Exhausted Protein Sorting Capacity Impairs Beta-Cell Function in Type 2 Diabetes
Abstract
Small clusters of cells within the pancreas, known as islet beta-cells, regulate blood sugar by controlled release of the hormone insulin. Insulin is made in the islet beta-cell as an inactive precursor molecule, proinsulin, where it is packaged into small vesicles. Within these vesicles, or granules, proinsulin is converted to the active version, insulin, where it is stored until needed. Following a rise in blood sugar during a meal, insulin is released from islet beta-cells into the bloodstream where it travels to major tissues, such as muscle, fat, and liver, and signals nutrient uptake. Through this mechanism, islet beta-cells regulate blood sugar. It is important to note that insulin is the only hormone in the body capable of directly reducing blood sugar, and thus understanding insulin production in the islet beta-cell, which includes packaging and storage, remains a critical area of basic science research. In Type 2 diabetes, islet beta-cell stores of insulin are depleted in an attempt to overcome insulin resistance and lower blood sugar. As a countermeasure to restore insulin supplies, islet beta-cells increase proinsulin production. Though the specific mechanisms of how islet beta-cells regulate proinsulin production in this context remain a mystery, our research into this process has discovered that islet beta-cells have a finite capacity to supervise proinsulin/insulin production. We hypothesize that during the progression of insulin resistance to Type 2 diabetes, the systems regulating insulin production are overwhelmed as proinsulin synthesis exceeds the sorting and packaging capacity of the cell. This leads to defects in proinsulin packaging, which include delays in proinsulin vesicle formation, sorting proinsulin into the wrong vesicles, and/or sorting proinsulin into vesicles that lack key proinsulin processing factors. The net result is that the islet beta-cell produces a series of defective proinsulin/insulin vesicles that are no longer responsive to signals for storage or release. Long term, this can result in too much insulin being released at the wrong times, which can directly elevate blood pressure, impair heart functions, cause weight gain, and exacerbate insulin resistance. In addition, we hypothesize that the persistent over-production and hyper-secretion of insulin from the islet beta-cell during the progression to Type 2 diabetes results in a futile cycle causing beta-cell exhaustion and ultimately complete failure of the islet beta-cell to regulate insulin production and release. Extending from this, reducing insulin release and allowing islet beta-cells to rest may offer islet beta-cells time to restore insulin supplies and thereby “reset their system controls.” To study this, we have developed state-of-the-art imaging techniques to visualize the packaging of insulin and monitor the movement of insulin vesicles within islet beta-cells. We can also examine the contents of insulin vesicles to determine how packaging changes with various treatments. We propose to examine insulin packaging and release directly in cell culture models of the beta-cell, beta-cells from rodent models of Type 2 diabetes, and islets from human Type 2 diabetes patients. We will also test the ability of clinically used Type 2 diabetes treatments, which either exacerbate or inhibit insulin release, to promote or perturb islet beta-cell functions long term in rodent models of Type 2 diabetes and human islets from Type 2 diabetic patients. Collectively, our studies will unveil novel mechanisms of how islet beta-cell function is lost in Type 2 diabetes and offer strategies to promote the retention or restoration of islet beta-cell function.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010200
Entities
People
- Samuel B Stephens
Organizations
- United States Army
- University of Iowa