ObjectiveThe objective of this study was to quantify hormones that regulate energy and glucose homeostasis in order to establish possible mechanisms for the greater efficacy of Roux-en-Y gastric bypass (RYGB) compared with laparascopic adjustable gastric banding (LAGB) in achieving weight loss and improved insulin sensitivity.DesignLongitudinal study of patients undergoing LAGB (n=15) and RYGB (n=28) who were studied prior to surgery and at 2, 12, 26 and 52 wks afterwards.MeasurementsFasting blood samples were drawn at each visit. Postprandial blood samples were also obtained prior to surgery and at 26 and 52 wks. Samples were assayed for peptide YY (PYY), ghrelin, glucagon-like peptide-1 (GLP-1), glucose, insulin, leptin, thyrotropic hormone (TSH), free T4 and free T3.ResultsAt one year there was greater weight loss in RYGB compared with LAGB patients (30% vs 15%), but final body mass index was similar (34 vs 33 kg/m2). At wk 52, area under the curve (AUC) for PYY in RYGB subjects was greater than LAGB (P<0.01). GLP-1 levels at 30 min post-meal were three-fold greater after RYGB compared with LAGB (P<0.001). Conversely, ghrelin AUC increased after LAGB at wk 52 (P<0.05) but tended to decrease after RYGB. Fasting glucose, insulin, and leptin, and HOMA-IR decreased in both groups over time but were significantly lower at wk 52 after RYGB compared with LAGB. The change in leptin correlated significantly with weight loss in LAGB (r=0.86) and RYGB (r=0.77), however, HOMA-IR correlated significantly with weight loss only in LAGB (r=0.78), and not RYGB (r=0.15). There was a significant decrease in free T3 (P<0.01) after RYGB.ConclusionsDifferences in levels of gut hormones may play a role in promoting greater weight loss and insulin sensitivity after RYGB compared with LAGB, however, weight loss may be limited by decreases in free T3 and leptin.

Marked improvement in glycemic control occurs in patients with type 2 diabetes mellitus shortly after Roux-en-Y gastric bypass surgery (RYGB) and before there is major weight loss. The objective of this study was to determine whether the magnitude of this change is primarily due to caloric restriction or is unique to the surgical procedure. We studied eleven subjects who underwent RYGB and fourteen subjects mean-matched for BMI, HbA1c, and diabetes duration who were admitted to our inpatient research unit and given a very low–calorie diet (VLCD) of 500 kcal/day with a macronutrient content similar to that consumed by patients after RYGB. Frequently sampled intravenous glucose tolerance tests were performed before and after interventions. Both groups lost an equivalent amount of weight over a mean study period of 21 days. Insulin sensitivity, acute insulin secretion after intravenous glucose administration, and β-cell function as determined by disposition index improved to a similar extent in both groups. Likewise, changes in fasting glucose and fructosamine levels were similar. Based on these data, VLCD improves insulin sensitivity and β-cell function just as well as RYGB in the short term.

Weight-loss independent mechanisms may play an important role in the improvement of glucose homeostasis after Roux-en-Y gastric bypass (RYGB). The objective of this analysis was to determine whether RYGB causes greater improvement in glucostatic parameters as compared with laparoscopic adjustable gastric banding (LAGB) or low calorie diet (LCD) after equivalent weight loss and independent of enteral nutrient passage. Study 1 recruited participants without type 2 diabetes mellitus (T2DM) who underwent LAGB (n = 8) or RYGB (n = 9). Study 2 recruited subjects with T2DM who underwent LCD (n = 7) or RYGB (n = 7). Insulin-supplemented frequently-sampled intravenous glucose tolerance test (fsIVGTT) was performed before and after equivalent weight reduction. MINMOD analysis of insulin sensitivity (Si), acute insulin response to glucose (AIRg) and C-peptide (ACPRg) response to glucose, and insulin secretion normalized to the degree of insulin resistance (disposition index (DI)) were analyzed. Weight loss was comparable in all groups (7.8 ± 0.4%). In Study 1, significant improvement of Si, ACPRg, and DI were observed only after LAGB. In Study 2, Si, ACPRg, and plasma adiponectin increased significantly in the RYGB-DM group but not in LCD. DI improved in both T2DM groups, but the absolute increase was greater after RYGB (258.2 ± 86.6 vs. 55.9 ± 19.9; P < 0.05). Antidiabetic medications were discontinued after RYGB contrasting with 55% reduction in the number of medications after LCD. No intervention affected fasting glucagon-like peptide (GLP)-1, peptide YY (PYY) or ghrelin levels. In conclusion, RYGB produced greater improvement in Si and DI compared with diet at equivalent weight loss in T2DM subjects. Such a beneficial effect was not observed in nondiabetic subjects at this early time-point.

Background Laparoscopic sleeve gastrectomy (SG) has surpassed Roux-en-Y gastric bypass (RYGB) as the most prevalent bariatric procedure worldwide. While RYGB and SG demonstrate equivalent short-term weight loss, long-term weight loss tends to be greater after RYGB. Differences in the effect of these procedures on gastrointestinal hormones that regulate energy homeostasis are felt to partially underlie differences in outcomes. The objective of this study was to prospectively quantify blood levels of gut hormones of energy and glucose homeostasis at one year follow up to delineate possible reasons for greater efficacy of RYGB over SG in achieving weight loss. Methods Patients undergoing SG (n = 19) and RYGB (n = 40) were studied before surgery and at 2,12, 26, and 52 weeks postoperatively. Blood samples drawn in the fasted state and after a liquid mixed meal were assayed at baseline, 26, and 52 weeks for peptide YY (PYY), glucagon-like peptide-1 (GLP-1), ghrelin, insulin, glucose, and leptin. Fasting and postprandial appetitive sensations were assessed by visual analog scale. Results At 1 year there was greater weight loss in RYGB compared with SG patients (30% vs 27%; P = 0.03). Area under the curve (AUC) after the mixed meal for PYY was greater in RYGB patients (P<0.001). RYGB patients had significant increases in GLP-1 AUC compared to baseline (P = 0.002). Ghrelin levels decreased only after SG compared to baseline (P<0.001) but were not significantly different from RYGB. There was a trend toward decreased sweet cravings in RYGB patients (P = 0.056).

Objective Obese individuals have high levels of circulating leptin and are resistant to the weight-reducing effect of leptin administration at physiological doses. Although Roux-en-Y gastric bypass (RYGB) is an effective weight loss procedure, there is a plateau in weight loss and most individuals remain obese. This plateau may be partly due to the decline in leptin resulting in a state of relative leptin insufficiency. The main objective of this study was to determine whether leptin administration to post-RYGB patients would promote further weight reduction. Design and Methods This was a randomized, double-blind, placebo-controlled cross-over study of 27 women who were at least 18 months post-RYGB and lost on average 30.8% of their pre-surgical body weight. Subjects received either leptin or placebo via subcutaneous injection twice daily for 16 weeks, then crossed over to receive the alternate treatment for 16 weeks. Results Weight change after 16 weeks of placebo was not significantly different from that after 16 weeks of leptin. No changes were observed in percent fat mass, resting energy expenditure, thyroid hormones, or cortisol levels. Conclusions Contrary to our hypothesis, we did not observe a significant effect of leptin treatment on body weight in women with relative hypoleptinemia after RYGB.

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Objective We hypothesized that DA and L-DOPA derived from nutritional tyrosine and the resultant observed postprandial plasma excursions of L-DOPA and DA might affect glucose tolerance via their ability to be taken-up by beta cells and inhibit glucose-stimulated β-cell insulin secretion. Methods To investigate a possible circuit between meal-stimulated 3,4-dihydroxy-L-phenylalanine (L-DOPA) and dopamine (DA) production in the GI tract and pancreatic β-cells, we: 1) mapped GI mucosal expression of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC); 2) measured L-DOPA and DA content of GI mucosal tissues following meal challenges with different L-tyrosine (TYR) content, 3) determined whether meal TYR content impacts plasma insulin and glucose excursions; and 4) characterized postprandial plasma excursions of L-DOPA and DA in response to meal tyrosine content in rodents and a population of bariatric surgery patients. Next, we characterized: 1) the metabolic transformation of TYR and L-DOPA into DA in vitro using purified islet tissue; 2) the metabolic transformation of orally administrated stable isotope labeled TYR into pancreatic DA, and 3) using a nuclear medicine technique, we studied endocrine beta cells in situ release and binding of DA in response to a glucose challenge. Results We demonstrate in rodents that intestinal content and circulatory concentrations L-DOPA and DA, plasma glucose and insulin are responsive to the tyrosine (TYR) content of a test meal. Intestinal expression of two enzymes, Tyrosine hydroxylase (TH) and Aromatic Amino acid Decarboxylase (AADC), essential to the transformation of TYR to DA was mapped and the metabolism of metabolism of TYR to DA was traced in human islets and a rodent beta cell line in vitro and from gut to the pancreas in vivo. Lastly, we show that β cells secrete and bind DA in situ in response to glucose stimulation. Conclusions We provide proof-of-principle evidence for the existence of a novel postprandial circuit of glucose homeostasis dependent on nutritional tyrosine. DA and L-DOPA derived from nutritional tyrosine may serve to defend against hypoglycemia via inhibition of glucose-stimulated β-cell insulin secretion as proposed by the anti-incretin hypothesis.

Bariatric surgery is a treatment option for obese patients with type 2 diabetes mellitus (T2DM). Although sleeve gastrectomy (SG) is growing in favor, some randomized trials show less weight loss and HbA1c improvement compared with Roux-en-Y gastric bypass (RYGB). The study objective was to compare changes in beta-cell function with similar weight loss after SG and RYGB in obese patients with T2DM. Subjects undergoing SG or RYGB were studied with an intravenous glucose tolerance test before surgery and at 5–12% weight loss post-surgery. The primary endpoint was change in the disposition index (DI). Baseline BMI, HbA1c, and diabetes-duration were similar between groups. Mean total weight loss percent was similar (8.4% ± 0.4, p = 0.22) after a period of 21.0 ± 1.7 days. Changes in fasting glucose, acute insulin secretion (AIR), and insulin sensitivity (Si) were similar between groups. Both groups showed increases from baseline to post-surgery in DI (20.2 to 163.3, p = 0.03 for SG; 31.2 to 232.9, p = 0.02 for RYGB) with no significant difference in the change in DI between groups (p = 0.53). Short-term improvements in beta-cell function using an IVGTT were similar between SG and RYGB. It remains unclear if longer-term outcomes are better after RYGB due to greater weight loss and/or other factors.