Anna Severino1, Lidia Castagneto-Gissey2, Marco Raffaelli2, Amalia Gastaldelli3, Esmeralda Capristo1, Amerigo Iaconelli1, Caterina Guidone1, Cosimo Callari2, Rocco Bellantone2, Geltrude Mingrone4. 1. Department of Internal Medicine, Catholic University, Rome, Italy. 2. Department of Surgery, Catholic University, Rome, Italy. 3. Cardiometabolic Risk Unit, CNR Institute of Clinical Physiology, Pisa, Italy. 4. Department of Internal Medicine, Catholic University, Rome, Italy; Department of Medicine III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany; Diabetes and Nutritional Sciences, Hodgkin Building, Guy's Campus, King's College, London, UK. Electronic address: gmingrone@rm.unicatt.it.
Abstract
BACKGROUND: A large body of literature indicates the rapidity with which Roux-en-Y gastric bypass (RYGB) improves glycemic control. However, the underlying physiologic mechanisms are still a matter of debate. SETTING: Catholic University, School of Medicine, Rome, Italy. METHODS: Ten morbidly obese patients, before and 4 weeks after RYGB, and 10 healthy controls were studied. We measured insulin sensitivity as the homeostasis model assessment-estimated insulin resistance (HOMA-IR) and by the euglycemic hyperinsulinemic clamp, and phosphorylation of protein kinase B (Akt) on Ser473 and Thr308 and of GSK3 α-β on Ser 9 and Ser21 in skeletal muscle biopsy specimens by Western blot analysis. RESULTS: Obese patients before RYGB displayed reduced insulin sensitivity (M value) and clearance and increased fasting Akt phosphorylation on Ser473 compared with controls. M significantly increased after surgery (from 2.6 ± 0.6 to 2.8 ± 0.7 mg/kg fat free mass/min, P = .026) but remained far below the values in controls (10.0 ± 3.8 mg/kg fat free mass/min, P<.001). Insulin clearance increased from 453.5 ± 117.5 to 555.2 ± 61.6 (P = .00076), becoming similar to that of controls 582.2 ± 59.0 mU/m(2)/min. HOMA-IR decreased from 4.1 ± 0.07 to 2.3 ± 0.5 (P = .004), becoming comparable with controls (2.2 ± 0.9). The hyperphosphorylation of Akt on Ser473 observed at fasting before RYGB was significantly reduced thereafter, becoming similar to that of healthy controls; the other phosphorylation states remained unchanged. CONCLUSIONS: Following RYGB, we found a prompt improvement of hepatic insulin resistance with normalization of hepatic insulin clearance and a small amelioration of whole-body insulin sensitivity. The supranormal levels of Akt Ser473 observed at fast in the skeletal muscle tissue at baseline were normalized after RYGB, and their changes correlated with those of both hepatic and peripheral insulin resistance. Although other mechanisms of action, such as the effect of weight loss and reduced food intake, cannot be excluded, the reduction of muscle Akt hyperphosphorylation on the serine residue can play a role in the early improvement of insulin sensitivity.
BACKGROUND: A large body of literature indicates the rapidity with which Roux-en-Y gastric bypass (RYGB) improves glycemic control. However, the underlying physiologic mechanisms are still a matter of debate. SETTING: Catholic University, School of Medicine, Rome, Italy. METHODS: Ten morbidly obesepatients, before and 4 weeks after RYGB, and 10 healthy controls were studied. We measured insulin sensitivity as the homeostasis model assessment-estimated insulin resistance (HOMA-IR) and by the euglycemic hyperinsulinemic clamp, and phosphorylation of protein kinase B (Akt) on Ser473 and Thr308 and of GSK3 α-β on Ser 9 and Ser21 in skeletal muscle biopsy specimens by Western blot analysis. RESULTS:Obesepatients before RYGB displayed reduced insulin sensitivity (M value) and clearance and increased fasting Akt phosphorylation on Ser473 compared with controls. M significantly increased after surgery (from 2.6 ± 0.6 to 2.8 ± 0.7 mg/kg fat free mass/min, P = .026) but remained far below the values in controls (10.0 ± 3.8 mg/kg fat free mass/min, P<.001). Insulin clearance increased from 453.5 ± 117.5 to 555.2 ± 61.6 (P = .00076), becoming similar to that of controls 582.2 ± 59.0 mU/m(2)/min. HOMA-IR decreased from 4.1 ± 0.07 to 2.3 ± 0.5 (P = .004), becoming comparable with controls (2.2 ± 0.9). The hyperphosphorylation of Akt on Ser473 observed at fasting before RYGB was significantly reduced thereafter, becoming similar to that of healthy controls; the other phosphorylation states remained unchanged. CONCLUSIONS: Following RYGB, we found a prompt improvement of hepatic insulin resistance with normalization of hepatic insulin clearance and a small amelioration of whole-body insulin sensitivity. The supranormal levels of AktSer473 observed at fast in the skeletal muscle tissue at baseline were normalized after RYGB, and their changes correlated with those of both hepatic and peripheral insulin resistance. Although other mechanisms of action, such as the effect of weight loss and reduced food intake, cannot be excluded, the reduction of muscle Akt hyperphosphorylation on the serine residue can play a role in the early improvement of insulin sensitivity.
Authors: Jonathan D Douros; Jingjing Niu; Sophia Sdao; Trillian Gregg; Kelsey Fisher-Wellman; Manish Bharadwaj; Anthony Molina; Ramamani Arumugam; MacKenzie Martin; Enrico Petretto; Matthew J Merrins; Mark A Herman; Jenny Tong; Jonathan Campbell; David D'Alessio Journal: JCI Insight Date: 2019-03-21