Glycosylation of cellular proteins is linked to an increasing number of important ontogenic and pathogenic mechanisms. As an enzymatic process, glycosylation is essential for all forms of life and produces a large repertoire of glycan structures that comprise the glycome of cells and organisms. At the molecular level, individual glycan structures can play distinct roles on different glycoproteins, analogous to how the phosphorylation of different proteins yields distinct biological outcomes. Recent investigations of glycan structure and function in pancreatic beta cells have revealed an important role of protein N-glycosylation in the pathogenesis of diet- and obesity-associated diabetes. The GnT-4a glycosyltransferase is encoded by the MGAT4A gene in mammals and produces an N-glycan linkage that is essential for pancreatic beta cell function in healthy humans and mice. Expression of MGAT4A in beta cells has been recently found to require FOXA2 and HNF1A transcription factors. These factors are down-regulated in beta cells of mice with diet- and obesity-associated diabetes, as well as in beta cells of humans with Type 2 diabetes, and this response can be mimicked by the exposure of normal beta cells to elevated levels of fre fatty acids. The resulting decrement of beta cell GnT-4a glycosylation disables glucose transport in provoking multiple disease signs including impaired glucose tolerance, hyperglycemia, failure of glucose-stimulated insulin secretion, hepatic steatosis, and insulin resistance in muscle and adipose tissue. Preservation of beta cell GnT-4a glycosylation and glucose transport imparts resistance to disease in the diet- and obesity-induced mouse model of Type 2 diabetes. This molecular pathway is further implicated in multiple metabolic roles including the pathogenesis of human Mature Onset Diabetes of the Young subtype 3 (MODY3), susceptibility to diabetes among mammalian populations, and the physiological response to nutrient deprivation during fasting. Experiments proposed herein will determine whether GnT-4a deficiency may contribute to the pathogenesis of MODY3 caused by inherited mutations in the HNF1A gene, and which can be modeled in the mouse. These studies may provide a mechanistic unification of two different types of diabetes. Studies proposed herein will also determine whether dietary responses leading to insufficient GnT-4a and glucose transport are responsible for strain-specific disease susceptibility. The unexpected conservation of this diabetogenic pathway in mammals suggests the possibility that diminished GnT-4a glycosylation and glucose transport may be advantageous in some contexts. This hypothesis will also be tested as recent findings suggest that this pathway evolved in mammals to support core metabolism during periods of nutrient deprivation and starvation. Combined, the proposed research is structured to achieve a more integrated understanding of the pathogenesis of diabetes and the molecular mechanisms governing metabolism, which could translate to more effective therapeutic approaches.
The research proposed follows the discovery by the PI's laboratory of a molecular pathway governing pancreatic beta cell dysfunction in mouse and human species that is responsible for the onset of diet- and obesity-induced diabetes and which appears to contribute to the current global epidemic of human diabetes. This research will determine the role of this pathway in disease susceptibility spanning multiple forms of diabetes, identify additional molecular components involved, and investigate the hypothesis that this pathway was conserved in mammals as an advantageous response to nutrient deprivation preceding starvation.
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