短链脂肪酸在2型糖尿病发病机制中的作用

短链脂肪酸(SCFA)是由肠道菌群发酵膳食纤维产生的代谢产物,饮食结构变化通过改变肠道菌群结构与功能,影响SCFA的产生.近来研究发现,SCFA通过调节胃肠道激素分泌、胰岛素敏感性及糖、脂代谢,参与了2型糖尿病的发生、发展.对SCFA的深入研究,为阐明2型糖尿病发病机制及其预防和治疗提供了新的思路和靶点.     

胰腺脂肪浸润与代谢综合征

2型糖尿病、肥胖和脂肪肝是代谢综合征的重要组成部分.研究显示,胰腺脂肪浸润与代谢综合征密切相关,其多发生于肥胖人群,尤其是腹型肥胖的人群,并且能够损伤胰岛β细胞功能,减少糖负荷下胰岛素的分泌.另外,胰腺脂肪浸润往往与脂肪肝共存,并且二者存在先后关系.但胰腺脂肪浸润与2型糖尿病的关系尚不明确,它与脂肪肝发病的先后顺序尚存在争议.     

Skeletal muscle – A bystander or influencer of metabolic syndrome?

Background and aimsMetabolic syndrome is the concurrent presentation of multiple cardiovascular risk factors, including obesity, insulin resistance, hyperglycemia, dyslipidemia and hypertension. It has been suggested that some of these risk factors can have detrimental effects on the skeletal muscle while others can be a direct result of skeletal muscle abnormalities, showing a two-way directionality in the pathogenesis of the condition. This review aims to explore this bidirectional correlation by discussing the impact of metabolic syndrome on skeletal muscle tissue in general and will also discuss ways in which skeletal muscle alterations may contribute to the pathogenesis of metabolic syndrome.MethodsLiterature searches were conducted with key words (e.g. metabolic syndrome, skeletal muscle, hyperglycemia) using PubMed, EBSCOhost, Science Direct and Google Scholar. All article types were included in the search.ResultsThe pathological mechanisms associated with metabolic syndrome, such as hyperglycemia and inflammation, have been associated with changes in skeletal muscle fiber composition, metabolism, insulin sensitivity, mitochondrial function, and strength. Additionally, some skeletal muscle alterations, particularly mitochondrial dysfunction and insulin resistance, are suggested to contribute to the development of metabolic syndrome. For example, the suggested underlying mechanisms of sarcopenia development are also contributors to metabolic syndrome pathogenesis.ConclusionWhilst numerous studies have identified a relationship between metabolic syndrome and skeletal muscle abnormalities, further investigation into the underlying mechanisms is needed to elucidate the best prevention and management strategies for these conditions.     

The impact of ethnicity on glucose regulation and the metabolic syndrome following gestational diabetes

Aims/hypothesis We assessed the impact of ethnic origin on metabolism in women following gestational diabetes mellitus (GDM). Materials and methods Glucose regulation and other features of the metabolic syndrome were studied at 20.0 (18.2–22.1) months (geometric mean [95% CI]) post-partum in women with previous GDM (185 European, 103 Asian-Indian, 80 African-Caribbean). They were compared with the same features in 482 normal control subjects who had normal glucose regulation during and following pregnancy. Results Impaired glucose regulation or diabetes by WHO criteria were present in 37% of women with previous GDM (diabetes in 17%), especially in those of African-Caribbean and Asian-Indian origin (50 and 44%, respectively vs 28% in European, p=0.009). BMI, waist circumference, diastolic blood pressure, fasting triglyceride and insulin levels, and insulin resistance by homeostatic model assessment (HOMA), were increased following GDM (p<0.001 for all, vs control subjects). Where glucose regulation was normal following GDM, basal insulin secretion (by HOMA) was high (p<0.001 vs control subjects). Irrespective of glucose regulation in pregnancy, Asian-Indian origin was associated with high triglyceride and low HDL cholesterol levels, and African-Caribbean with increased waist circumference, blood pressure, and insulin levels, together with insulin resistance and low triglyceride concentrations. Nonetheless, the GDM-associated features were consistent within each ethnic group. The metabolic syndrome by International Diabetes Federation criteria was present in 37% of women with previous GDM, especially in non-Europeans (Asian-Indian 49%, African-Caribbean 43%, European 28%, p=0.001), and in 10% of controls. Conclusions/interpretation Following GDM, abnormal glucose regulation and the metabolic syndrome are common, especially in non-European women, indicating a need for diabetes and cardiovascular disease prevention strategies.     

肥胖症与脂质代谢

肥胖是一种常见疾病，是体内脂肪过多的表现，与脂质代谢紊乱密切相关，二者互为因果。其脂质代谢紊乱表现为摄食过多使脂肪合成的原料增加，棕色脂肪含量减少使能量消耗减少素和降脂激素调节失常使脂肪合成增加，降解减少。同时也可由于脂肪动员增加使血中游离脂肪酸，甘油三酯增加，极低密度脂蛋白和低密度脂蛋白清除减少。高胰岛素血症和胰岛素抵抗既是肥胖的结果，也是肥胖患者脂质代谢紊乱的主要原因，其它如瘦素等也起重要作用。     

骨钙素与代谢综合征

代谢综合征(MS)是多种代谢成分异常聚集的病理状态.骨钙素(OC)是成骨细胞合成和分泌的一种非胶原蛋白,越来越多的动物及临床证据表明OC参与了MS的发生和发展.OC能调节脂肪吸收,诱导脂肪细胞分泌脂联素,促进胰岛素释放,减少胰岛素抵抗,且可能参与高血压及动脉粥样硬化性疾病的发生、发展,故对OC的研究将有助于探索MS治疗...     

Ⅱ型糖尿病合并高血压对脂代谢及胰岛素敏感性的影响

目的：观察Ⅱ型糖尿病合并高血压对脂代谢及胰岛素敏感性的影响。方法：对20例Ⅱ型糖尿病合并高血压患者和20例Ⅱ型糖尿病无高血压患者的空腹血糖（FBG）,血脂,胰岛素（FINS）,C肽（FCP）,胰岛素敏感指数（ISI）进行对照,结果：Ⅱ型糖尿病合并高血压组与无高血压组比较,甘油三酯（TG）,FINS,FCP水平显著升高（P＜0．05）,高密度脂蛋白（HDL）,ISI水平显著降低（P＜0．05）,结论：Ⅱ型糖尿病合并高血压时脂代谢紊乱及胰岛素抵抗更加明显。     

CaMKII and its role in cardiac arrhythmia

Calcium/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase widely distributed in a number of tissue types. Activation of CaMKII has been linked to important downstream physiological processes, including apoptosis, hypertrophy, and arrhythmia in the heart. Pharmacological or genetic inhibition of CaMKII has been shown to improve health outcomes in a number of animal models. In this review, we summarize the structural and functional properties of CaMKII and detail its role in cardiac arrhythmia, structural heart disease, and sudden death.     

脂肪细胞型脂肪酸结合蛋白与肥胖及代谢综合征

脂肪细胞型脂肪酸结合蛋白(A-FABP)主要在脂肪组织中大量表达,其主要生理作用为参与细胞内部的脂肪酸转运和靶向定位.近期的研究发现,A-FABP是全身胰岛素敏感性以及糖脂代谢的重要调节冈素,与肥胖及代谢综合征的发生发展有紧密联系.     

代谢综合征的分子机制与治疗展望——解读2007年第67届美国糖尿病协会杰出科学成就奖报告

美国糖尿病协会第67届科学大会宣布Hotamisligil医学博士获得本届杰出科学成就奖。Hotamisligil提出肥胖能够促进炎性反应的发生并且与胰岛素抵抗、2型糖尿病以及其他慢性疾病相关。其研究发现很多导致炎性反应和代谢疾病的关键机制,包括脂蛋白、c-Jun氨基末端激酶和内质网应激的作用,并且也描述了这些机制如何干扰机体对胰岛素的正常反应及对代谢的调节。这为糖尿病的治疗提供了新的途径。     

AMP活化蛋白激酶研究进展

能量代谢失衡是肥胖、糖尿病及代谢综合征的主要原因.AMP活化蛋白激酶(AMPK)是一种重要的蛋白激酶,可以调节能量代谢,开启分解代谢途径,如脂肪酸氧化和糖酵解,从而增加ATP的产生,同时关闭合成代谢途径,如多种脂类、蛋白质及糖原的合成,减少ATP的消耗.在增加骨骼肌对匍萄糖的摄取、增强胰岛素敏感性、增加脂肪酸氧化以及调节基因转录等方面发挥重要作用.AMPK不仅町以在细胞水平作为"能量调节器",在整体水平还可以通过激素和细胞因子,如瘦素、脂联素和ghrelin调节机体的能量代谢.凼而,阐明AMPK在不同组织细胞及整体水平上调节糖脂代谢的机制是今后该领域的研究热点,也是临床治疗肥胖、2型糖尿病及代谢综合征等疾病的有效靶点.     

Effect of lipid oxidation on the regulation of glucose utilization in obese patients

The effect of changes in lipid oxidation on glucose utilization (storage and oxidation) was studied in seven nondiabetic obese patients. They participated in three protocols in which: (1) Intralipid (to raise plasma FFA concentrations), (2) -pyridylcarbinol [a precursor of nicotinic acid, to lower plasma free fatty acids (FFA) concentrations], or (3) isotonic saline were infused over 2 h. Thereafter, these infusions were discontinued, and a 2-h cuglycemic, hyperinsulinemic clamp was performed to measure glucose uptake. All studies were carried out in combination with indirect calorimetry to measure oxidative and nonoxidative glucose disposal (glucose storage). The high plasma FFA concentrations (1024±57 mol/l) and lipid oxidation rates (1.1±0.1 mg/kg·min) found at the end of the Intralipid infusion and the low plasma FFA concentrations (264±26 mol/l and lipid oxidation rates 0.7±0.1 mg/kg·min) found at the end of the -pyridylcarbinol infusions resulted in significantly different rates of total and nonoxidative glucose disposal during the insulin clamp. The values were 2.6±0.6 mg/kg·min after Intralipid and 4.1±1.0 mg/kg·min after -pyridylcarbinol for total glucose disposal, and 0.4±0.4 and 1.6±0.8, respectively for nonoxidative glucose disposal. In conclusion, these observations show that changes in lipid oxidation rates preceding a glucose load influence glucose disposal and glycogen storage in obese subjects.     

Oxidized to non-oxidized lipoprotein ratios are associated with arteriosclerosis and the metabolic syndrome in diabetic patients

Background and aimType 2 diabetic patients have a greater prevalence of the metabolic syndrome, oxidative stress and accelerated atherosclerosis, compared to non-diabetics. We examined the association between biomarkers of lipid peroxidation and the presence of atherosclerosis and the metabolic syndrome in diabetic patients.Methods and resultsWe studied oxidized LDL (OxLDL), OxLDL/LDL, OxLDL/HDL, lipoperoxides, autoantibodies against OxLDL (OxLDL-Ab), diene formation of LDL (lag phase), vitamin E, vitamin E/cholesterol and PON1 polymorphisms (−108C > T, 55T > A, and 192A > G) in 166 non-smoking type 2 diabetic patients, 119 fulfilling the criteria for the metabolic syndrome, 73 with atherosclerosis and 93 without atherosclerosis. Patients with macrovascular disease had higher values of OxLDL/LDL (11%; P = 0.016), OxLDL/HDL (18%; P = 0.024) and OxLDL-Ab (12%; P = 0.046). OxLDL/LDL and OxLDL/HDL were correlated with the number of components of the metabolic syndrome (P < 0.001). PON1 polymorphisms were not associated to LDL oxidation markers, only PON1 (−108TT) was weakly associated with higher OxLDL-Ab concentrations (22%; P = 0.040) in patients with atherosclerosis.ConclusionOxLDL/LDL, OxLDL/HDL and OxLDL-Ab are the most useful clinical parameters of lipoprotein oxidation for discriminating the presence of macrovascular disease in diabetic patients. The presence of the metabolic syndrome in these patients is also associated with an increase in the oxidized lipoprotein ratios.     

Type 2 diabetes mellitus is becoming the most common type of diabetes in school children

Abstract. Obesity, now an epidemic in the USA, northern Europe, and Italy, is associated with several co-morbidities that shorten life expectancy, in particular type 2 diabetes mellitus (T2DM), arterial hypertension, and hyperlipidemia. The impact of obesity on mortality is evident in all ages, and is especially strong in young persons. Obesity, especially visceral obesity, associated with a sedentary lifestyle, is among the strongest risk factors for T2DM, and a diagnosis of T2DM seems to increase linearly as a function of duration of obesity. The pathogenesis of T2DM is based on a dual defect, i. e. increased insulin resistance coupled with defective insulin release. The main abnormality in obesity is increased insulin resistance, while insulin release, even though defective compared with body needs, is usually abundant.The incidence of obesity among children aged 6-16 years is now even greater than that among adults: in Italy, figures up to 30% have been reported. As in adults, obesity is a cause, among children, of arterial hypertension, left ventricular hypertrophy, hyperlipidemia, non-alcoholic-steato hepatitis, sleep apnea syndrome (SAS), and orthopedic, psychological, and social problems. Together with an increase in body weight, there is an increase of visceral fat. Obesity in children has also led to a tremendous increase in the prevalence of impaired glucose tolerance (IGT); the percentages span from 25% in a multiethnic cohort in the USA, to 4% in Italian Caucasians. Management of obesity and of T2DM in children has to face the issue of poor compliance; there is consensus that dietary treatment of obese T2DM children is a failure, so that drugs are required; the only drug evaluated in a formal trial is metformin, that behaves in terms of efficacy and of minor side effects as in adults. In conclusion, obesity in children is not pure obesity, but is accompanied by co-morbidities that cluster to form the metabolic syndrome just like in the adults. If this epidemics continues and is not properly challenged, in the next decades we will face an epidemic of early cardiovascular morbidity and mortality.     

Alcohol consumption and metabolic syndrome among Shanghai adults： A randomized multistage stratified cluster sampling investigation

AIM： To examine the relations of alcohol consumption to the prevalence of metabolic syndrome in Shanghai adults. METHODS： We performed a cross-sectional analysis of data from the randomized multistage stratified cluster sampling of Shanghai adults, who were evaluated for alcohol consumption and each component of metabolic syndrome, using the adapted U.S. National Cholesterol Education Program criteria. Current alcohol consumption was defined as more than once of alcohol drinking per month. RESULTS： The study population consisted of 3953 participants （1524 men） with a mean age of 54.3 ± 12.1 years. Among them, 448 subjects （11.3%） were current alcohol drinkers, including 405 males and 43 females. After adjustment for age and sex, the prevalence of current alcohol drinking and metabolic syndrome in the general population of Shanghai was 13.0% and 15.3%, respectively. Compared with nondrinkers, the prevalence of hypertriglyceridemia and hypertension was higher while the prevalence of abdominal obesity, low serum high-density-lipoprotein cholesterol （HDL-C） and diabetes mellitus was lower in subjects who consumed alcohol twice or more per month, with a trend toward reducing the prevalence of metabolic syndrome. Among the current alcohol drinkers, systolic blood pressure, HDL-C, fastingplasma glucose, and prevalence of hypertriglyceridemia tended to increase with increased alcohol consumption. However, low-density-lipoprotein cholesterol concentration, prevalence of abdominal obesity, low serum HDL-C and metabolic syndrome showed the tendency to decrease. Moreover, these statistically significant differences were independent of gender and age.CONCLUSION： Current alcohol consumption is associated with a lower prevalence of metabolic syndrome irrespe- ctive of alcohol intake （g/d）, and has a favorable influence on HDL-C, waist circumference, and possible diabetes mellitus. However, alcohol intake increases the likelihood of hypertension, hypertriglyceridemia and hyperglycemia. The clinical signi     

Shortcomings in methodology complicate measurements of serum retinol binding protein (RBP4) in insulin-resistant human subjects

Aims/hypothesis Levels of retinol binding protein (RBP4) are increased in the serum of insulin-resistant human subjects even before overt diabetes develops. RBP4 levels correlate with insulin resistance, BMI, WHR, dyslipidaemia and hypertension. Improvement of insulin sensitivity with exercise training is associated with reduction in serum RBP4 levels. Therefore serum RBP4 may be useful for early diagnosis of insulin resistance and for monitoring improvements in insulin sensitivity. We sought to determine the performance of assays for this application. Subjects and methods We compared quantitative western blotting and three commercially available multiwell immunoassays in parallel measurements of RBP4 concentrations in serum from insulin-sensitive subjects and from insulin-resistant subjects with impaired glucose tolerance or type 2 diabetes. Results The assays yielded different absolute values and magnitudes of elevation of serum RBP4. Western blotting and a sandwich ELISA reported RBP4 concentrations that highly inversely correlated with insulin sensitivity measured by euglycaemic–hyperinsulinaemic clamp. However, western blotting yielded concentrations with a greater dynamic range and less overlap between control and insulin-resistant subjects. Two competitive enzyme-linked immunoassays undervalued serum RBP4 concentrations in insulin-resistant subjects, possibly due to assay saturation. Poor linearity of dilution also limited assay utility. All assays tested exhibited greater immunoreactivity with urinary (C-terminal proteolysed) RBP4 than with full-length RBP4, the predominant form in serum. Conclusions/interpretations These findings support the use of quantitative western blotting standardised to full-length RBP4 protein as a ‘gold standard’ method for measuring serum RBP4 in insulin-resistant states. Other assays should use full-length RBP4 and be extensively cross-validated using other methods.     

脑利钠肽与糖脂代谢的关系

脑利钠肽作为内分泌激素主要通过调节水盐平衡维持机体内环境稳态,现已被广泛用于心血管疾病的临床诊断及判断预后,而近年来的研究表明其对代谢系统也有一定影响.脑利钠肽能通过加强脂质分解与脂肪动员作用改善脂代谢,而与糖代谢的关系尚存争议.多数研究显示其与血糖水平呈负相关,这主要与增加葡萄糖利用及扩血管作用有关.故脑利钠肽在减重、预防糖尿病及代谢综合征的发展中均有一定临床应用前景.     

Dysregulation of muscle fatty acid metabolism in type 2 diabetes is independent of malonyl-CoA

Aims/hypothesis An elevated lipid content within skeletal muscle cells is associated with the development of insulin resistance and type 2 diabetes mellitus. We hypothesised that in subjects with type 2 diabetes muscle malonyl-CoA (an inhibitor of fatty acid oxidation) would be elevated at baseline in comparison with control subjects and in particular during physiological hyperinsulinaemia with hyperglycaemia. Thus, fatty acids taken up by muscle would be shunted away from oxidation and towards storage (non-oxidative disposal).Materials and methods Six control subjects and six subjects with type 2 diabetes were studied after an overnight fast and during a hyperinsulinaemic (0.5 mU kg⁻¹ min⁻¹), hyperglycaemic clamp (with concurrent intralipid and heparin infusions) designed to increase muscle malonyl-CoA and inhibit fat oxidation. We used stable isotope methods, femoral arterial and venous catheterisation, and performed muscle biopsies to measure palmitate kinetics across the leg and muscle malonyl-CoA.Results Basal muscle malonyl-CoA concentrations were similar in control and type 2 diabetic subjects and increased (p<0.05) in both groups during the clamp (control, 0.14±0.05 to 0.24±0.05 pmol/mg; type 2 diabetes, 0.09±0.01 to 0.20±0.02 pmol/mg). Basal palmitate oxidation across the leg was not different between groups at baseline and decreased in both groups during the clamp (p<0.05). Palmitate uptake and non-oxidative disposal were significantly greater in the type 2 diabetic subjects at baseline and during the clamp (p<0.05).Conclusions/interpretation Contrary to our hypothesis, the dysregulation of muscle fatty acid metabolism in type 2 diabetes is independent of muscle malonyl-CoA. However, elevated fatty acid uptake in type 2 diabetes may be a key contributing factor to the increase in fatty acids being shunted towards storage within muscle.