People who do not put on a lot of excess weight, and the excess visceral fat tissue that goes with it, are very unlikely to develop type 2 diabetes. It is a metabolic disease in which the primary, addressable cause is the presence of too much visceral fat. Adoption of a low calorie diet and undergoing the consequent weight loss is a curative strategy, and can reverse the course of type 2 diabetes even in late stages of the condition. With all that said, typically, overweight people develop type 2 diabetes later in life. It takes a great deal of visceral fat tissue to push someone into type 2 diabetes in earlier adulthood. So clearly the mechanisms and dysfunctions of degenerative aging do play a role. Here, researchers focus specifically on the aging of the immune system and its interaction with the metabolic dysfunction that leads to type 2 diabetes.
Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance (IR), inflammation, and dysregulation in glucose metabolism. The disease is spreading globally, partly due to aging, which can damage the immune system and speed up the progression of the metabolic disorder. This review primarily delves into the triggers for T2D within the framework of the ominous octet, which emphasizes 8 principal factors that contribute to high blood glucose and associated metabolic disorders. The octet includes impaired insulin secretion, diminished incretin effect, increased lipolysis, heightened hepatic glucose production (HGP), neurotransmitter dysfunction, augmented renal glucose reabsorption, reduced glucose uptake in muscle, and inflammation-driven IR in adipose tissue (AT).
We further discuss the interplay of hyperinsulinemia, mitochondrial dysfunction (MD), and endoplasmic reticulum (ER) stress with immune aging in driving disease progression affecting each component of the octet. MD and ER stress can result in defects in insulin signaling, ultimately leading to pancreatic β-cell death. Chronic inflammation associated with aging, also known as inflammaging, especially affects older adults by worsening IR and glucose regulation, which creates a continuous sequence of metabolic problems. Thus, the "ominous octet" framework provides fundamental knowledge to develop personalized treatment approaches that target metabolic dysfunction together with ER stress, MD, and immune system imbalances. These strategies show promising potential to improve treatments for T2D and may lead to better health outcomes for older adults dealing with this condition.
Link: http://doi.org/10.14218/ERHM.2025.00018
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