Metabolic Abnormalities in the Pathogenesis of Type 1 Diabetes

Abstract

Clinical onset of Type 1 Diabetes (T1D) is thought to result from a combination of overt beta cell loss and beta cell dysfunction. However, our understanding of how beta cell metabolic abnormalities arise during the pathogenesis of disease remains incomplete. Despite extensive research on the autoimmune nature of T1D, questions remain regarding the time frame and nature of beta cell destruction and dysfunction. This review focuses on the characterizations of beta cell dysfunction in the pre-diabetic and T1D human and mouse model. Studies have shown evidence supporting progressive loss of beta cell mass and function prior to T1D onset, while other scientists argue beta cell destruction occurs later in the disease process. Determining the time frame of beta cell destruction and identifying metabolic mechanisms that drive beta cell dysfunction has high potential for successful interventions to maintain insulin secretion for individuals with established T1D as well as those with pre-diabetes.

Positive Feedback Amplifies the Response of Mitochondrial Membrane Potential to Glucose Concentration in Clonal Pancreatic Beta Cells

“…Critically, plasma glucose homeostasis is achieved through alterations in insulin levels by a metabolically exceptional cell type (pancreatic β-cells) in which the programmed lack of homeostasis of cellular energization state allows the signaling machinery of insulin secretion to sense and respond to changes in blood glucose concentration. This signaling machinery is dysfunctional in diabetes (type 2 and pre-type 1) [8–14], making the understanding of β-cell bioenergetic function and dysfunction vital for understanding and treating diabetes. In T2D, ΔψM in β-cells becomes less sensitive to changes in blood glucose [16,46–48] by unknown mechanisms.…”

“…The canonical pathway of glucose-stimulated insulin secretion (GSIS) relies on hyperpolarization of mitochondrial membrane potential (ΔψM) (more strictly, hyperpolarization of the protonmotive force) leading to increased mitochondrial production of ATP, and is largely responsible for the first phase of insulin secretion [2–7]. Both type 1 and type 2 diabetes (T2D) in humans are characterized by early impairment of this phase [8–14], suggesting a possible role of disturbed cellular energy metabolism. While rare mitochondrial defects can cause diabetes [15], it is possible that more subtle derangements in cellular energy metabolism contribute more generally to β-cell impairment in diabetes.…”

Innate inflammation in type 1 diabetes

“…T1D is one of the most common chronic diseases of childhood with peak ages of onset at 5–7 years of age and again peri-pubertally (1). While residual β-cells have been detected in patients with even long-standing T1D, evidence supports that individuals present clinically after a significant loss of β-cell mass and function (2, 3), at which point glucose homeostasis can no longer be maintained. As such, hyperglycemia develops with classic symptoms of polyuria, polydipsia, and weight loss.…”

Resealable, optically accessible, PDMS-free fluidic platform for ex vivo interrogation of pancreatic islets

“…All too often, however, the sophistication of these devices discourages the widespread distribution and their use by the islet research community. Nonetheless, the ability to apply physiological perturbations and fluidically introduce pathological stressors, such as the effects of immune cells, makes these fluidic microdevices powerful tools for studying pathways for onset of diabetes 16, 17 , discovering biomarkers of beta cell death 18 , and investigating strategies for the targeting and regeneration of functional beta cell mass 19, 20 .…”