasting. Given the beneficial effects of myostatin antagonists in animal models, clinical trials are underway with myostatin antibodies, peptibodies and soluble receptor. Therefore, this review article on the role of myostatin in muscle wasting is highly relevant to current themes in muscle biology.     

Association of insulin resistance with serum ferritin and aminotransferases-iron hypothesis

AIM: To investigate the relationship of iron indices with diabetes mellitus(DM) in those without hemochromatosis.METHODS: This cross-sectional study examined data collected during the Third National Health and Nutrition Examination Survey(NHANES III). Only those who fasted properly and were not anemic with transferrin saturation 45% were included(n = 6849). Insulin sensitivity and beta cell function were calculated from fasting glucose and insulin concentrations. Indices of iron metabolism were examined in the presence or absence of DM. We examined the relationship of insulin sensitivity and beta cell function with serum ferritin concentration. The influence of C-reactive protein and liver enzymes was also investigated.RESULTS: Serum ferritin concentration was significantly higher in diabetic subjects(P = 0.0001 to 0.000001). The difference remained significant after adjustment for age, body mass index, alcohol consumption, and mineral/iron supplement(P = 0.03 to 0.000001). In those who did not take insulin, serum ferritin concentration was negatively associated with insulin sensitivity(P = 0.05 to 0.00001), but not with beta cell function. The alanine aminotransferase was correlated with serum ferritin concentration(P = 0.02 to 0.000001) but not with insulin sensitivity, suggesting the role of the liver in iron-associated insulin resistance.CONCLUSION: As most of diabetes is type 2 diabetes and insulin resistance is a cardinal feature of type 2diabetes, disordered iron metabolism could play a role in the pathogenesis of insulin resistance and type 2diabetes through its effect on liver function.     

Analysis of factors influencing nitrogen balance during acute starvation in obese subject with and without type 2 diabetes

BACKGROUND & AIMS: Patients with type 2 diabetes (T2DM) tend to loose more lean body mass during both long-term weight reduction and short-term very-low-calorie diet. We ask what factors influence protein loss during acute starvation in T2DM. METHODS: In a prospective in-hospital observational study, we compared 10 subjects with T2DM and 10 age-weight-sex matched obese controls (OB) during 60 h of fasting and used frequent blood sampling and indirect calorimetry to describe metabolic and endocrine response. We analyzed factors influencing nitrogen balance using stepwise multiple regressions. RESULTS: Despite comparable pattern of plasma insulin, free fatty acid, 3-hydroxybutyrate and almost identical behavior of growth hormone axis, our T2DM subjects remained hyperglycaemic and in contrast to OB subjects they failed to reduce the rate of protein oxidation, even though muscle protein breakdown rate declined similarly in both groups. Regression analysis revealed that protein oxidation rate in T2DM group was enhanced by hyperglycemia and sympathetic activity and suppressed by circulating insulin and 3-hydroxybutyrate. Liver insulin resistance increases peripheral insulin concentrations and enhances the conversion of non-esterified fatty acids (NEFA) to ketones and thus it might be a protein-saving factor. CONCLUSION: Relative deficiency of circulating insulin and hyperglycemia play a pivotal role in the impairment of protein sparing in T2DM during a short-term fasting.     

Plasma resistin, insulin concentration in non-diabetic and diabetic, overweight/obese Thai

This study investigated levels of fasting plasma glucose (FBS), homeostasis model of the assessment of the insulin resistance (HOMA), lipid profile, insulin, and resistin hormones in 202 individuals, divided into four groups. Two groups had type II diabetes mellitus (DM): one group had been overnourished (DM/OB) (body mass index: BMI equal or above 25) and the other had not (DM/nOB). Two additional groups not suffering from diabetes were either overnourished (nDM/OB) or of normal nutritional status (nDM/nOB). Only the DM/OB group had insulin levels elevated above the other three groups. Resistin levels had been lowest in the nDM/nOB group. When participants of the two nOB groups were pooled into one group and the subjects of the two OB groups were combined into another group, the median plasma resistin levels of the OB groups were significantly higher compared with the nOB groups. Likewise the DM groups had higher resistin levels than the nDM groups. A significant correlation of plasma resistin with BMI, waist circumference, waist-to-hip ratio, FBS, and HOMA score had been observed. The result suggests that plasma resistin has a role in linking central obesity and obesity-related insulin resistance to type II diabetes mellitus.     

Gene therapy with anabolic growth factors to prevent muscle atrophy

PURPOSE OF REVIEW: Many situations cause muscle atrophy. When severe, muscle atrophy is associated with an increase in morbidity and mortality. This loss of muscle mass is thought to be due to an imbalance between catabolic and anabolic pathways, resulting in an increase of muscle protein proteolysis and in a decrease in protein synthesis. Changes in muscle levels of muscle growth factors are thought to play a major role in this imbalance. Despite recent better understanding of the metabolic and molecular derangements leading to muscle wasting, therapy of muscle atrophy still has a poor success rate. RECENT FINDINGS: The recent demonstration that changes in local growth factors, such as insulin-like growth factor-I and myostatin, occur during muscle atrophy has stimulated research interest to prevent muscle mass loss by delivering these growth factors or their inhibitors into the muscle. During the last few years, several advances in the field of muscle gene transfer, using electroporation or recombinant adeno-associated viral vectors, have opened novel therapeutic ways to deliver growth factors able to counteract the loss of muscle mass. SUMMARY: Preventing decrease of insulin-like growth factor-I muscle, or inhibiting myostatin action by local genes over-expression, may provide a clinically relevant avenue for the preservation, attenuation or reversal of disease-related muscle loss.     

甘精胰岛素用于Ⅱ型糖尿病患者术后血糖控制的探讨

目的:探讨甘精胰岛素用于II型糖尿病患者手术后血糖控制的可行性。方法:选择51例接受外科手术后的II型糖尿病患者,分为甘精胰岛素治疗组(LAN组)16例,常规生物合成人胰岛素治疗组(MSII组)19例,胰岛素泵治疗组(CSII组)16例。LAN组患者术后使用甘精胰岛素,视空腹血糖变化情况调整其剂量,患者如进食则于餐前给予短效胰岛素。MSII组术后用静脉胰岛素输注,患者进食后可逐渐采用传统胰岛素强化治疗方案(R+R+R+NPH)。CSII组每天24 h持续泵入短效胰岛素,禁食期只给予基础量,进食后给予基础和餐时量。观察各组患者治疗前后血糖变化、胰岛素用量、低血糖发生率及术后并发症发生率,酮症发生率。结果:各组治疗后血糖均明显低于治疗前,LAN组治疗后血糖低于MSII组,与CSII组无明显差异;LAN组低血糖发生率低于MSII组,而与CSII比较无显著性差异。结论:II型糖尿病患者术后禁食或进食不规律阶段,使用常规胰岛素治疗,血糖波动较大且患者依从性差;甘精胰岛素在糖尿病患者手术后降糖效果显著,能迅速、平稳控制血糖且患者依从性好,是一种安全、有效且患者易接受的用于II型糖尿病患者术后治疗的药物。     

Role of fatty acids in the development of insulin resistance and type 2 diabetes mellitus

Insulin resistance is defined as the reduced responsiveness to normal circulating levels of insulin. It is the basic condition of type 2 diabetes mellitus, in which both experimental animals and humans accumulate lipids intracellularly in skeletal muscle and liver. Measurement of these lipids in humans, using nuclear magnetic resonance spectroscopy after lipid infusion, indicated they could cause inhibition of the glucose transporter GLUT4, thereby suppressing glucose entry into cells and inhibiting glucose oxidation and glycogen synthesis in muscle. Furthermore, it is known that the enzyme acetyl-CoA carboxylase2 (ACC2) suppresses the oxidation of fatty acids by inhibiting the entry of fatty acids into mitochondria. Further support for the lipocentric hypothesis of the pathogenesis of insulin resistance was provided by knocking out the gene coding for ACC2 in mice; this led to greater fatty acid oxidation, reduced fat mass and, in consequence, greatly enhanced insulin sensitivity. These studies suggest that a specific inhibitor of ACC2 would have therapeutic potential for type 2 diabetes mellitus.     

初诊2型糖尿病患者胰岛素强化治疗恢复胰岛功能的研究

目的研究胰岛素强化治疗对初发2型糖尿病患者胰岛β细胞功能的影响。方法选取初发2型糖尿病患者50例，实验前测患者空腹和葡萄糖负荷后0．5h及2h胰岛素分泌水平，经过3个月胰岛素强化治疗后，再进行空腹及葡萄糖刺激下胰岛素分泌测定。结果胰岛素强化治疗3个月，葡萄糖负荷后0．5h胰岛素释放量增加明显，空腹及2h胰岛素分泌量有所下降。结论胰岛素强化控制血糖，可改善胰岛β细胞功能早期胰岛素分泌缺陷。     

Effect of taurine treatment on insulin secretion and action, and on serum lipid levels in overweight men with a genetic predisposition for type II diabetes mellitus

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) is increasing with an epidemic growth rate. Animal studies with taurine supplementation have shown increased insulin secretion and action, suggesting that taurine supplementation may have a potential to prevent T2DM. OBJECTIVE: To assess the effect of taurine treatment on insulin secretion and action, and on plasma lipid levels in overweight men with a positive history of T2DM. DESIGN: 20 nondiabetic subjects were included in a double-blinded, randomized, crossover study, receiving a daily supplementation of 1.5 g taurine or placebo for two periods of 8 weeks. The subjects were overweight first-degree relatives of T2DM patients. An intravenous glucose tolerance test (IVGTT) was used to measure first-phase insulin secretory response, and a euglycemic hyperinsulinemic clamp was used to determine peripheral insulin action. RESULTS: Mean plasma taurine concentration was 39 +/- 7 (s.d.) micromol/l after placebo and 131 +/- 62 micromol/l after taurine intervention (P < 0.0001). There was no significant difference after taurine intervention compared to placebo in incremental insulin response (Insincr.) neither during the IVGTT, nor in insulin-stimulated glucose disposal during the clamp. Insulin secretion, adjusted for insulin sensitivity, was also unchanged. There was no significant effect of taurine supplementation on blood lipid levels as well. CONCLUSION: Daily supplementation with 1.5 g taurine for 8 weeks had no effect on insulin secretion or sensitivity, or on blood lipid levels. These findings in persons with an increased risk of T2DM are in contrast to those from animal studies, and do not support the assumption that dietary supplementation with taurine can be used to prevent the development of T2DM.     

不同年龄和体重的多囊卵巢综合征患者糖耐量异常的研究

目的:研究不同年龄阶段和不同体重指数的PCOS患者糖耐量异常的发生率,探讨糖代谢异常与年龄、体重的关系。方法:495例PCOS患者,口服75 g葡萄糖,行糖耐量及胰岛素释放实验。用卡方检验及偏相关分析方法比较不同年龄与体重的PCOS患者糖耐量的差异。结果:495例患者中糖尿病发生率为4.0%(20例),糖耐量低减的发生率为16.6%(82例);根据胰岛素敏感性指数分析,胰岛素敏感性高者275例,占55.6%,胰岛素敏感性低者220例,占44.4%;偏相关分析发现,不同年龄段的PCOS患者糖尿病和糖耐量低减的发生率不同,两者呈正相关,r=0.172,有统计学差异(P=0.000),不同年龄患者的胰岛素敏感性相比,无显著性差异;不同体重指数的PCOS患者糖尿病发生率和糖耐量低减的发生率不同,两者呈正相关,r=0.318,有统计学差异(P=0.000),胰岛素敏感性相比,两者呈负相关,r=-0.434,有显著性差异(P=0.000)。结论:PCOS患者随着年龄和体重的增加,糖耐量异常的发生率增加;肥胖患者的胰岛素抵抗更严重。     

Intensification of therapy and no increase in body mass index with longer disease duration in type 2 diabetes mellitus (ZODIAC-5)

BACKGROUND: Decreased insulin sensitivity and beta-cell failure are the two key components in the pathogenesis of type 2 diabetes mellitus (T2DM). Secondary treatment failure is often attributed to the development of obesity-related insulin resistance in combination with continued loss of beta-cell function. OBJECTIVE: Assess metabolic control, body mass index (BMI) and treatment in relationship to diabetes duration to study these mechanisms. METHODS: Cross-sectional study of 7875 patients with T2DM in primary care in The Netherlands. Clinical data and laboratory results were obtained for the 2005 annual visit. Patients were grouped according to diabetes duration in 2-year intervals. Each step in the traditional treatment sequence was considered as a sign of progression of beta-cell failure. RESULTS: Complete data regarding duration and treatment were available for 6850 patients (87%). After the initial years following diagnosis, treatment with diet alone decreases and oral hypoglycaemic agents (OHA) are prescribed to an increasing percentage of patients. Treatment with OHA diminishes after approximately 10 years following diagnosis and treatment with insulin increases until approximately two-thirds of patients with diabetes duration of more than 20 years are being treated with insulin. BMI does not increase with longer disease duration. CONCLUSION: The concept of beta-cell failure as the primary determinant of the chronic progression of T2DM is supported by these results, whereas a deterioration of obesity-related insulin sensitivity as indicator is not supported.     

2型糖尿病一级亲属中血清抵抗素、内脂素与胰岛素抵抗及胰岛p细胞功能的相关性研究

目的 了解2型糖尿病(T2DM)患者不同糖代谢状态的一级亲属血清抵抗素(RES)、内脂素(VIS)与胰岛素抵抗(IR)和胰岛β细胞功能的关系,并探讨其在T2DM发病中的作用以及临床检测的意义.方法 收集既往无糖耐量异常史的T2DM一级亲属229例,其中经75 g葡萄糖耐量试验分为糖耐量正常(NGT组)174例、空腹血糖受损(IFG)或糖耐量低减(IGT)(IFG/IGT组)55例,收集71例新发T2DM(T2DM组);同时收集上述一级亲属配偶或亲友中无糖尿病家族史的糖耐量正常者114例作为正常对照组.酶联免疫法测定上述人群的血清空腹真胰岛素(FTI)、胰岛素原(FPI)、RES和VIS水平,用HOMA-IR评价IR状态,以HOMA-β及空腹PI和PI/TI比值评价β细胞功能,同时进行人体测量学、脂代谢、肝肾功能、血尿酸及生活习惯的调查.结果 (1)血清RES水平各组间差异无统计学意义(P＞0.05),与HOMA-IR、HOMA-β和肥胖指标均未见相关性(P＞0.05).(2)T2DM组、IGT/IFG组和NGT组较正常对照组血清VIS水平降低(P＜0.05);T2DM组、IGT/IFG组和NGT组之间差异无统计学意义.血清VIS水平与HOMA-IR、肥胖指标未见相关性(P＞0.05),与空腹和2 h血糖、血压负相关(P＜0.05).结论 T2DM一级亲属在糖耐量异常发生前,具有改善糖代谢作用的VIS水平明显降低,提示上述脂肪细胞因子在IR的形成及T2DM的发病中起一定作用     

妊娠糖尿病子代红细胞膜胰岛素受体与胰岛素抵抗的关系

目的:探讨妊娠糖尿病(GDM)子代红细胞膜胰岛素受体与胰岛素抵抗之间的关系。方法:32例妊娠糖尿病患者的儿童,22例正常妊娠者的儿童,测定空腹血糖(FBG)、空腹胰岛素(FINS)、餐后2 h血糖(2h BG)、餐后2 h胰岛素(2 h INS)、胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL),并检测高、低亲和力红细胞膜胰岛素受体数目(R1、R2)和亲和力常数(K1、K2),计算胰岛素抵抗指数(IRI)。结果:GDM组儿童R1、R2低于对照组(P<0.05);GDM组儿童体重、BMI、FINS水平高于正常对照组(P<0.05)。多元线性逐步回归分析结果显示,进入回归方程的因素有体重(t=32.186,P<0.05)、BMI(t=3.362,P<0.05)、R1(t=-2.613,P<0.05)、R2(t=-2.541,P<0.05),提示以上因素是影响GDM组儿童IR的主要危险因素。结论:妊娠糖尿病(GDM)子代存在胰岛素抵抗,且与红细胞膜胰岛素受体数目减少、亲和力下降及体重指数有密切关系。     

Myostatin: a therapeutic target for skeletal muscle wasting

PURPOSE OF REVIEW: This review discusses recent developments in myostatin research, focusing on the basic actions of myostatin on skeletal muscle, the identification of key regulatory elements of the myostatin pathway, and the promise of myostatin as a therapeutic target in muscle-related disorders. RECENT FINDINGS: In addition to a well-characterized role in muscle development, recent research advances have solidified the importance of myostatin in adult muscle, although questions remain. A number of possible regulatory proteins for myostatin have been identified, showing a complex picture of myostatin regulation that requires clarification. The identification of an antimyostatin monoclonal antibody (JA16) shows the promise of myostatin as a target for muscle-wasting disorders; the antibody has already been shown to increase muscle mass in healthy older mice and muscle function in postnatal mdx mice. SUMMARY: Since its discovery in 1997, myostatin has quickly been established as a key regulator of skeletal muscle mass. Recent developments strengthen the idea that myostatin will be an important therapeutic target for muscle-wasting-related disorders, and as more details of myostatin regulation and its mechanisms of action are clarified, myostatin will continue to dominate the skeletal muscle development and muscle-wasting literature.     

Myostatin Inhibition-Induced Increase in Muscle Mass and Strength Was Amplified by Resistance Exercise Training,and Dietary Essential Amino Acids Improved Muscle Quality in Mice

It has been frequently reported that myostatin inhibition increases muscle mass, but decreases muscle quality (i.e., strength/muscle mass). Resistance exercise training (RT) and essential amino acids (EAAs) are potent anabolic stimuli that synergistically increase muscle mass through changes in muscle protein turnover. In addition, EAAs are known to stimulate mitochondrial biogenesis. We have investigated if RT amplifies the anabolic potential of myostatin inhibition while EAAs enhance muscle quality through stimulations of mitochondrial biogenesis and/or muscle protein turnover. Mice were assigned into ACV (myostatin inhibitor), ACV+EAA, ACV+RT, ACV+EAA +RT, or control (CON) over 4 weeks. RT, but not EAA, increased muscle mass above ACV. Despite differences in muscle mass gain, myofibrillar protein synthesis was stimulated similarly in all vs. CON, suggesting a role for changes in protein breakdown in muscle mass gains. There were increases in MyoD expression but decreases in Atrogin-1/MAFbx expression in ACV+EAA, ACV+RT, and ACV+EAA+RT vs. CON. EAA increased muscle quality (e.g., grip strength and maximal carrying load) without corresponding changes in markers of mitochondrial biogenesis and neuromuscular junction stability. In conclusion, RT amplifies muscle mass and strength through changes in muscle protein turnover in conjunction with changes in implicated signaling, while EAAs enhance muscle quality through unknown mechanisms.     

糖耐量减低者胰岛素分泌功能及胰岛素抵抗状态初探

[目的 ]　探讨糖耐量减低者的胰岛素分泌及胰岛素抵抗状态。　 [方法 ]　选择 162例研究对象进行口服葡萄糖耐量试验 (OGTT)后 ,分为 3组 :正常糖耐量 (NGT)组 49例 ,糖耐量减低 (IGT)组 5 8例 ,糖尿病 (DM )组 5 5例。查空腹和餐后 2h胰岛素 ,应用稳态模式胰岛素抵抗指数 (HOMA -IR )作为胰岛素抵抗指标 ,稳态模式胰岛 β细胞功能指数(HBCI)及胰岛素分泌指数 (IS)作为胰岛素分泌指标 ,对 3组患者的这些指标及临床特征进行分析。　 [结果 ]　与NGT组比较 ,IGT组HOMA -IR( 1.4± 0 .6)、FINS( 2 1± 15 )mU/L、2hINS( 61± 3 8)mU /L、HBCI( 5 .7± 0 .9)、IS ( 1.3± 0 .6)均增高 ,P值均 <0 .0 0 1。　 [结论 ]　IGT人群可能以外围组织的胰岛素抵抗为主及胰岛素持续的高分泌状态 ,IGT者胰岛素的分泌功能已有明显受损接近DM。     

Caloric Restriction and L‐Carnitine Administration Improves Insulin Sensitivity in Patients With Impaired Glucose Metabolism

Background: Reduced circulating and tissue carnitine levels, possibly leading to impaired mitochondrial function, have been postulated to be involved in the pathogenesis of insulin resistance. However, whether L‐carnitine administration may improve insulin sensitivity in patients with impaired fasting glucose (IFG) or type 2 diabetes mellitus (DM‐2) is still controversial. The aim of the study was to explore the role of L‐carnitine supplementation in influencing insulin sensitivity. Methods: A randomized controlled study involving adult outpatients was designed. Adult patients referred to the outpatient clinic and within 10 days of the diagnosis of IFG or DM‐2 were consecutively enrolled. Exclusion criteria were concomitant antidiabetic therapy and modifications of lifestyle during the previous 4 weeks. Patients were randomly assigned to receive a hypocaloric diet for 10 days (group C; n = 8) or the same dietetic regimen in addition to oral L‐carnitine (2 g twice daily) supplementation (group LC; n = 8). Oral glucose tolerance test (OGTT), fasting plasma insulin levels, and homeostasis model assessment of insulin resistance (HOMA‐IR) were assessed at the beginning and end of the study. Data were statistically analyzed using the Student t test for paired and unpaired data. Results: OGTT at 2 hours improved in both groups. Only in the L‐carnitine–supplemented group did plasma insulin levels and HOMA‐IR significantly decrease when compared to baseline values. Conclusions: Considering the role of caloric restriction in increasing the intestinal uptake of carnitine, the results suggest that oral L‐carnitine administration, when associated with a hypocaloric feeding regimen, improves insulin resistance and may represent an adjunctive treatment for IFG and DM‐2.     

2型糖尿病与抵抗素基因多态性关系的研究

2型糖尿病（diabetes mellitus type 2,T2DM）是一种复杂的代谢性疾病,是21世纪威胁人类健康的主要疾病之一,可导致严重的发病率和死亡率,是以血糖升高,碳水化合物、蛋白质和脂类代谢调节紊乱为特征。胰岛素抵抗是T2DM发病的一个主要因素,有研究显示抵抗素（resistin,RETN）与胰岛素抵抗呈正相关。RETN是脂肪细胞分泌的因子之一,并且在T2DM、肥胖介导的炎症和胰岛素抵抗中起决定性因素。随着研究的不断探索,抵抗素基因的多态性逐渐被认识,充分理解抵抗素基因在T2DM中的多态性表达,有助于更加合理的将其应用于T2DM的诊治及预防中。