The Effects of One-Anastomosis Gastric Bypass on Glucose Metabolism in Goto-Kakizaki Rats

Background

The improvement in glucose metabolism after bariatric surgery is well established. The aim of this study was to investigate the hormones and glycemic control in diabetes after a one-anastomosis gastric bypass (OAGB) variant in an animal model of non-obese type 2 diabetes mellitus.

Methods

Thirty-six Goto-Kakizaki rats were randomly assigned to undergo one of the following procedures: OAGB (18 rats) or sham intervention (18 rats). Each group was subdivided into three additional groups according to the time of surgery (early—12 weeks; intermediate—16 weeks; and late—20 weeks). Weight, fasting glycemia, glucose tolerance test (OGTT), and hormone levels (glucagon, insulin, glucagon-like peptide-1 [GLP-1], and glucose-dependent insulinotropic peptide [GIP]) were measured.

Results

All rats maintained their weight. The OGTT showed a significant improvement in glycemic levels in rats with OAGB in all time groups (p?<?0.002, for all groups at 60 min). Insulin levels decreased significantly in all animals with OAGB, but glucagon levels increased (glucagon paradoxical response). GLP-1 and GIP increased in rats with OAGB at all times, but was only statistically significant in the early surgery group of GLP-1 (p?<?0.005).

Conclusion

OAGB in a non-obese diabetic rat model improves glycemic control, with a significant decrease in glucose and insulin levels. This reduction without weight loss suggests a surgically induced enhancement of pancreatic function. It appears that this improvement occurs, although the GLP-1 levels were significantly increased only in the early stages. The paradoxical response of glucagon should be further evaluated.

     

Exaggerated glucagon-like peptide-1 and blunted glucose-dependent insulinotropic peptide secretion are associated with Roux-en-Y gastric bypass but not adjustable gastric banding

BACKGROUND: The aim of this study was to measure the circulating levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon in patients who had undergone adjustable gastric banding (BND) or Roux-en-Y gastric bypass (RYGB) to understand the differences in glucose and insulin regulation after these procedures. METHODS: This was a cross-sectional study of 3 groups of women matched for age and body mass index: group 1, overweight controls (n = 13); group 2, BND (n = 10); and group 3, RYGB (n = 13). Venous blood was drawn with the patient in the fasted state and throughout a 3-hour period after a liquid meal. RESULTS: The fasting glucose level was similar between the 2 surgery groups; however, the fasting insulin concentrations were greater in the BND (10.0 microU/mL) than in the RYGB (6.2 microU/mL; P <0.05) group. The glucose level at 60 minutes was significantly lower in the RYGB group (70 mg/dL, range 38-82) than in the BND group (83 mg/dL, range 63-98). The GLP-1 levels at 30 minutes were more than threefold greater in the RYGB group (96 pmol/L) compared with the BND and overweight control (28 pmol/L) groups. The GLP-1 and insulin concentrations correlated at 30 minutes only in the RYGB group (r = .66; P = .013). The glucose-dependent insulinotropic peptide levels at 30 minutes were lower in the RYGB group (20 pmol/L) than in the BND group (31 pmol/L) or overweight control group (33 pmol/L). The peak glucagon levels were similar among the 3 groups. CONCLUSION: Exaggerated postprandial GLP-1 and blunted glucose-dependent insulinotropic peptide secretion after RYGB might contribute to the greater weight loss and improved glucose homeostasis compared with BND.     

Impact of biliopancreatic diversion with duodenal switch on glucose homeostasis and gut hormones and their correlations with appetite

BackgroundBiliopancreatic diversion with duodenal switch (BPD/DS) results in lifelong changes in gastrointestinal physiology with unclear associations with appetite perception.ObjectiveTo explore mixed meal–induced changes in glucose homeostasis and gut hormones and their correlations with appetite perception.SettingUniversity hospital.MethodsOf 28 patients studied preoperatively (age: 38.4 ± 11.3 years; body mass index [BMI]: 56.5 ± 5.1 kg/m²; 14 women), 19 (68%) returned for postoperative follow-up. Plasma was sampled for 180 minutes during a 260-kcal standardized mixed meal. Concentrations of leptin, glucose, insulin, triglycerides, active acyl-ghrelin, motilin, total glucose-dependent insulinotropic polypeptide (GIP), active glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY) were measured. Subjective appetite sensations were scored.ResultsBPD/DS resulted in 66.1% ± 23.3% excess BMI loss. Leptin was halved. Glucose and insulin levels were reduced, blunting a preoperative peak at 30 minutes, giving a lower homeostasis model assessment for insulin resistance (HOMA-IR; 13.9 versus 4.8). In contrast, reduced ghrelin and motilin concentrations were accompanied by pronounced peaks 20–30 minutes prior to meal responses. GIP was reduced, whereas GLP-1 and PYY responses were markedly increased, with an early postprandial peak (P < .05, for all). HOMA-IR correlated with insulin (r = .72) and GIP (r = .57). Postoperatively, satiety correlated with GLP-1 (r = .56), whereas the gastric motility index correlated with the desire to eat (r = .60), percentage excess BMI loss (r = –.55), and percentage total weight loss (r = –.49). Delta insulin, GLP-1, and leptin correlated positively with percentage total weight loss (r = .51, r = .48, and r = .58, respectively).ConclusionsBPD/DS reduces leptin, HOMA-IR, and GIP while markedly increasing GLP-1 and PYY. This study marks the magnitude change in GLP-1 with additional effects of PYY as important factors for weight loss.     

胃袖带切除术对GK大鼠2型糖尿病的影响及其机理

目的研究胃袖带切除术（sleevegastrectomy,SG）对GK大鼠2型糖尿病（type2diabetesmellitus,T2DM）的治疗作用及其可能机理。方法将13只12周龄的GK大鼠随机分为2组：SG组7只和假手术组（SO组）6只,分别行SG术和假手术。于术前及术后1、4、10和26周测量2组大鼠的体质量、24h进食量、空腹血糖值、血清胰高血糖素样肽-1（glucagon-likepeptide-1,GLP-1）和血清生长激素释放肽（Ghrelin）浓度;于术后10周检测2组大鼠的粪便能量含量,并进行口服葡萄糖耐量实验（OGTT）和胰岛素耐受性实验（ITT）。结果①体质量：各时点2组大鼠的体质量比较差异均无统计学意义（P〉0．05）;与术前比较,术后1周2组大鼠的体质量均降低（P〈0．01）,术后10和26周的体质量均增加（P〈0．01）。②24h进食量：与SO组比较,术后4和10周SG组大鼠的24h进食量均较低（P〈0。05）。与术前比较,SG组大鼠术后1、4及10周的进食量均较低（P〈0．05）,SO组大鼠术后1周的进食量低于术前（P〈0．05）。③空腹血糖值：与SO组比较,术后各时点SG组大鼠的空腹血糖值均较低（P〈0．01）。与术前比较,SG组大鼠术后各时点的空腹血糖值均较低（P〈0．01）,而SO组大鼠仅术后1周明显低于术前∽〈0．OD。④血清GLP-1水平：与SO组比较,术后4、10及26周SG组大鼠的血清GLP．1水平均较高（P〈0．05）。与术前比较,术后4、10及26周SG组大鼠的血清GLP-1水平较高（P〈0．05）,而术后SO组大鼠的血清GLP．1水平无明显变化（P〉0．05）。⑤血清Ghrelin水平：与SO组比较,术后各时点SG组大鼠的血清Ghrelin水平均较低（P〈0．01）。与术前比较,术后各时点SG组大鼠的血清Ghrelin水平均较低（P〈0．001）,而SO组大鼠的血清Ghrelin水平无明显变化（P〉0．05）。⑥曲线下面积（AUC）：SG组大鼠的AUC（OGTT和ITT）均较SO组低（P〈0．01）。结论SG术可以明显降低GK大鼠的空腹血糖值,改善葡萄糖耐量及增强胰岛素敏感性,该作用可能是GLP．1、Grelin等多种胃肠道激素共同作用的结果。SG术可能是潜在的非肥胖型T2DM的治疗方法。     

Importance of Small Bowel Peptides for the Improved Glucose Metabolism 20 Years after Jejunoileal Bypass for Obesity

Background: Obese patients operated with jejunoileal bypass (JIB) have reduced plasma concentrations of insulin and glucose. Gastric inhibitory peptide/glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) have been found to have a profound incretin effect in humans. The aim of the present study was to examine the long-term effect of JIB on glucose metabolism. Methods: Four groups (lean, nonoperated obese, obese 9 months after JIB and obese 20 years after JIB) of six females each were given a mixed meal (280 kcal). Plasma samples were obtained every 10 min for 60 min postprandially and were analyzed for glucose, insulin, GIP and GLP-1. Results: A reduction in body mass index (kg/m²) was seen for the two patient groups operated with JIB (12.1, at 9 months post-op; 13.1, at 20 years post-op). Surgery by JIB resulted in a reduction of glucose and insulin values. Concomitantly there was an elevation of postprandial GIP and GLP-1 plasma concentrations. In the obese subjects 20 years after JIB both fasting and postprandial GIP and GLP-1 values were markedly elevated compared with the other three groups; and plasma glucose and insulin concentrations were maintained at normal levels. Conclusions: The improvement in glucose metabolism seen after JIB may be due to reduced insulin resistance after weight loss and/or increased levels of the incretin hormones GIP and GLP-1. Progressively, elevated levels of GIP and GLP-1 seem to be necessary to maintain glucose homeostasis at longterm follow-up after this procedure.     

Effects of duodenal-jejunal exclusion on beta cell function and hormonal regulation in Goto-Kakizaki rats

BackgroundThe aim of our work was to investigate the hormones that control glycemic status and in vitro β-cell function in diabetes mellitus after a duodenal-jejunal exclusion in Goto-Kakizaki rats (Taconic, Denmark).MethodsTwenty-three rats (age, 12–14 wk) were randomized as follows: group 1 (n = 14), no intervention (control); or group 2 (n = 9), duodenal-jejunal exclusion.ResultsIn group 2, levels of glucagon and leptin were lower than in group 1 at 1 week and at 8 weeks. Glucagon-like peptide 1 levels had a significant increase at 8 weeks from basal value in group 2 and this value was higher than in group 1. The insulin secretion at 60 minutes in group 2 was higher than in group 1 (group 1, 12.9 ± 12.0 μg/L vs group 2, 41.9 ± 36.3 μg/L; P < .05). Messenger RNA (mRNA) expression of insulin at 2 months was higher in the rat pancreas of the experimental group than in the control group (group 1, .99 ± .48 mRNA amount vs group 2, 1.66 ± .33 mRNA amount; P < .05).ConclusionsGastrojejunal bypass in this model improves glucose ratios, with a significant increase of glucagon-like peptide 1 and decrease of homeostasis model assessment, glucagon, and leptin levels after surgery. This type of surgery improves mRNA insulin expression in pancreatic islets and insulin secretion as well.     

Changes in Glucagon-like Peptide-1 (GLP-1) Secretion after Biliopancreatic Diversion or Vertical Banded Gastroplasty in Obese Subjects

Background: Bariatric operations promote weight loss and improve glucose homeostasis. Glucagon-like peptide-1 (GLP-1) is considered as a possible mediator of the antidiabetic effects of such operations. Methods: The present study aimed to gain information on the time course for changes in glucose tolerance, as well as insulin, glucagon and GLP-1 secretion, during an oral glucose tolerance test (OGTT), in 31 obese patients examined 1, 3 and 6 months after Larrad's biliopancreatic diversion (BPD) or 6 months after vertical banded gastroplasty (VBG). Results: A time-related progressive decrease in body weight coincided with lowering of plasma triglycerides, decrease of basal plasma glucose and its incremental area during OGTT, and reduction of basal plasma insulin together with an increase of its incremental area. The time-related decrease of plasma glucagon during OGTT was comparable before and after surgery. Both the basal plasma GLP-1 concentration and its incremental area during the OGTT increased strikingly after surgery, a steady-state situation being reached 3 months after surgery. The most striking differences between the somewhat older and less glucose-tolerant subjects of VBG compared to BPD after surgery, consisted in a decrease in cholesterol and LDL only observed in BPD and a much more pronounced increase in basal and incremental plasma GLP-1 in BPD. GLP-1, like glucagon, increased lipolysis, but failed to duplicate the lipogenetic action of insulin in isolated adipocytes obtained at the time of surgery. Conclusion: These findings support the postulated role of GLP-1, secreted by the hindgut, as a key mediator of the antidiabetic effects of bariatric operations.     

Early Improvement of Glucose Tolerance after Ileal Transposition in a Non-obese Type 2 Diabetes Rat Model

Background: Surgical operations which shorten the intestinal tract between the stomach and the terminal ileum result in an early improvement in type 2 diabetes, and one possible explanation is the arrival of undigested food in the terminal ileum. This study was designed to evaluate the role of the distal ileum in the improvement of glucose control in type 2 diabetic patients who underwent bariatric surgery. Methods: An ileal transposition (IT) to the jejunum was performed in lean diabetic Goto-Kakizaki (GK) rats. The IT was compared to sham-operated diabetic rats and a control group of diabetic rats. Non-diabetic controls were age-matched Sprague-Dawley (SD) rats, which underwent IT and no operation. Food intake and body weight were measured. An oral glucose tolerance test (OGTT) was performed 10 days before the operation and 10 days, 30 days and 45 days after the surgery. GLP-1 and insulin were measured during the OGTT 45 days after surgery. An insulin tolerance test (ITT) was performed 50 days after surgery. Results: Glucose tolerance improved in the IT diabetic group compared with both the sham-operated animals and control diabetic group 30 days and 45 days after surgery (P=0.029 and P=0.023, respectively). Insulin sensitivity, as measured by an ITT, was not significantly different between diabetic groups and the normal groups respectively after surgery. No differences in basal glucose and glucose tolerance were noted between non-diabetic operated animals and control non-diabetic rats. No differences were recorded between the diabetic rat groups and the non-diabetic rats in terms of weight and food intake. GLP-1 levels were significantly higher in the IT diabetic group compared with the sham-operated rats (P=0.05). Conclusions: Ileal transposition is effective in inducing an improvement in glucose tolerance in lean diabetic rats without affecting weight and food intake. The possible mechanism underlying the early improvement of diabetes after bariatric surgery may be due to the action of the terminal ileum through an insulin-independent action.     

Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived incretins that potentiate glucose clearance following nutrient ingestion. Elimination of incretin receptor action in GIPR(-/-) or GLP-1R(-/-) mice produces only modest impairment in glucose homeostasis, perhaps due to compensatory upregulation of the remaining incretin. We have now studied glucose homeostasis in double incretin receptor knockout (DIRKO) mice. DIRKO mice exhibit normal body weight and fail to exhibit an improved glycemic response after exogenous administration of GIP or the GLP-1R agonist exendin-4. Plasma glucagon and the hypoglycemic response to exogenous insulin were normal in DIRKO mice. Glycemic excursion was abnormally increased and levels of glucose-stimulated insulin secretion were decreased following oral but not intraperitoneal glucose challenge in DIRKO compared with GIPR(-/-) or GLP-1R(-/-) mice. Similarly, glucose-stimulated insulin secretion and the response to forskolin were well preserved in perifused DIRKO islets. Although the dipeptidyl peptidase-IV (DPP-IV) inhibitors valine pyrrolidide (Val-Pyr) and SYR106124 lowered glucose and increased plasma insulin in wild-type and single incretin receptor knockout mice, the glucose-lowering actions of DPP-IV inhibitors were eliminated in DIRKO mice. These findings demonstrate that glucose-stimulated insulin secretion is maintained despite complete absence of both incretin receptors, and they delineate a critical role for incretin receptors as essential downstream targets for the acute glucoregulatory actions of DPP-IV inhibitors.     

Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 on insulin secretion and gut motility

Glucose-induced insulin secretion from pancreatic beta-cells depends critically on ATP-sensitive K(+) channel (K(ATP) channel) activity, but it is not known whether K(ATP) channels are involved in the potentiation of insulin secretion by glucose-dependent insulinotropic polypeptide (GIP). In mice lacking K(ATP) channels (Kir6.2(-/-) mice), we found that pretreatment with GIP in vivo failed to blunt the rise in blood glucose levels after oral glucose load. In Kir6.2(-/-) mice, potentiation of insulin secretion by GIP in vivo was markedly attenuated, indicating that K(ATP) channels are essential in the insulinotropic effect of GIP. In contrast, pretreatment with glucagon-like peptide-1 (GLP-1) in Kir6.2(-/-) mice potentiated insulin secretion and blunted the rise in blood glucose levels. We also found that GLP-1 inhibited gut motility whereas GIP did not. Perfusion experiments of Kir6.2(-/-) mice revealed severely impaired potentiation of insulin secretion by 1 nmol/l GIP and substantial potentiation by 1 nmol/l GLP-1. Although both GIP and GLP-1 increase the intracellular cAMP concentration and potentiate insulin secretion, these results demonstrate that the GLP-1 and GIP signaling pathways involve the K(ATP) channel differently.     

Changes in Gastrointestinal Hormone Responses, Insulin Sensitivity, and Beta-Cell Function Within 2 Weeks After Gastric Bypass in Non-diabetic Subjects

Background

Roux-en-Y gastric bypass (RYGB) surgery causes profound changes in secretion of gastrointestinal hormones and glucose metabolism. We present a detailed analysis of the early hormone changes after RYGB in response to three different oral test meals designed to provide this information without causing side effects (such as dumping).

Methods

We examined eight obese non-diabetic patients before and within 2?weeks after RYGB. On separate days, oral glucose tolerance tests (25 or 50?g glucose dissolved in 200?mL of water) and a liquid mixed meal test (200?mL 300?kcal) were performed. We measured fasting and postprandial glucose, insulin, C-peptide, glucagon, total and intact glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY_3-36 (PYY), cholecystokinin (CCK), total and active ghrelin, gastrin, somatostatin, pancreatic polypeptide (PP), amylin, leptin, free fatty acids (FFA), and registered postprandial dumping. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance.

Results

Fasting glucose, insulin, ghrelin, and PYY were significantly decreased and FFA was elevated postoperatively. Insulin sensitivity increased after surgery. The postprandial response increased for C-peptide, GLP-1, GLP-2, PYY, CCK, and glucagon (in response to the mixed meal) and decreased for total and active ghrelin, leptin, and gastrin, but were unchanged for GIP, amylin, PP, and somatostatin after surgery. Dumping symptoms did not differ before and after the operation or between the tests.

Conclusions

Within 2?weeks after RYGB, we found an increase in insulin secretion and insulin sensitivity. Responses of appetite-regulating intestinal hormones changed dramatically, all in the direction of reducing hunger.     

Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4

In the Goto-Kakizaki (GK) rat, a genetic model of type 2 diabetes, the neonatal beta-cell mass deficit is considered to be the primary defect leading to basal hyperglycemia, which is detectable for the first time 3 weeks after birth. We investigated in GK females the short- and the long-term effects of a treatment with glucagon-like peptide-1 (GLP-1) or its long-acting analog exendin-4 (Ex-4) during the first postnatal week (during the prediabetic period). GK rats were treated with daily injections of glucagon-like peptide-1 (400 microg x kg(-1) x day(-1)) or Ex-4 (3 microg x kg(-1) x day(-1)) from day 2 to day 6 after birth and were evaluated against Wistar and untreated GK rats. Under these conditions, on day 7 both treatments enhanced pancreatic insulin content and total beta-cell mass by stimulating beta-cell neogenesis and regeneration. Follow-up of biological characteristics from day 7 to adult age (2 months) showed that such a GLP-1 or Ex-4 treatment exerted long-term favorable influences on beta-cell mass and glycemic control at adult age. As compared to untreated GK rats, 2-month-old treated rats exhibited significantly decreased basal plasma glucose. Their glucose-stimulated insulin secretion, in vivo after intravenous glucose load or in vitro using isolated perfused pancreas, was slightly improved. This contributed at least partly to improve the in vivo plasma glucose disappearance rate, which was found to be increased in both treated GK groups compared to the untreated GK group. These findings in the GK model indicated, for the first time, that GLP-1 or Ex-4 treatment limited to the prediabetic period delays the installation and limits the severity of type 2 diabetes. Under these conditions, GLP-1 represents a unique tool because of its beta-cell replenishing effect in spontaneously diabetic rodents. It may prove to be an invaluable agent for the prevention of human type 2 diabetes.     

胃转流术对非肥胖性2型糖尿病患者葡萄糖负荷后血糖和胰高血糖素样肽1水平的影响

目的 观察胃转流术对非肥胖性2型糖尿病的疗效及其对胰高血糖素样肽1(GLP-1)的影响.方法 前瞻性入选行胃转流术的32例胃溃疡合并非肥胖性2型糖尿病患者,检测术前及术后1周、1、3、6个月体质量指数(BMI)、口服葡萄糖耐量试验后0、30、60、120、180 min血糖和GLP-1水平,分析术后并发症和6个月时糖尿病转归情况.结果 术前卒腹血糖为(9.5±1.0)mmol/L,术后分别降至1周时(7.4±1.0)mmol/L、1个月时(6.5±1.2)mmol/L、3个月时(8.0±1.6)mmol/L及6个月时(5.8±1.0)mmol/L,P＜0.01;术前口服葡萄糖耐量试验血糖峰值为(17.5±2.0)mmol/L,术后分别降至(12.6±1.7)mmol/L、(11.0±1.7)mmol/L、(12.4±1.7)mmol/L和(10.8±1.7)mmol/L,P＜0.01;术前口服葡萄糖耐量试验血糖曲线下面积为(2455±281)mmol·min/L,术后分别降至(1842±237)mmol·min/L、(1638±261)mmol·min/L、(1828±239)mmol·min/L和(1541±253)mmol·min/L,P＜0.01.术前口服葡萄糖耐量试验过程中GLP-1峰值为(20±3)pmol/L,术后分别升至(83±15)pmol/L、(86±20)pmol/L、(87±22)pmol/L和(92±20)pmol/L,P＜0.01;术前口服葡萄糖耐量试验过程中GLP-1曲线下面积为(2457±395)pmol·min/L,术后分别升至(6499±1227)pmol·min/L、(7275±1475)pmol·min/L、(7307±1575)pmol·min/L和(7974±1594)pmol·min/L,P＜0.01,术后各时间点BMI较术前无显著变化(P＞0.05).术后出现切口感染1例,顽固性呃逆1例,术后6个月糖尿病总控制率均值为78%.结论 胃转流术可显著降低非肥胖性2型糖尿病患者血糖,改善口服葡萄糖耐量试验,胃转流术控制血糖可能与增加GLP-1释放进而促进胰岛素分泌有关,其对血糖的控制不依赖于体草的降低.     

The early effect of the Roux-en-Y gastric bypass on hormones involved in body weight regulation and glucose metabolism

OBJECTIVE: To evaluate the early effect of Roux-en-Y (RYGB) gastric bypass on hormones involved in body weight regulation and glucose metabolism. SIGNIFICANT BACKGROUND DATA: The RYGB is an effective bariatric procedure for which the mechanism of action has not been elucidated yet. Reports of hormonal changes after RYGB suggest a possible endocrine effect of the operation; however, it is unknown whether these changes are the cause or rather the effect of surgically induced weight loss. We speculated that if the mechanism of action of the RYGB involves an endocrine effect, then hormonal changes should occur early after surgery, prior to substantial body weight changes. METHODS: Ten patients with a mean preoperative body mass index (BMI) of 46.2 kg/m (40-53 kg/m) underwent laparoscopic RYGB. Six patients had type 2 diabetes treated by oral hypoglycemic agents. Preoperatively and 3 weeks following surgery, all patients were tested for fasting glucose, insulin, glucagon, insulin-like growth factor 1 (IGF-1), leptin, gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), adrenocorticotropic hormone (ACTH), corticosterone, and neuropeptide Y (NPY). RESULTS: Changes in mean BMI were rather minimal (43.2 kg/m; P = not significant), but there was a significant decrease in blood glucose (P = 0.005), insulin (P = 0.02), IGF-1 (P < 0.05), leptin (P = 0.001), and an increase in ACTH levels (P = 0.01). The other hormones were not significantly changed by surgery. All the 6 diabetic patients had normal glucose and insulin levels and did not require medications after surgery. The RYGB reduced GIP levels in diabetic patients (P < 0.01), whereas no changes in GIP levels were found in nondiabetics. CONCLUSIONS: Roux-en-Y gastric bypass determines considerable hormonal changes before significant BMI changes take place. These results support the hypothesis of an endocrine effect as the possible mechanism of action of RYGB.     

Type 2 Diabetes Control in a Nonobese Rat Model Using Sleeve Gastrectomy with Duodenal–Jejunal Bypass (SGDJB)

Background

As a new bariatric procedure, sleeve gastrectomy with duodenal?Cjejunal bypass (SGDJB) needs further assessment. We compared the diabetic control between SGDJB and sleeve gastrectomy (SG) in Goto?CKakizaki (GK) rats, a nonobese rat model of type 2 diabetes. Our aim is firstly to develop a nonobese diabetic rat model for SGDJB and secondly to investigate the feasibility and safety of SGDJB to induce diabetes remission.

Methods

Fifty 11-week-old male GK rats were divided into five groups: sham-operated SG (SOSG), sham-operated SGDJB (SOSGDJB), control, SG, and SGDJB. Rats were observed for 16?weeks after surgery. The body weight, food intake, glycemic control outcomes, ghrelin, peptide YY (PYY), insulin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic peptide were measured.

Results

The operated groups showed lower food intake since 4?weeks postoperation and significant weight loss since 6?weeks postoperation. SGDJB and SG surgeries induced a decreased fasting ghrelin level and increased levels of glucose-stimulated insulin, GLP-1, and PYY secretion at 2 and 16?weeks postoperation. Compared with the SG group, the SGDJB group showed higher glucose-stimulated GLP-1 levels. Both SGDJB and SG groups exhibited significant improvement in oral glucose tolerance and insulin tolerance compared with sham-operated and control groups, but there was no difference between the operated groups.

Conclusions

This nonobese diabetic rat model may be valuable in studying the effect of SGDJB on diabetic control. SGDJB shows similar improvement of glucose metabolism with SG. Our findings do not provide evidence for the foregut-mediated amelioration in glucose homeostasis.     

Evaluation of insulin secretion after pancreas autotransplantation by oral or intravenous glucose challenge.

Segmental pancreatic autotransplantation is accompanied by surgical alterations to the pancreas that may have consequences for carbohydrate metabolism. Four mongrel dogs were evaluated before operation and sequentially until 40 weeks after total pancreatectomy and autotransplantation of the splenic lobe of the pancreas with bolus intravenous and oral administration. Intravenous glucose tolerance test (IVGTT) (0.5 g/kg) revealed maintenance of fasting euglycemia for as long as 40 weeks after operation. Peak glucose and integrated glucose values did not show significant changes as a result of autotransplantation. Following transplantation, a delayed peak insulin response was seen; however, basal, peak, and integrated insulin values were largely unaltered. Only K values, a measure of glucose disposal, showed severe alterations (2.44 +/- 0.21 before operation to 1.24 +/- 0.30 at 40 weeks after operation). Oral glucose tolerance tests (OGTT) (2.0 g/kg) demonstrated an increased peak hyperglycemic response after autotransplantation with increased integrated glucose responses. Insulin levels remained at those levels seen before operation, and glucose-dependent insulinotropic polypeptide (GIP) responses were unchanged during the OGTT as late as 20 weeks after operation. In conclusion, pancreas autotransplantation after total pancreatectomy results in significant metabolic alterations that the IVGTT fails to detect with absolute glucose or insulin levels. However, K values are significantly lowered, which indicates alterations in cellular glucose transport. The OGTT demonstrates hyperglycemia without increased insulin or GIP levels, which suggests an altered beta cell response to the enteric stimulus of insulin release. These changes are nonetheless well tolerated by animals that have remained clinically healthy and euglycemic in the basal state.     

不同胃转流手术对2型糖尿病大鼠降血糖作用研究

目的:探讨不同胃转流术(RYGB)对2型糖尿病大鼠的降血糖作用及其机制.方法:将50只用链脲佐菌素成功制备2型糖尿病模型的SD大鼠随机均分为5组:A组(假手术组),B组(旷置十二指肠RYGB组),C组(旷置近段空肠RYGB组),D组(旷置十二指肠和近段空肠RYGB组),E组(无旷置的胃-空肠短路组).测定各组大鼠术前及术后1,3,6,12周的体质量、空腹血糖( FBG)、糖依赖性胰岛素释放肽(GIP)及胰高血糖素样肽1(GLP-1)的变化.E组大鼠12周后再次开腹,于胃窦下闭合十二指肠,旷置十二指肠和近段空肠,观察再次术后1,3,6周FBG,GIP,GLP-1的变化.结果:与术前比较,术后1周各组体质量均无明显改变(均P＞0.05),A,B,C组术后3,6周仍无明显变化(均P＞0.05),但术后12周明显增加,且A组增加最为明显(均P＜0.05),D,E组术后3,6周体质量有所降低(均P＜0.05),至术后12周基本接近术前水平(均P＞0.05).与术前比较,A组术后各时间点FBG,GIP,GLP-1均无明显改变(均P＞0.05);D组FBG水平在术后1周开始明显且逐渐降低,B,C,E组FBG水平在术后3周开始明显且逐渐降低(均P＜0.05),同时间点比较,D组FBG降低最为明显,E组最小(均P＜0.05),B,C组间无明显差异(均P＞0.05);B,C,D组GIP值术后1周开始明显并逐渐降低,且同时间点D组降低最为明显(均P＜0.05),B,C组间无明显差异(均P＞0.05),而E组GIP值术后时间点均无明显改变(均P＞0.05);D,E组GLP-1值术后1周开始均明显并逐渐升高,B,C组GLP-1值术后3周开始均明显并逐渐升高,且同时间点D,E组GLP-1升高程度明显大于B,C组(均P＜0.05);E组再次手术后FBG和GIP水平较再次术前均明显降低(均P＜0.05),而GLP-1水平无明显变化(均P＞0.05).结论:旷置十二指肠和近段空肠RYGB对2型糖尿病大鼠有较好的降血糖作用,其机制与术后食物不经过十二指肠和近段空肠引起GIP低分泌以及食物过早到达远段空肠和回肠引起GLP-1高分泌有关.     

Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats

Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that is released postprandially from the small intestine and acts in concert with glucagon-like peptide (GLP)-1 to potentiate glucose-induced insulin secretion from the pancreatic beta-cell. In type 2 diabetes, there is a decreased responsiveness of the pancreas to GIP; however, the insulin response to GLP-1 remains intact. The literature suggests that the ineffectiveness of GIP in type 2 diabetes may be a result of chronic homologous desensitization of the GIP receptor. Yet, there has been no conclusive evidence suggesting that GIP levels are elevated in diabetes. The hypothesis of the present study is that one cause of decreased responsiveness to GIP in type 2 diabetes is an inappropriate expression of the GIP receptor in the pancreatic islet. This hypothesis was tested using a strain of diabetic fatty Zucker rats. The obese rats displayed basal GIP levels similar to the control animals; however, they were unresponsive to a GIP infusion (4 pmol.min(-1). kg(-1)), whereas the lean animals displayed a significant reduction in blood glucose (GIP levels, 50% control after 60 min, P < 0.05) as well as a significant increase in circulating insulin. GIP also potently stimulated first-phase insulin secretion from isolated perifused islets (10.3 +/- 3.0 x basal), and GIP and GLP-1 potentiated insulin secretion from the perfused pancreas (6 x control area under the curve [AUC]) from lean animals. GIP yielded no significant effect in the Vancouver diabetic fatty Zucker (VDF) rat pancreases, whereas GLP-1 elicited an eightfold increase of insulin secretion from the perfused VDF pancreas. Islets from lean animals subjected to static incubations with GIP showed a 2.2-fold increase in cAMP, whereas GIP failed to increase islet cAMP in the VDF islets. Finally, the expression of both GIP receptor mRNA and protein was decreased in islets from VDF rats. These data suggest that the decreased effectiveness of GIP in the VDF rat and in type 2 diabetes may be a result of a decreased receptor expression in the islet.