Roux-en-Y gastric bypass (RYGB) increases the risk of postprandial hypoglycemia, whereas pregnancy decreases insulin sensitivity, which could be expected to counteract hypoglycemia. We examined if RYGB performed prior to pregnancy altered the postprandial glucose metabolism and enteropancreatic hormone responses to a mixed meal test (MMT).

Twenty-three women with RYGB and 23 women matched on prepregnancy body mass index and parity underwent a 4-hour MMT in the first and third trimester of pregnancy with measurement of circulating levels of glucose, insulin, C-peptide, glucose-dependent insulin peptide (GIP), glucagon-like peptide 1 (GLP-1), glucagon, free fatty acids, and lactate. Biochemical hypoglycemia was defined as plasma glucose <3.5 mmol/L.

Women with RYGB had earlier and higher peak glucose, lower nadir glucose levels, and a higher frequency of biochemical hypoglycemia compared with women without RYGB in both the first and third trimester. The lower glucose levels were preceded by markedly elevated total GLP-1 and insulin levels in women with RYGB, whereas total GIP levels were unaltered. The glucagon levels were lower in women with RYGB. In the first trimester MMT, peak and area under the curve of total plasma GLP-1 and serum insulin levels were negatively associated with nadir plasma glucose, while the early postmeal response of plasma glucagon was positively associated with nadir plasma glucose in the third trimester.

These results provide novel insights into the combined effects of RYGB and pregnancy on postmeal glucose metabolism and enteropancreatic hormone responses during pregnancy, and how these changes associate with an increased risk of postprandial hypoglycemia.

NCT03713060.

Triacylglycerol (TAG) plasma excursions after a high-fat meal are blunted after Roux-en-Y gastric bypass (RYGB), but underlying mechanisms are poorly understood. We studied TAG absorption and metabolism in 12 RYGB-operated individuals and 12 unoperated controls (CON) matched on sex, age, and BMI.

Participants followed a 7-day controlled diet and on day 4 underwent 1H-MR Spectroscopy of liver TAG and a high-fat liquid meal with oral and intravenous labeled stable isotope metabolites, subcutaneous abdominal fat biopsies, and indirect calorimetry. Subsequently, participants collected stool for 96 h.

Overall fat absorption from the controlled diet was moderately lower in RYGB than CON (88 % versus 93 %, P < 0.01), without indication of greater specific malabsorption of fat from the high-fat test meal (recovery of TAG and labeled TAG in 96-h stool samples). After an overnight fast, plasma TAG concentrations and incorporation of plasma fatty acids (IV tracer) into TAG did not differ between groups. The postprandial 6-h iAUC of plasma TAG plasma concentrations was markedly lower in RYGB than CON (15 versus 70 mmol/L × min, P = 0.03). The postprandial chylomicron (CM) particle response (plasma ApoB48) was initially higher in RYGB, but with lower CM-TAG plasma concentrations and appearance of labeled palmitate from the oral tripalmitin tracer over the 6 h.

Fat absorption is only moderately lower after RYGB compared with unoperated matched controls. Nevertheless, postprandial TAG and CM plasma kinetics after a high-fat meal are markedly altered after RYGB with substantially lower TAG and CM-TAG concentrations despite a faster CM particle release.

This meta-analysis aimed to evaluate the effectiveness of Roux-en-Y gastric bypass (RYGB) in people living with type 2 diabetes mellitus (T2DM). A comprehensive search was conducted in the PubMed database up to January 2024. A random-effects model was used to calculate the pooled standard mean differences (SMDs) and odds ratios (ORs). Ten studies were included in our review. The RYGB group demonstrated significantly better outcomes compared to the non-surgical group in multiple measures. These included higher triple criteria compliance rates (OR 9.04, 95% CI 3.22-25.36), complete T2DM remission (OR 15.37, 95% CI 4.42-53.41), and partial T2DM remission (OR 11.49, 95% CI 3.57-37.03). Additionally, improvements were observed in glycated hemoglobin A1c (HbA1c) levels (SMD - 1.41, 95% CI - 2.22 to - 0.61), with HbA1c < 6.0% (OR 8.54, 95% CI 3.38-21.62) and HbA1c < 7.0% (OR 5.62, 95% CI 3.20-9.86). Fasting blood glucose (FBG) levels also showed improvement (SMD - 0.43, 95% CI - 0.71 to - 0.14), with a higher proportion achieving FBG < 100 mg/dl (OR 11.83, 95% CI 4.75-29.43). Other notable outcomes included significant percentage of total weight loss (%TWL: SMD 1.88, 95% CI 1.39-2.37), reductions in body mass index (BMI: SMD - 2.28, 95% CI - 3.52 to - 1.04), and improvements in lipid profiles, including low-density lipoprotein (LDL) levels (SMD - 1.01, 95% CI - 1.91 to - 0.11) and LDL < 2.59 mmol/L (OR 3.65, 95% CI 1.94-6.87). In addition, high-density lipoprotein (HDL) levels increased (SMD 1.30, 95% CI 0.55-2.05), while triglycerides (SMD - 1.11, 95% CI - 1.70 to - 0.52), systolic blood pressure (SBP: SMD - 0.38, 95% CI - 0.70 to - 0.06), and diastolic blood pressure (DBP: SMD - 0.41, 95% CI - 0.63 to - 0.18) decreased. A greater proportion of patients in the RYGB group achieved SBP < 130 mmHg (OR 3.15, 95% CI 1.61-6.13). Moreover, reductions were noted in insulin use (OR 0.25, 95% CI 0.14-0.46), diabetes medication use (SMD - 1.95, 95% CI - 3.32 to - 0.57), and peripheral neuropathy (OR 0.13, 95% CI 0.02-0.79). However, no significant differences were observed in hypertension medication use or retinopathy between the two groups. RYGB was found to be effective in improving glycemic control, promoting weight loss, enhancing lipid profiles, and managing blood pressure. It also significantly reduced the need for postoperative diabetes medications and the incidence of diabetic peripheral neuropathy in people living with T2DM.

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP.

In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases.

Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.

Glucagon-like peptide-1 (GLP-1) is a 30-amino acid intestinal insulin-stimulating factor, which is mainly secreted by L cells in the distal ileum and colon. It has various physiological functions, such as promoting insulin secretion and synthesis, stimulating β-cell proliferation, inducing islet regeneration, inhibiting β-cell apoptosis and glucagon release, delaying gastric emptying and controlling appetite, etc. It plays a role through a specific GLP-1 receptor (GLP-1R) distributed in many organs or tissues and participates in the regulation of glucose homeostasis in the body. GLP-1 receptor agonists (GLP-1RAs) has the similar physiological function of GLP-1. Because of its structural difference from natural GLP-1, it is not easy to be degraded by dipeptidyl peptidase-4 (DPP-4), thus prolonging the action time. GLP-1RAs have been recognized as a new type of hypoglycemic drugs and widely used in the treatment of type 2 diabetes mellitus (T2DM). Compared with other non-insulin hypoglycemic drugs, it can not only effectively reduce blood glucose and glycosylated hemoglobin (HbA1c), but also protect cardiovascular system, nervous system and kidney function without causing hypoglycemia and weight gain. Therefore, GLP-1RAs has good application prospects and potential for further development.

Bariatric surgery (BS) is an effective intervention for obesity and related metabolic disorders, significantly improving metabolic health and alleviating hormonal imbalances. However, it induces complex endocrine changes that can lead to dysfunctions, impacting the somatotropic, gonadal, thyroid, pancreatic, and adrenal axes. This review highlights the dual effects of BS on the endocrine system. A comprehensive review of peer-reviewed studies using PRISMA guidelines was conducted, focusing on human research evaluating pre and postoperative endocrine parameters. Studies were selected for their relevance and quality in elucidating the endocrine consequences of BS. BS restores growth hormone secretion and improves fertility but may disrupt insulin-like growth factor-1 recovery and sex hormone balance, leading to bone loss and catabolic states. Postprandial insulin hypersecretion can result in hyperinsulinemic hypoglycemia, with impaired counter-regulatory hormone responses. Secondary hyperparathyroidism and reduced bone density highlight additional risks. Changes in thyroid hormone levels have implications for both hypothyroid and euthyroid patients. These findings underscore the interplay between improved metabolic control and potential endocrine dysfunctions. The current evidence predominantly comprises association studies that may not be of quality for safe clinical decision-making, highlighting the need for high-quality research to establish causality and refine therapeutic strategies. Bridging knowledge gaps in the mechanisms underlying these changes is crucial to optimizing BS outcomes. A holistic approach integrating preoperative screening, individualized postoperative care, and targeted therapies is essential to mitigate complications while maximizing benefits.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play critical roles in co-ordinating postprandial metabolism, including modulation of insulin secretion and food intake. They are secreted from enteroendocrine cells in the intestinal epithelium following food ingestion, and act at multiple target sites including pancreatic islets and the brain. With the recent development of agonists targeting GLP-1 and GIP receptors for the treatment of type 2 diabetes and obesity, and the ongoing development of new incretin-based drugs with improved efficacy, there is great interest in understanding the physiology and pharmacology of these hormones.

Glucagon-like peptide-1(GLP-1) is a hormone often measured in the short-term following Roux-en-Y gastric bypass (RYGB) due to its elevation and association with improvement of glucose metabolism. We examined the durability of this effect in patients with type 2 diabetes mellitus (DM) in the long term after RYGB.

Obese patients with type 2 DM who had received RYGB 10 years ago (n = 10) were enrolled and a meal tolerance test (MTT) was performed. A matched control group with type 2 DM (n = 5) underwent MTT.

Glucose levels during the MTT did not differ between patients with RYGB and the nonsurgical group. Insulin, C-peptide and GLP-1 levels during MTT were significantly higher in patients with RYGB compared with the nonsurgical group (Area under the curve [AUC] of insulin; 57.4 ± 22.9 vs. 27.7 ± 11.1 mIU/L•hr, P = 0.008; AUC of total GLP-1; 189.4 ± 74.72 vs. 52.13 ± 10.23 pM •hr, P = 0.002), and in particular, peak insulin, C-peptide and GLP-1 levels observed 30-45 min after eating were markedly different from those in the nonsurgical group. Bile acids (BAs) and fibroblast growth factor 19 (FGF-19) levels during MTT were higher in patients with RYGB compared with the nonsurgical group. Peak BAs and FGF-19 levels tended to be higher in the RYGB.

An enhanced GLP-1 response was noted 10 years after RYGB, strongly suggesting a durability of this effect. BAs and FGF-19 were increased in the RYGB group, but not as much as the pronounced increase in GLP-1 secretion.

Gut L-type enteroendocrine cells (EECs) are intestinal chemosensory cells that secrete satiety hormones GLP-1 and PYY in response to activation of G-protein coupled receptors (GPCRs) by luminal components of nutrient digestion and microbial fermentation. Regulator of G-protein Signaling (RGS) proteins are negative regulators of GPCR signaling. The expression profile of RGS in EECs, and their potential role in satiety hormone secretion and obesity is unknown.

Transcriptomic profiling of RGS was completed in native colonic EECs was completed using single-cell RNA sequencing (scRNA-Seq) in lean and obesity, and human jejunal EECs with data obtained from a publicly available RNAseq dataset (GSE114853). RGS validation studies were completed using whole mucosal intestinal tissue obtained during endoscopy in 61 patients (n = 42 OB, n = 19 Lean); a subset of patients' postprandial plasma was assayed for GLP-1 and PYY. Ex vivo human intestinal cultures and in vitro NCI-H716 cells overexpressing RGS9 were exposed to GLP-1 secretagogues in conjunction with a nonselective RGS-inhibitor and assayed for GLP-1 secretion.

Transcriptomic profiling of colonic and jejunal enteroendocrine cells revealed a unique RGS expression profile in EECs, and further within GLP-1+ L-type EECs. In obesity the RGS expression profile was altered in colonic EECs. Human gut RGS9 expression correlated positively with BMI and negatively with postprandial GLP-1 and PYY. RGS inhibition in human intestinal cultures increased GLP-1 release from EECs ex vivo. NCI-H716 cells overexpressing RGS9 displayed defective nutrient-stimulated GLP-1 secretion.

This study introduces the expression profile of RGS in human EECs, alterations in obesity, and suggests a role for RGS proteins as modulators of GLP-1 and PYY secretion from intestinal EECs.

AA is supported by the NIH(C-Sig P30DK84567, K23 DK114460), a Pilot Award from the Mayo Clinic Center for Biomedical Discovery, and a Translational Product Development Fund from The Mayo Clinic Center for Clinical and Translational Science Office of Translational Practice in partnership with the University of Minnesota Clinical and Translational Science Institute.

It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve gastrectomy but not after gastric banding. It has therefore been speculated that increased secretion of particularly GLP-1 and Peptide YY (PYY), which both inhibit appetite and food intake, may be involved in the weight loss effects of surgery and for improvements in glucose tolerance. Experiments involving inhibition of hormone secretion with somatostatin, blockade of their actions with antagonists, or blockade of hormone formation/activation support this notion. However, differences between results of bypass and sleeve operations indicate that distinct mechanisms may also be involved. Although the reductions in ghrelin secretion after sleeve gastrectomy would seem to provide an obvious explanation, experiments with restoration of ghrelin levels pointed towards effects on insulin secretion and glucose tolerance rather than on food intake. It seems clear that changes in GLP-1 secretion are important for insulin secretion after bypass and appear to be responsible for postbariatric hypoglycemia in glucose-tolerant individuals; however, with time the improvements in insulin sensitivity, which in turn are secondary to the weight loss, may be more important. Changes in bile acid metabolism do not seem to be of particular importance in humans.

Obesity and chronic kidney disease are two ongoing progressive clinical pandemics of major public health and clinical care significance. Because of their growing prevalence, chronic indolent course and consequent complications both these conditions place significant burden on the health care delivery system especially in developed countries like the United States. Beyond the chance coexistence of both of these conditions in the same patient based on high prevalence it is now apparent that obesity is associated with and likely has a direct causal role in the onset, progression and severity of chronic kidney disease. The causes and underlying pathophysiology of this are myriad, complicated and multi-faceted. In this review, continuing the theme of this special edition of the journal on " The Cross roads between Endocrinology and Nephrology" we review the epidemiology of obesity related chronic kidney disease (ORCKD), and its various underlying causes and pathophysiology. In addition, we delve into the consequent comorbidities and complications associated with ORCKD with particular emphasis on the cardio metabolic consequences and then review the current body of evidence for available strategies for chronic kidney disease modulation in ORCKD as well as the potential unique role of weight reduction and management strategies in its improvement and risk reduction.

A systematic search was conducted in Medline Ovid, Embase, Scopus, and Cochrane Central Register of Controlled Trials up until March 2021 following PRISMA guidelines. Studies included evaluated ghrelin, GLP-1, PYY or appetite sensation via visual analogue scales (VASs) before and after Roux-en-Y gastric bypass (RYGB) in adults. A multilevel model with random effects for study and follow-up time points nested in study was fit to the data. The model included kcal consumption as a covariate and time points as moderators. Among the 2559 articles identified, k = 47 were included, among which k = 19 evaluated ghrelin, k = 40 GLP-1, k = 22 PYY, and k = 8 appetite sensation. Our results indicate that fasting ghrelin levels are decreased 2 weeks post-RYGB (p = 0.005) but do not differ from baseline from 6 weeks to 1-year post-RYGB. Postprandial ghrelin and fasting GLP-1 levels were not different from pre-surgical values. Postprandial levels of GLP-1 increased significantly from 1 week (p < 0.001) to 2 years post-RYGB (p < 0.01) compared with pre-RYGB. Fasting PYY increased at 6 months (p = 0.034) and 1 year (p = 0.029) post-surgery; also, postprandial levels increased up to 1 year (p < 0.01). Insufficient data on appetite sensation were available to be meta-analyzed.

'Globesity' is a foremost challenge to the healthcare system. The limited efficacy and adverse effects of available oral pharmacotherapies pose a significant obstacle in the fight against obesity. The biology of the leading incretin hormone glucagon-like-peptide-1 (GLP-1) has been highly captivated during the last decade owing to its multisystemic pleiotropic clinical outcomes beyond inherent glucoregulatory action. That fostered a pharmaceutical interest in synthetic GLP-1 analogues to tackle type-2 diabetes (T2D), obesity and related complications. Besides, mechanistic insights on metabolic surgeries allude to an incretin-based hormonal combination strategy for weight loss that emerged as a forerunner for the discovery of injectable 'unimolecular poly-incretin-agonist' therapies. Physiologically, intestinal enteroendocrine L-cells (EECs) are the prominent endogenous source of GLP-1 peptide. Despite comprehending the potential of various G protein-coupled receptors (GPCRs) to stimulate endogenous GLP-1 secretion, decades of translational GPCR research have failed to yield regulatory-approved endogenous GLP-1 secretagogue oral therapy. Lately, a dual/poly-GPCR agonism strategy has emerged as an alternative approach to the traditional mono-GPCR concept. This review aims to gain a comprehensive understanding by revisiting the pharmacology of a few potential GPCR-based complementary avenues that have drawn attention to the design of orally active poly-GPCR agonist therapy. The merits, challenges and recent developments that may aid future poly-GPCR drug discovery are critically discussed. Subsequently, we project the mechanism-based therapeutic potential and limitations of oral poly-GPCR agonism strategy to augment intestinal GLP-1 for weight loss. We further extend our discussion to compare the poly-GPCR agonism approach over invasive surgical and injectable GLP-1-based regimens currently in clinical practice for obesity.

In this study, we investigated how Roux-en-Y gastric bypass (RYGB) enhances glucagon-like peptide 1 (GLP-1) response in GK rats and explored the potential link between RYGB-stimulated BAs/FXR signalling and GLP-1R-linked signalling in β-cells, a key pathway that regulates glucose-stimulated insulin secretion (GSIS). Here we show that RYGB restores GLP-1R expression in GK rat islets. This involves increased total BAs as well as chenodeoxycholic acid (CDCA), leading to FXR activation, increasing FXR binding to the promoter of Glp-1r and enhancing occupancy of histone acetyltransferase steroid receptor coactivator-1 (SRC1), thus increasing histone H3 acetylation at the promoter. These coordinated events bring about increased GLP-1R expression, resulting in greater GLP-1 response in β-cells. Moreover, ablation of FXR suppressed the stimulatory effects of GLP-1. Thus, this study unravels the crucial role of the BAs/FXR/SRC1 axis-controlled GLP-1R expression in β-cells, which results in enhanced incretin effect and normalized blood glucose of GK rats after RYGB.

Post-bariatric hypoglycaemia (PBH) is a metabolic complication of bariatric surgery (BS), consisting of low post-prandial glucose levels in patients having undergone bariatric procedures. While BS is currently the most effective and relatively safe treatment for obesity and its complications, the development of PBH can significantly impact patients' quality of life and mental health. The diagnosis of PBH is still challenging, considering the lack of definitive and reliable diagnostic tools, and the fact that this condition is frequently asymptomatic. However, PBH's prevalence is alarming, involving up to 88% of the post-bariatric population, depending on the diagnostic tool, and this may be underestimated. Given the prevalence of obesity soaring, and an increasing number of bariatric procedures being performed, it is crucial that physicians are skilled to diagnose PBH and promptly treat patients suffering from it. While the milestone of managing this condition is nutritional therapy, growing evidence suggests that old and new pharmacological approaches may be adopted as adjunct therapies for managing this complex condition.

Roux-en-Y gastric bypass surgery (RYGB) improves glucose-stimulated insulin secretion (GSIS) in type 2 diabetes (T2D) patients. SNAP25 plays an essential role in GSIS. Clinical studies indicate that enhanced GLP-1 signaling is an important contributor to the improved β-cell function in T2D. We aimed to explore whether GLP-1-regulated SNAP25 is involved in the enhanced secretory function of β-cells in diabetic Goto-Kakizaki (GK) rats after RYGB.

RYGB or sham surgery was conducted in GK rats. mRNA and protein expression of SNAP25 was assessed by qPCR and Western blot, respectively. Occupancy of CREB and acetyltransferase CBP and acetylation of histone H3 (ACH3) at the Snap25 promoter were determined using ChIP assay. RYGB led to increased SNAP25 expression and CREB phosphorylation in islets from GK rats. Increased SNAP25 improved GSIS in β-cells cultured in high glucose conditions. Consistent with increased plasma GLP-1 after RYGB, GLP-1R agonist exendin4 increased SNAP25 expression and CREB phosphorylation in β-cells. Mechanistically, exendin4 promoted the recruitment of CREB and CBP, thereby increasing ACH3 at the Snap25 promoter. Consistently, inhibition of CBP attenuated the effect of exendin4 on SNAP25 expression. Furthermore, the knockdown of SNAP25 diminished the increase of GSIS potentiated by chronic GLP-1 culture in INS-1 832/13 cells.

Our findings unravel the novel mechanisms of RYGB-enhanced SNAP25 expression in β-cells, and SNAP25 may contribute to the improved β-cell secretory function induced by RYGB.

The causes for failure of metabolic improvement and inadequate weight loss after metabolic surgery (MS) in Chinese patients with type 2 diabetes (T2D) have not been fully elucidated. The effect of insulin resistance (IR) on the outcome of T2D, hypertension, hyperlipidemia, and obesity after MS in Chinese patients with T2D and a body mass index (BMI) of 25-32.5 kg/m2 warrants further study.

Patients with T2D and a BMI of 25-32.5 kg/m2 who underwent MS between July 2019 and June 2021 were included.

University hospital, China.

IR levels were evaluated with the glucose disposal rate (GDR). Improvement of T2D, hypertension, and hyperlipidemia was assessed with the composite triple endpoint (CTEP), and weight loss was assessed with the percent of total weight loss (%TWL). Partial correlation analysis, binary logistic regression analysis, multiple linear regression analysis, receiver operating characteristic curve (ROC) analysis, and subgroup analysis were used to analyze the relationship between the CTEP, %TWL at 1 year postoperative, and GDR preoperative.

This study analyzed the data of 51 patients with T2D and a BMI of 25-32.5 kg/m2 (30 men and 21 women) with a mean preoperative GDR of 3.72 ± 1.48 mg/kg/min. Partial correlation coefficients between CTEP, %TWL, and GDR were .303 (P = .041) and .449 (P = .001), respectively. The preoperative GDR was significantly positively correlated with CTEP (OR = 1.610, P = .024) and %TWL (β = 1.38, P = .003). The preoperative GDR predicted cutoff values of 4.36 and 5.35 mg/kg/min for CTEP attainment and %TWL ≥ 20%, respectively.

IR levels predicted metabolic improvement and weight loss 1 year after MS in Chinese patients with T2D and a BMI of 25-32.5 kg/m2.

Abdominal pain and postbariatric hypoglycemia (PBH) are common after bariatric surgery.

This study aimed to explore the potential relationship between abdominal pain, gastrointestinal symptoms, and PBH more than a decade after Roux-en-Y gastric bypass (RYGB) and whether continuous glucose monitoring (CGM) with dietary intervention has an educational role in reducing symptoms.

At two public hospitals in Norway (one University Hospital) 22 of 46 invited patients who reported abdominal pain more than weekly took part. Recruited from a prospective follow-up study of 546 patients 14.5 years after RYGB.

They used a CGM for two 14-day periods, with a dietary intervention between periods. The Gastrointestinal Symptom Rating Scale (GSRS) and the Dumping Severity Score (DSS) questionnaires were completed at the start and end of the study.

The 22 women had preoperative age 39.6 ± 7.7 years and body mass index (BMI) 42.0 ± 4.0 kg/m2, present age 54.6 ± 7.7 years and BMI 29.8 ± 4.8 kg/m2. The total GSRS score and DSS of early dumping decreased after the diet intervention. The number of events with Level 1 (<3.9 mmol/L) or Level 2 (<3.0 mmol/L) hypoglycemia did not change in the second period. Half of the patients had fewer, three had unchanged, and eight had more frequent events with Level 1 hypoglycemia after the intervention. Ten patients had Level 2 hypoglycemia.

Though inconclusive findings, a personalized dietary intervention reduces GSRS. This intervention was accompanied by lower mean absolute glucose in patients with recurrent abdominal pain after bariatric surgery. However, further studies are needed to explore the benefits of CGM in this setting.

Gut hormones orchestrate pivotal physiological processes in multiple metabolically active tissues, including the pancreas, liver, adipose tissue, gut and central nervous system, making them attractive therapeutic targets in the treatment of obesity and type 2 diabetes mellitus. Most gut hormones are derived from enteroendocrine cells, but bioactive peptides that are derived from other intestinal epithelial cell types have also been implicated in metabolic regulation and can be considered gut hormones. A deeper understanding of the complex inter-organ crosstalk mediated by the intestinal endocrine system is a prerequisite for designing more effective drugs that are based on or target gut hormones and their receptors, and extending their therapeutic potential beyond obesity and diabetes mellitus. In this Review, we present an overview of gut hormones that are involved in the regulation of metabolism and discuss their action in the gastrointestinal system and beyond.

β-cell dysfunction and insulin resistance are the main mechanisms causing glucose intolerance in type 2 diabetes (T2D). Bariatric surgeries, i.e., sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), are procedures both known to induce weight loss, increase insulin action, and enhance β-cell function, but hepatic insulin extraction and glucose effectiveness may also play a role.

To determine the contribution of these regulators on glucose tolerance after bariatric surgery, an oral glucose tolerance test (OGTT) was performed before and 2 months after surgery in 9 RYGB and 7 SG subjects. Eight healthy subjects served as metabolic controls. Plasma glucose, insulin, C-peptide, GLP-1, and GIP were measured during each OGTT. Insulin sensitivity and secretion, glucose effectiveness, and glucose rate of appearance were determined via oral minimal models.

RYGB and SG resulted in similar weight reductions (13%, RYGB (p < 0.01); 14%, SG (p < 0.05)). Two months after surgery, insulin secretion (p < 0.05) and glucose effectiveness both improved equally in the two groups (11%, RYGB (p < 0.01); 8%, SG (p > 0.05)), whereas insulin sensitivity remained virtually unaltered. Bariatric surgery resulted in a comparable increase in the GLP-1 response during the OGTT, whereas GIP concentrations remained unaltered. Following surgery, oral glucose intake resulted in a comparable increase in hepatic insulin extraction, the response in both RYGB and SG patients significantly exceeding the response observed in the control subjects.

These results demonstrate that the early improvement in glucose tolerance in obese T2D after RYGB and SG surgeries is attributable mainly to increased insulin secretion and glucose effectiveness, while insulin sensitivity seems to play only a minor role. This trial is registered with NCT02713555.

Prandial hyperinsulinemia after Roux-en-Y gastric bypass surgery (GB), and to lesser degree after sleeve gastrectomy (SG), has been attributed to rapid glucose flux from the gut and increased insulinotropic gut hormones. However, β-cell sensitivity to exogenous incretin is reduced after GB. This study examines the effect of GB versus SG on prandial glycemia and β-cell response to increasing concentrations of endogenous incretins.

Glucose kinetics, insulin secretion rate (ISR), and incretin responses to 50-g oral glucose ingestion were compared between ten nondiabetic participants with GB versus nine matched individuals with SG and seven nonoperated normal glucose tolerant control individuals (CN) with and without administration of 200 mg of sitagliptin.

Fasting glucose and hormonal levels were similar among three groups. Increasing plasma concentrations of endogenous incretins by two- to three-fold diminished prandial glycemia and increased β-cell secretion in all three groups (p < 0.05), but insulin secretion per insulin sensitivity (i.e., disposition index) was increased only in GB (p < 0.05 for interaction). However, plot of the slope of ISR (from premeal to peak values) versus plasma glucagon-like peptide-1 concentration was smaller after GB compared with SG and CN.

After GB, increasing incretin activity augments prandial β-cell response whereas the β-cell sensitivity to increasing plasma concentrations of endogenous incretin is diminished.

Background: Bariatric surgery delivers substantial weight loss for obese patients with comorbidities like diabetes mellitus. We aimed to investigate the impacts of bariatric surgery on diabetic markers after 5 years of follow-up. Methods: This is a retrospective study on patients with diabetes and a history of bariatric surgery between 2016-2017. The diabetic markers before and 5 years following surgery, including a lipid profile, glucose level, and the required antidiabetic medications, were evaluated. Results: 34 consecutive patients were included, 30 (88.2%) women, with a mean age of 52.71±8.53 years. The majority (65%) of surgeries were Roux-en-Y gastric bypass (RYGB), and the remaining were one anastomosis gastric bypass (OAGB) and sleeve gastrectomy (SG). The serum levels of diabetic markers reduced during follow-up (P=0.001), except for high-density lipoprotein levels and serum total cholesterol, which increased (P=0.011, P=0.838). Low-density lipoprotein levels reduced, but it was insignificant (P=0.194). Surgery types had affected the changes of diabetic markers (P>0.05). Demand for oral medication was reduced significantly, but insulin injection reduction was not significant (P=0.006 and P=0.099, respectively). Conclusion: Our study showed favorable bariatric surgery results on patients with diabetes in long-term follow-up. However, dyslipidemia is still a concern.

With a rise in obesity and more patients opting for bariatric surgery, it becomes crucial to understand associated complications like postprandial hypoglycemia (PPH). After bariatric surgery, significant changes are seen in insulin sensitivity, beta cell function, glucagon-like peptide 1 (GLP-1) levels, the gut microbiome, and bile acid metabolism. And in a small subset of patients, exaggerated imbalances in these functional and metabolic processes lead to insulin-glucose mismatch and hypoglycemia. The main treatment for PPH involves dietary modifications. For those that do not respond, medications or surgical interventions are considered to reverse some of the imbalances. We present a few case reports of patients that safely tolerated GLP-1 agonists. However, larger randomized control trials are needed to further characterize PPH and understand its treatment.

Obesity is an increasingly widespread disease worldwide because of lifestyle changes. It is associated with an increased risk of cardiovascular disease, primarily type 2 diabetes mellitus, with an increase in major cardiovascular adverse events. Bariatric surgery has been shown to be able to reduce the incidence of obesity-related cardiovascular disease and thus overall mortality. This result has been shown to be the result of hormonal and metabolic effects induced by post-surgical anatomical changes, with important effects on multiple hormonal and molecular axes that make this treatment more effective than conservative therapy in determining a marked improvement in the patient's cardiovascular risk profile. This review, therefore, aimed to examine the surgical techniques currently available and how these might be responsible not only for weight loss but also for metabolic improvement and cardiovascular benefits in patients undergoing such procedures.

BackgroundThe effects of diet-induced weight loss (WL) and WL after Roux-en-Y gastric bypass (RYGB) surgery on β cell function (BCF) are unclear because of conflicting results from different studies, presumably because of differences in the methods used to measure BCF, the amount of WL between treatment groups, and baseline BCF. We evaluated the effect of WL after RYGB surgery or reduced energy intake alone on BCF in people with obesity with and without type 2 diabetes.MethodsBCF (insulin secretion in relationship to plasma glucose) was assessed before and after glucose or mixed-meal ingestion before and after (a) progressive amounts (6%, 11%, 16%) of WL induced by a low-calorie diet (LCD) in people with obesity without diabetes, (b) ~20% WL after RYGB surgery or laparoscopic adjustable gastric banding (LAGB) in people with obesity without diabetes, and (c) ~20% WL after RYGB surgery or LCD alone in people with obesity and diabetes.ResultsDiet-induced progressive WL in people without diabetes progressively decreased BCF. Marked WL after LAGB or RYGB in people without diabetes did not alter BCF. Marked WL after LCD or RYGB in people with diabetes markedly increased BCF, without a difference between groups.ConclusionMarked WL increases BCF in people with obesity and diabetes but not in people with obesity without diabetes. The effect of RYGB-induced WL on BCF is not different from the effect of matched WL after LAGB or LCD alone.trial registrationNCT00981500, NCT02207777, NCT01299519.FundingNIH grants R01 DK037948, P30 DK056341, P30 DK020579, UL1 TR002345.

Metabolic and morphological adaptations of the intestine have been suggested to play a role in the various therapeutic benefits of Roux-en-Y Gastric Bypass (RYGB) surgery. However, the precise underlying mechanisms remain unclear. In this study, the effects of physical properties of ingested food and redirection of biliopancreatic secretions on intestinal remodeling were investigated in RYGB operated rats.

RYGB employing two different Roux Limb (RL) lengths was performed on high fat diet induced obese rats. Post-operatively, rats were fed either Solid or isocaloric Liquid diets. Metabolic and morphological remodeling of intestine was compared across both diet forms (Solid and Liquid diets) and surgical models (Short RL and Long RL).

RYGB surgery in rats induced weight loss and improved glucose tolerance which was independent of physical properties of ingested food and biliopancreatic secretions. Intestinal glucose utilization after RYGB was not determined by either food form or biliopancreatic secretions. The GLUT-1 expression in RL was not influenced by physical properties of food. Furthermore, both physical properties of food and biliopancreatic secretions showed no effects on intestinal morphological adaptations after RYGB.

Results of this study demonstrate that physical properties of food and bile redirection are not major determinants of intestinal remodeling after RYGB in rats.

Prandial hyperinsulinemia after Roux-en Y gastric bypass surgery (GB), and to lesser degree after sleeve gastrectomy (SG), has been attributed to rapid glucose flux from the gut and increased insulinotropic gut hormones. However, β-cell sensitivity to exogenous incretin is markedly reduced after GB. This study examines the effect of GB versus SG on prandial glycemia and β-cell response to increasing concentrations of endogenous incretins.

Glucose kinetics, insulin secretion rate (ISR), and incretin responses to 50-gram oral glucose ingestion were compared between 10 non-diabetic subjects with GB versus 9 matched individuals with SG and 7 non-operated normal glucose tolerant controls (CN) on two days with and without administration of 200 mg sitagliptin.

Fasting glucose and hormonal levels were similar among 3 groups. Increasing plasma concentrations of endogenous incretins by 2-3-fold diminished post-OGTT glycemia and increased β-cell secretion in all 3 groups (p<0.05), but insulin secretion per insulin sensitivity (i.e., disposition index) was increased only in GB (p<0.05 for interaction). As a result, sitagliptin administration led to hypoglycemia in 3 of 10 GB. Yet, plot of the slope of ISR versus the increase in endogenous incretin concentration was smaller after GB compared to both SG and CN.

Augmented glycemic-induced β-cell response caused by enhanced incretin activity is unique to GB and not shared with SG. However, the β-cell sensitivity to increasing concentrations of endogenous incretin is smaller after bariatric surgery, particularly after GB, compared to non-operated controls, indicating a long-term adaptation of gut-pancreas axis after these procedures.

What is known?: Glycemic effects of gastric bypass (GB) and sleeve gastrectomy (SG) is attributed to rapid nutrient flux and enhanced insulinotropic effects of gut hormones but β-cell sensitivity to exogenous GLP-1 or GIP is diminished after GB. What the present findings add?: Post-OGTT β-cell sensitivity to enhanced endogenous incretins by DPP4i is markedly reduced in bariatric subjects versus non-operated controls, and yet insulin secretory response (disposition index) is increased leading to hypoglycemia in GB and not SG. Significance?: Blunted sensitivity to GLP-1 may represent β-cell adaptation to massive elevation in GLP-1 secretion following bariatric surgery to protect against hypoglycemia.The differential effect of enhanced concentrations of incretins on post-OGTT insulin response (disposition index) among GB versus SG highlights a distinct adaptive process among the two procedures.Augmented insulinotropic effects of gut hormones on postprandial insulin secretory response after GB despite a reduced beta-cell sensitivity to plasma concentrations of GLP-1 makes a case for non-hormonal mechanisms of GLP-1 action after GB.Better understanding of long-term effects of bariatric surgery on gut-pancreas axis activity is critical in development of GLP-1-based strategies to address glucose abnormalities (both hyperglycemia and hypoglycemia) in these settings.

Obesity causes genetic instability, which plays a key-role in the etiology of cancer and aging. We investigated the impact of bariatric surgery (BS) on DNA repair, oxidative DNA damage, telomere lengths, alterations of antioxidant enzymes and, selected proteins which reflect inflammation. The study was realized with BS patients (n = 35). DNA damage, base oxidation, BER, and NER were measured before and 1 month and 6 months after surgery with the single-cell gel electrophoresis technique. SOD and GPx were quantified spectrophotometrically, malondealdehyde (MDA) was quantified by HPLC. Telomere lengths were determined with qPCR, and plasma proteome profiling was performed with high-resolution mass spectrophotometry. Six months after the operations, reduction of body weight by 27.5% was observed. DNA damage decreased after this period, this effect was paralleled by reduced formation of oxidized DNA bases, a decline in the MDA levels and of BER and NER, and an increase in the telomere lengths. The activities of antioxidant enzymes were not altered. Clear downregulation of certain proteins (CRP, SAA1) which reflect inflammation and cancer risks was observed. Our findings show that BS causes reduced oxidative damage of DNA bases, possibly as a consequence of reduction of inflammation and lipid peroxidation, and indicate that the surgery has beneficial long-term health effects.

Islet β-cell dysfunction is a basic pathophysiological characteristic of type 2 diabetes mellitus (T2DM). Appropriate assessment of islet β-cell function is beneficial to better management of T2DM. Protecting islet β-cell function is vital to delay the progress of type 2 diabetes mellitus. Therefore, the Pancreatic Islet β-cell Expert Panel of the Chinese Diabetes Society and Endocrinology Society of Jiangsu Medical Association organized experts to draft the "Clinical expert consensus on the assessment and protection of pancreatic islet β-cell function in type 2 diabetes mellitus." This consensus suggests that β-cell function can be clinically assessed using blood glucose-based methods or methods that combine blood glucose and endogenous insulin or C-peptide levels. Some measures, including weight loss and early and sustained euglycemia control, could effectively protect islet β-cell function, and some newly developed drugs, such as Sodium-glucose cotransporter-2 inhibitor and Glucagon-like peptide-1 receptor agonists, could improve islet β-cell function, independent of glycemic control.

Enhanced secretion of glucagon-like peptide 1 (GLP-1) seems to be essential for improved postprandial β-cell function after Roux-en-Y gastric bypass (RYGB) but is less studied after sleeve gastrectomy (SG). Moreover, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. We studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed-meal tests in unoperated (CON), SG-operated, and RYGB-operated people with no history of diabetes. Postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. The effect of GLP-1R versus GIPR blockade differed between groups. GLP-1R blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the surgical groups but had no effect in CON. GIPR blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. Our results support that GIP is the most important incretin hormone in unoperated people, whereas GLP-1 and GIP are equally important after SG, and GLP-1 is the most important incretin hormone after RYGB.

The aim of this systematic review was to synthesise the study findings on whether GLP-1 secretion in response to a meal tolerance test is affected by the presence of type 2 diabetes (T2D). The influence of putative moderators such as age, sex, meal type, meal form, and assay type were also explored.

A literature search identified 32 relevant studies. The sample mean and SD for fasting GLP-1TOTAL and GLP-1TOTAL iAUC were extracted and used to calculate between-group standardised mean differences (SMD), which were meta-analysed using a random-effects model to derive pooled estimates of Hedges' g and 95 % prediction intervals (PI).

Pooled across 18 studies, the overall SMD in GLP-1TOTAL iAUC between individuals with T2D (n = 270, 1047 ± 930 pmol·L-1·min) and individuals without T2D (n = 402, 1204 ± 937 pmol·L-1·min) was very small, not statistically significant and heterogenous across studies (g = -0.15, p = 0.43, PI: -1.53, 1.23). Subgroup analyses demonstrated an effect of assay type whereby Hedges' g for GLP-1 iAUC was greater in individuals with, versus those without T2D when using ELISA or Mesoscale (g = 0.67 [moderate], p = 0.009), but not when using RIA (g = -0.30 [small], p = 0.10). Pooled across 30 studies, the SMD in fasting GLP-1TOTAL between individuals with T2D (n = 580, 16.2 ± 6.9 pmol·L-1) versus individuals without T2D (n = 1363, 12.4 ± 5.7 pmol·L-1) was small and heterogenous between studies (g = 0.24, p = 0.21, PI: -1.55, 2.02).

Differences in fasting GLP-1TOTAL and GLP-1TOTAL iAUC between individuals with, versus those without T2D were generally small and inconsistent between studies. Factors influencing study heterogeneity such as small sample sizes and poor matching of groups may help to explain the wide prediction intervals observed. Considerations to improve comparisons of GLP-1 secretion in T2D and potential mediating factors more important than T2D diagnosis per se are outlined.

CRD42020195612.

Pancreatic β-cell function impairment and insulin resistance are central to the development of obesity-related type 2 diabetes mellitus (T2DM). Bariatric surgery (BS) is a practical treatment approach to treat morbid obesity and achieve lasting T2DM remission. Traditionally, sustained postoperative glycemic control was considered a direct result of decreased nutrient intake and weight loss. However, mounting evidence in recent years implicated a weight-independent mechanism that involves pancreatic islet reconstruction and improved β-cell function. In this article, we summarize the role of β-cell in the pathogenesis of T2DM, review recent research progress focusing on the impact of Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) on pancreatic β-cell pathophysiology, and finally discuss therapeutics that have the potential to assist in the treatment effect of surgery and prevent T2D relapse.

The Diabetes risk index (DRI) is a composite of NMR-measured lipoproteins and branched chain amino acids predictive of diabetes mellitus development. Bariatric surgery is indicated in patients with severe obesity, many of whom are at high-risk for developing diabetes. Substantial weight loss occurs following bariatric surgery and sustained weight loss likely contributes to reductions in the development of diabetes and cardiovascular disease. However, some evidence suggests that bariatric surgical procedures themselves may contribute to reducing risk of these conditions independent of weight loss. We aimed to investigate DRI and its association with reductions in body weight and adiposity over one year following bariatric surgery.

We examined 51 severely obese premenopausal women without diabetes. DRI, BMI, body weight and waist measurements were made before and at 1, 6 and 12 months after Roux-en-Y Gastric Bypass (RYGB) or Sleeve Gastrectomy. Values were compared to healthy women with normal BMI (18.5-24.9 kg/m2; n = 15).

Non-diabetic women with severe obesity (BMI 44.7 ± 6.2 kg/m2) exhibited significantly elevated DRI scores prior to surgery versus controls (35 [26, 39] vs 12 [1, 20]; p < 0.0001). At 1 month after surgery, BMI decreased 5.1 ± 1.1 kg/m2, but DRI decreased so that it no longer differed from that of normal BMI controls (1.9 [1, 17] vs control 12 [1, 20]; p = 0.35). Subjects continued to lose weight, whereas DRI remained similar, throughout follow-up with DRI 1.0 [1, 7] at 12 months. Changes in DRI did not correlate with changes in BMI, body weight or waist circumference at any time during follow-up. There was no difference in change in DRI between surgical procedures or pre-operative metabolic syndrome status.

Our analysis of DRI scores supports the capacity of bariatric surgery to reduce risk of developing diabetes in severely obese individuals. Our findings suggest that bariatric surgical techniques may have inherent effects that improve cardiometabolic risk independent of reductions in body weight or adiposity.

Postprandial hyperinsulinemic hypoglycemia with neuroglycopenia is an increasingly recognized complication of Roux-en-Y gastric bypass and gastric sleeve surgery that may detrimentally affect patient quality of life. One likely causal factor is glucagon-like peptide-1 (GLP-1), which has an exaggerated rise following ingestion of carbohydrates after bariatric surgery. This paper sought to assess the role of GLP-1 receptor agonists (GLP-1RAs) in managing postprandial hypoglycemia following bariatric surgery.

MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Scopus were systematically and critically appraised for all peer-reviewed publications that suitably fulfilled the inclusion criteria established a priori. This systematic review was developed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P). It followed methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions and is registered with PROSPERO (International Prospective Register of Systematic Reviews; identifier CRD420212716429).

Postprandial hyperinsulinemic hypoglycemia remains a notoriously difficult to manage metabolic complication of bariatric surgery. This first, to the authors' knowledge, systematic review presents evidence suggesting that use of GLP-1RAs does not lead to an increase of hypoglycemic episodes, and, although this approach may appear counterintuitive, the findings suggest that GLP-1RAs could reduce the number of postprandial hypoglycemic episodes and improve glycemic variability.

Bariatric surgery is a highly effective obesity treatment resulting in substantial weight loss and improved glucose metabolism. We hereby aimed to summarize available evidence of the effect of the 2 most common bariatric surgery procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), on dynamic measures of β-cell function (BCF). A systematic search of the literature was conducted in 3 bibliographic databases for studies reporting effects of RYGB and/or SG on BCF assessed using dynamic metabolic perturbation (oral or intravenous bolus stimulation), performed before and 1 year (±3 months) after surgery. Twenty-seven unique studies (6 randomized controlled trials and 21 observational studies), involving a total of 1856 obese adults, were included for final analysis. Twenty-five and 9 studies report effects of RYGB and SG on BCF, respectively (7 studies compared the 2 procedures). Seven studies report results according to presurgical diabetes status. Owing to variable testing procedures and BCF indices reported, no meta-analysis was feasible, and data were summarized qualitatively. For both surgical procedures, most studies suggest an increase in BCF and disposition index, particularly when using oral stimulation, with a more pronounced increase in diabetic than nondiabetic individuals. Additionally, limited indications for greater effects after RYGB versus SG were found. The quality of the included studies was, in general, satisfactory. The considerable heterogeneity of test protocols and outcome measures underscore the need for a harmonization of BCF testing in future research.

Type 2 diabetes mellitus (T2DM) is a progressive disease with a growing prevalence, associated with an increased risk of complications. The introduction of new classes of antidiabetic drugs into clinical practice has dramatically changed the landscape of diabetes therapy. However, despite the progress made in the pharmacotherapy of T2DM, mitigating the burden of the disease on individuals, societies and health care systems remains a challenge. Remission has recently emerged as a therapeutic target in T2DM, achievable through a wide range of interventions. Recent studies have shown that extensive lifestyle changes, such as weight reduction, bariatric surgery, and intensive glucose lowering therapy, can prompt the remission of diabetes, but some unanswered questions remain regarding its long-term effects on diabetic complications. Metabolic surgery and novel classes of glucose-lowering medications are currently the most effective interventions to induce weight loss and by extension remission in patients with diabetes; however, the ideal strategy to achieve the long-term maintenance of remission remains doubtful. In this narrative review, we discuss the available therapeutic approaches to target the remission of diabetes through personalized multimodal care, based on the latest evidence.