Beta Cell Physiological Dynamics and Dysfunctional Transitions in Response to Islet Inflammation in Obesity and Diabetes

Abstract

Beta cells adapt their function to respond to fluctuating glucose concentrations and variable insulin demand. The highly specialized beta cells have well-established endoplasmic reticulum to handle their high metabolic load for insulin biosynthesis and secretion. Beta cell endoplasmic reticulum therefore recognize and remove misfolded proteins thereby limiting their accumulation. Beta cells function optimally when they sense glucose and, in response, biosynthesize and secrete sufficient insulin. Overnutrition drives the pathogenesis of obesity and diabetes, with adverse effects on beta cells. The interleukin signaling system maintains beta cell physiology and plays a role in beta cell inflammation. In pre-diabetes and compromised metabolic states such as obesity, insulin resistance, and glucose intolerance, beta cells biosynthesize and secrete more insulin, i.e., hyperfunction. Obesity is entwined with inflammation, characterized by compensatory hyperinsulinemia, for a defined period, to normalize glycemia. However, with chronic hyperglycemia and diabetes, there is a perpetual high demand for insulin, and beta cells become exhausted resulting in insufficient insulin biosynthesis and secretion, i.e., they hypofunction in response to elevated glycemia. Therefore, beta cell hyperfunction progresses to hypofunction, and may progressively worsen towards failure. Preserving beta cell physiology, through healthy nutrition and lifestyles, and therapies that are aligned with beta cell functional transitions, is key for diabetes prevention and management.

Pharmaceutical Drugs and Natural Therapeutic Products for the Treatment of Type 2 Diabetes Mellitus

“…Impaired β-cell function leads to a decrease in glucose responsiveness [ 15 ] and its insufficient treatment reduces the number of pancreatic β-cells and affects long-term blood glucose control [ 16 ]. Insulin doses are high during chronic hyperglycaemia and T2DM, leading to the exhaustion of β-cells and deficiency in insulin biosynthesis and secretion [ 17 ]. Generally, insulin synthesis begins as preproinsulin production through kinase-dependent signalling pathways (PI3K, p38MAPK, PKA, calmodulin kinase).…”

“…These conditions are influenced by hyperglycaemia (glucotoxicity), hyperlipidaemia (lipotoxicity), and chronic inflammation. Inflammation is characterized by an imbalance between compensatory mechanisms and elevated levels of pro-inflammatory cytokines and chemokines [ 17 , 21 ]. In the diabetic state, a defect in hepatic glucose production is recorded.…”

NADPH Oxidase (NOX) Targeting in Diabetes: A Special Emphasis on Pancreatic β-Cell Dysfunction

“…Furthermore, there is strong evidence that suggests that chronically elevated levels of reactive oxygen species (ROS) lead to increased oxidative stress in β-cells. Given the ability of ROS to directly damage and oxidize DNA, proteins, and lipids, β-cell functioning is worsened in terms of insulin secretion and action [ 5 , 6 ]. NADPH oxidase (NOX) proteins are membrane-associated multiunit enzymes that play a physiological role in response to various factors, as well as pathophysiological roles in diabetic pancreatic β-cells.…”

Gastric bypass prevents diabetes in genetically modified mice and chemically induced diabetic mice

“…Obesity is associated with insulin resistance and type 2 diabetes (T2D) and is considered a public health crisis, responsible for an exponential increase in health care costs [ 1 ]. In response to insulin resistance, pancreatic β-cells compensate by increasing insulin secretion characterized by hyperglycemia and hyperinsulinemia or normal insulinemia [ 2 ]. This metabolic setting can be maintained for long periods of time [ 3 – 6 ].…”