Early effect of Roux-en-Y gastric bypass on insulin sensitivity and signaling.
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.


METHODS
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.
Department of Internal Medicine, Catholic University, Rome, Italy.
Anna
A
Severino
Department of Surgery, Catholic University, Rome, Italy.
Lidia
L
Castagneto-Gissey
Department of Surgery, Catholic University, Rome, Italy.
Marco
M
Raffaelli
Cardiometabolic Risk Unit, CNR Institute of Clinical Physiology, Pisa, Italy.
Amalia
A
Gastaldelli
Department of Internal Medicine, Catholic University, Rome, Italy.
Esmeralda
E
Capristo
Department of Internal Medicine, Catholic University, Rome, Italy.
Amerigo
A
Iaconelli
Department of Internal Medicine, Catholic University, Rome, Italy.
Caterina
C
Guidone
Department of Surgery, Catholic University, Rome, Italy.
Cosimo
C
Callari
Department of Surgery, Catholic University, Rome, Italy.
Rocco
R
Bellantone
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.
Geltrude
G
Mingrone
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D015390:Gastric Bypass; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009767:Obesity, Morbid / Q000097:blood / Q000601:surgery*; D015398:Signal Transduction; D013997:Time Factors
D001786:Blood Glucose; D007328:Insulin
Gastric bypass; Insulin sensitivity; Insulin signaling