Sleeve Gastrectomy Improves Glycemia Independent of Weight Loss by Restoring Hepatic Insulin Sensitivity

Abstract

Bariatric surgery dramatically improves glycemic control, yet the underlying molecular mechanisms remain controversial because of confounding weight loss. We performed sleeve gastrectomy (SG) on obese and diabetic leptin receptor-deficient mice (/). One week postsurgery, mice weighed 5% less and displayed improved glycemia compared with sham-operated controls, and islets from SG mice displayed reduced expression of diabetes markers. One month postsurgery SG mice weighed more than preoperatively but remained near-euglycemic and displayed reduced hepatic lipid droplets. Pair feeding of SG and sham / mice showed that surgery rather than weight loss was responsible for reduced glycemia after SG. Although insulin secretion profiles from islets of sham and SG mice were indistinguishable, clamp studies revealed that SG causes a dramatic improvement in muscle and hepatic insulin sensitivity accompanied by hepatic regulation of hepatocyte nuclear factor-α and peroxisome proliferator-activated receptor-α targets. We conclude that long-term weight loss after SG requires leptin signaling. Nevertheless, SG elicits a remarkable improvement in glycemia through insulin sensitization independent of reduced feeding and weight loss.

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

“…In addition, this adds to the growing literature that SG, in the absence of weight loss, leads to changes in metabolic physiology. [9,14,15] Indirect calorimetry corroborated these findings. The RER, or the ratio of CO2 produced to O2 consumed, is a function of the substrate of cellular respiration.…”

“…To date, most murine studies of SG have utilized a diet-induced model of obesity (DIO) or a genetically obese model, combined with sham pair-feeding, in an attempt to recapitulate and study SG physiology. [9,11,14,15,[39][40][41] While mice in these studies become obese and have hyperglycemia similar to the target patient population, investigations are limited by differences in food intake via pair-feeding and/or differences in body weight between the surgical intervention and sham groups. Furthermore, in most experiments, pair feeding induces weight loss.…”

“…Investigators have tried to address this by using sham pair-feeding and have shown that SG can lead to adipose adaptive immune cell changes, improved muscle and hepatic insulin sensitivity, and reduced hepatic steatosis in the absence of significant weight loss. [9,14,15] However, one major limitation to these studies is that they are derived in obese models where animals lose weight following surgery and are maintained on non-physiologic, high-fat diets indefinitely. This makes it increasingly difficult to define the SG-specific, weight-loss specific, and diet-specific changes that are occurring after SG.…”

Sleeve gastrectomy rapidly enhances islet function independently of body weight

“…This is clearly seen in diabetic patients who experience reductions in both fasting and prandial glucose levels after surgery (1,26). Surgical improvements to glucose control are largely attributed to reduced BW and improved insulin resistance (27,28). Although the glucose-lowering effects of RYGB have been attributed entirely to weight-loss in some studies (11)(12)(13), it has long been observed that surgery lowers blood glucose in diabetic patients prior to significant weight loss (15,16).…”

α-Synuclein-induced Kv4 channelopathy in mouse vagal motoneurons causes non-motor parkinsonian symptoms

“…Stomach and intestine histology: After 200 nl AAV1/2-A53T-SNCA (the same virus used for vagal injection) intramuscularly injected in the stomach, two weeks after surgery, the mouse was euthanized for immunofluorescent staining. The staining procedure was processed as previously described (Abu-Gazala et al, 2018).…”