The effect of bariatric surgery and gastrointestinal hormone secretion on glycemic control and beta-cell mass - Lessons learned from the diabetic Goto-Kakizaki rat
MetadataVis full innførsel
This thesis reports the results from experimental animal studies assessing the effect of bariatric surgery on type 2 diabetes mellitus (T2DM) and gastrointestinal hormone secretion. After bariatric surgery in obese patients with T2DM, a rapid remission/improvement of this disease before significant weight loss has been observed. There are many theories to this phenomenon; several of these emphasizes the postoperative alterations of gastrointestinal hormones influencing glucose homeostasis. Several hormones have been proposed to promote diabetes remission following bariatric surgery, but to our knowledge, gastrin has not been previously mentioned or studied in this context. Gastrin is a gastrointestinal hormone whose main physiological action is stimulation of acid secretion in the stomach. In the new millennium, several publications have proposed a link between gastrin secretion and glucose homeostasis, but only very scarce documentation exists about alterations in gastrin secretion following bariatric surgery. Paper I studied the effect of the bariatric surgical procedures duodenojejunostomy and sleeve gastrectomy on gastrointestinal hormone secretion and glycemic parameters in a lean, diabetic rat model; the Goto-Kakizaki rat. Significant differences between in body weight between the bariatric interventions and sham-operation were observed only the first four weeks postoperatively. After 36 postoperative weeks of follow-up, only sleeve gastrectomy had significantly improved glycemic parameters and serum lipid values. Simultaneously, a marked increase in gastrin levels was observed after sleeve gastrectomy compared to duodenojejunostomy and sham-operation. Duodenojejunostomy enhanced glucagon-like peptide 1 (GLP-1) without impact on glycemic parameters. We therefore proposed a theory that alterations in gastrin secretion after sleeve gastrectomy may lead to the improvement glycemic control. In Paper II, the three-dimensional imaging technique optical projection tomography (OPT) was used for the quantification of beta-cell mass in this experimental model. After 46 weeks of follow up, the rats also reported in Paper I were euthanized and the pancreata analyzed with OPT-technique. It was demonstrated that sleeve gastrectomy significantly preserved total beta-cell mass and number of islets compared to duodenojejunostomy and sham-operation. We also observed enduring elevated gastrin secretion after sleeve gastrectomy. It was concluded that elevated gastrin levels after sleeve gastrectomy may contribute to increased survival of pancreatic beta-cells. Paper III explored if the findings following sleeve gastrectomy in rats could be reproduced by inducing hypergastrinemia with the proton-pump inhibitor pantoprazole. In this study, we found that pantoprazole had a lowering effect on fasting blood glucose and glycosylated hemoglobin with corresponding hypergastrinemia comparable to that of sleeve gastrectomy during 18 postoperative weeks. The importance of hypergastrinemia following sleeve gastrectomy and pantoprazole was modest. We did not detect any differences in betacell mass evaluated by OPT, suggesting that the findings in Paper II may be a result of a considerable longer observation period. In conclusion, sleeve gastrectomy raises serum gastrin levels and is superior to duodenojejunostomy as treatment for type 2 diabetes in rats. Hypergastrinemic rats treated with pantoprazole show comparable results to sleeve gastrectomy. Whether these findings are directly related to elevated serum gastrin requires further investigation.