PROBLEM: Following transplantation into mice, SC-β cell function is comparable to human islets, but the magnitude and consistency of response in vitro are less robust than observed in cadaveric islets.
NOVEL APPROACH: We profile metabolism of SC-β cells and islets to quantify their capacity to sense glucose and identify reduced anaplerotic cycling in the mitochondria as the cause of reduced glucose-stimulated insulin secretion in SC-β cells. This activity can be rescued by challenging SC-β cells with intermediate metabolites from the TCA cycle and late but not early glycolysis, downstream of the enzymes glyceraldehyde 3-phosphate dehydrogenase and phosphoglycerate kinase.
FINDINGS: Bypassing this metabolic bottleneck results in a robust, bi-phasic insulin release in vitro that is identical in magnitude to functionally mature human islets.
Our goal is to develop significant new treatments for diabetes. We aim to eliminate the present practice of regular blood checks and insulin injections, replacing them with insulin-producing cell transplants, specifically pancreatic beta cells that measure glucose levels and secrete just the right amount of insulin.
Our approach is best characterized as applying developmental biology to understand and change the course of diabetes.
The methods we have developed to make hundreds of millions of functional beta cells from human stem cells (ES or iPS cells) form the central theme for our research. In one instance, we study how to make all the islet endocrine cells, including alpha (glucagon-producing) and delta (somatostatin-producing) cells and produce islet-like clusters. These human stem cell-derived islet clusters are used both in vitro and in vivo for metabolic studies on islet function.