Plasma N-Acetylaspartate Is Related to Age, Obesity, and Glucose Metabolism: Effects of Antidiabetic Treatment and Bariatric Surgery.

Background: N-acetylaspartate (NAA) is synthesized only by neurons and is involved in neuronal metabolism and axonal myelination. NAA is the strongest signal on brain magnetic resonance spectroscopy, and its concentration have been associated with cognitive dysfunction in neurodegenerative diseases, obesity, and type 2 diabetes (T2D). Materials and Methods: We explored the impact of obesity and T2D on circulating NAA as well as the impact of bariatric surgery and antidiabetic treatments. We developed an LC-MS method for the accurate measurements of fasting plasma NAA levels in 505 subjects (156 subjects with normal glucose tolerance, 24 subjects with impaired glucose tolerance, and 325 patients with T2D) to examine the associations of NAA with obesity and dysglycemia. To validate cross-sectional findings, plasma NAA was measured 6 months after Roux-en-Y Gastric Bypass (RYGB) in 55 morbidly obese subjects, and after 1 year of antidiabetic treatment (with dapagliflozin, exenatide, or dapagliflozin plus exenatide) in 192 T2D patients. Results: In the whole population, NAA was associated with age (r = 0.31, p <0.0001) and BMI (r = -0.20, p <0.0001). Independently of age and BMI, NAA was reciprocally related to HbA1c and fasting plasma glucose (partial r = -0.13, both p = 0.01). Surgically-induced weight loss raised NAA (by 18 nmol/L on average, p <0.02). Glucose lowering treatment increased NAA in proportion to the drop in HbA1c (r = 0.31, p <0.0001) regardless of the agent used. Conclusions: Circulating NAA concentrations are modulated by age, obesity, and glycemic control. Whether they may mark for the corresponding metabolic effects on brain function remains to be established by joint measurements of spectroscopic signal and cognitive function.

Differential unfolded protein response in skeletal muscle from non-diabetic glucose tolerant or intolerant patients with obesity before and after bariatric surgery.

AIMS: Not all people with obesity become glucose intolerant, suggesting differential activation of cellular pathways. The unfolded protein response (UPR) may contribute to the development of insulin resistance in several organs, but its role in skeletal muscle remains debated. Therefore, we explored the UPR activation in muscle from non-diabetic glucose tolerant or intolerant patients with obesity and the impact of bariatric procedures. METHODS: Muscle biopsies from 22 normoglycemic (NG, blood glucose measured 120 min after an oral glucose tolerance test, G120 < 7.8 mM) and 22 glucose intolerant (GI, G120 between 7.8 and 11.1 mM) patients with obesity were used to measure UPR activation by RTqPCR and western blot. Then, UPR was studied in biopsies from 7 NG and 7 GI patients before and 1 year after bariatric surgery. RESULTS: Binding immunoglobulin protein (BIP) protein was ~ 40% higher in the GI compared to NG subjects. Contrastingly, expression of the UPR-related genes BIP, activating transcription factor 6 (ATF6) and unspliced X-box binding protein 1 (XBP1u) were significantly lower and C/EBP homologous protein (CHOP) tended to decrease (p = 0.08) in GI individuals. While BIP protein positively correlated with fasting blood glucose (r = 0.38, p = 0.01), ATF6 and CHOP were associated with G120 (r = - 0.38 and r = - 0.41, p < 0.05) and the Matsuda index (r = 0.37 and r = 0.38, p < 0.05). Bariatric surgery improved metabolic parameters, associated with higher CHOP expression in GI patients, while ATF6 tended to increase (p = 0.08). CONCLUSIONS: CHOP and ATF6 expression decreased in non-diabetic GI patients with obesity and was modified by bariatric surgery. These genes may contribute to glucose homeostasis in human skeletal muscle.

Impact of Gastric Banding Versus Metformin on ß-Cell Function in Adults With Impaired Glucose Tolerance or Mild Type 2 Diabetes.

OBJECTIVE: Type 2 diabetes (T2D) results from progressive loss of ß-cell function. The BetaFat study compared gastric banding and metformin for their impact on ß-cell function in adults with moderate obesity and impaired glucose tolerance (IGT) or recently diagnosed, mild T2D. RESEARCH DESIGN AND METHODS: Eighty-eight people aged 21-65 years, BMI 30-40 kg/m2, with IGT or diabetes known for <1 year, were randomized to gastric banding or metformin for 2 years. Hyperglycemic clamps (11.1 mmol/L) followed by arginine injection at maximally potentiating glycemia (>25 mmol/L) were performed at baseline, 12 months, and 24 months to measure steady-state C-peptide (SSCP) and acute C-peptide response to arginine at maximum glycemic potentiation (ACPRmax) and insulin sensitivity (M/I). RESULTS: At 24 months, the band group lost 10.7 kg; the metformin group lost 1.7 kg (P < 0.01). Insulin sensitivity increased 45% in the band group and 25% in the metformin group (P = 0.30 between groups). SSCP adjusted for insulin sensitivity fell slightly but not significantly in each group (P = 0.34 between groups). ACPRmax adjusted for insulin sensitivity fell significantly in the metformin group (P = 0.002) but not in the band group (P = 0.25 between groups). HbA1c fell at 12 and 24 months in the band group (P < 0.004) but only at 12 months (P < 0.01) in the metformin group (P > 0.14 between groups). Normoglycemia was present in 22% and 15% of band and metformin groups, respectively, at 24 months (P = 0.66 between groups). CONCLUSIONS: Gastric banding and metformin had similar effects to preserve ß-cell function and stabilize or improve glycemia over a 2-year period in moderately obese adults with IGT or recently diagnosed, mild T2D.

Temporal changes in plasma markers of oxidative stress following laparoscopic sleeve gastrectomy in subjects with impaired glucose regulation.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for obesity and associated metabolic complications. Obesity and type 2 diabetes are associated with increased oxidative stress. Previous studies have examined changes in plasma oxidative stress after laparoscopic Roux-en-Y gastric bypass, but there is limited evidence of the effects of LSG. OBJECTIVES: To examine the effects of LSG on plasma thiobarbituric acid reactive substances (TBARS) and total antioxidant status (TAOS) at 1 and 6 months after LSG in patients with obesity and impaired glucose regulation. SETTING: University hospital, United Kingdom. METHODS: Twenty-two participants with impaired glucose homeostasis undergoing LSG (body mass index 50.1 kg/m2, glycated hemoglobin 53 mmol/mol) were studied. Measurements of fasting and 120-minute TBARS and TAOS were performed during an oral glucose tolerance test preoperatively and postoperatively. RESULTS: Compared with preoperative levels, significant decreases were seen 6 months postoperatively in fasting TBARS (61.0±17.9 versus 39.4±13.8 ng/mL, P = .04) and 120-minute TBARS (76.0±29.5 versus 46.5±16.3 ng/mL, P = .02). No significant changes were observed in plasma TAOS. No significant association was observed between changes in TBARS and other clinical or biochemical measures. CONCLUSION: We observed a significant reduction in TBARS, a global measure of lipid peroxidation 6 months after LSG in participants with obesity and impaired glucose regulation.

Lipocalin-type prostaglandin D2 synthase (L-PGDS) modulates beneficial metabolic effects of vertical sleeve gastrectomy.

BACKGROUND: Vertical sleeve gastrectomy (VSG) ameliorates metabolic complications in obese and diabetic patients through unknown mechanisms. OBJECTIVE: The objective of this study was to investigate the role of lipocalin-type prostaglandin D2 synthase (L-PGDS) in glucose regulation in response to VSG using L-PGDS knock-out (KO), knock-in (KI), and C57BL/6 (wild type) mice. SETTING: Winthrop University Hospital Research Institute. METHODS: Animals were divided into 6 groups: L-PGDS KO sham/VSG (n = 5), L-PGDS KI sham/VSG (n = 5), and C57BL/6 (wild type) sham/VSG (n = 5). Related parameters were measured in fasting animals after 10 weeks. RESULTS: Our intraperitoneal glucose tolerance tests and homeostatic model assessment insulin resistance results showed significant glycemic improvement 10 weeks post-VSG in both C57BL/6 and KI groups compared with the sham group. In contrast, the KO group developed glucose intolerance and insulin resistance similar to or greater than the sham group 10 weeks post-VSG. Interestingly, weight gain was insignificant 10 weeks post-VSG in all the groups and even trended higher in the KO group compared with sham. Peptide YY levels in the KO group post-VSG were slightly increased but significantly less than other groups. Similarly, the KO group showed significantly less leptin sensitivity in response to VSG compared with the KI group. Total cholesterol level remained unchanged in all groups irrespective of sham or surgery but interestingly, the KO group had significantly higher cholesterol levels. In parallel, adipocyte size was also found to be significantly increased in the KO group post-VSG compared with the sham group. CONCLUSION: Our findings propose that L-PGDS plays an important role in the beneficial metabolic effects observed after VSG.

Subcutaneous fat transplantation alleviates diet-induced glucose intolerance and inflammation in mice.

AIMS/HYPOTHESIS: Adipose tissue (AT) distribution is a major determinant of mortality and morbidity in obesity. In mice, intra-abdominal transplantation of subcutaneous AT (SAT) protects against glucose intolerance and insulin resistance (IR), but the underlying mechanisms are not well understood. METHODS: We investigated changes in adipokines, tissue-specific glucose uptake, gene expression and systemic inflammation in male C57BL6/J mice implanted intra-abdominally with either inguinal SAT or epididymal visceral AT (VAT) and fed a high-fat diet (HFD) for up to 17 weeks. RESULTS: Glucose tolerance was improved in mice receiving SAT after 6 weeks, and this was not attributable to differences in adiposity, tissue-specific glucose uptake, or plasma leptin or adiponectin concentrations. Instead, SAT transplantation prevented HFD-induced hepatic triacylglycerol accumulation and normalised the expression of hepatic gluconeogenic enzymes. Grafted fat displayed a significant increase in glucose uptake and unexpectedly, an induction of skeletal muscle-specific gene expression. Mice receiving subcutaneous fat also displayed a marked reduction in the plasma concentrations of several proinflammatory cytokines (TNF-α, IL-17, IL-12p70, monocyte chemoattractant protein-1 [MCP-1] and macrophage inflammatory protein-1ß [ΜIP-1ß]), compared with sham-operated mice. Plasma IL-17 and MIP-1ß concentrations were reduced from as early as 4 weeks after transplantation, and differences in plasma TNF-α and IL-17 concentrations predicted glucose tolerance and insulinaemia in the entire cohort of mice (n = 40). In contrast, mice receiving visceral fat transplants were glucose intolerant, with increased hepatic triacylglycerol content and elevated plasma IL-6 concentrations. CONCLUSIONS/INTERPRETATION: Intra-abdominal transplantation of subcutaneous fat reverses HFD-induced glucose intolerance, hepatic triacylglycerol accumulation and systemic inflammation in mice.

Immediate enhancement of first-phase insulin secretion and unchanged glucose effectiveness in patients with type 2 diabetes after Roux-en-Y gastric bypass.

Roux-en-Y gastric bypass surgery (RYGB) in patients with type 2 diabetes often leads to early disease remission, and it is unknown to what extent this involves improved pancreatic ß-cell function per se and/or enhanced insulin- and non-insulin-mediated glucose disposal (glucose effectiveness). We studied 30 obese patients, including 10 with type 2 diabetes, 8 with impaired glucose tolerance, and 12 with normal glucose tolerance before, 1 wk, and 3 mo after RYGB, using an intravenous glucose tolerance test (IVGTT) to estimate first-phase insulin response, insulin sensitivity (Si), and glucose effectiveness with Bergman's minimal model. In the fasting state, insulin sensitivity was estimated by HOMA-S and ß-cell function by HOMA-ß. Moreover, mixed-meal tests and oral GTTs were performed. In patients with type 2 diabetes, glucose levels normalized after RYGB, first-phase insulin secretion in response to iv glucose increased twofold, and HOMA-ß already improved 1 wk postoperatively, with further enhancements at 3 mo. Insulin sensitivity increased in the liver (HOMA-S) at 1 wk and at 3 mo in peripheral tissues (Si), whereas glucose effectiveness did not improve significantly. During oral testing, GLP-1 responses and insulin secretion increased regardless of glucose tolerance. Therefore, in addition to increased insulin sensitivity and exaggerated postprandial GLP-1 levels, diabetes remission after RYGB involves early improvement of pancreatic ß-cell function per se, reflected in enhanced first-phase insulin secretion to iv glucose and increased HOMA-ß. A major role for improved glucose effectiveness after RYGB was not supported by this study.

Roux-en-Y gastric bypass surgery, but not calorie restriction, reduces plasma branched-chain amino acids in obese women independent of weight loss or the presence of type 2 diabetes.

OBJECTIVE: Obesity and type 2 diabetes mellitus (T2DM) have been associated with increased levels of circulating branched-chain amino acids (BCAAs) that may be involved in the pathogenesis of insulin resistance. However, weight loss has not been consistently associated with the reduction of BCAA levels. RESEARCH DESIGN AND METHODS: We included 30 obese normal glucose-tolerant (NGT) subjects, 32 obese subjects with T2DM, and 12 lean female subjects. Obese subjects underwent either a restrictive procedure (gastric banding [GB], a very low-calorie diet [VLCD]), or a restrictive/bypass procedure (Roux-en-Y gastric bypass [RYGB] surgery). Fasting blood samples were taken for the determination of amine group containing metabolites 4 weeks before, as well as 3 weeks and 3 months after the intervention. RESULTS: BCAA levels were higher in T2DM subjects, but not in NGT subjects, compared with lean subjects. Principal component (PC) analysis revealed a concise PC consisting of all BCAAs, which showed a correlation with measures of insulin sensitivity and glucose tolerance. Only after the RYGB procedure, and at both 3 weeks and 3 months, were circulating BCAA levels reduced. CONCLUSIONS: Our data confirm an association between deregulation of BCAA metabolism in plasma and insulin resistance and glucose intolerance. Three weeks after undergoing RYGB surgery, a significant decrease in BCAAs in both NGT as well as T2DM subjects was observed. After 3 months, despite inducing significant weight loss, neither GB nor VLCD induced a reduction in BCAA levels. Our results indicate that the bypass procedure of RYGB surgery, independent of weight loss or the presence of T2DM, reduces BCAA levels in obese subjects.

Transplantation of betacellulin-transduced islets improves glucose intolerance in diabetic mice.

Type 1 diabetes is an autoimmune disease caused by permanent destruction of insulin-producing pancreatic ß cells and requires lifelong exogenous insulin therapy. Recently, islet transplantation has been developed, and although there have been significant advances, this approach is not widely used clinically due to the poor survival rate of the engrafted islets. We hypothesized that improving survival of engrafted islets through ex vivo genetic engineering could be a novel strategy for successful islet transplantation. We transduced islets with adenoviruses expressing betacellulin, an epidermal growth factor receptor ligand, which promotes ß-cell growth and differentiation, and transplanted these islets under the renal capsule of streptozotocin-induced diabetic mice. Transplantation with betacellulin-transduced islets resulted in prolonged normoglycemia and improved glucose tolerance compared with those of control virus-transduced islets. In addition, increased microvascular density was evident in the implanted islets, concomitant with increased endothelial von Willebrand factor immunoreactivity. Finally, cultured islets transduced with betacellulin displayed increased proliferation, reduced apoptosis and enhanced glucose-stimulated insulin secretion in the presence of cytokines. These experiments suggest that transplantation with betacellulin-transduced islets extends islet survival and preserves functional islet mass, leading to a therapeutic benefit in type 1 diabetes.

FXR is a molecular target for the effects of vertical sleeve gastrectomy.

Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.

Nutrient infusion bypassing duodenum-jejunum improves insulin sensitivity in glucose-tolerant and diabetic obese subjects.

The mechanisms of type 2 diabetes remission after bariatric surgery is still not fully elucidated. In the present study, we tried to simulate the Roux-en-Y gastric bypass with a canonical or longer biliary limb by infusing a liquid formula diet into different intestinal sections. Nutrients (Nutrison Energy) were infused into mid- or proximal jejunum and duodenum during three successive days in 10 diabetic and 10 normal glucose-tolerant subjects. Plasma glucose, insulin, C-peptide, glucagon, incretins, and nonesterified fatty acids (NEFA) were measured before and up to 360 min following. Glucose rate of appearance (Ra) and insulin sensitivity (SI), secretion rate (ISR), and clearance were assessed by mathematical models. SI increased when nutrients were delivered in mid-jejunum vs. duodenum (SI × 104 min⁻¹·pM⁻¹: 1.11 ± 0.44 vs. 0.62 ± 0.22, P < 0.015, in controls and 0.79 ± 0.34 vs. 0.40 ± 0.20, P < 0.05, in diabetic subjects), whereas glucose Ra was not affected. In controls, Sensitivity of NEFA production was doubled in mid-jejunum vs. duodenum (2.80 ± 1.36 vs. 1.13 ± 0.78 × 106, P < 0.005) and insulin clearance increased in mid-jejunum vs. duodenum (2.05 ± 1.05 vs. 1.09 ± 0.38 l/min, P < 0.03). Bypass of duodenum and proximal jejunum by nutrients enhances insulin sensitivity, inhibits lipolysis, and increases insulin clearance. These results may further our knowledge of the effects of bariatric surgery on both insulin resistance and diabetes.

The role of the gut hormone GLP-1 in the metabolic improvements caused by ileal transposition.

BACKGROUND: Bariatric surgery alters the gastrointestinal hormonal milieu leading to improved glucose homeostasis, though the mechanism leading to these changes is poorly understood. Ileal transposition (IT) is a procedure that is neither restrictive nor malabsorptive but nevertheless produces profound improvements in glucose regulation. Ileal transposition involves a short segment of distal ileum being transposed to the proximal jejunum in an isoperistaltic direction, thereby avoiding any gastric resection or intestinal bypass. METHODS: Diet-induced obese rats underwent either ileal transposition (IT) or Sham procedures. The Sham operated rats were pair-fed to the IT surgical group to control for the effects of reduced food intake. Body composition data were recorded at specific time points, and glucose tolerance tests were performed at 5 and 6 wk, both in the presence and absence of Exendin 9-39, a known glucose-like peptide 1 (GLP-1) receptor antagonist. A subset of naïve rats were also maintained for comparison. RESULTS: IT and Sham operated rats had no differences in food intake and body weight, however, IT rats had a significant decrease in their body fat composition (P < 0.05). No difference existed in glucose tolerance when exposed to an intraperitoneal glucose load, however, IT rats showed markedly improved glucose tolerance when submitted to an oral glucose tolerance test (P < 0.001). Blocking GLP-1 receptors reversed these important improvements in rats with IT surgery. CONCLUSIONS: The present work recapitulates what is seen in rodents and humans that IT improves glucose tolerance and body composition. The present data provide compelling evidence that these improvements are a product of increased GLP-1 secretion that results from placing the key GLP-1 secreting cells closer to chyme coming from the stomach. Such data support the notion that rather than restriction or malabsorption, the underling molecular mechanisms that mediate the potent improvements produced by bariatric procedures involve increased activation of GLP-1 signaling.

Resveratrol fails to improve marginal mass engraftment of transplanted islets of Langerhans in mice.

One limitation of current islet transplantation protocols is the loss of up to 70% of the transplanted islet mass. Inflammatory events play a major role in islet loss including the cytokines TNFα and IL-1. Resveratrol, a compound with anti-inflammatory and anti-oxidant properties, has the potential to mitigate islet loss. Using a syngeneic marginal  after mouse islet transplantation model we tested the ability of resveratrol to enhance islet engraftment. We failed to show a difference in diabetes reversal between mice treated with vehicle and those treated with either 10 mg/kg (47.1% for resveratrol vs. 35.3% for control) or 50 mg/kg (20% for resveratrol vs. 22.2% for control) of resveratrol daily for three weeks. In addition, at one month there was no difference in glucose tolerance or graft survival (10 mg/kg: 552.6 ng/ml resveratrol group vs. 576.6 ng/ml control group; 50 mg/kg: 463 ng/ml resveratrol group vs. 444.1 ng/ml control group). In summary, over a wide range of doses, resveratrol did not exert a benefit on mouse islet engraftment. Further studies should be conducted with human islets before deeming resveratrol ineffective in islet engraftment and survival.

Glucose intolerance and diabetes mellitus in endocrine disorders - two case reports and a review.

Impaired glucose tolerance and diabetes mellitus are a manifestation of several well recognised endocrine disorders. Hyperglycaemia subsides upon removal of the underlying cause in these conditions - usually a hormone secreting tumour. We describe two subjects who were cured of their poorly controlled diabetes mellitus following surgical removal of a phaeochromocytoma and a cortisol secreting adrenal adenoma and review the mechanisms underlying glucose intolerance in endocrine disorders. The reported incidence of diabetes is variable in these conditions and may range between 2-95%. The severity is also variable as some affected individuals have only minor glucose intolerance while others have frank symptomatic diabetes mellitus which forms a major manifestation of their illness. The mechanisms causing hyperglycaemia are (a) insulin resistance, (b) increased hepatic glucose production and output, (c) decreased insulin production and release and (d) increased intestinal glucose absorption. Multiple intermediate mechanisms which include electrolyte perturbations and hormone receptor and post receptor mediated effects are responsible for these abnormalities. An understanding of these mechanisms and diagnostic strategies is important as these may be used to advantage in managing these patients. We describe some of these in greater detail below.

Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat.

The hindgut hypothesis posits improvements in Type 2 diabetes after gastric bypass surgery are due to enhanced delivery of undigested nutrients to the ileum, which increase incretin production and insulin sensitivity. The present study investigates the effect of ileal interposition (IT), surgically relocating a segment of distal ileum to the proximal jejunum, on glucose tolerance, insulin sensitivity, and glucose transport in the obese Zucker rat. Two groups of obese Zucker rats were studied: IT and sham surgery ad libitum fed (controls). Changes in food intake, body weight and composition, glucose tolerance, insulin sensitivity and tissue glucose uptake, and insulin signaling as well as plasma concentrations of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide were measured. The IT procedure did not significantly alter food intake, body weight, or composition. Obese Zucker rats demonstrated improved glucose tolerance 3 wk after IT compared with the control group (P < 0.05). Euglycemic, hyperinsulinemic clamp and 1-[(14)C]-2-deoxyglucose tracer studies indicate that IT improves whole body glucose disposal, insulin-stimulated glucose uptake, and the ratio of phospho- to total Akt (P < 0.01 vs. control) in striated muscle. After oral glucose, the plasma concentration of glucagon-like peptide-1 was increased, whereas GIP was decreased following IT. Enhanced nutrient delivery to the ileum after IT improves glucose tolerance, insulin sensitivity and muscle glucose uptake without altering food intake, body weight, or composition. These findings support the concept that anatomic and endocrine alterations in gut function play a role in the improvements in glucose homeostasis after the IT procedure.

Skeletal myoblast transplantation for attenuation of hyperglycaemia, hyperinsulinaemia and glucose intolerance in a mouse model of type 2 diabetes mellitus.

AIMS/HYPOTHESIS: We aimed to demonstrate the feasibility and efficacy of intra-muscular transplantation of human skeletal myoblasts (hSkMs) for attenuation of hyperglycaemia and improvement of insulin sensitivity using a mouse model of type 2 diabetes mellitus. METHODS: KK Cg-Ay/J mice, aged 12 to 14 weeks, underwent an initial intraperitoneal glucose tolerance test (GTT) and were divided into the following groups: KK control group, basal medium (M199) only; KK myoblast group, with hSkM transplantation; KK fibroblast group, with human fibroblast transplantation. Non-diabetic C57BL mice were used as an additional normal control and also had hSkM transplantation. Cells were transplanted intra-muscularly into the skeletal muscles of the mice. All animals were treated with ciclosporin for 6 weeks only. HbA(1c) and fasting GTT, as well as serum adiponectin, cholesterol, insulin and triacylglycerol were studied. RESULTS: Immunohistochemistry studies showed extensive survival of the transplanted hSkMs in the skeletal muscles at 12 weeks, with nuclei of the hSkMs integrated into the host muscle fibres. Repeat GTT showed a significant decrease in glucose concentrations in the KK myoblast group compared with the KK control and KK fibroblast groups. The KK myoblast group also had reduced mean HbA(1c), cholesterol, insulin and triacylglycerol, and increased adiponectin compared with the KK control and KK fibroblast groups. C57BL mice showed no change in glucose homeostasis after hSkM transplant. CONCLUSIONS/INTERPRETATION: Human skeletal myoblast transplantation attenuated hyperglycaemia and hyperinsulinaemia and improved glucose tolerance in the KK mouse. This novel approach of improving muscle insulin resistance may be a potential alternative treatment for type 2 diabetes mellitus.

Duodenal-jejunal exclusion improves glucose tolerance in the diabetic, Goto-Kakizaki rat by a GLP-1 receptor-mediated mechanism.

BACKGROUND: Gastric bypass results in the rapid resolution of type 2 diabetes. No causal evidence exists to link specific gut hormone changes with improvements in glucose homeostasis post-operatively. We hypothesized that surgical augmentation of the glucoregulatory factor GLP-1 would improve glucose tolerance in diabetic GK rats. We compared two procedures that increase distal small bowel stimulation, ileal interposition (IT), and duodenal-jejunal exclusion (DJE). METHODS: DJE, IT, DJE Sham, or IT Sham were performed in GK rats. Glucose tolerance was tested at 4 and 6 weeks, the latter with and without Exendin-[9-39], a GLP-1 receptor antagonist. Small bowel segments were harvested for GLP-1 protein content 2 weeks after DJE or Sham surgery. RESULTS: Despite similar weight profiles, a significant improvement in the OGTT was noted at 4 weeks after DJE and IT. Plasma GLP-1 levels were significantly elevated after DJE and IT. Intestinal GLP-1 was increased in the mid-jejunum and ileum after DJE. Exendin-[9-39] abolished the improvement in glucose tolerance after DJE. CONCLUSIONS: DJE increased GLP-1 secretion and improved glucose tolerance, an effect that was reversed by GLP-1 receptor antagonism. This study provides direct evidence that improvement of glucose tolerance following a gastric bypass-like surgery is mediated by enhanced GLP-1 action.

Glucose tolerance in the proximal versus the distal small bowel in Wistar rats.

BACKGROUND: Type 2 diabetes is an epidemic and insulin resistance is the central etiology of this disease. Obesity increases insulin resistance and glucose intolerance and also exacerbates metabolic abnormalities present in type 2 diabetes. Bariatric surgery is the most effective treatment for severe obesity. Most reported series show that return to euglycemia and normal insulin levels occur days after gastric bypass and biliopancreatic diversion, long before major weight loss has taken place. The mechanisms underlying this dramatic reversal of type 2 diabetes following these bariatric procedures are not well understood. METHODS: Twelve Wistar rats were fed with a palatable hyperlipidic diet for 12 weeks. Body weight, glucose, and intraperitoneal glucose tolerance test were measured regularly. On day 91, they were randomized in two groups (hindgut and controls) and operated. Twenty-one days later, the tests were done again and the hindgut group re-operated. A duodenal exclusion was done. The results of an intraperitoneal glucose tolerance test were compared after the procedures. RESULTS: Body weight increased regularly in all the rats. Some rats developed hyperglycemia 28 days after beginning hyperlipidic diet, but these levels returned to baseline on days 56 and 84. The glucose tolerance test showed an improvement in glycemic levels in the hindgut group 21 days after the first operation (151 +/- 21mg/dl). After the second operation, despite weight loss, the glucose tolerance test of the foregut group worsened again (267 +/- 53 mg/dl) (p < 0.01). CONCLUSION: Comparing the "hindgut hypothesis" and the "foregut hypothesis", our data show an improvement in the 30 min glucose tolerance test in the hindgut group.

Role of the incretin system in the remission of type 2 diabetes following bariatric surgery.

AIMS: It has been observed, as a collateral outcome of bariatric surgery, that morbidly obese patients with frank type 2 diabetes mellitus or impaired glucose tolerance undergone Roux-en-Y Gastric Bypass (RYGB) or bilio-pancreatic diversion (BPD) became and remained euglycemic since surgery. But, most interestingly, the conversion to euglycemia happened within few days from the operation, long before a significant weight loss could intervene. The purpose of this viewpoint is to try to elucidate the mechanisms involved in the resolution/remission of diabetes after bariatric surgery, in particular highlighting the role played by the modifications in incretin secretion. DATA SYNTHESIS: The effect of purely restrictive procedures in improving glucose control is directly proportional to the degree of weight loss. In contrast, either RYGB or BPD, the first a mainly restrictive and the second a quite purely malabsorptive bariatric technique, operate through a different mechanism, as a probable consequence of the small intestine bypass. The bypass of different intestinal portions covers a central role in the mechanisms of action of these two surgical procedures. In fact, while RYGB does not affect insulin resistance but increases insulin secretion via the stimulation of nutrient-mediated incretin secretion, BPD induces a full normalization of insulin resistance and, consequently, a significant reduction of insulin secretion. The insulin resistance reversion is only partially explained by the incretin level changes after BPD. CONCLUSION: A role of incretins in type 2 diabetes improvement or resolution is ascertained although it is possible that other, not yet identified, hormone(s) can cooperate with them.