Mechanisms of type 2 diabetes resolution after Roux-en-Y gastric bypass

BackgroundBariatric surgery is the most effective treatment for the reduction of weight and resolution of type 2 diabetes mellitus (T2 DM). The objective of this study was to longitudinally assess hormonal and tissue responses after RYGB.MethodsEight patients (5 with T2 DM) were studied before and after RYGB. A standardized test meal (STM) was administered before and at 1, 3, 6, 9, 12, and 15 months. Separately, a 2-hour hyperinsulinemic-euglycemic clamp (E-clamp) and a 2-hour hyperglycemic clamp (H-clamp) were performed before and at 1, 3, 6, and 12 months. Glucagon-like peptide-1 (GLP-1) was infused during the last hour of the H-clamp. Body composition was assessed with DXA methodology.ResultsEnrollment body mass index was 49±3 kg/m² (X±SE). STM glucose and insulin responses were normalized by 3 and 6 months. GLP-1 level increased dramatically at 1, 3, and 6 months, normalizing by 12 and 15 months. Insulin sensitivity (M of E-clamp) increased progressively at 3–12 months as fat mass decreased. The insulin response to glucose alone fell progressively over 12 months but the glucose clearance/metabolism (M of H-clamp) did not change significantly until 12 months. In response to GLP-1 infusion, insulin levels fell progressively throughout the 12 months.ConclusionThe early hypersecretion of GLP-1 leads to hyperinsulinemia and early normalization of glucose levels. The GLP-1 response normalizes within 1 year after surgery. Enhanced peripheral tissue sensitivity to insulin starts at 3 months and is associated with fat mass loss. β-cell sensitivity improves at 12 months and after the loss of ≈33% of excess weight. There is a tightly controlled feedback loop between peripheral tissue sensitivity and β-cell and L-cell (GLP-1) responses.     

Insulin secretion and insulin sensitivity defects are a common feature of mild,clinically homogeneous,recently diagnosed type II (Non-insulin-dependent) diabetics

Summary Alteration in insulin secretion and reduced peripheral sensitivity to the hormone have been reported in type II diabetes. In this paper, a comparison is made of basal glucose production (³H-6 glucose), insulin secretion and insulin sensitivityin vivo (hyperglycemic clamp) andin vitro (binding to circulating monocytes) in 24 patients with recently diagnosed type II diabetes, matched for age and fasting glycemia and divided into non-obese (14 subjects) and moderately obese (10 subjects), and in 9 non-obese controls. The non-obese diabetics were slightly hyperinsulinemic during fasting (10.8±1.0vs 4.8±0.8 μU/ml in controls, p < 0.0005), with a significant reduction in early and late insulin secretion (14.0±1.5vs 20.8 ± 2.0 μU/ml, p<0.01 and 24.8±3.3vs 34.7±2.14 μU/ml, p<0.025). The insulin sensitivity index MCR/I was significantly reduced (2.30±0.32vs 4.14±0.40, p<0.005). Endogenous glucose production was significantly increased (107±10.2vs 84±3.7 mg/m² per min, p<0.025) and displayed a positive correlation with fasting glycemia (r=0.51, p<0.05). Insulin binding to monocytes was significantly lower than in controls (2.36±0.22%vs 4.06±0.32%, p<0.0005). Moderately obese diabetics also were significantly hyperinsulinemic in the fasting state (18.1±2.8 μU/ml, p<0.0005vs controls) but, typically, lacked the early secretory phase (20.6±3.6 μU/mlvs baseline, n.s.). A similar increase of hepatic glucose production (107±11.2 mg/m² per min, p<0.025vs controls, n.s.vs non-obese diabetics) and decrease of peripheral sensitivity to insulin (MCR/I=1.78±0.31, p<0.0005vs controls, n.s.vs non-obese diabetics) was found in moderately obsese diabetics, as well as a significant reduction of insulin binding to insolated monocytes (2.62±0.4% p<0.01vs controls, n.s.vs non-obese diabetics). These results confirm that common defects of both non-obese and moderately obese type II diabetics are: lack of early phase of glucose induced insulin secretion, increase in hepatic glucose production and decrease of peripheral insulin sensitivity together with reduction of insulin binding to circulating monocytes. The hypothesis of a unique defect as a cause of hyperglycemia in type II diabetes in early clinical phase is not borne out by the results of this study. Moderate obesity, even if able to reduce insulin sensitivity, seems to be less important in determining hyperglycemia. This study was supported by a grant fromConsiglio Nazionale delle Ricerche, P.F. Medicina Preventiva, SP4,Malattie Degenerative, N. 84.02449.56.     

高葡萄糖钳夹技术在评估糖尿病患者胰岛B细胞功能中应用探讨

目的探讨高葡萄糖钳夹技术（HGCT）在糖尿病患者胰岛B细胞功能评估中的应用。方法研究对象分为糖尿病非胰岛素注射组（NIns组,n=8）和糖尿病胰岛素注射组（Ins组,n=10）及正常对照组（NC组,n=10）。用改良评估法与传统计算方法计算HGCT过程中胰岛素增加值,评价对糖尿病患者胰岛B细胞功能。结果NIns组按胰岛素增加值计算有8例判为第一时相胰岛素分泌（1PH）减退,6例判为第二时相胰岛素分泌（2PH）及最大胰岛素分泌量（MIS）减退,与传统计算方法比较差异无统计学意义（P〉0．05）。Ins组按传统法计算的1PH、2PH及MIS均高于NIns组,与临床实际情况不符,而按胰岛素增加值计算Ins组的△2PH及△MIS均低于Nlns组。结论对于需外源性胰岛素治疗的2型糖尿病患者,改良计算法优于传统计算法。     

健脾益气 调肝活血法对高血糖大鼠CCL4所致慢性肝损伤的影响

目的观察具有健脾益气、调肝活血作用的糖肝宁合剂对高血糖大鼠CCL4所致慢性化学性肝损伤肝功能（ALT、AST）、TNF-α、IL-6的影响,肝脏结构的病理改变。方法除正常组外,所有动物均制作高血糖大鼠,再用四氯化碳腹腔注射以造成肝损伤模型。同时将动物分为模型组、糖肝宁大剂量组、糖肝宁小剂量组组、降糖甲组,并予以相应的药物灌胃。灌胃3个月后检查大鼠肝功能、肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）,并在光镜下观察肝脏结构的病理改变。结果糖肝宁大剂量组能显著改善CCL4所导致高血糖慢性肝损伤大鼠异常的肝功能,TNF-a、IL-6的水平。结论糖肝宁合剂能有效的防治四氯化碳所致高血糖大鼠肝功能。其作用机制可能与抗炎性因子有关。     

快速相胰岛素分泌功能的评价

目的　 ( 1)研究正常糖耐量者应用高葡萄糖钳夹试验所形成的第一相胰岛素分泌功能 ( 1PH) (快速相胰岛素分泌 ) ,与口服葡萄糖耐量试验 (OGTT )、精氨酸刺激试验中反映早期胰岛素分泌功能指标的关系 ;( 2 )探讨评价胰岛 β细胞早期分泌功能的简易方法。 方法　对 2 8例正常体重、正常糖耐量的个体分别进行高葡萄糖钳夹试验、OGTT及精氨酸刺激试验。结果　 ( 1)OGTT 3 0min胰岛素、胰岛素净增值及胰岛素净增值与血糖净增值的比值与 1PH均无明显相关 ;( 2 )OGTT 10min胰岛素值 (r =0 .5 8,P <0 .0 1)及胰岛素净增值 (r =0 .45 ,P <0 .0 5 )、2 0min胰岛素值 (r =0 .42 ,P <0 .0 5 )及胰岛素净增值与血糖净增值的比值 (r =0 .49,P <0 .0 1) ,均分别与 1PH显著相关 ;( 3 )精氨酸刺激试验的结果与 1PH明显相关 (r =0 .5 2 ,P <0 .0 1)。结论　OGTT 10min胰岛素值及胰岛素净增值、2 0min胰岛素值及胰岛素净增值与血糖净增值的比值 ,以及精氨酸刺激试验的结果可作为估测机体快速相胰岛素分泌较为可靠的参数。     

A case of hyperglycemic hyperosmolar state associated with Graves' hyperthyroidism: a case report

Hyperglycemic hyperosmolar state (HHS) is an acute complication mostly occurring in elderly type 2 diabetes mellitus (DM). Thyrotoxicosis causes dramatic increase of glycogen degradation and/or gluconeogenesis and enhances breakdown of triglycerides. Thus, in general, it augments glucose intolerance in diabetic patients. A 23-yr-old female patient with Graves' disease and type 2 DM, complying with methimazole and insulin injection, had symptoms of nausea, polyuria and generalized weakness. Her serum glucose and osmolarity were 32.7 mM/L, and 321 mosm/kg, respectively. Thyroid function tests revealed that she had more aggravated hyperthyroid status; 0.01 mU/L TSH and 2.78 pM/L free T3 (reference range, 0.17-4.05, 0.31-0.62, respectively) than when she was discharged two weeks before (0.12 mU/L TSH and 1.41 pM/L free T3). Being diagnosed as HHS and refractory Graves' hyperthyroidism, she was treated successfully with intravenous fluids, insulin and high doses of methimazole (90 mg daily). Here, we described the case of a woman with Graves' disease and type 2 DM developing to HHS.     

Cadmium and mercury-induced hyperglycemia in the fresh water crab, Oziotelphusa senex senex: involvement of neuroendocrine system

The effect of exposure to sublethal concentrations of cadmium chloride and mercuric chloride on hemolymph glucose levels of the freshwater crab, Oziotelphusa senex senex, was studied. Intact crabs exposed to cadmium or mercury exhibited a significant hyperglycemia compared to controls, but no significant differences in hemolymph glucose level were detected among the eyestalkless crabs after exposure to metals, suggesting that the effect of metals could be on the sinus gland in the eyestalks, increasing secretion of the hyperglycemic hormone. To test this hypothesis, eyestalks were collected from control and metal exposed crabs, and tested for hyperglycemic effect and also for the hyperglycemic hormone levels. The levels of hyperglycemic hormone and the hyperglycemic effect were significantly low in the eyestalks collected from metal exposed crabs when compared with eyestalks from control crabs. These results strongly suggest that metals act, at least in part, by triggering the secretion of hyperglycemic hormone from the eyestalk.     

Effect of retinoic acid on hemolymph glucose regulation in the fresh water edible crab Oziotelphusa senex senex

9-cis-Retinoic acid (9CRA) and all-trans-retinoic acid (ATRA) are known to be involved in the regulation of glucose homeostasis in vertebrates by inducing insulin release and expression of glucose reporter proteins. In view of the fact that 9CRA and ATRA are endogenous in crustaceans and a retinoic acid X-receptor exists in crabs, we investigated whether 9CRA and ATRA also plays a role in glucose homeostasis in freshwater crab, Oziotelphusa senex senex. Injection of 9CRA into intact crabs significantly increased the hemolymph glucose level in a dose-dependent manner. Such 9CRA-induced hyperglycemia was apparently mediated by the CHH since injection of 9CRA into eyestalk-ablated crabs did not result in hyperglycemia. In support of this, administration of 9CRA in to crabs resulted in reduced hyperglycemic activity of eyestalks and elevated titers of CHH in hemolymph. ATRA injection did not cause any changes in hemolymph glucose and CHH levels. The results provide the first evidence that 9-cis-retinoic acid, but not all-trans-retinoic acid, is involved in the regulation of glucose homeostasis and apparently mediated by the eyestalk hormone CHH.     

太白楤木总皂苷对糖尿病小鼠血糖 血脂及抗氧化作用的影响

目的观察太白楤木总皂苷对四氧嘧啶糖尿病小鼠血糖、血脂的调节作用。方法将小鼠随机分为正常组、模型组、二甲双胍组及太白楤木总皂苷（total saponin of Aralia taibaiensis，SAT）30、60、120mg·kg^-1剂量组，连续4周灌胃给药，末次给药后尾静脉取血测定血糖、血脂指标；分离肝组织测定抗氧化指标。结果太白楤木总皂苷60、120mg·kg^-1剂量组可显著降低四氧嘧啶糖尿病小鼠的血糖（P〈0．01），且以高剂量120mg·kg^-1的降糖作用最明显。4周治疗结束后，上述两剂量组的血清中总胆固醇（TC）、甘油三酯（TG）、游离脂肪酸（FFA）和丙二醛（MDA）含量显著降低（P〈0．01或P〈0．05），胰岛素含量、高密度脂蛋白（HDL-c）含量、过氧化物酶（SOD）及及胰岛素敏感指数（ISI）显著升高（P〈0．05或P〈0．01），但低密度脂蛋白（LDL-c）含量变化不明显（P〉0．05）。在太白楤木总皂苷的剂量为120mg·kg^-1时，其降血糖、降血脂及其抗氧化效果同二甲双胍相当（P〉0．05）。结论太白楤木总皂苷可降低糖尿病小鼠的血糖，其降糖机制可能与其提高糖尿病小鼠抗氧化能力，改善血脂代谢紊乱，提高肝脏及外周组织胰岛素敏感性，改善胰岛素抵抗有关。