Unique features of β‐cell metabolism are lost in type 2 diabetes.

Pancreatic β cells play an essential role in the control of systemic glucose homeostasis as they sense blood glucose levels and respond by secreting insulin. Upon stimulating glucose uptake in insulin‐sensitive tissues post‐prandially, this anabolic hormone restores blood glucose levels to pre‐prandial levels. Maintaining physiological glucose levels thus relies on proper β‐cell function. To fulfill this highly specialized nutrient sensor role, β cells have evolved a unique genetic program that shapes its distinct cellular metabolism. In this review, the unique genetic and metabolic features of β cells will be outlined, including their alterations in type 2 diabetes (T2D). β cells selectively express a set of genes in a cell type‐specific manner; for instance, the glucose activating hexokinase IV enzyme or Glucokinase (GCK), whereas other genes are selectively "disallowed", including lactate dehydrogenase A (LDHA) and monocarboxylate transporter 1 (MCT1). This selective gene program equips β cells with a unique metabolic apparatus to ensure that nutrient metabolism is coupled to appropriate insulin secretion, thereby avoiding hyperglycemia, as well as life‐threatening hypoglycemia. Unlike most cell types, β cells exhibit specialized bioenergetic features, including supply‐driven rather than demand‐driven metabolism and a high basal mitochondrial proton leak respiration. The understanding of these unique genetically programmed metabolic features and their alterations that lead to β‐cell dysfunction is crucial for a comprehensive understanding of T2D pathophysiology and the development of innovative therapeutic approaches for T2D patients. [ABSTRACT FROM AUTHOR]