Weight loss surgery has shown more effectiveness in patients with type 2 diabetes (T2D) who underwent gastric bypass surgery resulting in better insulin production in 6 months to a year without the need of further medication. An extraordinary thing happens to some patients with type 2 diabetes who undergo weight-loss surgery: Within days of the procedure, they improve their insulin production and need fewer or no diabetes medications. Although it’s well established that losing weight, especially around the waistline, improves pancreas function and insulin sensitivity, it generally takes 6 months to a year after bariatric surgery before a patient sheds a substantial number of pounds.
Bariatric surgery and diabetes remission:
Type 2 diabetes mellitus (T2DM) and obesity are increasingly common and major global health problems. Obesity itself triggers insulin resistance and thereby poses the risk of T2DM. Both obesity and T2DM have been associated with higher morbidity and mortality and this calls for institution of effective therapies to deal with the rising trend of complications arising out of this dual menace. Although lifestyle changes form the cornerstone of therapy for both the ailments, sustained results from this modalities is far from satisfactory. Bariatric surgery has been seen to associate with substantial and sustained weight loss in morbidly obese patients. Interestingly, bariatric surgeries also induce higher rates of short and long-term diabetes remission. Although the exact mechanism behinds this diabetes remission are not well understood; improved insulin action, beta-cell function and complex interplay of hormones in the entero-insular axis appears to play a major role. This article reviews the effectiveness of bariatric procedures on remission or improvement in diabetes and put a perspective on its implicated mechanisms.
Both Type 2 diabetes mellitus (T2DM) and obesity are increasingly common global health problems, Dietary changes, lifestyle modification (LSM) form the cornerstone of therapy for both the ailments. Pharmacotherapy for obesity is another approach if LSM alone is inadequate.
Bariatric surgery could be the most effective therapy for obesity that also provides significantly higher rates of resolution or improvement of T2DM. Bariatric surgeries lead to substantial and sustained weight loss for most patients, with the magnitude varying according to the procedure performed. Additionally, bariatric surgery is associated with improvements or remission of diabetes in up to 80%, and reduction in incidental diabetes by 73%, apart from the improvement in hypertension and dyslipidemia. Furthermore, bariatric surgery was associated with reduced incidence of myocardial infarction (29%), stroke (34%), cancer in women (42%), and overall mortality (30–40%).However; many consider bariatric surgery as a draconian last-resort step for obesity and diabetes management, in part due to surgical risks as well as uncertainty about long-term efficacy.
Principally, bariatric surgeries can be of three types-
1) Restrictive procedure-adjustable gastric band (AGB), sleeve gastrectomy (SG)
2). malabsorptive procedure-duodeno jejunal bypass and
3) mixed procedure-biliopancreatic diversion (BPD),
biliopancreatic diversion with duodenal switch (BPD-DS), and Roux-en-Y gastric bypass (RYGB). Restrictive procedures resulted in delayed glycemic control related majorly to weight loss however the malabsorptive procedures lead to remission of T2DM very early within days to few weeks after surgery and much before significant weight loss has occurred. RYGB is currently the gold standard technique.
Moreover, a nonsurgical duodenal-jejunal bypasses liner (DJBL), delivered and retrieved endoscopically, has been developed to mimic RYGB-related proximal small intestinal exclusion. The DJBL is a 60 cm long impermeable liner, anchored proximally at duodenal bulb and works as a barrier for bile as well as enzymes to get mixed with food in foregut. However, unlike RYGB, the anatomy of the stomach and small intestine is not affected enabling mechanistic studies focusing exclusively on the role of the proximal intestine in T2DM. Efficacy of bariatric surgery on remission of diabetes in patient with body mass index >35 kg/m2
Improvement or remission of diabetes as a secondary outcome
Severely obese subjects (mean BMI 41 kg/m2) who underwent either bariatric surgery or conventionally treated, found a higher rate of recovery from diabetes, hypertension and hypertriglyceridemia, apart from showing a significantly higher sustained and long term weight loss in the surgical arms.
The major mechanism of the decrease in plasma glucose after bariatric surgery is acute negative calorie balance. Negative calorie produced same effect on blood glucose that was produced by gastric bypass itself. Induction of sudden negative calorie balance by any means would normalize plasma glucose levels within days, and this appears to be the predominant mechanism underlying the early metabolic changes after bariatric surgery. Additionally, surgically induced direct delivery of nutrients to GLP-1 producing distal jejunum will increase GLP-1 substantially and this complex interplay of hormones in the entero-insular axis appears to play another major role in enhancing the insulin response and thereby improving diabetes.
Improvement in hepatic and peripheral insulin sensitivity
There was an early and marked improvement in hepatic insulin sensitivity, 1-week after RYGB, which persisted for up to 1-year. This dramatic improvement in hepatic insulin sensitivity was observed even before any significant weight reduction has occurred. However, the peripheral insulin sensitivity at skeletal muscle and adipose tissue were unchanged during the early postoperative period which only improved gradually thereafter. It is believed that calorie restriction in early postoperative period would decrease intrahepatic fat content and might be playing a crucial role in improving early hepatic insulin sensitivity while improvement in peripheral insulin sensitivity is only observed after substantial weight loss following RYGB. Although, there are many mechanisms for improved insulin sensitivity after RYGB, weight loss induced improvement in insulin sensitivity is of utmost importance.
Role of ghrelin
Ghrelin is an orexigenic hormone produced maximally in the gastric fundus. Des acyl ghrelin is activated to acyl ghrelin in the stomach through ghrelin O-acyltransferase enzyme (GOAT). Ghrelin exerts its orexigenic action through specific modulation of sirtuin1/P53 and activated protein kinase pathways to increase the agouti-related protein and neuropeptide Y expression in the hypothalamic arcuate nucleus. Ghrelin stimulates hypothalamic expression of mammalian target of rapamycin signaling pathway (mTOR). The mTOR pathways and ghrelin/GOAT axis interact reciprocally.
Role of incretin
It appears that endogenous native GLP-1 following bariatric surgery increases by approximately 20-folds. This GLP1 increment is significantly higher and sustained compared to exogenous GLP-1 agonist injection or dipeptidyl peptidase (DPP)-4 inhibitors therapy. Typically malabsorptive bariatric procedures result in rapid increment in postprandial GLP-1 secretion while no increase noticed after restrictive bariatric procedure alone. In contrast reduction in postprandial GIP levels observed 2 weeks after jejunoileal bypass or RYGB or BPD; however GIP may be elevated after SG.
Role of cholecystokin
The study shown, lipids and proteins produce cholecystokin (CCK) from I cells which has two main receptors-CCK1R and CCK2R. CCK1R is responsible for reduction of food intake, while CCK2R regulates glucose homeostasis. In vitro, CCK stimulates glucagon release and increases pancreatic β cell proliferation. This contributes to the higher circulating levels of CCK, which potentially leads to suppression of food intake and stimulation of insulin secretion.
Role of enteroglucagon
The enteroglucagon peptide is expressed primarily in the distal intestinal L cells. It refers to the intestinal GLPs, glicentin and oxyntomodulin (OXM). Glicentin acts as a double agonist for the GLP-1 receptor with a very low affinity. It stimulates the secretion of insulin and inhibits glucagon and gastric acid secretion; and regulates intestinal motility. It reduces appetite by acting directly on the hypothalamic centers to reduce appetite. OXM increases insulin secretion and inhibits pancreatic β cell apoptosis and is inactivated rapidly by DPP-4. An increase of OXM after 1-month of RYGB (n = 20), but not on following diet (n = 10) induced equivalent weight loss and increase in OXM was significantly correlated with an increase in GLP-1 and PYY.
Role of peptide tyrosine tyrosine
Peptide tyrosine tyrosine is released by the intestinal L cells of ileum, colon, and rectum in response to lipids and carbohydrates. PYY inhibits gastrointestinal motility, exocrine pancreas and gastric secretions. It also reduces lipolysis, therefore increases insulin sensitivity by decreasing the concentration of circulating fatty acids. The truncate form PYY (3–36) is inducing satiety via the Y2 receptor in the hypothalamus. After malabsorptive surgeries, there is postprandial increase in PYY in the earliest postsurgical period even before weight loss occurs.
Altered bile acid metabolism
Bile acids have been implicated in the glucose homeostasis. Mechanistically, two nuclear receptors, farnesoid X receptor (FXR) and TGR5, are believed to mediate the genomic and nongenomic effects of bile acids, respectively. Bile acid activation by FXR reduces the expression of gluconeogenetic genes such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. FXR also modulate hepatic glucose production and may have a partial regulatory role in peripheral insulin sensitivity. These all mechanism implicated in improving glucose mediated via bile acid following bariatric surgery. Plasma levels of bile acids have been found to be increased both after RYGB or SG.
Changes in gut microbiota
Alterations in the composition and capacity of gut microbiota have been seen to potentially contribute obesity and insulin resistance leading to systemic inflammation as well as to nonalcoholic fatty liver disease development. In obese humans a shift toward more firmicutes and reduced bacteriodetes observed. The microbe Faecalibacterium prausnitzii, less abundant in diabetics and obese persons is inversely related to inflammatory markers. A substantial change in gut microbiota happens following bariatric surgery. Interestingly, transfer of gut microbiota from mice subjected to RYGB, to nonoperated germ-free mice, resulted in significant weight loss and decreased fat mass.
Predictive factors for Type 2 diabetes mellitus remission after bariatric surgery
Older age, long duration of diabetes, current insulin use, and poor glycemic control were associated with negative predictors of diabetes remission. While gender and preoperative BMI had no significant association for both Asian and nonAsian, other observational studies also echoed the same predictive factor.
As with any surgical intervention, bariatric surgery is also associated with some complications. While the risk of early mortality ranges from 0.1% to 2.0% depending on the surgical procedure, The Longitudinal Assessment of Bariatric Surgery (LABS) consortium reported 0.3% mortality rate with RYGB at postoperative day 30. The most dreaded complications include postoperative sepsis, bleeding, anastomotic leaks, venous thromboembolism and rarely fatal pulmonary embolism. Male gender, age older than 65 years, reduced cardiorespiratory fitness levels associated with increased mortality apart from surgeon’s experience. Long-term changes in the gastrointestinal tract anatomy will also likely cause deficiencies in Vitamin B12, folate and iron. Calcium, Vitamin D and trace element deficiencies could also occur months to years after the procedure. However, these issues can be overcome with proper supplementation.
It is also important to recognize that long-term follow-up is required in considering the usefulness of bariatric surgery, before assigning these modalities having extraordinary therapeutic effect primarily because of the potential for weight regain or relapse of diabetes. It should also be realized that a certain percentage of patients will suffer from relapse of their diabetes as diabetes is a lifelong disease.