High-molecular weight adiponectin isoforms increase after biliopancreatic diversion in obese subjects

Objective: Our objective was to test the effect of biliopancreatic diversion (BDP) in adiponectin multimerization. Adiponectin, the major protein secreted by adipose tissue, circulates in plasma in different isoforms. The most clinically relevant oligomers are high‐molecular weight (HMW) multimers and low‐molecular weight (LMW) trimers. Contrasting data on the effect of weight loss on adiponectin isoforms have been reported. Research Methods and Procedures: We measured total plasma adiponectin and HMW and LMW adiponectin oligomers (by Western blot analysis) before and 1 month after BPD, in 18 severely obese subjects. Results: One month after BPD, body weight decreased ～11%. Total adiponectin showed significant increase after BPD. In addition, we found a significant increase in HMW (percentage) adiponectin oligomers. We found a significant inverse correlation between HMW (percentage) and BMI before and after BPD. Homeostasis model of assessment‐insulin resistance decreased significantly after the BPD, without any significant correlation with total serum adiponectin and adiponectin oligomers. Discussion: A moderate weight loss after BPD increases total and HMW adiponectin oligomers. The significant correlation between BMI and HMW (percentage) adiponectin oligomers but not between BMI and total adiponectin might indicate a role of body fat mass in regulation of adiponectin multimerization. These data suggest that HMW oligomers represent a very sensitive parameter to short‐term BMI changes after BPD.     

Upregulation of plasma insulin-like growth factor binding protein 2 levels after biliopancreatic diversion in humans

The biliopancreatic diversion surgery with duodenal switch (BPD-DS) is a surgical procedure that not only induces significant weight loss, but also promotes remission of diabetes. However, the mechanism responsible for this insulin-potentiating effect (both on sensitivity and production) is not yet clearly understood. The insulin-like growth factor (IGF) binding protein 2 (IGFBP-2) is a 36 kDa circulating protein that has been recently suggested to modulate insulin sensitization and fat accumulation. In humans, a low-circulating concentration of IGFBP-2 has been associated with obesity and insulin resistance. We thus tested the hypothesis that BPD-DS would trigger an increase in IGFBP-2 levels. Plasma IGFBP-2 was quantified by enzyme-linked immunosorbent assay in 77 severely obese men and women before and up to 1 year after BPD-DS surgery. Baseline IGFBP-2 levels were 159 ± 17 ng/ml. Plasma IGFBP-2 levels increased significantly as soon as 24 h after BPD-DS surgery and were further augmented at both 6 months and 1 year after the surgery, reaching 748 ± 65 ng/ml. Changes in IGFBP-2 concentrations were significantly and negatively associated with blood glucose, insulin, triglycerides, and total cholesterol levels. The present findings suggest that the rise in IGFBP-2 levels is associated with the improvements in glucose and lipid metabolism in the short- and long-term after BPD-DS. The mechanisms for the augmentation in IGFBP-2 after BPD-DS and its contribution to insulin sensitization remain to be elucidated.     

Study of insulin response to oral glucose load after acute and chronic glycemic control in type 2 diabetic subjects

To investigate whether correction of fasting hyperglycemia per se improves the insulin secretion in type 2 diabetic subjects, plasma insulin response to 75 g oral glucose load has been studied after acute and chronic normalization of fasting plasma glucose levels in 7 overt type 2 diabetic subjects. For the acute normalization of elevated fasting plasma glucose levels, an artificial endocrine pancreas was employed. Although fasting plasma glucose concentrations were normalized before the oral glucose challenge, insulin response to oral glucose was not improved compared to those without normalization of fasting plasma glucose levels. After 1-3 month control of hyperglycemia, the insulin response to glucose in the subjects was significantly improved compared to those without treatments. Results indicate that chronic metabolic control is essential for the improvement of insulin response to glucose in type 2 diabetic subjects, and also suggest that the impaired insulin secretion in type 2 diabetes is not due to hyperglycemia per se, but due to the metabolic derangements which lead to chronic hyperglycemia.     

胰高血糖素样多肽-1拮抗2型糖尿病胰岛细胞凋亡损伤

胰高血糖素样多肽-1（glucogen like peptide 1, GLP-1）在胰岛素分泌过程中扮演重要角色,并在改善β细胞功能方面有着令人瞩目的效应,但有关其作用机制尚需更深入研究。本研究探讨GLP-1对2型糖尿病（type 2 diabetes mellitus, T2DM）大鼠模型胰岛细胞损伤的影响,观察GLP-1在T2DM大鼠胰岛细胞凋亡损伤机制中所发挥的作用。HE染色结果发现,糖尿病大鼠胰岛损伤。ELISA结果表明,糖尿病患者和糖尿病大鼠血清中GLP-1表达水平上调。放射免疫结果表明,GLP-1和谷氧还蛋白1（Grx1）促进HIT-T 15细胞分泌胰岛素,Cd抑制胰岛素的分泌。免疫组化结果表明,糖尿病大鼠GLP-1加药处理后,各组与糖尿病组相比,药物提高了Grx1和胰岛素表达水平,降低了胰高血糖素表达水平,同时降低了活性胱天蛋白酶3（caspase-3）的表达。本研究结果提示,GLP-1在肥胖T2DM大鼠胰岛细胞凋亡中起保护作用,同时可调节胰岛素和胰高血糖素水平,其机制可能与Grx1相关     

Restoration of the acute phase response after infection in cyclophosphamide-treated mice by granulocyte colony-stimulating factor

The therapeutic effect of granulocyte colony-stimulating factor (G-CSF) against intramuscular infection withPseudomonas aeruginosa in cyclophosphamide (CY)-treated mice was analyzed by measuring plasma levels of amyloid P-component (APC) and proinflammatory cytokine levels. CY (100mg/kg) treatment of mice significantly suppressed plasma concentrations of APC and tumor-necrosis factor- (TNF-) following infection withP. aeruginosa, in associated with enhanced susceptibility of the treated mice to this bacterium. A 4-day treatment of CY-treated mice with recombinant human G-CSF (rhG-CSF) increased resistance of CY-treated mice, together with the marked restoration of APC and TNF- productions. The capacity to produce interleukin 1- and TNF- of peritoneal macrophages and also that to produce IL-6 of spleen cells were significantly enhanced by thein vivo administration of rhG-CSF in CY-treated mice. These results indicate that G-CSF may increase the functions of monocytes/macrophages directly or indirectlyin vivo. Therefore, the therapeutic effect of rhG-CSF seems to consist of not only increases in the number and functions of neutrophills but also enhancement of monocyte/macrophage functions.Abbreviations rhG-CSF recombinant human granulocyte-colony stimulating factor - PMNs polymorphonuclear leukocytes - CY cyclophosphamide - HBSS Hanks' balanced salt solution - APC amyloid P-component - IEP immunoelectrophoresis - CFU colony-forming units - TNF- tumor-necrosis factor- - d IL interleukin     

Impaired pancreatic polypeptide response to insulin hypoglycemia in obese subjects

We have studied the effect of insulin hypoglycemia on the secretion of pancreatic polypeptide (PP) in 14 obese subjects with normal glucose tolerance and in 6 normal controls. Infusion of insulin 0.1 U/kg/h in controls and 0.12 U/kg/h in the obese, for one hour, produced a progressive hypoglycemia, similar in both groups (nadir 2 mmol/l at 50 min). The secretion of PP was less in obese subjects than in controls (peak 116 mmol/l vs 184 pmol/l, P less than 0.01) (integrated secretion sigma delta PP 288 vs 472 pmol/l, P less than 0.01) and was also delayed in the obese subjects beginning at 50 min instead of 40 min. The secretion of glucagon and of C-peptide were not different in the two groups, but the integrated response of ACTH was higher in the obese (sigma delta ACTH 52 pmol/l vs 25 pmol/l, P less than 0.01). The secretory response of growth hormone (STH) was smaller in the obese group (peak 8.6 +/- 1.28 vs 21.4 +/- 6.4 ng/ml, P less than 0.01). The reduced secretion of PP in obese subjects could be due to impaired sensitivity to hypoglycemia of the central control mechanism for PP release. The similarity of the reductions in the secretion of both PP and STH support this hypothesis, although a reduction in the secretory capacity of pancreatic PP cells cannot be excluded.     

Metabolic response to insulin induced hypoglycaemia in lean and obese subjects

Metabolic response to insulin induced hypoglycaemia was examined in 8 lean and 11 obese subjects. The metabolic rate increased in lean and obese subjects during the hypoglycaemia. The mean response (as the sum of all the values above basal) was not significantly different between lean and obese subjects. The mean decrease in blood glucose and the mean hormonal response (increase in cortisol, adrenaline and noradrenaline) were not different between lean subjects and obese subjects. However, the metabolic response and noradrenaline response were variable in obese subjects and some obese subjects showed a poor response. These results suggest that in some obese subjects, there may be reduced thermogenic response to insulin induced hypoglycaemia.     

SGLT-2 Inhibitor Therapy Added to GLP-1 Agonist Therapy in the Management of T2DM

Objective: To assess the real-world efficacy and safety of canagliflozin therapy added to type 2 diabetes mellitus (T2DM) patients who have received a minimum 1 year of glucagon-like peptide-1 (GLP-1) agonist therapy.Methods: This pre-post observational study assessed the efficacy and safety of canagliflozin in a group of T2DM patients from a community endocrinology practice who received GLP-1 agonist therapy for a minimum of 12 months. The primary study outcome was change in mean glycated hemoglobin (HbA1c) level from baseline. Secondary endpoints included changes in average weight, and comparison of the percentage of patients obtaining an HbA1c <7%.Results: A total of 75 patients met all the study criteria. Baseline patient characteristics were as follows: average age, 58 ± 9 years; mean duration of T2DM, 14 ± 6 years; 56% male; 92% Caucasian; baseline body mass index (BMI), 39.4 ± 9.4 kg/m²; and mean baseline HbA1c, 7.94 ± 0.69%. HbA1c and weight were significantly reduced by 0.39% and 4.6 kg, respectively. Adverse effects were reported by 13 (17.3%) patients, including 4 (5.3%) who discontinued canagliflozin because of adverse reactions.Conclusion: Canagliflozin was generally well tolerated and significantly further reduced mean HbA1c levels and body weight in patients with T2DM when added to GLP-1 regimen.Abbreviations:BP = blood pressureBUN = blood urea nitrogenCANTATA = Canagliflozin Treatment and Trial AnalysisDBP = diastolic blood pressureDKA = diabetic ketoacidosisDPP-4 = dipeptidyl peptidase-4EMR = electronic medical recordFDA = Food and Drug AdministrationGFR = glomerular filtration rateGLP-1 = glucagon-like peptide-1HbA1c = glycated hemoglobinHDL-C = high-density lipoprotein cholesterolLDL-C = low-density lipoprotein cholesterolSCr = serum creatinineSGLT-2 = sodium glucose cotransporter 2T2DM = type 2 diabetes mellitusTZD = thiazolidinedioneUTI = urinary tract infection     

The glucose tolerance, insulin response and pancreatic exocrine function in patients after acute pancreatitis

In 25 patients having a history of acute pancreatitis (AP) in anamnesis one year ago and in 12 control subjects the insulin response to oral glucose was investigated and in some cases the exocrine function of pancreas was evaluated. The disturbances in glucose tolerance occurred in about 30% of the patients and were associated with impairment of insulin response and deterioration of exocrine pancreatic function. The double cortisone and glucose load did not influence the glucose tolerance in the patients. In persons investigated during AP and one year later only slight improvement of insulin response was noted. The results support the significance of follow-up studies of carbohydrate tolerance and insulin response in patients after AP for the evaluation of the diabetic risk in such cases.     

TH1/TH2 cytokine secretion of first degree relatives of T1DM patients

Th1/Th2 cytokine imbalance has been demonstrated in Type 1 diabetes (T1DM) patients. We characterized the peak levels, secretory pattern and total cytokine production of the Th1 cytokines (IL-2 and IFN gamma) and Th2 cytokines (IL-4 and IL-10), by stimulated peripheral blood mononuclear cells of twenty six first-degree relatives of T1DM patients, and eleven matched controls. At enrollment, first degree relatives demonstrated a significant increase in peak and overall secretion of IL-2; P<0.01 and P<0.005 respectively and IL-4 cytokine; P<0.05 and P<0.01 respectively, as compared to normal controls. Their mean IFN gamma secretion increased significantly, P<0.05, after one year while their higher IL-2 and IL-4 secretion remained unchanged. Ab-negative and Ab-positive relatives demonstrated a similar cytokine secretion pattern. Four relatives all Ab positive, developed diabetes: Peak IL-4 levels were low in three and markedly decreased within one year in one of these relatives, while peak IL-2 and IFN gamma levels were elevated in all of them. These data demonstrate that secretion of both Th1 and Th2 cytokines is increased in first-degree relatives of T1DM patients independently of their diabetes-associated autoantibodies. The presence of low IL-4 and elevated IL-2 and IFN gamma levels in autoAb positive relatives is associated with progression to overt disease.     

The effect of T1 and T2 cytokines on the cytotoxic T cell response to mannan-MUC1

MUC1 is a mucin over-expressed in breast cancer and a proposed target for immunotherapy. By immunising mice with MUC1 conjugated to mannan (M-FP), CD8⁺ MHC-class-I restricted cytotoxic T lymphocytes (CTL), of high CTL precursor (CTLp) frequency (1/8000) and with significant tumour protection, can be induced. The effect of various cytokines [interleukin-2 (IL-2), IL-4, IL-6, IL-7, interferon γ (IFNγ), and granulocyte/macrophage-colony-stimulating factor (GM-CSF)] on the MUC1 CTL immune response was investigated (a) by measuring the frequencies of CTLp in mice immunised with vaccinia virus constructs containing recombinant cytokines and M-FP, or (b) by immunising cytokine- or cytokine-receptor-knockout (−/−) mice with M-FP. Vaccinia virus (VV) constructs containing recombinant cytokines were used either individually or in combination in vivo with M-FP immunisation. M-FP immunisations combined with VV-IL-2, VV-IL-7 and VV-GM-CSF, and combinations of VV-IFNγ + VV-IL-2, VV-IFNγ + VV-IL-4 or VV-GM-CSF + VV-IL-7 increased CTLp frequencies up to threefold (1/17 666: M-FP + VV-GM-CSF + VV-IL-7) compared to M-FP (1/77 500) alone. By contrast, M-FP combined with VV-IL-4 decreased the CTLp frequency threefold whereas VV-IL-6 and VV-IFNγ had no effect. Studies in cytokine- and cytokine-receptor-gene-knockout (−/−) mice demonstrated that mice that are IL-2 −/− and IL-7 receptor −/− produce the same CTLp response to M-FP as do control mice, whereas responses in the IL-6 −/−, IL-10 −/− and IFNγ−/− mice were marginally improved and responses to M-FP in IL-4 −/− and tumour necrosis factor receptor 2 −/− mice were weaker. In spite of the increase in CTLp frequency, this was not reflected in an in vivo tumour model. Tumour challenges using MUC1⁺ P815 cells, demonstrated that the addition of cytokines had little additive effect on the already effective tumour-regression capabilities of M-FP alone. Received: 24 September 1998 / Accepted: 21 September 1999     

Behavior of plasma insulin and GIP in obese patients subjected to biliopancreatic bypass

Biliopancreatic bypass for obesity entails a 2/3 distal gastrectomy with Roux-en-Y reconstruction, being the small bowel transected at its midpoint and the enteroenteroanastomosis placed 50 cm proximal to the ileocecal valve. Insulin and GIP fasting and meal-stimulated plasma concentrations were determined in 13 nonobese healthy volunteers, in 13 nonoperated obese patients, in 11 subjects within two months, in 12 subjects four to twelve months, and in 7 subjects fifteen to twenty months after operation. Insulin in the obese patients was significantly higher than in the control group. Postoperatively these patients showed a sharp reduction in basal and postprandial values. Plasma insulin levels, both basally and following the test meal, were very similar in the 15-20 month and the control group. Plasma GIP fasting level, meal-stimulated peak and integrated response in the obese group were higher than in control group. Due to the extreme variability among subjects in the obese group, the difference was significant only for the mean peak response. All values were greatly reduced after surgery. The mean fasting level in the 15-20 month group was very similar to that in the control group, and both peak and integrated responses were significantly lower than in the preoperative and control groups.     

Glucagon-like peptide 1 (GLP-1) secretion and plasma dipeptidyl peptidase IV (DPP-IV) activity in morbidly obese patients undergoing biliopancreatic diversion.

BACKGROUND: The physiological inhibitory control of glucagon-like Peptide 1 (GLP-1) on gastric emptying and the contribution of this peptide in the regulation of food intake as a satiety factor suggest that impaired secretion and/or activity of GLP-1 may be involved in the pathogenesis of obesity. We investigated food-mediated GLP-1 secretion as well as plasma activity of dipeptidyl-peptidase IV (DPP-IV), the enzyme responsible for rapid inactivation of the circulating peptide, in morbidly obese patients, before and after weight loss resulting from biliopancreatic diversion. METHODS: Twenty-two morbidly obese non-diabetic patients (BMI = 47.5 +/- 1.8) and 9 age-matched healthy volunteers were studied. A mixed meal (700 kcal) was administered to all subjects and blood samples were collected at 0, 15, 30, 60, 120 min for the determination of circulating glucose, insulin, GLP-1 (7 - 36 amide) concentrations and plasma DPP-IV activity. The patients repeated the test meal after 50 % overweight reduction resulting from surgical treatment (BMI = 33.8 +/- 1.1). RESULTS: While nutrient ingestion significantly increased plasma GLP-1 levels in the control group (30', 60': p < 0.01), the test-meal failed to modify basal peptide values in the obese patients, and an overall reduction in circulating GLP-1 occurred during the observation period (p < 0.001). Plasma DPP-IV activity in the same patients resulted as being significantly higher than controls, both at fasting and in response to the meal (p < 0.05). With respect to preoperative values, an overall increase in circulating GLP-1 levels occurred in all patients following biliopancreatic diversion (p < 0.001). Plasma DPP-IV activity, on the other hand, continued to be abnormally increased, even after considerable weight loss (p < 0.05 vs. controls). CONCLUSIONS: First: In morbid obesity, the accelerated inactivation of circulating GLP-1 could at least partially account for plasma peptide levels lower than normal, the defective availability of such a satiety factor possibly contributing to eating behaviour abnormalities; Second: plasma DPP-IV hyperactivity in the obese did not seem to be affected by the overweight degree, the increase in postoperative GLP-1 levels mainly resulting from hyperstimulation of GLP-1 secretory cells due to surgical manipulation of gastrointestinal tract. If the abnormally accelerated degradation of GLP-1 in obesity is confirmed, selective DPP-IV inhibitors could actually represent an ideal approach to obesity management.     

遗传背景不同的2型糖尿病患者胰岛素第一时相分泌变化和胰岛素抵抗状态对比分析

目的:对比分析新诊2型糖尿病(DM2)无遗传史者与有遗传史糖耐量正常一级亲属胰岛素第一时相分泌改变和胰岛素抵抗状态以及与DM2发病机制的关系.方法:选新诊DM2无遗传史者[TH(-)]25名及已确诊的DM2患者糖耐量正常的一级亲属[NH(+)]25名为研究组,无DM2遗传史糖耐量正常的健康人[NH(-)]25名为对照组.电化学发光免疫分析法测定各组空腹胰岛素(Flns)及静脉葡萄糖耐量试验(IGTT)后2min、4min、6rain血清Ins含量.结果:①TH(-)组与NH(-)组比较,BMI、HOMA-IR升高有统计学差异(P＜0.05),胰岛素各时段分泌水平无统计学意义(P＞0.05),但空腹水平增高,IGTT负荷后,第一时相分泌达不到正常对照组水平;②NH(+)组与NH(-)比较,HOMA-IR无统计学差异(P＞0.05),胰岛素空腹及第一时相各段分泌水平下降有统计学意义(P＜0.01,4).05);③TH(-)与Nil(+)组比较,TH(-)组HOMA-IR、Fins、6minIns水平高于Nil(+)组有统计学差异(P＜0.01～0.05).结论:无遗传史新诊DM2患者存在明显的胰岛素抵抗,有遗传史正常糖耐量非肥胖一级亲属第一时相胰岛素分泌功能下降.不同人群2型糖尿病发病的始动因素可能不同,临床在预防、诊治时应区别对待给予不同的干预措施.     

The correlation between CT features and insulin resistance levels in patients with T2DM complicated with primary pulmonary tuberculosis

The aim is to investigate the correlation between computed tomography (CT) features and insulin resistance levels in patients with type 2 diabetes mellitus (T2DM) complicated with primary pulmonary tuberculosis (PTB). Nearly, 268 untreated PTB patients complicated with T2DM were divided into two groups according to the optimal cutoff value of HOMA-IR score for the Chinese population: HOMA-IR ≤ 2.69 (Group I: 74 patients), >2.69 (Group II: 194 patients). The basic characteristics and changes of CT manifestations were analyzed. In the two groups, the detection rate of large segmented leafy shadow was 39.2% and 78.9%; the air bronchogram sign detection rate was 40.5% and 80.9%; the discovery rate of mouth-eaten cavity was 33.8% and 73.7%; the thin-walled cavity detection rate was 2.7% and 16.0%; the rate of multiple cavities was 35.1% and 69.6%; and bronchial tuberculosis was found in 4.1% and 35.6%, respectively. The detection rates of lesions in Group II were significantly higher than in Group I (p < .05). HOMA-IR was found independently associated with large segmented leafy shadow, air bronchial sign, thin-walled cavity, and bronchial tuberculosis. The level of insulin resistance can effectively reflect the severity of PTB patients with T2DM. CT scan can directly provide image information in clinics. These two examinations can guide clinicians to accurately formulate subsequent treatment plans.