Laparoscopic Greater Curvature Plication in Morbidly Obese Women with Type 2 Diabetes: Effects on Glucose Homeostasis,Postprandial Triglyceridemia and Selected Gut Hormones

Background

Laparoscopic greater curvature plication (LGCP) is an emerging bariatric procedure that reduces the gastric volume without implantable devices or gastrectomy. The aim of this study was to explore changes in glucose homeostasis, postprandial triglyceridemia, and meal-stimulated secretion of selected gut hormones [glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), ghrelin, and obestatin] in patients with type 2 diabetes mellitus (T2DM) at 1 and 6 months after the procedure.

Methods

Thirteen morbidly obese T2DM women (mean age, 53.2?±?8.76 years; body mass index, 40.1?±?4.59 kg/m²) were prospectively investigated before the LGCP and at 1- and 6-month follow-up. At these time points, all study patients underwent a standardized liquid mixed-meal test, and blood was sampled for assessment of plasma levels of glucose, insulin, C-peptide, triglycerides, GIP, GLP-1, ghrelin, and obestatin.

Results

All patients had significant weight loss both at 1 and 6 months after the LGCP (p?≤?0.002), with mean percent excess weight loss (%EWL) reaching 29.7?±?2.9 % at the 6-month follow-up. Fasting hyperglycemia and hyperinsulinemia improved significantly at 6 months after the LGCP (p?<?0.05), with parallel improvement in insulin sensitivity and HbA1c levels (p?<?0.0001). Meal-induced glucose plasma levels were significantly lower at 6 months after the LGCP (p?<?0.0001), and postprandial triglyceridemia was also ameliorated at the 6-month follow-up (p?<?0.001). Postprandial GIP plasma levels were significantly increased both at 1 and 6 months after the LGCP (p?<?0.0001), whereas the overall meal-induced GLP-1 response was not significantly changed after the procedure (p?>?0.05). Postprandial ghrelin plasma levels decreased at 1 and 6 months after the LGCP (p?<?0.0001) with no significant changes in circulating obestatin levels.

Conclusion

During the initial 6-month postoperative period, LGCP induces significant weight loss and improves the metabolic profile of morbidly obese T2DM patients, while it also decreases circulating postprandial ghrelin levels and increases the meal-induced GIP response.     

Early Improvement of Postprandial Lipemia After Bariatric Surgery in Obese Type 2 Diabetic Patients

Background

Bariatric surgery (BS) is able to positively influence fasting lipid profile in obese type 2 diabetic patients (T2DM), but no data is available on the impact of BS on postprandial lipid metabolism neither on its relation with incretin hormones. We evaluated the short-term (2 weeks) effects of BS on fasting and postprandial lipid metabolism in obese T2DM patients and the contribution of changes in active GLP-1.

Methods

We studied 25 obese T2DM patients (age?=?46?±?8 years, BMI?=?44?±?7 kg/m²), of which 15 underwent sleeve gastrectomy and 10 underwent gastric bypass. Lipid and incretin hormone concentrations were evaluated for 3 h after ingestion of a liquid meal before and 2 weeks after BS.

Results

After BS, there was a significant reduction in body weight (p?<?0.001), fasting plasma glucose (p?<?0.001), fasting plasma insulin (p?<?0.05), HOMA-IR (p?<?0.001), and fasting plasma lipids (p?<?0.05). The meal response of plasma triglycerides, total cholesterol, and HDL cholesterol was significantly lower compared to pre-intervention (p?<?0.05, p?<?0.001). In particular, the incremental area under the curve (IAUC) of plasma triglycerides decreased by 60 % (p?<?0.005). The meal-stimulated response of active GLP-1 increased, reaching a statistical significance (p?<?0.001).

Conclusions

BS leads to an early improvement of fasting and postprandial lipemia. The fall in fasting triglycerides is associated with an improvement of insulin resistance, while the reduction of postprandial lipemia is likely related to reduced intestinal lipid absorption consequent to bariatric surgery.     

Incretin Response to a Standard Test Meal in a Rat Model of Sleeve Gastrectomy with Diet-Induced Obesity

Background

Currently, the most effective treatment for obesity is bariatric surgery. Gastroduodenal bypass surgery produces sustained weight loss and improves glycemic control and insulin sensitivity. Previous studies have shown that sleeve gastrectomy (SG) produces similar results and implicate changes in incretin hormone release in these effects.

Methods

Male Sprague–Dawley rats were divided into four groups; lean control (lean), diet-induced obesity (DIO), DIO animals that had undergone SG (SG), and DIO animals that had undergone a sham operation (sham).

Results

After a 2-week recovery period, the incretin response to a standard test meal was measured. Blood sampling was performed in free-moving rats at various time points using chronic vascular access to the right jugular vein. There was a significant increase in the bodyweight of DIO animals fed a high-fat/high-sugar diet compared with the lean animals, which was reversed by SG. DIO caused an impairment of the GLP-1 response to a standard test meal, but not the GIP response. SG resulted in a dramatic increase in the GLP-1 response to a standard test meal but had no effect on the GIP response.

Conclusions

A rapid rise in blood sugar was observed in the SG group following a standard test meal that was followed by reactive hypoglycemia. SG dramatically increases the GLP-1 response to a standard test meal but has no effect on GIP in a rat model of DIO.     

GLP-1 Response to a Mixed Meal: What Happens 10 Years after Roux-en-Y Gastric Bypass (RYGB)?

Background

Oral meal consumption increases glucagon-like peptide 1 (GLP-1) release which maintains euglycemia by increasing insulin secretion. This effect is exaggerated during short-term follow-up of Roux-en-y gastric bypass (RYGB). We examined the durability of this effect in patient with type 2 diabetes (T2DM) >10?years after RYGB.

Methods

GLP-1 response to a mixed meal in the 10-year post-RYGB group (n?=?5) was compared to lean (n?=?9), obese (n?=?6), and type 2 diabetic (n?=?10) controls using a cross-sectional study design. Analysis of variance (ANOVA) was used to evaluate GLP-1 response to mixed meal consumption from 0 to 300?min, 0?C20?min, 20?C60?min, and 60?C300?min, respectively. Weight, insulin resistance, and T2DM were also assessed.

Results

GLP-1 response 0?C300?min in the 10-year post-RYGB showed a statistically significant overall difference (p?=?0.01) compared to controls. Furthermore, GLP-1 response 0?C20?min in the 10-year post-RYGB group showed a very rapid statistically significant rise (p?=?0.035) to a peak of 40?pM. GLP-1 response between 20 and 60?min showed a rapid statistically significant (p?=?0.041) decline in GLP-1 response from ~40?pM to 10?pM. GLP-1 response in the 10-year post-RYGB group from 60 to 300?min showed no statistically significant difference from controls. BMI, HOMA, and fasting serum glucose before and >10?years after RYGB changed from 59.9????40.4, 8.7????0.88, and 155.2????87.6?mg/dl, respectively, and were statistically significant (p?Conclusions An exaggerated GLP-1 response was noted 10?years after RYGB, strongly suggesting a durability of this effect. This phenomenon may play a key role in maintaining type 2 diabetes remission and weight loss after RYGB.     

The Enteroinsular Axis and the Recovery from Type 2 Diabetes after Bariatric Surgery

The Roux-en-Y gastric bypass (RYGBP) and the biliopancreatic diversion (BPD) induce long-term control of type 2 diabetes in morbidly obese individuals. The reasons for such an effect on glycemic metabolism are thought to be secondary to reduced food intake, weight loss and modifications of the enteroinsular axis which is impaired in type 2 diabetic patients. Both GLP-1 and GIP have an impaired secretin effect in type 2 diabetics, and surgery can restore this function. GIP is a peptide secreted by the duodenal K-cells in response to ingested fat and carbohydrate. In obese type 2 diabetes patients, its receptor on β-cells is down-regulated. GLP-1 is a peptide secreted by the gut L-cells, and, in type 2 diabetes, its secretion is impaired. Both RYGBP and BPD provide durable GLP-1 delivery, both during fasting and after meal ingestion, inducing L-cell stimulation by early arrival of nutrients in the distal ileum. The secretion of GLP-1 influences glucose metabolism by inhibiting glucagon secretion, stimulating insulin secretion, delaying gastric emptying and stimulating glycogenogenesis. In conclusion, the early arrival of a meal in the terminal ileum seems to be the common feature of both operations that leads to an improvement in glycemic metabolism and to resolution of type 2 diabetes.     

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.     

Effects of Sleeve Gastrectomy and Gastric Bypass on Postprandial Lipid Profile in Obese Type 2 Diabetic Patients: a 2-Year Follow-up

Background

Bariatric surgery (BS) is known to favorably impact fasting lipid profile. Fasting and postprandial lipids were evaluated before and 2 years after BS in obese type 2 diabetic (T2DM) patients.

Methods

A prospective study was conducted in 19 obese T2DM patients: ten undergoing sleeve gastrectomy (SG) and nine undergoing Roux-en-Y gastric bypass (RYGB). Before and 2 years after BS, clinical parameters and the response of lipid and incretin hormones to a mixed meal (MM) were assessed.

Results

The two groups had similar characteristics at baseline. After BS, weight loss was similar in the two groups (p?≤?0.01). Fasting glucose, insulin, and triglycerides decreased while HDL cholesterol increased in a similar way (p?<?0.05); in contrast, fasting LDL cholesterol decreased only after RYGB (p?<?0.05). Post-meal glucose concentrations decreased while early insulin response significantly improved after both procedures (p?<?0.001 for both). Postprandial triglycerides decreased after both procedures (p?<?0.05) while postprandial LDL cholesterol decreased only after RYGB (p?<?0.05). Meal-GLP-1 increased postoperatively in both groups although to a greater extent after RYGB (p?<?0.001 vs. SG). GIP decreased after both procedures, especially after RYGB (p?=?0.003). At multivariate analysis, GLP-1 peak was the best predictor of LDL reduction (β?=??0.552, p?=?0.039) while the improvement of HOMA-IR (β?=?0.574, p?=?0.014) and weight loss (β?=?0.418, p?=?0.036) predicted triglycerides reduction.

Conclusions

Both surgical procedures markedly reduce fasting and postprandial triglycerides and increase HDL cholesterol levels. LDL cholesterol decreases only after RYGB through a mechanism likely mediated by the restoration of GLP-1.

     

Hormone changes and diabetes resolution after biliopancreatic diversion and laparoscopic sleeve gastrectomy: a comparative prospective study

BackgroundBiliopancreatic diversion (BPD) is the most effective bariatric procedure in terms of weight loss and remission of diabetes type 2 (T2DM), but it is accompanied by nutrient deficiencies. Sleeve gastrectomy (SG) is a relatively new operation that has shown promising results concerning T2DM resolution and weight loss. The objective of this study was to evaluate and compare prospectively the effects of BPD long limb (BPD) and laparoscopic SG on fasting, and glucose-stimulated insulin, glucagon, ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) secretion and also on remission of T2DM, hypertension, and dyslipidemia in morbidly obese patients with T2DM.MethodsTwelve patients (body mass index [BMI] 57.6±9.9 kg/m²) underwent BPD and 12 (BMI 43.7±2.1 kg/m²) underwent SG. All patients had T2DM and underwent an oral glucose tolerance test (OGTT) before and 1, 3, and 12 months after surgery.ResultsBMI decreased more after BPD, but percent excess weight loss (%EWL) was similar in both groups (P = .8) and T2DM resolved in all patients at 12 months. Insulin sensitivity improved more after BPD than after SG (P = .003). Blood pressure, total and LDL cholesterol decreased only after BPD (P<.001). Triglycerides decreased after either operation, but HDL increased only after SG (P<.001). Fasting ghrelin did not change after BPD (P = .2), but decreased markedly after SG (P<.001). GLP-1 and PYY responses during OGTT were dramatically enhanced after either procedure (P = .001).ConclusionsSG was comparable to BPD in T2DM resolution but inferior in improving dyslipidemia and blood pressure. SG and BPD enhanced markedly PYY and GLP-1 responses but only SG suppressed ghrelin levels.     

Equivalent Weight Loss with Marked Metabolic Benefit Observed in a Matched Cohort with and Without Type 2 Diabetes 12?Months Following Gastric Bypass Surgery

Background

Bariatric surgery results in dramatic weight loss and improves metabolic syndrome and type 2 diabetes (T2DM). However, previous studies have noted that morbidly obese patients with T2DM experience less weight loss benefits than non-diabetic patients following bariatric surgery. We sought to determine longitudinal effects of laparoscopic Roux-en-Y gastric bypass (LRYGB) on percent excess body mass index (BMI) loss (%EBMIL) and clinical metabolic syndrome parameters in patients with T2DM compared with appropriately matched cohort without T2DM.

Methods

Retrospective cohort analysis of T2DM patients (n?=?126) to non-T2DM patients (n?=?126) matched on age (M?=?48.1?±?9.5), sex (81?% female), race (81?% Caucasian), and pre-surgical BMI (M?=?49.3?±?9.5). Lipids, glucose, hemoglobin A1c, blood pressure, co-morbidities of obesity, medications for co-morbidities, and T2DM medications were collected at baseline, 6?months and 12?months post-surgery. %EBMIL was collected at 1, 3, 6, 9, and 12?months post-surgery. One-way analyses of variance with effect sizes estimates were conducted to compare the two groups.

Results

As expected, T2DM subjects had significantly greater pre-surgical HbA1c, blood glucose, blood pressure, and lipid parameters at baseline vs. non-T2DM (all p values of<0.05). At 1, 3, 6, 9, and 12?months after LRYRB, both groups had similar reduction in %EBMIL (p?>?0.10). At 6?months, there was a significant reduction in HbA1c, blood glucose, and lipid in the T2DM cohort compared with pre-surgical levels (p?<?0.0001). At 12?months, these values were not different to that of the non-T2DM subjects (p?>?0.10).

Conclusions

When matched on appropriate factors associated with weight loss outcomes, severely obese patients with T2DM have similar post-LRYGB weight loss outcomes in the first 12?months following surgery compared with non-T2DM patients. Furthermore, T2DM surgical patients achieved significant improvement in metabolic syndrome components.     

Lower Glycemic Fluctuations Early After Bariatric Surgery Partially Explained by Caloric Restriction

Background

We assessed the acute impact of laparoscopic Roux-en-Y gastric bypass (GBP) or sleeve gastrectomy (SG) compared to caloric-matched control group without surgery on glucose excursion in obese patients with type 2 diabetes, and examined if this was mediated by changes in insulin resistance, early insulin response or glucagon-like peptide (GLP)-1 levels.

Methods

Six-day subcutaneous continuous glucose monitoring (CGM) recordings were obtained from patients beginning 3 days before GBP (n?=?11), SG (n?=?10) or fasting in control group (n?=?10). GLP-1, insulin and glucose were measured during 75 g oral glucose tolerance testing at the start and end of each CGM.

Results

Post-operative hyperglycaemia occurred after both surgeries in the first 6 h, with a more rapid decline in glycaemia after GBP (p?<?0.001). Beyond 24 h post-operatively, continuous overlapping of net glycaemia action reduced from baseline after GBP (median [interquartile range]) 1.6 [1.2–2.4] to 1.0 [0.7–1.3] and after SG 1.4 [0.9–1.8] to 0.7 [0.7–1.0]; p?<?0.05), similar to controls (2.2 [1.7–2.5] to 1.3 [0.8–2.8] p?<?0.05). Higher log GLP-1 increment post-oral glucose occurred after GBP (mean ± SE, 0.80?±?0.12 vs. 0.37?±?0.09, p?<?0.05), but not after SG or control intervention. Among subgroup with baseline hyperglycaemia, a reduction in HOMA-IR followed GBP. Reduction in time and level of peak glucose and 2-h glucose occurred after both surgeries but not in controls.

Conclusions

GBP and SG have a similar acute impact on reducing glycaemia to caloric restriction; however, with a superior impact on glucose tolerance.     

Endoscopic Duodenal–Jejunal Bypass Liner Rapidly Improves Type 2 Diabetes

Background

Bariatric procedures excluding the proximal small intestine improve glycemic control in type 2 diabetes within days. To gain insight into the mediators involved, we investigated factors regulating glucose homeostasis in patients with type 2 diabetes treated with the novel endoscopic duodenal–jejunal bypass liner (DJBL).

Methods

Seventeen obese patients (BMI 30–50 kg/m²) with type 2 diabetes received the DJBL for 24 weeks. Body weight and type 2 diabetes parameters, including HbA_1c and plasma levels of glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon, were analyzed after a standard meal before, during, and 1 week after DJBL treatment.

Results

At 24 weeks after implantation, patients had lost 12.7?±?1.3 kg (p?<?0.01), while HbA_1c had improved from 8.4?±?0.2 to 7.0?±?0.2 % (p?<?0.01). Both fasting glucose levels and the postprandial glucose response were decreased at 1 week after implantation and remained decreased at 24 weeks (baseline vs. week 1 vs. week 24: 11.6?±?0.5 vs. 9.0?±?0.5 vs. 8.6?±?0.5 mmol/L and 1,999?±?85 vs. 1,536?±?51 vs. 1,538?±?72 mmol/L/min, both p?<?0.01). In parallel, the glucagon response decreased (23,762?±?4,732 vs. 15,989?±?3,193 vs. 13,1207?±?1,946 pg/mL/min, p?<?0.05) and the GLP-1 response increased (4,440?±?249 vs. 6,407?±?480 vs. 6,008?±?429 pmol/L/min, p?<?0.01). The GIP response was decreased at week 24 (baseline—115,272?±?10,971 vs. week 24—88,499?±?10,971 pg/mL/min, p?<?0.05). Insulin levels did not change significantly. Glycemic control was still improved 1 week after explantation.

Conclusions

The data indicate DJBL to be a promising treatment for obesity and type 2 diabetes, causing rapid improvement of glycemic control paralleled by changes in gut hormones.     

Long-term effects of laparoscopic sleeve gastrectomy, gastric bypass, and adjustable gastric banding on type 2 diabetes

Background  

This study aimed to compare the efficacy of laparoscopic sleeve gastrectomy (SG) with that of laparoscopic gastric bypass (GBP) and laparoscopic adjustable gastric banding (AGB) for glucose homeostasis in morbidly obese subjects with type 2 diabetes mellitus (T2DM) at a 3-year follow-up assessment and to elucidate the role of weight loss in the T2DM resolution after SG.     

Relevance of beta-cell function for improved glycemic control after gastric bypass surgery

BackgroundResidual beta-cell function and gastrointestinal hormones have been suggested as relevant determinants of improved glycemic control ensuing Roux-en-Y gastric bypass (RYGB). The objective of this study was to compare the glycemic control up to 24 months after RYGB in C-peptide negative morbidly obese (MO) type 1 diabetes mellitus (T1 DM) women (n = 7) and C-peptide positive (>.6 ng/mL) MO women with type 2 diabetes mellitus (T2 DM, n = 7) on basal-bolus insulin therapy. The glucagon-like peptide 1 (GLP-1) and glucagon response to a mixed meal challenge were also compared between groups.MethodsPercent excess weight loss (%EWL), HbA_1c, and daily insulin dose (DID) after RYGB were compared between groups. The GLP-1 and glucagon response (area under the curve 0–120 minutes) after a mixed meal at last follow-up visit were also compared.ResultsAt 24-months, marked %EWL was observed in women with T1 DM and women with T2 DM (mean±standard error, 82.6%±11.3% and 87.4%±30.5%, respectively; P = .722]. In women with T1 DM, HbA_1c (4 months, P<.05) and DID improved transiently (P<.05, up to 8 months) but were comparable to baseline thereafter (HbA_1c: baseline, 8.3±1.2 and 24 months, 8.2±.9, P = 1.00; DID: baseline, .61±.17 and 24 months .62±.12 IU/kg/d, P = 1.00]. In contrast, in MO women with T2 DM, HbA_1c decreased significantly throughout follow–up, with 2 patients presenting diabetes remission and all but one an HbA_1c<7% at 24 months. The GLP-1 response was comparable between groups (P = .612), and was not accompanied by suppression of the glucagon response to meal intake.ConclusionsIn the absence of residual beta-cell, RYGB results in no significant benefit on glycemic control, despite a marked response of GLP-1 to meal intake.     

First-phase insulin secretion, insulin sensitivity, ghrelin, GLP-1, and PYY changes 72?h after sleeve gastrectomy in obese diabetic patients: the gastric hypothesis

Background

The aim of this study was to evaluate the possible role of sleeve gastrectomy (SG) per se in the reversibility of diabetes.

Methods

Insulin secretion and peripheral insulin sensitivity using the intravenous glucose tolerance test (IVGTT) were assessed in 18 obese type 2 diabetic patients and in 10 nondiabetic obese patients before and 3?days after SG, before any food intake and any weight change occurrence. At the same time, ghrelin, GLP-1, and PYY levels were determined.

Results

In diabetic patients who had the disease less than 10.5?years, the first phase of insulin secretion promptly improved after SG. The early insulin area under the curve (AUC) significantly increased at the postoperative IVGTT, indicating an increased glucose-induced insulin secretion. The second phase of insulin secretion (late AUC) significantly decreased after SG in all groups, indicating an improved insulin peripheral sensitivity. In all groups, pre- and postoperatively, intravenous glucose stimulation determined a decrease in ghrelin values and an increase in GLP-1 and PYY values. However, in the group of patients with disease duration >10.5?years, the differences were not significant except for the late insulin AUC. Postoperative basal and intravenous glucose-stimulated ghrelin levels were lower than preoperative levels in all groups of patients. Basal and intravenous stimulated GLP-1 and PYY postoperative values were higher than preoperative levels in all groups.

Conclusions

Restoration of the first phase of insulin secretion and improved insulin sensitivity in diabetic obese patients immediately after SG, before any food passage through the gastrointestinal tract and before any weight loss, seem to be related to ghrelin, GLP-1, and PYY hormonal changes of possible gastric origin and was neither meal- nor weight-change-related. Duration of the disease up to 10.5?years seems to be a major cut off in the pathophysiological changes induced by SG. A ??gastric?? hypothesis may be put forward to explain the antidiabetes effect of SG.     

Exogenous Glucose�CDependent Insulinotropic Polypeptide Worsens Post prandial Hyperglycemia in T ype 2 Diabetes

OBJECTIVE

Glucose-dependent insulinotropic polypeptide (GIP), unlike glucagon-like peptide (GLP)-1, lacks glucose-lowering properties in patients with type 2 diabetes. We designed this study to elucidate the underlying pathophysiology.

RESEARCH DESIGN AND METHODS

Twenty-two insulin-naïve subjects with type 2 diabetes were given either synthetic human GIP (20 ng · kg⁻¹ · min⁻¹) or placebo (normal saline) over 180 min, starting with the first bite of a mixed meal (plus 1 g of acetaminophen) on two separate occasions. Frequent blood samples were obtained over 6 h to determine plasma GIP, GLP-1, glucose, insulin, glucagon, resistin, and acetaminophen levels.

RESULTS

Compared with placebo, GIP induced an early postprandial increase in insulin levels. Intriguingly, GIP also induced an early postprandial augmentation in glucagon, a significant elevation in late postprandial glucose, and a decrease in late postprandial GLP-1 levels. Resistin and acetaminophen levels were comparable in both interventions. By immunocytochemistry, GIP receptors were present on human and mouse α-cells. In αTC1 cell line, GIP induced an increase in intracellular cAMP and glucagon secretion.

CONCLUSIONS

GIP, given to achieve supraphysiological plasma levels, still had an early, short-lived insulinotropic effect in type 2 diabetes. However, with a concomitant increase in glucagon, the glucose-lowering effect was lost. GIP infusion further worsened hyperglycemia postprandially, most likely through its suppressive effect on GLP-1. These findings make it unlikely that GIP or GIP receptor agonists will be useful in treating the hyperglycemia of patients with type 2 diabetes.In response to glucose and fat in digested food, two enteroendocrine hormones, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), are secreted froml- andk-cells, respectively, in the gut. GLP-1 and GIP play important roles in postprandial glucose homeostasis. In healthy individuals, the potent insulinotropic effects of GLP-1 and GIP account for up to 60% of the insulin secreted postprandially (1). Exogenous GLP-1 acts to improve glycemic control in patients with type 2 diabetes by 1) stimulating insulin secretion in a glucose concentration–dependent manner during the fasted state, 2) suppressing glucagon secretion in the presence of hyperglycemia and euglycemia but not hypoglycemia, and 3) decelerating gastric emptying, leading to a delay in the absorption of ingested nutrients and a dampening of postprandial glucose excursion (2–4). However, it is still unclear which of these properties of exogenous GLP-1 plays a more prominent role in lowering postprandial glucose (5). GIP has not been studied as extensively as GLP-1. Similar to GLP-1, the insulinotropic effect of GIP in healthy humans is glucose concentration dependent under glucose clamp conditions (6). Unlike GLP-1, the administration of GIP in healthy humans was reported to have a dose-dependent glucagonotropic effect during euglycemia and no effect during hyperglycemic clamp conditions (6–8). Also, unlike GLP-1, GIP has no effect on gastric emptying (9).In patients with type 2 diabetes compared with healthy subjects, the ability of GLP-1 to stimulate insulin was noted to be 71%, while that of GIP was 46%; however, the glucose-lowering effect of GLP-1 was relatively preserved while that of GIP was absent (7,10–12). The underlying pathophysiology associated with this loss of glucose-lowering effect of GIP in humans is not known. Some hypotheses include defective expression of GIP receptors (13), accelerated degradation of GIP receptors (14), and downregulation of GIP signaling (15). It is argued that genetic components or GIP receptor defects do not play a role in the reduced insulinotropic response to GIP because patients with different types of diabetes, such as from chronic pancreatitis, latent autoimmune diabetes in adults, maturity-onset diabetes in the young, and newly diagnosed type 1 diabetes, also have impaired insulin response to GIP, thus suggesting that metabolic abnormalities may be the cause (16).The underlying pathophysiology associated with this loss of glucose-lowering effect of GIP despite still having some insulinotropic effect in humans is not known. The aims of this study were 1) to ascertain if a dose of GIP designed to elevate plasma GIP levels to fivefold of that observed postmeal might lower blood glucose in patients with type 2 diabetes and 2) to gain insight into the pathophysiology underlying the seeming lack of effects of GIP on glucose homeostasis in patients with type 2 diabetes.     

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.

     

Weight loss independently predicts urinary albumin excretion normalization in morbidly obese type 2 diabetic patients undergoing bariatric surgery

Background

Despite obesity being closely associated with two common risk factors for albuminuria, namely type 2 diabetes mellitus (T2DM) and hypertension, information on the impact of weight loss on albumin excretion rate in morbidly obese (MO) subjects is scarce.

Objective

To evaluate the independent contribution of weight loss following bariatric surgery (BS) to the improvement of the albumin-to-creatinine ratio (ACR) in MO subjects with T2DM.

Subjects and methods

Observational prospective study, including consecutive (n = 255) patients undergoing Roux-en-Y gastric bypass (GBP) or sleeve gastrectomy (SG) of whom 37.6 % (n = 96) presented with T2DM. Stepwise logistic regression analysis was used to assess the contribution of T2DM-related, hypertension-related, and weight loss-related variables, and type of surgery to normalization of ACR (<30 mg/g) at 12 and 24 months follow-up.

Results

In T2DM subjects, baseline ACR was 85.7 ± 171 mg/g with ACR ≥30 mg/g being present in 45.7 % of the cohort. At 12 months, the ACR significantly decreased in T2DM subjects (42.2 ± 142.8 mg/g; p < 0.005) with no further reduction at 24 months after surgery (44.4 ± 227.7; p = 0.862). Among T2DM subjects with ACR ≥30 mg/g at baseline, the ACR became <30 mg/g in 58.5 % and 76.9 % at 12 and 24 months, respectively (p < 0.001 relative to baseline). Body mass index (BMI) change from baseline was the only independent predictor of ACR normalization at 12 months [Exp(B) 1.373, 95 % confidence interval 1.075–1.703; p < 0.05]. None of the evaluated variables appeared as an independent predictor of ACR normalization at 24 months.

Conclusions

Our data suggest that, in MO subjects with T2DM, interventions aiming at slowing the progression of nephropathy should not only focus on optimization of glucose and blood pressure control but also include effective weight loss strategies.     

Gastrin Secretion After Bariatric Surgery—Response to a Protein-Rich Mixed Meal Following Roux-En-Y Gastric Bypass and Sleeve Gastrectomy: a Pilot Study in Normoglycemic Women

Background

Recent investigations have linked elevated gastrin levels to the improvement of type 2 diabetes mellitus (T2DM). Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are effective treatments for T2DM, but it is not known if this is related to postoperative alterations of gastrin secretion.

Methods

Twenty women previously operated with RYGB or SG and 13 female controls were enrolled and evaluated for body mass index, lipids, C-peptide, HbA1c, and anti-H. pylori IgG. Glucose, gastrin, insulin, and glucagon-like peptide 1 (GLP-1) concentrations were measured before and 30, 60, 90, and 120 min after ingestion of a protein-rich mixed meal.

Results

Six participants primarily selected were excluded due to usage of proton pump inhibitors, positive H.pylori IgG, or history of T2DM, yielding the following groups: RYGB (n?=?9), SG (n?=?8), and controls (n?=?10). There were no differences in age, body mass index, HbA1c, or C-peptide levels between groups. RYGB had significantly lower area under the curve (AUC) for glucose during the test compared to controls (p?=?0.013). RYGB showed lower serum gastrin levels compared to SG and controls (p?<?0.05 for all). There was a non-significant increased gastrin release in SG compared to controls (p?=?0.091). For SG and controls, there was a negative correlation between glucose and gastrin response (p?=?0.0043).

Conclusion

Gastrin secretion is diminished after RYGB. Hypergastrinemia was not present after SG, but a tendency of enhanced gastrin secretion was observed. These findings require further investigation in prospective studies.

     

Influence of hemodialysis on incretin hormones and insulin secretion in diabetic and non-diabetic patients

Background

Incretin hormones are secreted in the gut after a meal and stimulate insulin production. Both major incretins, that is, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are eliminated by the kidneys. Little is known about the influence of end-stage renal disease (ESRD) on the incretin axis. The aim of the study was to assess the effect of the commencement of chronic hemodialysis (HD) therapy on serum GLP-1 and GIP, and insulin sensitivity in diabetic and non-diabetic patients.

Subjects and methods

The study comprised 56 patients (23 F, 33 M; mean age 57 ± 14 years) with ESRD in the course of diabetic nephropathy (n = 23) and non-diabetic renal diseases (n = 34) who started chronic HD. Glucose metabolism, including incretin hormones concentration, was assessed before the first HD session and repeated after the first 6 months of the therapy.

Results

After 6 months of HD, a significant increase in fasting GLP-1 concentration was observed in both diabetic and non-diabetic patients [by 2.27 pmol/l (45 %) and 1.28 pmol/l (22 %), respectively, p = 0.0003]. Serum GIP increased significantly only in diabetic patients [by 30.9 pg/ml (55 %); p = 0.008]. No significant change of fasting glucose was found but HOMA-IR and serum insulin decreased significantly in diabetic patients (p = 0.01 and p = 0.008, respectively). In contrast, HOMA-B was unchanged in both groups. Changes of HOMA-IR did not significantly correlate with serum GLP-1 or GIP concentrations.

Conclusion

Our results indicate that starting the hemodialysis therapy helps to restore the incretin axis in particular in patients with the diabetic kidney disease.