β-cell secretory capacity as an adaptive mechanism during the development of type 2 diabetes

Type 2 diabetes (T2D) impacts millions of Americans and is characterized by three primary features: persistently high insulin levels, elevated blood sugar levels, and insulin resistance, which hampers the body’s ability to efficiently respond to insulin. While numerous therapies focus on addressing insulin resistance and high blood sugar, the significance of elevated insulin levels is often overlooked. This occurs as pancreatic islet beta-cells attempt to compensate for insulin resistance by producing more insulin to lower blood sugar levels. Understanding insulin production within these islet beta-cells and its release is crucial for developing more effective treatments, given that insulin is the sole hormone capable of directly reducing blood sugar levels.

Insulin is initially produced within the islet beta-cell as an inactive form called proinsulin, which is then packaged into small vesicles within the Golgi apparatus, a cellular organelle responsible for processing, sorting, and packaging proteins for transport. Recently, we observed that in response to increased insulin secretion and elevated glucose levels, there is an expansion of the Golgi apparatus. Through my research involving pharmacological and genetic approaches, I discovered the critical role of Inositol-Requiring Enzyme 1 alpha (IRE1α;) in regulating this Golgi expansion and the concurrent increase in insulin production during this early adaptive phase of diabetes.

Over time, the development of overt T2D can occur when the islet beta-cells lose functionality, rending them unable to surmount this adaptive compensatory increase in insulin packaging and secretion. My investigations further revealed that dysfunctional islet beta-cells exhibit impaired proinsulin vesicle formation and release from the Golgi apparatus, along with structural changes to the Golgi morphology. Interestingly, maintaining proper acidification (pH) of the Golgi apparatus is essential for proinsulin vesicle formation, my research suggests that altering Golgi pH has only a modest effect on its structure and does not directly impact insulin production or release. Overall, these findings significantly enhance our understanding of the molecular mechanisms involved in insulin regulation during the progression of T2D.

Lastly, persistent over-production and hyper secretion of insulin from the islet beta-cell during the progression to T2D is thought to result in a futile cycle causing beta-cell exhaustion and ultimately complete failure of the islet beta-cell to regulate insulin production and release. My data demonstrates that agents that reduce insulin secretion in a rodent model of islet dysfunction lead to improvements in beta-cell function, whereas agents that directly increase insulin secretion result in further impairments in beta-cell function.

Collectively, my research has provided new discoveries into compensatory changes that beta-cells undergo to meet increased insulin demands and has elucidated how these mechanisms become dysregulated in later stages of T2D. Furthermore, my research advances our understanding of how clinically approved T2D medications impact beta-cell function, thus providing valuable information for physicians to guide their therapeutic decisions for patients.