Intestinal Gluconeogenesis Research Articles

Nutropioids regulate gut-brain circuitry controlling food intake.

The modulation of hunger sensations by the µ-opioid receptor (MOR) present in the brain is an established fact. That MORs expressed in the periphery could have a similar role was outstanding. Using portal infusions of agonists and/or antagonists of MOR in conscious rodents, we have shown that MORs present in the walls of the portal vein nervous system control a gut-brain circuit of induction of intestinal gluconeogenesis (IGN), a function controlling hunger sensations. Then, we have shown that peptides and proteins promote a MOR-dependent induction of IGN. Peptides have no effect in mice knockout for MOR. MOR-KO mice are also insensitive to satiety induced by protein-enriched diets. In addition, portal infusions of MOR modulators have no effect on food intake in mice deficient for IGN. Thus, the regulation by portal MORs and peptides of a gut-brain neural circuit of induction of IGN is a causal link in the phenomenon of satiety induced by dietary protein.

Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits

Soluble dietary fibers promote metabolic benefits on body weight and glucose control, but underlying mechanisms are poorly understood. Recent evidence indicates that intestinal gluconeogenesis (IGN) has beneficial effects on glucose and energy homeostasis. Here, we show that the short-chain fatty acids (SCFAs) propionate and butyrate, which are generated by fermentation of soluble fiber by the gut microbiota, activate IGN via complementary mechanisms. Butyrate activates IGN gene expression through a cAMP-dependent mechanism, while propionate, itself a substrate of IGN, activates IGN gene expression via a gut-brain neural circuit involving the fatty acid receptor FFAR3. The metabolic benefits on body weight and glucose control induced by SCFAs or dietary fiber in normal mice are absent in mice deficient for IGN, despite similar modifications in gut microbiota composition. Thus, the regulation of IGN is necessary for the metabolic benefits associated with SCFAs and soluble fiber.

Intestinal gluconeogenesis is crucial to maintain a physiological fasting glycemia in the absence of hepatic glucose production in mice

ObjectiveSimilar to the liver and kidneys, the intestine has been strongly suggested to be a gluconeogenic organ. However, the precise contribution of the intestine to endogenous glucose production (EGP) remains to be determined. To define the quantitative role of intestinal gluconeogenesis during long-term fasting, we compared changes in blood glucose during prolonged fasting in mice with a liver-deletion of the glucose-6 phosphatase catalytic (G6PC) subunit (LKO) and in mice with a combined deletion of G6PC in both the liver and the intestine (ILKO). Materials/MethodsThe LKO and ILKO mice were studied after 6h and 40h of fasting by measuring metabolic and hormonal plasmatic parameters, as well as the expression of gluconeogenic enzymes in the liver, kidneys and intestine. ResultsAfter a transient hypoglycemic episode (approximately 60mg/dL) because of their incapacity to mobilize liver glycogen, the LKO mice progressively re-increased their plasma glucose to reach a glycemia comparable to that of wild-type mice (90mg/dL) from 30h of fasting. This increase was associated with a rapid induction of renal and intestinal gluconeogenic gene expression, driven by glucagon, glucocorticoids and acidosis. The ILKO mice exhibited a similar induction of renal gluconeogenesis. However, these mice failed to re-increase their glycemia and maintained a plasma glucose level of only 60mg/dL throughout the 48h-fasting period. ConclusionsThese data indicate that intestinal glucose production is essential to maintain glucose homeostasis in the absence of hepatic glucose production during fasting. These data provide a definitive quantitative estimate of the capacity of intestinal gluconeogenesis to sustain EGP during long-term fasting.

Satiety and the role of μ-opioid receptors in the portal vein

Mu-opioid receptors (MORs) are known to influence food intake at the brain level, through their involvement in the food reward system. MOR agonists stimulate food intake. On the other hand, MOR antagonists suppress food intake. MORs are also active in peripheral organs, especially in the small intestine where they control the gut motility. Recently, an indirect role in the control of food intake was ascribed to MORs in the extrinsic gastrointestinal neural system. MORs present in the neurons of the portal vein walls sense blood peptides released from the digestion of dietary protein. These peptides behave as MOR antagonists. Their MOR antagonist action initiates a gut-brain circuitry resulting in the induction of intestinal gluconeogenesis, a function controlling food intake. Thus, periportal MORs are a key mechanistic link in the satiety effect of protein-enriched diets.

Leucine Supplementation Protects from Insulin Resistance by Regulating Adiposity Levels

BackgroundLeucine supplementation might have therapeutic potential in preventing diet-induced obesity and improving insulin sensitivity. However, the underlying mechanisms are at present unclear. Additionally, it is unclear whether leucine supplementation might be equally efficacious once obesity has developed.Methodology/Principal FindingsMale C57BL/6J mice were fed chow or a high-fat diet (HFD), supplemented or not with leucine for 17 weeks. Another group of HFD-fed mice (HFD-pairfat group) was food restricted in order to reach an adiposity level comparable to that of HFD-Leu mice. Finally, a third group of mice was exposed to HFD for 12 weeks before being chronically supplemented with leucine. Leucine supplementation in HFD-fed mice decreased body weight and fat mass by increasing energy expenditure, fatty acid oxidation and locomotor activity in vivo. The decreased adiposity in HFD-Leu mice was associated with increased expression of uncoupling protein 3 (UCP-3) in the brown adipose tissue, better insulin sensitivity, increased intestinal gluconeogenesis and preservation of islets of Langerhans histomorphology and function. HFD-pairfat mice had a comparable improvement in insulin sensitivity, without changes in islets physiology or intestinal gluconeogenesis. Remarkably, both HFD-Leu and HFD-pairfat mice had decreased hepatic lipid content, which likely helped improve insulin sensitivity. In contrast, when leucine was supplemented to already obese animals, no changes in body weight, body composition or glucose metabolism were observed.Conclusions/SignificanceThese findings suggest that leucine improves insulin sensitivity in HFD-fed mice by primarily decreasing adiposity, rather than directly acting on peripheral target organs. However, beneficial effects of leucine on intestinal gluconeogenesis and islets of Langerhans's physiology might help prevent type 2 diabetes development. Differently, metabolic benefit of leucine supplementation is lacking in already obese animals, a phenomenon possibly related to the extent of the obesity before starting the supplementation.

Duodenal–Jejunal Bypass Surgery Up-Regulates the Expression of the Hepatic Insulin Signaling Proteins and the Key Regulatory Enzymes of Intestinal Gluconeogenesis in Diabetic Goto–Kakizaki Rats

Duodenal-jejunal bypass (DJB), which is not routinely applied in metabolic surgery, is an effective surgical procedure in terms of type 2 diabetes mellitus resolution. However, the underlying mechanisms are still undefined. Our aim was to investigate the diabetic improvement by DJB and to explore the changes in hepatic insulin signaling proteins and regulatory enzymes of gluconeogenesis after DJB in a non-obese diabetic rat model. Sixteen adult male Goto-Kakizaki rats were randomly divided into DJB and sham-operated groups. The body weight, food intake, hormone levels, and glucose metabolism were measured. The levels of protein expression and phosphorylation of insulin receptor-beta (IR-β) and insulin receptor substrate 2 (IRS-2) were evaluated in the liver. We also detected the expression of key regulatory enzymes of gluconeogenesis [phosphoenoylpyruvate carboxykinase-1 (PCK1), glucose-6-phosphatase-alpha (G6Pase-α)] in small intestine and liver. DJB induced significant diabetic improvement with higher postprandial glucagons-like peptide 1, peptide YY, and insulin levels, but without weight loss. The DJB group exhibited increased expression and phosphorylation of IR-β and IRS-2 in liver, up-regulated the expression of PCK1 and G6Pase-α in small intestine, and down-regulated the expression of these enzymes in liver. DJB is effective in up-regulating the expression of the key proteins in the hepatic insulin signaling pathway and the key regulatory enzymes of intestinal gluconeogenesis and down-regulating the expression of the key regulatory enzymes of hepatic gluconeogenesis without weight loss. Our study helps to reveal the potential role of hepatic insulin signaling pathway and intestinal gluconeogenesis in ameliorating insulin resistance after metabolic surgery.

Influence of diabetes surgery on a gut-brain-liver axis regulating food intake and internal glucose production.

It has long been known that the brain, especially the hypothalamus, can modulate both insulin secretion and hepatic glucose fluxes, via the modulation of the sympathetic system (promoting glycogen breakdown) and the parasympathetic system (stimulating glycogen deposition). Central insulin signalling or hypothalamic long-chain fatty acid oxidation can also control insulin's suppression of endogenous glucose production. Interestingly, intestinal gluconeogenesis can initiate a portal glucose signal, transmitted to the hypothalamus via the gastrointestinal nervous system. This signal may modulate the sensation of hunger and satiety and insulin sensitivity of hepatic glucose fluxes as well. The rapid improvements of glucose control taking place after gastric bypass surgery in obese diabetics has long been mysterious. Actually, the specificity of gastric bypass in obese diabetic mice relates to major changes in the sensations of hunger and to rapid improvement in insulin sensitivity of endogenous glucose production. We have shown that an induction of intestinal gluconeogenesis plays a major role in these phenomena. In addition, the restoration of the secretion of glucagon like peptide 1 and consequently of insulin plays a key additional role to improve postprandial glucose tolerance. Therefore, a synergy between incretin effects and intestinal gluconeogenesis might be a key feature explaining the rapid improvement of glucose control in obese diabetics after bypass surgery.

Diabetes surgery in type 2 BMI 24-29 vs IMC 30-34 diabetic patients: is there differences among restrictive, malabsorptive and gastric bypass procedures?

Diabetes mellitus (DM) is a public health problem with a prevalence of 345 million people worldwide that it may double by the year 2030 and have a high costs and mortality. Gastrointestinal surgery is accepted as a form of treatment that was already suggested for obese in 1987 by Pories, confirmed for obese patients by the metaanalysis of Buchwald and the direct comparison of gastric bypass with medical treatment in the study of Schauer that demonstrate a 4 fold greater resolution rate of DM with surgery. Improvement occurs immediately after surgery, before the patients lose weight in with BMI > 35; but there is doubt if the existent evidence is enough to extrapolate these results to patients with BMI < 35 and especially with BMI < 30, in spite that four reviews in patients with this BMI and DM2 demonstrated the same results when stomach, duodenum and part of jejunum is bypassed as happen gastric bypass (better results with this of one anastomosis than of two anastomosis, Roux-en-Y) BPD. For patients with a BMI between 30 and 35 restrictive techniques: LAGB and SGL are good but not better than the mixed: RYGB, BAGUA, or SG-DJB with remission from 60 to 100%, minor in the derivative: BPD and above on the IID with a 81% of remission. There are no differences in the metabolic control in comparison to the obese, It is progressively better with DJB, SDS, IID and BAGUA especially in patients who do not require insulin, have less time with disease, have normal C peptide levels, and not so much relation with the initial BMI that is only important to decide the degree of restriction. Although several mechanisms has been suggested for explaining these results such as caloric intake, hormonal changes, bypass of the anterior or early stimulation of posterior intestine, fundectomy, intestinal gluconeogenesis and others, new ones will appear in the near future.

Comment about intestinal gluconeogenesis after gastric bypass in human in relation with the paper by Hayes et al., Obes. Surg. 2011

Comment about intestinal gluconeogenesis after gastric bypass in human in relation with the paper by Hayes et al., Obes. Surg. 2011

Mu-Opioid Receptors and Dietary Protein Stimulate a Gut-Brain Neural Circuitry Limiting Food Intake

Intestinal gluconeogenesis is involved in the control of food intake. We show that mu-opioid receptors (MORs) present in nerves in the portal vein walls respond to peptides to regulate a gut-brain neural circuit that controls intestinal gluconeogenesis and satiety. In vitro, peptides and protein digests behave as MOR antagonists in competition experiments. In vivo, they stimulate MOR-dependent induction of intestinal gluconeogenesis via activation of brain areas receiving inputs from gastrointestinal ascending nerves. MOR-knockout mice do not carry out intestinal gluconeogenesis in response to peptides and are insensitive to the satiety effect induced by protein-enriched diets. Portal infusions of MOR modulators have no effect on food intake in mice deficient for intestinal gluconeogenesis. Thus, the regulation of portal MORs by peptides triggering signals to and from the brain to induce intestinal gluconeogenesis are links in the satiety phenomenon associated with alimentary protein assimilation.

A Synergy between Incretin Effect and Intestinal Gluconeogenesis Accounting for the Rapid Metabolic Benefits of Gastric Bypass Surgery

The early improvement of glucose control taking place shortly after gastric bypass surgery in obese diabetic patients has long been mysterious. A recent study in mice has highlighted some specific mechanisms underlying this phenomenon. The specificity of gastric bypass in obese diabetic mice relates to major changes in the sensations of hunger and to rapid improvement of glucose parameters. The induction of intestinal gluconeogenesis plays a major role in diminishing hunger, and in restoring insulin sensitivity of endogenous glucose production. In parallel, the restoration of the secretion of glucagon-like peptide 1 and insulin plays a key additional role, in this context of recovered insulin sensitivity, to improve postprandial glucose tolerance. Therefore, a synergy between an incretin effect and intestinal gluconeogenesis is a key feature accounting for the rapid improvement of glucose control in obese diabetic patients after bypass surgery.

Vagal Innervation of the Hepatic Portal Vein and Liver Is Not Necessary for Roux-En-Y Gastric Bypass Surgery-Induced Hypophagia, Weight Loss, and Hypermetabolism

To determine the role of the common hepatic branch of the abdominal vagus on the beneficial effects of Roux-en-Y gastric bypass (RYGB) on weight loss, food intake, food choice, and energy expenditure in a rat model. Although changes in gut hormone patterns are the leading candidates in RYGB's effects on appetite, weight loss, and reversal of diabetes, a potential role for afferent signaling through the vagal hepatic branch potentially sensing glucose levels in the hepatic portal vein has recently been suggested in a mouse model of RYGB. Male Sprague-Dawley rats underwent either RYGB alone (RYGB; n = 7), RYGB + common hepatic branch vagotomy (RYGB + HV; n = 6), or sham procedure (sham; n = 9). Body weight, body composition, meal patterns, food choice, energy expenditure, and fecal energy loss were monitored up to 3 months after intervention. Both RYGB and RYGB + HV significantly reduced body weight, adiposity, meal size, and fat preference, and increased satiety, energy expenditure, and respiratory exchange rate compared with sham procedure, and there were no significant differences in these effects between RYGB and RYGB + HV rats. Integrity of vagal nerve supply to the liver, hepatic portal vein, and the proximal duodenum provided by the common hepatic branch is not necessary for RYGB to reduce food intake and body weight or increase energy expenditure. Specifically, it is unlikely that a hepatic portal vein glucose sensor signaling RYGB-induced increased intestinal gluconeogenesis to the brain depends on vagal afferent fibers.

Cell Walls of Saccharomyces cerevisiae Differentially Modulated Innate Immunity and Glucose Metabolism during Late Systemic Inflammation

Background Salmonella causes acute systemic inflammation by using its virulence factors to invade the intestinal epithelium. But, prolonged inflammation may provoke severe body catabolism and immunological diseases. Salmonella has become more life-threatening due to emergence of multiple-antibiotic resistant strains. Mannose-rich oligosaccharides (MOS) from cells walls of Saccharomyces cerevisiae have shown to bind mannose-specific lectin of Gram-negative bacteria including Salmonella, and prevent their adherence to intestinal epithelial cells. However, whether MOS may potentially mitigate systemic inflammation is not investigated yet. Moreover, molecular events underlying innate immune responses and metabolic activities during late inflammation, in presence or absence of MOS, are unknown.Methods and Principal FindingsUsing a Salmonella LPS-induced systemic inflammation chicken model and microarray analysis, we investigated the effects of MOS and virginiamycin (VIRG, a sub-therapeutic antibiotic) on innate immunity and glucose metabolism during late inflammation. Here, we demonstrate that MOS and VIRG modulated innate immunity and metabolic genes differently. Innate immune responses were principally mediated by intestinal IL-3, but not TNF-α, IL-1 or IL-6, whereas glucose mobilization occurred through intestinal gluconeogenesis only. MOS inherently induced IL-3 expression in control hosts. Consequent to LPS challenge, IL-3 induction in VIRG hosts but not differentially expressed in MOS hosts revealed that MOS counteracted LPS's detrimental inflammatory effects. Metabolic pathways are built to elucidate the mechanisms by which VIRG host's higher energy requirements were met: including gene up-regulations for intestinal gluconeogenesis (PEPCK) and liver glycolysis (ENO2), and intriguingly liver fatty acid synthesis through ATP citrate synthase (CS) down-regulation and ATP citrate lyase (ACLY) and malic enzyme (ME) up-regulations. However, MOS host's lower energy demands were sufficiently met through TCA citrate-derived energy, as indicated by CS up-regulation.ConclusionsMOS terminated inflammation earlier than VIRG and reduced glucose mobilization, thus representing a novel biological strategy to alleviate Salmonella-induced systemic inflammation in human and animal hosts.

Type 2 Diabetes Mellitus: A Possible Surgically Reversible Intestinal Dysfunction

Type 2 diabetes mellitus (T2DM) is a global public health problem often associated with obesity. Bariatric surgery is effective for treating serious obesity, and techniques involving intestinal bypass have metabolic benefits, such as complete and early remission of T2DM. We present a literature review of the possible mechanisms of early normalization of glycemic homeostasis after bariatric surgery, including intestinal gluconeogenesis, increased antidiabetogenic signals from L cells located in the distal small intestine, and impaired secretion of diabetogenic signals in the upper part of the small intestine. Adding to these potential mechanisms, unknown factors that regulate insulin sensitivity may be involved and altered by bariatric surgery. This review discusses the various hypotheses about the mechanisms of glycemic control after bariatric surgery involving intestinal bypass. Further research is essential to better understand these mechanisms and to identify potential new mechanisms that might help in developing less invasive and safer alternatives for the treatment of T2DM and reveal novel pharmaceutical targets for glycemic control.

Diabetes resolution and hyperinsulinaemia after metabolic Roux‐en‐Y gastric bypass

The global prevalence of type 2 diabetes mellitus and impaired glucose metabolism continues to rise in conjunction with the pandemic of obesity. The metabolic Roux-en-Y gastric bypass operation offers the successful resolution of diabetes in addition to sustained weight loss and excellent long-term outcomes in morbidly obese individuals. The procedure consists of the physiological BRAVE effects: (i) Bile flow alteration; (ii) Reduction of gastric size; (iii) Anatomical gut rearrangement and altered flow of nutrients; (iv) Vagal manipulation and (v) Enteric gut hormone modulation. This operation provides anti-diabetic effects through decreasing insulin resistance and increasing the efficiency of insulin secretion. These metabolic outcomes are achieved through weight-independent and weight-dependent mechanisms. These include the foregut, midgut and hindgut mechanisms, decreased inflammation, fat, adipokine and bile metabolism, metabolic modulation, shifts in gut microbial composition and intestinal gluconeogenesis. In a small minority of patients, gastric bypass results in hyperinsulinaemic hypoglycaemia that may lead to nesidioblastosis (pancreatic beta-cell hypertrophy with islet hyperplasia). Elucidating the precise metabolic mechanisms of diabetes resolution and hyperinsulinaemia after surgery can lead to improved operations and disease-specific procedures including 'diabetes surgery'. It can also improve our understanding of diabetes pathogenesis that may provide novel strategies for the management of metabolic syndrome and impaired glucose metabolism.

Protein-induced satiety is abolished in the absence of intestinal gluconeogenesis

Protein-enriched diets are well known to initiate satiety effects in animals and humans. It has been recently suggested that this might be dependent on the induction of gluconeogenesis in the intestine. The resulting intestinal glucose release, detected by a “so-called” glucose sensor located within the walls of the portal vein and connected to peripheral afferents, activates hypothalamic nuclei involved in the regulation of food intake, in turn initiating a decrease in hunger. To definitively demonstrate the role of intestinal gluconeogenesis in this mechanism, we tested the food intake response to a protein-enriched diet in mice with an intestine-specific deletion (using an inducible Cre/loxP strategy) of the glucose-6 phosphatase gene (I- G6pc −/− mice) encoding the mandatory enzyme for glucose production. There was no effect on food intake in I- G6pc −/− mice fed on a standard rodent diet compared to their wild-type counterparts. After switching to a protein-enriched diet, the food intake of wild-type mice decreased significantly (by about 20% of daily calorie intake), subsequently leading to a decrease of 12 ± 2% of initial body weight after 8 days. On the contrary, I- G6pc −/− mice were insensitive to the satiety effect induced by a protein-enriched diet and preserved their body weight. These results provide molecular evidence of the causal role of intestinal gluconeogenesis in the satiety phenomenon initiated by protein-enriched diets.

Is Intestinal Gluconeogenesis a Key Factor in the Early Changes in Glucose Homeostasis Following Gastric Bypass?

In 2008, Troy et al. hypothesised that under fasting conditions, intestinal gluconeogenesis generates glucose levels in the portal vein which trigger the portal sensor to change insulin resistance and that this mechanism contributes to the effects of Roux-en-Y gastric bypass (RYGB) surgery on type 2 diabetes mellitus (T2DM). In a recent paper, Kashyap et al. (Int J Obes 34(3):426-471, 2010) cited this hypothesis as a potential explanation for the early changes in insulin sensitivity and beta cell function seen after RYGB. We proposed a study to examine this possibility. We simultaneously sampled fasting portal venous blood and central venous blood in 28 patients (eight diabetics and 20 non-diabetics) before and again six days after RYGB surgery in morbidly obese patients, for measurement of glucose levels. We found no significant difference in the glucose levels from the two sites either before or after RYGB in diabetic patients and a small, but significant difference in the post-operative glucose levels from non-diabetic patients (4.2 vs 4.0mM, p < 0.0001). Direct simultaneous measurement of fasting glucose in portal and central venous blood before and 6days after RYGB provides no evidence to support the hypothesis that intestinal gluconeogenesis contributes to the resolution of T2DM seen after RYGB.

Brain, liver, intestine: a triumvirate to coordinate insulin sensitivity of endogenous glucose production

The brain, especially the hypothalamus, can modulate hepatic glucose fluxes. The sympathetic system promotes glycogen breakdown. The parasympathetic system stimulates glycogen deposition. Central insulin signalling or hypothalamic long-chain fatty acid oxidation can both control insulin's suppression of endogenous glucose production. Intestinal gluconeogenesis initiates a portal glucose signal, transmitted to the brain via the gastrointestinal nervous system. This signal may modulate the sensation of hunger and satiety and insulin sensitivity of hepatic glucose fluxes as well, via the modulation of hypothalamic activity

Absence of intestinal gluconeogenesis in type 1 diabetic rats: carbon 13 NMR and arteriovenous concentration difference measurements

Recent reports have indicated that 48–72h of fasting, type 1 diabetes and high‐protein feeding induce gluconeogenesis in the small intestine of adult rats in vivo. Since this would (i) represent a dramatic revision of the prevailing view that only the liver and the kidneys are gluconeogenic, and (ii) have major consequences in the metabolism, nutrition and diabetes fields, we have thoroughly re‐examined this question in the situation reported to induce the highest rate of gluconeogenesis. For this, metabolically viable small intestinal segments from 72h‐fasted adult rats were incubated with [3‐13C]glutamine as substrate. After incubation, substrate utilization and product accumulation were measured by enzymatic and NMR methods. Although the segments utilized 13C‐glutamine at high rates and accumulated 13C‐labeled products linearly for 30 min in vitro, no substantial glucose synthesis could be detected. This was not due to the re‐utilization of 13C‐glucose initially synthesized. Arteriovenous metabolite concentration difference measurements across the portal vein‐drained viscera of 72h‐fasted Wistar and Sprague‐Dawley rats clearly indicated that glutamine, the main if not the only gluconeogenic precursor taken up, could not give rise to detectable glucose production in vivo. Therefore, we challenge the view that the small intestine of the adult rat is a gluconeogenic organ.

Mechanisms of early improvement / resolution of type 2 diabetes after bariatric surgery

Bariatric surgery represents the main option for obtaining substantial and long-term weight loss in morbidly obese subjects. In addition, malabsorptive (biliopancreatic diversion, BPD) and restrictive (roux-en-Y gastric bypass, RYGB) surgery, originally devised to treat obesity, has also been shown to help diabetes. Indeed, type 2 diabetes is improved or even reversed soon after these operations and well before significant weight loss occurs. Two hypotheses have been proposed to explain the early effects of bariatric surgery on diabetes—namely, the hindgut hypothesis and the foregut hypothesis. The former states that diabetes control results from the more rapid delivery of nutrients to the distal small intestine, thereby enhancing the release of hormones such as glucagon-like peptide-1 (GLP-1). The latter theory contends that exclusion of the proximal small intestine reduces or suppresses the secretion of anti-incretin hormones, leading to improvement of blood glucose control as a consequence. In fact, increased GLP-1 plasma levels stimulate insulin secretion and suppress glucagon secretion, thereby improving glucose metabolism. Recent studies have shown that improved intestinal gluconeogenesis may also be involved in the amelioration of glucose homoeostasis following RYGB. Although no large trials have specifically addressed the effects of bariatric surgery on the remission or reversal of type 2 diabetes independent of weight loss and/or caloric restriction, there are sufficient data in the literature to support the idea that this type of surgery—specifically, RYGB and BPD—can lead to early improvement of glucose control independent of weight loss.