Effects of an acute decrease in non-esterified fatty acid levels on muscle glucose utilization and forearm indirect calorimetry in lean NIDDM patients

Summary The aim of the study was to evaluate an acute decrease in NEFA levels during an oral glucose tolerance test and its effects on glucose tolerance, muscle glucose uptake and muscle indirect calorimetry in ten lean non-insulin-dependent diabetic subjects. Two 75-g oral glucose tolerance tests were performed in random order. Placebo or 250 mg acipimox (to inhibit lipolysis) were administered orally 2 h before the start of the oral glucose tolerance test. Two hours after acipimox administration (time 0), non-esterified fatty acid, glycerol and 3-hydroxybutyrate levels decreased by 84, 68 and 77% respectively, compared to basal levels. Concomitantly, muscle lipid oxidation and non-oxidative glycolysis also decreased significantly. After placebo administration, non-esterified fatty acids, glycerol and 3-hydroxybutyrate and lipid oxidation increased by 29, 28, 106 and 33%, respectively (NS vs basal levels; p<0.001 vs acipimox). There was a negative rate of net glucose storage (interpreted as glycogenolysis) during post-absorptive conditions and at time 0 after administration of both drugs. After oral glucose tolerance test, the incremental areas of blood glucose and insulin were significantly decreased by 18 and 19% after acipimox compared to placebo. In addition, the ratio between the incremental area of forearm muscle glucose uptake and the insulin levels was significantly increased by 45% during acipimox compared to placebo administration. Glucose oxidation and non-oxidative glycolysis were significantly higher while lipid oxidation was significantly lower after acipimox than after placebo. In conclusion, our study found that in lean non-insulin-dependent diabetic subjects, an acute decrease in non-esterified fatty acid levels improves glucose tolerance, muscle glucose uptake, glucose oxidation and non-oxidative glycolysis, but is unable to normalize glucose storage.Abbreviations NEFA Non-esterified fatty acids - NIDDM non-insulin-dependent diabetes mellitus - OGTT oral glucose tolerance test - FMGU forearm muscle glucose uptake - FMBF forearm muscle blood flow - M muscle     

Liraglutide,a once‐daily human GLP‐1 analogue,improves pancreatic B‐cell function and arginine‐stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus

Aims To assess the effect of liraglutide, a once‐daily human glucagon‐like peptide‐1 analogue on pancreatic B‐cell function. Methods Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First‐ and second‐phase insulin release were measured by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Arginine‐stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Results The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first‐phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second‐phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine‐stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity. Conclusions Fourteen weeks of treatment with liraglutide showed improvements in first‐ and second‐phase insulin secretion, together with improvements in arginine‐stimulated insulin secretion during hyperglycaemia.     

Rosiglitazone treatment of patients with extreme insulin resistance and diabetes mellitus due to insulin receptor mutations has no effects on glucose and lipid metabolism

BACKGROUND: Rosiglitazone, a thiazolidinedione (TZD), increases insulin sensitivity by reducing levels of plasma NEFA, triglycerides (TG), glucose and serum insulin. Rosiglitazone treatment decreases insulin resistance in type 2 diabetic patients, but no data exist concerning rosiglitazone treatment of patients with syndromes of extreme insulin resistance. OBJECTIVES: To evaluate whether hyperglycaemia in two lean patients with primary severe insulin resistance due to insulin receptor (IR) mutations and diabetes mellitus could be reduced by supplement of rosiglitazone for 180 days and secondary, to evaluate the effects on plasma NEFA, TG, Apo B, PAI-1 and serum insulin. SUBJECTS: Both patients (brothers) have known mutations in the IR gene localized to the tyrosine kinase domain and a deletion of exon 17 in part of their IR mRNA. Prior to the study the HbA1c values were higher than 10% in both patients for more than 12 months during treatment with insulin and metformin. RESULTS: After 180 days of rosiglitazone supplement (8 mg day(-1)), no changes were observed in fasting plasma glucose and HbA1c. Incremental plasma glucose areas under the curves during a 75-g oral glucose tolerance test (OGTT) were unchanged. Likewise, no improvements were seen in either first or second phase insulin secretion during a 0.3 g kg(-1) intravenous glucose tolerance test (IVGTT). Fasting plasma VLDL and HDL cholesterol, TG and Apo B levels were unchanged, whereas a small increase was seen in total and LDL cholesterol levels. Fasting plasma NEFA increased by 51% in KC after 90 days of treatment, and after 180 days plasma NEFA was still 26% higher, when compared with pretreatment levels. In BC an initial 16% decrease was seen in plasma NEFA after 90 days of treatment. Plasma NEFA was increased 14% after 180 days of treatment, when compared with pretreatment levels, but 35% when compared with day 90. Plasma PAI-1 decreased in both patients after 45 and 90 days of treatment but the decrease was only maintained in KC (47%). CONCLUSIONS: Rosiglitazone treatment, in combination with insulin and metformin, of patients with severe primary insulin resistance due to IR mutations and diabetes mellitus, had no impact on the measured estimates of glucose and lipid metabolism. These findings may suggest that the effect of rosiglitazone on glucose and lipid metabolism are dependent on the presence of intact IR protein.     

Fetal Growth and Insulin Resistance in Adult Life: Role of Plasma Triglyceride and Non-esterified Fatty Acids

Reduced fetal growth is associated with insulin resistance and a high prevalence of glucose intolerance in adult life. Because babies who are growth retarded have elevated levels of triglyceride and non-esterified fatty acids (NEFA), and because similar abnormalities are observed in subjects with the insulin resistance syndrome, impaired regulation of lipid metabolism could be one of the mechanisms explaining the link between reduced fetal growth and insulin resistance. We have, therefore, measured fasting plasma triglyceride and NEFA, and the insulin-mediated suppression of NEFA during an oral glucose tolerance test in 93 men and women aged 50, born in Preston, whose birthweight and body size at birth had been recorded. Elevated fasting plasma triglycerides and reduced NEFA suppression during the oral glucose tolerance test were associated with the male sex, glucose intolerance, central obesity as indicated by a high waist to hip ratio and insulin resistance as measured by a short insulin tolerance test. However there were no statistically significant relationships between the birth measurements and the circulating lipid levels. Moreover in regression analyses the relationships between thinness at birth and insulin resistance or glucose intolerance in adult life were unaffectived by the addition of triglyceride or NEFA in the models. These results suggest that the link between reduced fetal growth and insulin resistance in the adult is not mediated by an abnormal regulation of lipid metabolism.     

Peroxisome proliferator-activated receptor gamma agonism modifies the effects of growth hormone on lipolysis and insulin sensitivity

Context  Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists such as thiazolidinediones (TZDs) improve insulin sensitivity in type 2 diabetes mellitus (T2DM) through effects on fat metabolism whereas GH stimulates lipolysis and induces insulin resistance.
Objective  To evaluate the impact of TZDs on fat metabolism and insulin sensitivity in subjects exposed to stable GH levels.
Design  A randomized, placebo-controlled, double-blind parallel-group study including 20 GH-deficient patients on continued GH replacement therapy. The patients were studied before and after 12 weeks.
Intervention  Patients received either pioglitazone 30 mg ( N  = 10) or placebo ( N  = 10) once daily for 12 weeks.
Results  Adiponectin levels almost doubled during pioglitazone treatment ( P =  0·0001). Pioglitazone significantly decreased basal free fatty acid (FFA) levels ( P =  0·02) and lipid oxidation ( P =  0·02). Basal glucose oxidation rate ( P =  0·004) and insulin sensitivity ( P =  0·03) improved in the patients who received pioglitazone treatment. The change in insulin-stimulated adiponectin level after pioglitazone treatment was positively correlated to the change in insulin-stimulated total glucose disposal ( R  = 0·69, P  = 0·04).
Conclusion  The impact of GH on lipolysis and insulin sensitivity can be modified by administration of TZDs.     

The GLP-1 Receptor Agonist Liraglutide Increases Myocardial Glucose Oxidation Rates via Indirect Mechanisms and Mitigates Experimental Diabetic Cardiomyopathy

BackgroundType 2 diabetes (T2D) increases risk for cardiovascular disease. Of interest, liraglutide, a therapy for T2D that activates the glucagon-like peptide-1 receptor to augment insulin secretion, reduces cardiovascular-related death in people with T2D, though it remains unknown how liraglutide produces these actions. Notably, the glucagon-like peptide-1 receptor is not expressed in ventricular cardiac myocytes, making it likely that ventricular myocardium-independent actions are involved. We hypothesized that augmented insulin secretion may explain how liraglutide indirectly mediates cardioprotection, which thereby increases myocardial glucose oxidation.MethodsC57BL/6J male mice were fed either a low-fat diet (lean) or were subjected to experimental T2D and treated with either saline or liraglutide 3× over a 24-hour period. Mice were subsequently euthanized and had their hearts perfused in the working mode to assess energy metabolism. A separate cohort of mice with T2D were treated with either vehicle control or liraglutide for 2 weeks for the assessment of cardiac function via ultrasound echocardiography.ResultsTreatment of lean mice with liraglutide increased myocardial glucose oxidation without affecting glycolysis. Conversely, direct treatment of the isolated working heart with liraglutide had no effect on glucose oxidation. These findings were recapitulated in mice with T2D and associated with increased circulating insulin levels. Furthermore, liraglutide treatment alleviated diastolic dysfunction in mice with T2D, which was associated with enhanced pyruvate dehydrogenase activity, the rate-limiting enzyme of glucose oxidation.ConclusionsOur data demonstrate that liraglutide augments myocardial glucose oxidation via indirect mechanisms, which may contribute to how liraglutide improves cardiovascular outcomes in people with T2D.     

Perilipin expression in human adipose tissue is elevated with obesity

The perilipins are highly phosphorylated adipocyte proteins that are localized at the surface of the lipid droplet. With activation by protein kinase A, perilipins translocate away from the lipid droplet and allow hormone-sensitive lipase to hydrolyze the adipocyte triglycerides to release nonesterified fatty acids (NEFA). Because of the potential importance of adipocyte lipolysis to obesity and insulin resistance, we measured perilipin protein and mRNA levels in nondiabetic subjects with varying degrees of insulin resistance. By Northern and Western blotting, we could detect perilipin A, but not perilipin B. Perilipin A protein and mRNA levels were quantitated and were highly correlated with each other. There was a significant positive relationship between perilipin expression and obesity (r = 0.55; P < 0.01, perilipin mRNA vs. percent body fat). However, there was no significant relationship between perilipin expression and blood NEFA, nor was there a significant relationship between perilipin expression and insulin resistance, using the insulin sensitivity index derived from the iv glucose tolerance test with minimal modeling. In addition, there was no significant relationship between perilipin and adipocyte or systemic inflammatory markers, such as TNFalpha, IL-6, and adiponectin. Thus, perilipin was elevated in obese subjects, perhaps as a compensatory mechanism to limit basal lipolysis. However, there was no relationship between perilipin and insulin resistance.     

不同血糖状态下血清超敏C反应蛋白、纤溶酶原激活物抑制物-1水平的变化及与胰岛素抵抗的关系

目的检测不同血糖状态人群空腹血清超敏C反应蛋白（hs—CRP）、纤溶酶原激活物抑制物-1（PAI-1）水平,探讨hs—CRP、PAI-1与胰岛素抵抗之间的关系。方法选取健康对照组、糖耐量减低组、2型糖尿病组受试者各30例,测定受试者空腹血清hs—CRP、PAI-1、血脂、空腹胰岛素等项目,应用稳态模型评估法评价胰岛素抵抗。结果2型糖尿病组、糖耐量减低组、对照组依次比较,hs—CRP、PAI-1、胰岛素抵抗指数均有显著升高（P均〈0．05）;多元逐步回归分析显示体重指数、hs—CRP、PAI-1是影响胰岛素抵抗的重要危险因素。结论2型糖尿病人群、糖耐量减低人群存在明显的胰岛素抵抗,hs—CRP、PAI-1、BMI是加重胰岛素抵抗的危险因素;糖调节受损时期即可能存在慢性炎症反应,并出现大血管病变的一些病理生理改变。     

Effects of Heparin-induced Non-esterified Free Fatty Acid on Minimal Model-derived Insulin Sensitivity in Individuals with Varying Degrees of Glucose Intolerance

The effects of heparin-induced non-esterified free fatty acid (NEFA) release on insulin sensitivity index were studied in individuals with varying degrees of glucose intolerance and beta cell dysfunction during the frequently sampled intravenous glucose tolerance test (IVGTT). The groups comprised: Group 1 (n = 5): newly diagnosed Type 2 diabetic patients, Group 2 (n = 11): impaired glucose tolerance patients (IGT), and Group 3 (n = 16): healthy normal glucose tolerance subjects. The serum insulin and c-peptide levels were severely blunted in the diabetic patients when compared to both non-diabetic groups. Mean fasting and post-heparin plasma NEFA levels were approximately 1.8 fold greater (p < 0.05) in the diabetic patients when compared to the other two groups. The mean insulin sensitivity index was lowest in the diabetic patients, intermediate in the IGT patients, and highest in the healthy controls. A significant negative relationship was found between the insulin sensitivity index and stimulated NEFA (r = ?0.537, p < 0.008) but not with the fasting NEFA levels in our subjects. In summary, the frequently sampled IVGTT protocol that employs heparin flushes results in marked elevations in NEFA in Type 2 diabetic patients with poor beta cell dysfunction but not in subjects with intermediate or normal glucose tolerance. The higher plasma NEFA levels during heparin injections could worsen the model-derived, insulin sensitivity index and could impair the ability to achieve an acceptable modelling in Type 2 diabetic patients. We therefore suggest heparin should be avoided in such patients when using this protocol.     

Subcutaneous microdialysis before and after an oral glucose tolerance test: a method to determine insulin resistance in the subcutaneous adipose tissue in diabetes mellitus

AIMS: Subcutaneous microdialysis has been used for continuous glucose monitoring in patients with diabetes mellitus (DM) to facilitate tight regulation of blood glucose levels. The aims of this study were therefore to investigate (i) the relationship between capillary and interstitial glucose in patients with type 1 or 2 DM and healthy subjects and (ii) the feasibility of using microdialysis to assess local insulin sensitivity in adipose tissue. METHODS: Using subcutaneous microdialysis, interstitial glucose, lactate, pyruvate and glycerol were determined as measures of glucose and lipid metabolism in adipose tissue, before and after an oral glucose tolerance test (OGTT) in 14 patients and seven controls. The results were correlated to whole-body insulin sensitivity and insulin sensitivity in liver estimated from the levels of insulin-like growth factor-binding protein 1 (IGFBP-1). RESULTS: Capillary and interstitial glucose correlated before and after OGTT in healthy subjects and in type 1 DM but not in type 2 DM. In fasting state, the glycerol levels were higher in both type 1 and type 2 DM compared with controls. After the OGTT, the insulin levels were sufficient to suppress lipolysis in type 1 but not in type 2 DM. The glucose/lactate ratio was higher at fasting in type 1 DM and after OGTT in type 1 and 2 DM. In type 1 DM, basal interstitial glycerol levels correlated to whole-body glucose utilization. In type 2 DM, correlations were found between the basal glycerol levels and whole-body insulin sensitivity and between glucose/lactate and per cent decrease in IGFBP-1 levels 120 min after OGTT. CONCLUSION: Capillary and interstitial glucose correlated before and after OGTT in healthy subjects and patients with type 1 DM. Correlations were also found between insulin sensitivity in whole body and in adipose tissue in both type 1 and type 2 DM and between insulin sensitivity in subcutaneous adipose tissue and liver in type 2 DM. This study shows that microdialysis technique can be used to study in vivo insulin sensitivity in adipose tissue over time and may be useful in the evaluation of, for example, the effects of new drugs on insulin sensitivity.     

Influence of extended-release nicotinic acid on nonesterified fatty acid flux in the metabolic syndrome with atherogenic dyslipidemia

Nicotinic acid has favorable effects on atherogenic dyslipidemia. However, in some patients who have diabetes, crystalline nicotinic acid decreases glycemic control; this effect could be due to a marked rebound of nonesterified fatty acids (NEFAs) observed after nicotinic acid suppression of lipolysis in adipose tissue. Recent reports have indicated that small doses of extended-release nicotinic acid do not cause a substantial decrease in glucose levels. Therefore, in this study, we examined whether 2 g/day of extended-release nicotinic acid abolishes the NEFA rebound that is reported with crystalline nicotinic acid. Seventeen men who had the metabolic syndrome (8 did not have type 2 diabetes and 9 did) were treated for 4 months. At baseline and at 4 months, measurements were made of plasma glucose, insulin, and NEFA during an oral glucose tolerance test. At 3 months, effects of extended-release nicotinic acid on NEFA levels and flux rates were determined on 3 separate days at 3 separate intervals after the final dose of nicotinic acid (4, 9, and 28 hours). Values obtained at 28 hours were taken as baseline (i.e., no nicotinic acid remaining in the circulation). After 4 hours (percent baseline), NEFA levels were -30% without diabetes and -37% with diabetes, and flux rates were -21% without diabetes and -25% with diabetes; after 9 hours, NEFA levels were 43% without diabetes and 50% with diabetes, and flux rates were 38% without diabetes and 70% with diabetes. Extended-release nicotinic acid did not abolish NEFA rebound. Nonetheless, the rebound was much less than previously reported for crystalline nicotinic acid. Moreover, after 4 months of nicotinic acid therapy, levels of NEFA, glucose, and insulin during the oral glucose tolerance test were not significantly different from those before institution of nicotinic acid therapy, suggesting minimal changes in insulin sensitivity.     

Liraglutide Improves Glycemic and Blood Pressure Control and Ameliorates Progression of Left Ventricular Hypertrophy in Patients with Type 2 Diabetes Mellitus on Peritoneal Dialysis

Diabetes mellitus (DM) is a multifactorial disease associated with cardiovascular complications. Patients undergoing peritoneal dialysis also experience an increased incidence of cardiovascular disease. To prevent progression of cardiovascular complications in DM patients, glycemic control is important. In this study, we examined the efficacy and safety of the glucagon‐like peptide analog liraglutide for treating type 2 diabetes patients undergoing peritoneal dialysis. Sixteen type 2 diabetes patients on peritoneal dialysis were enrolled. Before liraglutide initiation, 11 patients were on insulin therapy, three were on oral antidiabetic agents, and two were on diet therapy. Of the 16 patients, 12 had switched to liraglutide because of severe hypoglycemia and four because of hyperglycemia. Echocardiography was performed at baseline and 12 months after liraglutide initiation. Hemoglobin A1c, glycosylated albumin, and fasting/postprandial glucose levels gradually decreased after liraglutide initiation. After 6 and 12 months of treatment, postprandial glucose levels showed a significant difference from baseline. Moreover, the mean daily glucose level and glycemic fluctuations decreased. Systolic blood pressure upon waking also decreased. In addition, after 12 months, left ventricular mass index (LVMI) decreased and left ventricular ejection fraction increased. Changes in LVMI positively correlated with morning systolic blood pressure and fasting glucose levels. One patient restarted insulin because of anorexia but severe hypoglycemia was not observed. These findings suggest that liraglutide therapy in type 2 diabetes patients undergoing peritoneal dialysis is safe and effective for decreasing glucose levels, glycemic fluctuations, and blood pressure, apart from improving left ventricular function.     

Study on the effect of insulin on carbohydrate and lipid metabolism in obese subjects with normal glucose tolerance]

In altogether 32 test persons with normal weight and obese test persons glucose-insulin-tolerance-tests were carried out. In obese persons with normal carbohydrate tolerance -- characterized by 50 g oral glucose tolerance test -- by the decreased glucose assimilation coefficients and the significantly increased level of glycaemia after intravenous application of glucose a disturbance of the glucose-insulin-homoeostasis is already implied. Basal and glucose-stimulated concentrations of IRI in the peripheral venous blood were significantly increased in obese persons. The parameters of lipolysis glycerol and free fatty acids show after a glucose-stimulated insulin excretion and after exogenic insulin application a somewhat retarded decrease in obese persons compared with the control group. In connection with the significantly increased insulin levels in obese persons these findings might refer to a decreased antilipolytic effect of insulin. The two fundamental physiological effects of insulin in the carbohydrate and fat metabolism -- glucose utilization and inhibition of lipolysis -- seem to be distrubed in the same way in obesity.     

不同糖耐量人群及糖尿病患者血浆内脂素与血糖及胰岛功能的关系研究

目的探讨不同糖耐量人群血浆内脂素的变化及其与体重指数(BMI)、腰围、血糖、胰岛素抵抗指数、胰岛B细胞功能、血脂等的关系。方法2006年4月至2006年10月在南京医科大学第一附属医院门诊常规健康体检及糖尿病初次就诊者95名,按WHO1999糖尿病诊断标准分为初诊2型糖尿病组(53例)、糖耐量减退组(7例)、正常糖耐量组(35名);以WHO1998肥胖诊断标准分为超重或肥胖组(50名)、正常体重组(45名)。检测受试者BMI、腰围、血压,测定空腹血浆内脂素、血糖、血脂、胰岛素等。结果初诊2型糖尿病患者空腹血浆内脂素明显高于正常糖耐量组(P<0.01)。超重或肥胖组与正常体重组间血浆内脂素差异无显著性意义。人群中血浆内脂素与空腹血糖(r=0.338,P<0.01)、餐后2h血糖(r=0.340,P<0.01)、胰岛素抵抗指数(r=0.227,P<0.05)呈正相关,与胰岛素分泌指数(HOMA-B)呈负相关(r=-0.296,P<0.05)。在2型糖尿病组,血浆内脂素与糖化血红蛋白(HbA1c)呈正相关(r=0.356,P<0.01)。多元线性逐步回归分析表明,餐后2h血糖是影响血浆内脂素的独立相关因素。结论初诊2型糖尿病患者血浆内脂素显著升高,可能是机体针对体内血糖增高、胰岛功能受损所发生的一种代偿效应。     

2型糖尿病心血管疾病风险管理及利拉鲁肽的潜在优势

T2DM不仅存在高血糖,且往往合并肥胖、IR、血脂异常及高血压等危险因素,使其并发心血管疾病的风险大大增加.因此,理想的糖尿病管理不应仅局限于血糖的控制,更应全面管理各项危险因素.基于肠促胰素治疗的利拉鲁肽,在降低血糖的同时有控制体重,改善血脂,降低SBP等多重益处,为T2DM患者早期及长期的管理提供更理想的选择.本文就T2DM心血管疾病风险管理的重要性及利拉鲁肽在心血管保护效应方面的优势进行简要综述.     

The interplay of insulin resistance and beta-cell dysfunction involves the development of type 2 diabetes in Chinese obeses

Type 2 diabetes mellitus (T2DM) is a heterogeneous disorder characterized by defects in insulin secretion and action and obesity plays an important role in the deterioration of glucose metabolism. In the present study we evaluated the degree of insulin resistance and first-phase insulin secretion of β-cell in obese subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and T2DM in Chinese. A total of 220 subjects underwent standard 75 g oral glucose tolerance test (OGTT) and insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity index (S _I) was assessed by the reduced sample number (n = 12) of Bergman’s minimal model method with FSIGT. Insulin secretion capacities were determined by the insulinogenic index (I _{30 min} − I _{0 min})/(G _{30 min} − G _{0 min}) in OGTT and the acute insulin response to glucose (AIR) in FSIGT. The disposition index (DI), the product of AIR and S _I was used to determine whether AIR was adequate to compensate for insulin resistance. The S _I in healthy lean control group was significantly higher than that in NGT, IGT, and T2DM group, but there was no significant difference among NGT, IGT, and T2DM group. The AIR in NGT group was significantly greater than that in control group, but then it was progressively decreased in IGT and T2DM group. The value of DI in control group was significantly higher than that in those three abnormal groups, and was decreased from NGT to IGT and T2DM group with significant difference. It indicates that obese subjects with different glucose tolerances have a similar degree of insulin resistance but differ in insulin secretion in Chinese Han population.     

Insulin resistance in porphyria cutanea tarda

It has been reported that patients with porphyria cutanea tarda (PCT) develop carbohydrate (CHO) intolerance and manifest diabetes melitus (DM) more frequently than the normal population. In order to verify whether this is due to insulin resistance we studied 5 patients with PCT and 5 normal subjects matched for age, sex and weight. In all the patients an evaluation consisted of the glycemic curve and insulin response to an iv glucose tolerance test (IVGTT: 0.33 g/kg) as well as of an evaluation of the circulating monocyte insulin receptors. Blood samples were drawn in the basal state to measure plasma levels of NEFA, glycerol, and intermediate metabolites. The patients with PCT showed normal glucose tolerance which was obtained, however, at the expense of the elevated insulin levels: therefore a condition of insulin resistance was demonstrated in these subjects. An involvement of the lipid metabolism, observed by the raised levels of plasma NEFA and glycerol, was also evident. The insulin binding to circulating monocytes was reduced but not enough to justify the degree of insulin resistance observed. Therefore, it could be hypothesized, in agreement with similar studies, that a postreceptor defect is responsible for the insulin-resistance observed in patients with PCT and that the reduction of insulin receptors is determined by the down regulation in response to elevated insulinemic levels. An alteration of the porphyrin metabolism might be responsible for this disorder.     

Effect of acute inhibition of lipolysis on operation of the glucose-fatty acid cycle in hepatic cirrhosis.

Hepatic cirrhosis is frequently associated with glucose intolerance and insulin resistance, but the mechanisms underlying the insulin insensitivity are unknown. Plasma concentrations of nonesterified fatty acids (NEFA) are typically elevated in cirrhosis, and the glucose-fatty acid cycle provides a mechanism by which fatty acids may play a role in regulating glucose metabolism. We have therefore investigated the effect of acute inhibition of lipolysis, using the nicotinic acid analogue, acipimox, in 10 male patients with cirrhosis. All subjects were studied in the postabsorptive state after a 10- to 12-hour fast and were given either acipimox 250 mg or a placebo orally 2 hours before a 75-g oral glucose tolerance test (OGTT) and an infusion of insulin (50 mU/kg/h) and glucose (6 mg/kg/min) (insulin sensitivity tests [IST]). The drug was taken in a double-blind crossover design for each test. During the 2 hours following acipimox, there were rapid decreases in plasma NEFA, glycerol, and 3-hydroxybutyrate, confirming inhibition of lipolysis, while there were significant decreases in glucose, insulin, and C-peptide (P less than .001) compared with patients receiving the placebo. Acipimox blunted the increase in glucose after oral glucose loading and decreased incremental glucose concentration (from 579 +/- 76 to 445 +/- 65 mmol/min/L, P less than .02) and incremental insulin concentration (from 13.4 +/- 2.5 to 9.0 +/- 1.4 U/min/L, P = .056) in the OGTT. Improvements in classification of glucose tolerance were seen in five subjects. During the IST, significant reductions occurred in steady-state blood glucose (to 8.8 +/- 1 mmol/L, P less than .02) and C-peptide (to 3.0 +/- 0.5 nmol/L, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Lixisenatide,a novel GLP‐1 receptor agonist: efficacy,safety and clinical implications for type 2 diabetes mellitus

Recent advances in therapies for the treatment of type 2 diabetes mellitus (T2DM) have led to the development of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), which, unlike insulin and sulphonylurea, are effective, with a low risk of hypoglycaemia. Lixisenatide is recommended as a once‐daily GLP‐1 RA for the treatment of T2DM. In persons with T2DM, lixisenatide 20 µg once‐daily given by bolus subcutaneous injection improves insulin secretion and suppresses glucagon secretion in a glucose‐dependent manner. Compared with the longer‐acting GLP‐1 RA liraglutide, lixisenatide achieved a significantly greater reduction in postprandial plasma glucose (PPG) during a standardized test breakfast in persons with T2DM otherwise insufficiently controlled on metformin alone. This is primarily due to the greater inhibition of gastric motility by lixisenatide compared with liraglutide. The efficacy and safety of lixisenatide was evaluated across a spectrum of T2DM in a series of phase III, randomized, placebo‐controlled trials known as the GetGoal programme. Lixisenatide monotherapy or as add‐on to oral antidiabetic agents or basal insulin achieved significant reductions in glycated haemoglobin, PPG and fasting plasma glucose, with either weight loss or no weight gain. The most frequent adverse events were gastrointestinal and transient in nature. Lixisenatide provides an easy, once‐daily, single‐dose, add‐on treatment to oral antidiabetic agents or basal insulin for the management of T2DM, with little or no increased risk of hypoglycaemia and a potential beneficial effect on body weight.     

利拉鲁肽诱导骨髓间充质干细胞定向分化及移植治疗1型糖尿病大鼠的研究

目的 体外研究利拉鲁肽诱导骨髓间充质干细胞（BM-MSCs）分化为胰岛素分泌细胞（IPCs）,并在体内进一步观察IPCs移植对1型糖尿病（T1DM）大鼠的治疗作用.方法 （1）体外采用密度梯度离心联合差壁培养法分离、纯化大鼠BM-MSCs,进一步分为未诱导组、高糖＋尼克酰胺诱导组、胰高血糖素样肽1（GLP-1）诱导组和利拉鲁肽诱导组;（2）倒置显微镜下观察各组细胞形态变化,双硫腙染色鉴定诱导后细胞,荧光定量PCR检测巢蛋白（Nestin）、胰十二指肠同源盒1（PDX-1）、葡萄糖转运蛋白2（Glut-2）、葡萄糖激酶（GK）、胰岛素和胰高血糖素等基因,细胞免疫荧光检测胰岛素和胰高血糖素等蛋白;（3）将180 ～ 220 g的30只雄性SD大鼠以60 mg/kg剂量腹腔注射链脲佐菌素制备T1DM模型,造模成功后按随机数字表法分为对照组（T1DM组,n=8）、未诱导的BM-MSCs移植组（BM-MSCs组,n=9）和经利拉鲁肽诱导的BM-MSCs移植组（LIRA＋ BM-MSCs组,n=9）,给予相应干预8周,待血糖基本稳定后,选取4只正常、同龄、雄性SD大鼠作为对照,行腹腔注射的葡萄糖耐量试验（IPGTT）进一步观察移植后细胞对高糖刺激的反应性.结果 （1）利拉鲁肽诱导后BM-MSCs形态逐渐变圆,呈明显的聚集性生长状态,双硫腙染色为阳性;与高糖＋尼克酰胺诱导组比较,利拉鲁肽诱导组细胞Nestin mRNA表达下调（0.003 8±0.000 4比0.007 5±0.003 0,P＜0.05）,胰岛素（0.000 20±0.000 03比0.000 08±0.000 02）和胰高血糖素（0.001 1±0.0004比0.000 7±0.000 1）等mRNA表达上调（F=7.26、10.06、4.92,均P＜0.05）,PDX-1、Glut-2、GK mRNA表达亦上调;利拉鲁肽诱导组和GLP-1诱导组细胞胰岛素或胰高血糖素蛋白表达均呈阳性.（2）体内实验示,与T1DM组比较,LIRA＋ BM-MSCs组和BM-MSCs组大鼠8周末血糖均明显降低[分别为（28.0±1.2）、（8.9±1.1）、（14.5±0.9）mmol/L,F=719.61,均P＜0.05];IPGTT提示移植IPCs后的大鼠血糖在30 min时升至峰值,150 min时降至空腹水平,血糖变化曲线与正常组类似.结论 体外利拉鲁肽可以在一定程度上促进BM-MSCs分化成为IPCs,且移植后的IPCs能够在体内进一步发挥降糖作用.