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.
Highlights
Obesity and diabetes are globally pervasive, increasing in prevalence, and occur over the life-course, often presenting earlier in life e.g., in childhood obesity and diabetes
As obesity progresses with weight gain with age, in parallel to chronic inflammation characterized by elevated pro-inflammatory cytokines and chemokines, compensatory mechanisms are induced that shift the homeostatic thresholds, which leads to the onset of diabetes [23]
Diabetes is a chronic inflammatory disease and typically islet cell inflammation can be induced in response to systemic inflammation and other stimuli. This increases the complexity in the prevention, pathogenesis and treatment of diabetes, and the preceding pathologies viz. obesity, insulin resistance, glucose intolerance, and beta cell death, dysfunction, and failure
Summary
Obesity and diabetes are globally pervasive, increasing in prevalence, and occur over the life-course, often presenting earlier in life e.g., in childhood obesity and diabetes. Urbanization, sedentary lifestyles, and unhealthy diets are some drivers of the global high prevalence of obesity and diabetes, with healthy nutrition important for obesity and diabetes prevention and management. In obesity and early diabetes, overnutrition (i.e., hypercaloric overconsumption, excess nutrients, or nutritional overload, such as chronic high-fat diet (HFD)/high saturated fatty acid (SFA). Exposure to chronic hyperglycemia (glucotoxicity) and lipids (lipotoxicity) trigger beta cell dysfunction and death [1,2,3], and in combination, i.e., an excess of glucose and lipids (glucolipotoxicity), synergize rapid and progressive beta cell demise [4,5]. Glucolipotoxicity is the combined deleterious consequences of elevated chronic glucose and SFA (e.g., palmitic acid) concentrations on specific organs (e.g., the pancreas), micro-organs (e.g., islets) and cells (e.g., beta cells) [6]
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