Remission of Type 2 Diabetes Mellitus following Bariatric Surgery: An investigation into relevant changes in gastrointestinal physiology

A rapid remission of type 2 diabetes mellitus occurs after gastric bypass surgery in the morbidly obese however, a unifying explanation for the associated normalisation of glucose and insulin parameters of diabetes of this surgery remains uncertain. While caloric restriction and gut peptides such as GLP-1 contribute to this normalisation, they fail to explain all of the components of improved glucose control after surgery. Instead, it is likely that manipulation of the gut through bariatric surgery induces other mechanisms to effect improvement in glucose control. Experimental work Three experimental components were undertaken within this body of work. A clinical arm was used to examine whether intestinal gluconeogenesis or upregulation of fasting portal peptides (GLP-1, GIP and PYY) were associated with improvements in fasting glycaemia after gastric bypass. The results demonstrated that these fasting portal peptide concentrations are not significantly elevated in patients with type 2 diabetes after gastric bypass surgery despite a normalisation of fasting glucose. These studies also confirmed that portal and central venous glucose levels were not significantly different before or six days after surgery, demonstrating that intestinal gluconeogenesis was unlikely to be involved in the rapid normalisation of fasting glucose after surgery. The animal model component of this work involved the development of an obese diabetic rat model of gastric bypass surgery. The Zucker Diabetic Fat (ZDF) rat is an obese rat strain, which may more closely model the morbidly obese individuals with type 2 diabetes who undergo gastric bypass surgery. The strain is also known for it’s peri-operative fragility that has limited its use in gastrointestinal surgery. A protocol was developed to overcome these issues and a study was performed to compare glucose control after gastric bypass or sleeve gastrectomy surgery; with pair-fed and sham-operated controls. The results demonstrated that gastric bypass surgery in this strain resulted in weight-independent and calorie-independent improvement in glucose control at one week following surgery that was not seen after sleeve gastrectomy, pair-feeding or pair-feeding with a sham-operation. The pancreatic islets of these rats were isolated at one week following surgery to directly assess islet function. In the absence of neural or blood borne factors, islets from gastric bypass rats demonstrated a significantly higher glucose-dependent insulin secretion compared to the other groups. This suggested that an improvement in insulin-dependent glucose secretion at the β-cell might have contributed to the improvements seen in these rats after gastric bypass. Conclusion This dissertation contributed to the literature in several ways. The improvements in fasting glucose control after gastric bypass surgery in humans was not associated with any increase in fasting GL-1, GIP and PYY concentrations and nor was it associated with the phenomenon of intestinal gluconeogenesis. A model of gastric bypass surgery in an obese type 2 diabetic rat strain demonstrated similar early improvements in glucose control to those seen in human patients. These improvements were calorie and weight-loss independent and did not occur after a sleeve gastrectomy. After gastric bypass, rats instead demonstrated an increased glucose-dependent secretion of insulin from their isolated pancreatic islets that was neither seen in sleeve gastrectomy rats nor pair-fed controls. The direct increase in insulin secretion from islets has not previously been recognised and may be another mechanism that assists in the remission of type 2 diabetes following gastric bypass surgery