Roux-en-Y Gastric Bypass Corrects Hyperinsulinemia Implications for the Remission of Type 2 Diabetes

Reed, Melissa; Pories, Walter J.; Chapman, William H.; Pender, John R.; Bowden, Rita C.; Barakat, Hisham A.; Gavin, Timothy P.; Green, Tom; Tapscott, Ed; Zheng, Donghai; Shankley, Nigel P.; Yieh, Lynn; Polidori, David; Piccoli, Steven P.; Brenner-Gati, Leona; Dohm, G. Lynis

doi:10.1210/jc.2011-0165

Cited by 104 publications

(95 citation statements)

References 20 publications

(30 reference statements)

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“…Preintervention S I measurements for both groups were similar, but substantially lower than those observed for normal-weight subjects of a similar age (3). Following the interventions, there was a significant time effect (P < 0.001), with both groups showing improved S I ( Table 2 and Figure 2).…”

Section: Resultsmentioning

confidence: 68%

“…The first is immediately after surgery, at which time hepatic, but not peripheral, S I improves in response to acute energy restriction (4-6), while greater, protracted weight loss appears to be more strongly associated with improved peripheral S I (7,8). Even with significant weight loss 1 year following RYBG surgery, peripheral S I is still low compared with that of lean metabolically healthy individuals (3,5,6,9).Exercise is considered a cornerstone for obesity treatment, and while it is not generally viewed to cause substantial body weight reduction (10), it can potently improve peripheral S I and glucose control (11-13) and can reduce the risk of T2D and cardiovascular disease (14,15). There is general consensus that even a single session of moderate intensity exercise can induce an improvement in S I (16).…”

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confidence: 99%

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Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity

Coen¹,

Tanner²,

Helbling³

et al. 2014

J. Clin. Invest.

115

189

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nondiabetic patients following RYGB surgery are typically quite modest compared with the presurgery condition (3). Moreover, there appear to be 2 discrete periods of improvement. The first is immediately after surgery, at which time hepatic, but not peripheral, S I improves in response to acute energy restriction (4-6), while greater, protracted weight loss appears to be more strongly associated with improved peripheral S I (7,8). Even with significant weight loss 1 year following RYBG surgery, peripheral S I is still low compared with that of lean metabolically healthy individuals (3,5,6,9).Exercise is considered a cornerstone for obesity treatment, and while it is not generally viewed to cause substantial body weight reduction (10), it can potently improve peripheral S I and glucose control (11-13) and can reduce the risk of T2D and cardiovascular disease (14,15). There is general consensus that even a single session of moderate intensity exercise can induce an improvement in S I (16). There is also evidence that exercise can BACKGROUND. Roux-en-Y gastric bypass (RYGB) surgery causes profound weight loss and improves insulin sensitivity (S I ) in obese patients. Regular exercise can also improve S I in obese individuals; however, it is unknown whether exercise and RYGB surgery-induced weight loss would additively improve S I and other cardiometabolic factors. METHODS.We conducted a single-blind, prospective, randomized trial with 128 men and women who recently underwent RYGB surgery (within 1-3 months). Participants were randomized to either a 6-month semi-supervised moderate exercise protocol (EX, n = 66) or a health education control (CON; n = 62) intervention. Main outcomes measured included S I and glucose effectiveness (S G ), which were determined from an intravenous glucose tolerance test and minimal modeling. Secondary outcomes measured were cardiorespiratory fitness (VO 2 peak) and body composition. Data were analyzed using an intention-to-treat (ITT) and per-protocol (PP) approach to assess the efficacy of the exercise intervention (>120 min of exercise/week).RESULTS. 119 (93%) participants completed the interventions, 95% for CON and 91% for EX. There was a significant decrease in body weight and fat mass for both groups (P < 0.001 for time effect). S I improved in both groups following the intervention (ITT: CON vs. EX; +1.64 vs. +2.24 min -1 /μU/ml, P = 0.18 for Δ, P < 0.001 for time effect). A PP analysis revealed that exercise produced an additive S I improvement (PP: CON vs. EX; +1.57 vs. +2.69 min

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Section: Resultsmentioning

confidence: 68%

mentioning

confidence: 99%

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confidence: 99%

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Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity

Coen¹,

Tanner²,

Helbling³

et al. 2014

J. Clin. Invest.

115

189

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“…In this context, hyperinsulinemia associated with leptin deficiency (ob/ob mice) or leptin receptor deficiency (db/db mice) may be explained by impaired tonic inhibition due to insufficient K ATP channel density at the surface membrane. Because there is a strong relationship among increased basal insulin levels, obesity, and diabetes in humans (36,37), a mechanism to dampen insulin secretion during fasting may provide therapeutic strategies for inhibiting development of obesity-related diabetes.…”

Section: Discussionmentioning

confidence: 99%

Leptin promotes K _ATP channel trafficking by AMPK signaling in pancreatic β-cells

Park

Ryu²,

Yu³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

101

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Leptin is a pivotal regulator of energy and glucose homeostasis, and defects in leptin signaling result in obesity and diabetes. The ATP-sensitive potassium (K ATP ) channels couple glucose metabolism to insulin secretion in pancreatic β-cells. In this study, we provide evidence that leptin modulates pancreatic β-cell functions by promoting K ATP channel translocation to the plasma membrane via AMP-activated protein kinase (AMPK) signaling. K ATP channels were localized mostly to intracellular compartments of pancreatic β-cells in the fed state and translocated to the plasma membrane in the fasted state. This process was defective in leptin-deficient ob/ob mice, but restored by leptin treatment. We discovered that the molecular mechanism of leptin-induced AMPK activation involves canonical transient receptor potential 4 and calcium/calmodulindependent protein kinase kinase β. AMPK activation was dependent on both leptin and glucose concentrations, so at optimal concentrations of leptin, AMPK was activated sufficiently to induce K ATP channel trafficking and hyperpolarization of pancreatic β-cells in a physiological range of fasting glucose levels. There was a close correlation between phospho-AMPK levels and β-cell membrane potentials, suggesting that AMPK-dependent K ATP channel trafficking is a key mechanism for regulating β-cell membrane potentials. Our results present a signaling pathway whereby leptin regulates glucose homeostasis by modulating β-cell excitability.T he K ATP channel, an inwardly rectifying K + channel that consists of pore-forming Kir6.2 and regulatory sulfonylurea receptor 1 (SUR1) subunits (1), functions as an energy sensor: its gating is regulated mainly by the intracellular concentrations of ATP and ADP. In pancreatic β-cells, K ATP channels are inhibited or activated in response to the rise or fall in blood glucose levels, leading to changes in membrane excitability and insulin secretion (2, 3). Thus, K ATP channel gating has been considered an important mechanism in coupling blood glucose levels to insulin secretion. Recently, trafficking of K ATP channels to the plasma membrane was highlighted as another important mechanism for regulating K ATP channel activity (4-6).AMP-activated protein kinase (AMPK) is a key enzyme regulating energy homeostasis (7). We recently demonstrated that K ATP channels are recruited to the plasma membrane in glucosedeprived conditions via AMPK signaling in pancreatic β-cells (6). Inhibition of AMPK signaling significantly reduces K ATP currents, even after complete wash-out of intracellular ATP (6). Given these results, we proposed a model that recruitment of K ATP channels to the plasma membrane via AMPK signaling is crucial for K ATP channel activation in low-glucose conditions. However, the physiological relevance of this model remains unclear because pancreatic β-cells had to be incubated in media containing less than 3 mM glucose to recruit a sufficient number of K ATP channels to the plasma membrane (6). We thus hypothesized that there should be an e...

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“…However, it remains unclear how much this ␤-cell mass increase contributes to HI as islets from these animals also have reduced insulin content (12,13). Interestingly, gastric bypass has been shown to quickly normalize HI in obese patients with and without T2D prior to significant changes in insulin sensitivity or substantial weight loss (14). Thus, because of the rapid nature of this reduction, functional changes seem likely to contribute to HI in addition to possible changes in ␤-cell mass.…”

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confidence: 99%

Chronic Exposure to Excess Nutrients Left-shifts the Concentration Dependence of Glucose-stimulated Insulin Secretion in Pancreatic β-Cells

Erion

Berdan

Burritt

et al. 2015

Journal of Biological Chemistry

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Background: Fasting insulin secretion is increased in obesity and type 2 diabetes. Results: Culture of ␤-cells in excess nutrients resulted in increased lipid stores and a left-shifted dose-response curve of glucose-stimulated insulin secretion due to an enhanced sensitivity of exocytosis to Ca 2ϩ . Conclusion: Intracellular lipid modulates the dose response of glucose-stimulated insulin secretion. Significance: A shift in ␤-cell glucose sensitivity may contribute to hyperinsulinemia.

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Roux-en-Y Gastric Bypass Corrects Hyperinsulinemia Implications for the Remission of Type 2 Diabetes

Cited by 104 publications

References 20 publications

Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity

Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity

Leptin promotes K _ATP channel trafficking by AMPK signaling in pancreatic β-cells

Chronic Exposure to Excess Nutrients Left-shifts the Concentration Dependence of Glucose-stimulated Insulin Secretion in Pancreatic β-Cells

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Roux-en-Y Gastric Bypass Corrects Hyperinsulinemia Implications for the Remission of Type 2 Diabetes

Cited by 104 publications

References 20 publications

Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity

Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity

Leptin promotes K ATP channel trafficking by AMPK signaling in pancreatic β-cells

Chronic Exposure to Excess Nutrients Left-shifts the Concentration Dependence of Glucose-stimulated Insulin Secretion in Pancreatic β-Cells

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Leptin promotes K _ATP channel trafficking by AMPK signaling in pancreatic β-cells