Siv H. Jacobsen

Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with Type 2 diabetes and normal glucose tolerance

Our aim was to study the potential mechanisms responsible for the improvement in glucose control in Type 2 diabetes (T2D) within days after Roux-en-Y gastric bypass (RYGB). Thirteen obese subjects with T2D and twelve matched subjects with normal glucose tolerance (NGT) were examined during a liquid meal before (Pre), 1 wk, 3 mo, and 1 yr after RYGB. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent-insulinotropic polypeptide (GIP), and glucagon concentrations were measured. Insulin resistance (HOMA-IR), β-cell glucose sensitivity (β-GS), and disposition index (D(β-GS): β-GS × 1/HOMA-IR) were calculated. Within the first week after RYGB, fasting glucose [T2D Pre: 8.8 ± 2.3, 1 wk: 7.0 ± 1.2 (P < 0.001)], and insulin concentrations decreased significantly in both groups. At 129 min, glucose concentrations decreased in T2D [Pre: 11.4 ± 3, 1 wk: 8.2 ± 2 (P = 0.003)] but not in NGT. HOMA-IR decreased by 50% in both groups. β-GS increased in T2D [Pre: 1.03 ± 0.49, 1 wk: 1.70 ± 1.2, (P = 0.012)] but did not change in NGT. The increase in DI(β-GS) was 3-fold in T2D and 1.5-fold in NGT. After RYGB, glucagon secretion was increased in response to the meal. GIP secretion was unchanged, while GLP-1 secretion increased more than 10-fold in both groups. The changes induced by RYGB were sustained or further enhanced 3 mo and 1 yr after surgery. Improvement in glycemic control in T2D after RYGB occurs within days after surgery and is associated with increased insulin sensitivity and improved β-cell function, the latter of which may be explained by dramatic increases in GLP-1 secretion.

Mechanisms of improved glycaemic control after Roux-en-Y gastric bypass

Roux-en-Y gastric bypass (RYGB) greatly improves glycaemic control in morbidly obese patients with type 2 diabetes, in many even before significant weight loss. Understanding the responsible mechanisms may contribute to our knowledge of the pathophysiology of type 2 diabetes and help identify new drug targets or improve surgical techniques. This review summarises the present knowledge based on pathophysiological studies published during the last decade. Taken together, two main mechanisms seem to be responsible for the early improvement in glycaemic control after RYGB: (1) an increase in hepatic insulin sensitivity induced, at least in part, by energy restriction and (2) improved beta cell function associated with an exaggerated postprandial glucagon-like peptide 1 secretion owing to the altered transit of nutrients. Later a weight loss induced improvement in peripheral insulin sensitivity follows.

Exaggerated Glucagon-Like Peptide 1 Response Is Important for Improved β-Cell Function and Glucose Tolerance After Roux-en-Y Gastric Bypass in Patients With Type 2 Diabetes

β-Cell function improves in patients with type 2 diabetes in response to an oral glucose stimulus after Roux-en-Y gastric bypass (RYGB) surgery. This has been linked to the exaggerated secretion of glucagon-like peptide 1 (GLP-1), but causality has not been established. The aim of this study was to investigate the role of GLP-1 in improving β-cell function and glucose tolerance and regulating glucagon release after RYGB using exendin(9-39) (Ex-9), a GLP-1 receptor (GLP-1R)–specific antagonist. Nine patients with type 2 diabetes were examined before and 1 week and 3 months after surgery. Each visit consisted of two experimental days, allowing a meal test with randomized infusion of saline or Ex-9. After RYGB, glucose tolerance improved, β-cell glucose sensitivity (β-GS) doubled, the GLP-1 response greatly increased, and glucagon secretion was augmented. GLP-1R blockade did not affect β-cell function or meal-induced glucagon release before the operation but did impair glucose tolerance. After RYGB, β-GS decreased to preoperative levels, glucagon secretion increased, and glucose tolerance was impaired by Ex-9 infusion. Thus, the exaggerated effect of GLP-1 after RYGB is of major importance for the improvement in β-cell function, control of glucagon release, and glucose tolerance in patients with type 2 diabetes.

Gut hormones, early dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass

Objective:To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (RYGB).Design:Cross-sectional study of patients with good (excess body mass index lost (EBL) >60%) and poor weight loss response (EBL <50%) >12 months after RYGB and a lean control group matched for age and gender.Materials and methods:Sixteen patients with good weight loss response, 17 patients with poor weight loss response, and eight control subjects were included in the study. Participants underwent dual energy X-ray absorptiometry scan, indirect calorimetry and a 9 h multiple-meal test with measurements of glucose, insulin, total bile acids (TBA), glucagon-like peptide (GLP)-1, peptide YY3–36 (PYY), cholecystokinin (CCK), ghrelin, neurotensin and pancreatic polypeptide (PP) as well as assessment of early dumping and appetite.Results:Suppression of hunger was more pronounced in the good than the poor responders in response to the multiple-meal test (P=0.006). In addition, the good responders had a larger release of GLP-1 (P=0.009) and a greater suppression of ghrelin (P=0.037) during the test, whereas the postprandial secretion of CCK was highest in the poor responders (P=0.005). PYY, neurotensin, PP and TBA release did not differ between the RYGB-operated groups. Compared with control subjects, patients had exaggerated release of GLP-1 (P<0.001), PYY (P=0.008), CCK (P=0.010) and neurotensin (P<0.001). Early dumping was comparable in the good and poor responders, but more pronounced than in controlled subjects. Differences in resting energy expenditure between the three groups were entirely explained by differences in body composition.Conclusion:Favorable meal-induced changes in hunger and gut hormone release in patients with good compared with poor weight loss response support the role of gut hormones in the weight loss after RYGB.

Early Enhancements of Hepatic and Later of Peripheral Insulin Sensitivity Combined With Increased Postprandial Insulin Secretion Contribute to Improved Glycemic Control After Roux-en-Y Gastric Bypass

Roux-en-Y gastric bypass (RYGB) improves glycemic control within days after surgery, and changes in insulin sensitivity and β-cell function are likely to be involved. We studied 10 obese patients with type 2 diabetes (T2D) and 10 obese glucose-tolerant subjects before and 1 week, 3 months, and 1 year after RYGB. Participants were included after a preoperative diet-induced total weight loss of −9.2 ± 1.2%. Hepatic and peripheral insulin sensitivity were assessed using the hyperinsulinemic- euglycemic clamp combined with the glucose tracer technique, and β-cell function was evaluated in response to an intravenous glucose-glucagon challenge as well as an oral glucose load. Within 1 week, RYGB reduced basal glucose production, improved basal hepatic insulin sensitivity, and increased insulin clearance, highlighting the liver as an important organ responsible for early effects on glucose metabolism after surgery. Insulin-mediated glucose disposal and suppression of fatty acids did not improve immediately after surgery but increased at 3 months and 1 year; this increase likely was related to the reduction in body weight. Insulin secretion increased after RYGB only in patients with T2D and only in response to oral glucose, underscoring the importance of the changed gut anatomy.

Fast pouch emptying, delayed small intestinal transit, and exaggerated gut hormone responses after Roux-en-Y gastric bypass.

Roux‐en‐Y gastric bypass (RYGB) causes extensive changes in gastrointestinal anatomy and leads to reduced appetite and large weight loss, which partly is due to an exaggerated release of anorexigenic gut hormones.

Increased Hepatic Insulin Clearance After Roux-en-Y Gastric Bypass

CONTEXT Roux-en-Y gastric bypass (RYGB) improves glucose tolerance and ameliorates fasting hyperinsulinemia within days after surgery. Improvements in hepatic insulin sensitivity and insulin clearance could contribute importantly to these effects. OBJECTIVE The objective of the investigation was to study changes in insulin clearance after RYGB. DESIGN This was a prospective study of fasting hepatic insulin clearance and, in a subgroup of patients, postprandial insulin clearance after a meal test before and 1 week, 3 months, and 1 year after RYGB. SETTING The study was conducted at Hvidovre Hospital (Hvidovre, Denmark). PATIENTS Patients included 2 groups of obese RYGB-patients: 1) type 2 diabetes (T2D) group: 32 patients with T2D (meal test, n = 13), 2) normal glucose tolerance (NGT) group: 32 patients with NGT (meal test, n = 12). INTERVENTION The intervention was RYGB. MAIN OUTCOME MEASURE Fasting hepatic insulin clearance (fasting C-peptide/fasting insulin). Postprandial insulin clearance (incremental areas under the curve of insulin secretion rates/incremental areas under the curve of insulin). RESULTS Fasting hepatic insulin clearance increased after 1 week (P < .01) and further at 3 months (P < .01), remaining elevated 1 year postoperatively (P < .01) with no difference between the T2D and NGT groups. Postprandial insulin clearance changed only in the T2D group with an increase at 1 week (P < .01) that was maintained at 3 months (P = .06) and 1 year (P < .01). CONCLUSIONS RYGB increases insulin clearance within 1 week after surgery, highlighting the liver as a key organ involved in the early beneficial effect on glucose metabolism. Postprandial insulin secretion may be underestimated postoperatively in patients with type 2 diabetes when evaluated by peripheral insulin concentrations instead of insulin secretion rates or C-peptide.

Accelerated protein digestion and amino acid absorption after Roux-en-Y gastric bypass

BACKGROUND Roux-en-Y gastric bypass (RYGB) involves exclusion of major parts of the stomach and changes in admixture of gastro-pancreatic enzymes, which could have a major impact on protein digestion and amino acid absorption. OBJECTIVE We investigated the effect of RYGB on amino acid appearance in the systemic circulation from orally ingested protein and from endogenous release. DESIGN Nine obese glucose-tolerant subjects, with a mean body mass index (in kg/m(2)) of 39.2 (95% CI: 35.2, 43.3) and mean glycated hemoglobin of 5.3% (95% CI: 4.9%, 5.6%), were studied before and 3 mo after RYGB. Leucine and phenylalanine kinetics were determined under basal conditions and during 4 postprandial hours by intravenous infusions of [3,3,3-(2)H3]-leucine and [ring-(2)D5]-phenylalanine combined with ingestion of [1-(13)C]-leucine intrinsically labeled caseinate as the sole protein source of the meal. Changes in body composition were assessed by dual-energy X-ray absorptiometry. RESULTS After RYGB, basal plasma leucine concentration did not change, but marked changes were seen postprandially with 1.7-fold increased peak concentrations (before—mean: 217 μmol/L; 95% CI: 191, 243 μmol/L; 3 mo—mean: 377 μmol/L; 95% CI: 252, 502 μmol/L; P = 0.012) and 2-fold increased incremental AUC (before-mean: 4.1 mmol ∙ min/L; 95% CI: 2.7, 5.5 mmol ∙ min/L; 3 mo-mean: 9.5 mmol ∙ min/L; 95% CI: 4.9, 14.2 mmol ∙ min/L; P = 0.032). However, the postprandial hyperleucinemia was transient, and concentrations were below basal concentrations in the fourth postprandial hour. These concentration differences were mainly caused by changes in leucine appearance rate from orally ingested caseinate: peak rate increased nearly 3-fold [before—mean: 0.5 μmol/(kg fat-free mass ∙ min); 95% CI: 0.4, 0.5 μmol/(kg fat-free mass ∙ min); 3 mo—mean 1.4 μmol/(kg fat-free mass ∙ min); 95% CI: 0.8, 1.9 μmol/(kg fat-free mass ∙ min); P = 0.002], and time to peak was much shorter (before—mean: 173 min; 95% CI: 137, 209 min; 3 mo—mean: 65 min; 95% CI: 46, 84 min; P < 0.001). Only minor changes were seen in endogenous leucine release after RYGB. CONCLUSIONS RYGB accelerates caseinate digestion and amino acid absorption, resulting in faster and higher but more transient postprandial elevation of plasma amino acids. Changes are likely mediated by accelerated intestinal nutrient entry and clearly demonstrate that protein digestion is not impaired after RYGB. This trial was registered at clinicaltrials.gov as NCT01559792.

Immediate enhancement of first-phase insulin secretion and unchanged glucose effectiveness in patients with type 2 diabetes after Roux-en-Y gastric bypass.

Roux-en-Y gastric bypass surgery (RYGB) in patients with type 2 diabetes often leads to early disease remission, and it is unknown to what extent this involves improved pancreatic β-cell function per se and/or enhanced insulin- and non-insulin-mediated glucose disposal (glucose effectiveness). We studied 30 obese patients, including 10 with type 2 diabetes, 8 with impaired glucose tolerance, and 12 with normal glucose tolerance before, 1 wk, and 3 mo after RYGB, using an intravenous glucose tolerance test (IVGTT) to estimate first-phase insulin response, insulin sensitivity (Si), and glucose effectiveness with Bergmans minimal model. In the fasting state, insulin sensitivity was estimated by HOMA-S and β-cell function by HOMA-β. Moreover, mixed-meal tests and oral GTTs were performed. In patients with type 2 diabetes, glucose levels normalized after RYGB, first-phase insulin secretion in response to iv glucose increased twofold, and HOMA-β already improved 1 wk postoperatively, with further enhancements at 3 mo. Insulin sensitivity increased in the liver (HOMA-S) at 1 wk and at 3 mo in peripheral tissues (Si), whereas glucose effectiveness did not improve significantly. During oral testing, GLP-1 responses and insulin secretion increased regardless of glucose tolerance. Therefore, in addition to increased insulin sensitivity and exaggerated postprandial GLP-1 levels, diabetes remission after RYGB involves early improvement of pancreatic β-cell function per se, reflected in enhanced first-phase insulin secretion to iv glucose and increased HOMA-β. A major role for improved glucose effectiveness after RYGB was not supported by this study.

Reduction in cardiovascular risk factors and insulin dose, but no beta-cell regeneration 1 year after Roux-en-Y gastric bypass in an obese patient with type 1 diabetes: A case report

Experience with Roux-en-Y gastric bypass in patients with type 1 diabetes is very limited, despite an increasing prevalence of obesity also in this population. We describe changes in anthropometric measures, insulin dose, HbA1c, blood pressure, lipid status, and metabolic response to a liquid mixed meal throughout the first year after RYGB in an obese patient with type 1 diabetes. No change in HbA1c was observed, but a 48% reduction in weight-adjusted insulin dose and improvements in cardiovascular risk factors was seen 1 year after surgery. Exaggerated secretions of anorexigenic gut hormones were seen during the meals.