Impact of bariatric surgery on control of type 2 diabetes : neuroendocrine mechanisms and clinical significance

Abstract

Background: Bariatric and metabolic surgery is an accepted treatment for obese patients with type 2 diabetes (T2D). However, the potential of gastrointestinal surgery regarding glycemic control in non-severely obese diabetic patients has yet to be defined. Along with weight loss itself, changes in gut hormone profiles after surgery play an important role in diabetes remission. Pathophysiology of T2D includes insulin resistance and insufficient insulin secretion, possibly modified by surgical procedures. Excessive or inadequate glucagon secretion promoting hepatic gluconeogenesis and glycogenolysis is also believed to contribute to hyperglycemia in diabetic patients. In the present experimental study, we explored the effect of established bariatric procedures, with and without duodenal exclusion, on glycemic control and pancreatic and gut hormone profile in Goto-Kakizaki (GK) rats, a lean animal model of T2D. Data obtained from our experimental model were supplemented by the results of a clinical study on the effects of sleeve gastrectomy (SG) on impaired fasting glucose (IFG) and T2D in obese patients. Methods: Forty 12- to 14-week-old GK rats were randomly assigned to four groups: control group (GKC), sham surgery (GKSS), sleeve gastrectomy (GKSG), and gastric bypass (GKGB). Ten age-matched Wistar rats served as a non-diabetic control group (WIC). Glycemic control and plasma lipids were assessed at the beginning of the observation period and four weeks after surgery. Fasting and mixed meal-induced plasma levels of insulin, glucagon, ghrelin, glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine (PYY) were measured. In the clinical study, SG as stand-alone treatment for severe or morbid obesity was performed in 23 patients with T2D or IFG. No post-operative complications occurred and patients were dismissed from hospital on day 2 after surgery. Body mass index (BMI), fasting plasma glucose (FPG) and fasting insulin were determined before and up to 24 months after surgery. Insulin resistance and beta-cell function were calculated using the modified homeostasis model assessment (HOMA2). Results: Glycemic control was improved in GKSG and GKGB groups. Fasting insulin and glucagon levels in WIC rats were similar to GKC or GKSS. Fasting glucagon levels were highest in GKGB. No significant meal-induced variations of glucagon levels were observed in WIC, GKC or GKSS rats, whereas in groups GKSG and GKGB a significant rise occurred 30 minutes after a mixed meal, maintained up to 60 minutes. Both GKSG and GKGB rats showed an elevated glucagon-insulin ratio at 60 minutes in comparison to all other groups. Mixed meal-induced gut hormone profiles in WIC rats were significantly different from GKC and GKSS. After SG and gastric bypass (GB), GK rats showed a similar postprandial decrease in ghrelin as observed in non-diabetic WIC rats. Following both surgical procedures, a significant meal-induced increase in PYY and GLP-1 could be demonstrated. In the clinical study, BMI, FPG and fasting insulin improved significantly as early as 3 months after surgery. A three-fold increase in pre-operative insulin resistance (3.05) decreased to near-normal values (1.14) during the same period. Interestingly, overall beta-cell function diminished at 12 months of follow-up (79.6%), in comparison to pre-operative values (117.8%). Patients with a markedly reduced preoperative beta-cell function (<40%) did not achieve a complete remission after surgery. Conclusions: SG and GB induced a similar improvement in overall glycemic control in lean diabetic rodents. GKC and GKSS rats showed similar glucagon levels in comparison to non-diabetic WIC rats, without variation after a mixed meal. GKSG or GKGB groups improved their overall glucose metabolism, albeit an augmented post-procedural glucagon secretion. Meal-induced profiles of ghrelin, GLP-1, and PYY in GK rats were significantly modified by SG and GB and became similar to non-diabetic Wistar rats. In obese patients with T2D or IFG, commonly characterized by an increased insulin resistance and insulin secretion, SG induced remission through reduction of insulin resistance. Our data does not support the hypothesis that duodenal exclusion and early contact of food with the ileal mucosa alone may explain changes in gut hormone profile in GK rats after gastrointestinal surgery. In our experimental study, an augmented glucagon secretion after surgery did not contribute to an impaired glucose tolerance. Pre-operative insulin resistance and beta-cell function calculated by mathematical models like HOMA2 might have prognostic value and should be studied in patients undergoing metabolic surgery.