Pathophysiology of Type 2 Diabetes

In former times, type 2 diabetes (T2D) was considered a disease associated with disruptions in the functioning of the pancreas. Later on, a surfeit of evidence revealed a series of additional factors that contribute to this annihilating disease. The understanding of T2D has evolved from recognizing the duo of pancreatic β-cell failure with defective insulin secretion and insulin resistance (IR) to the triumvirate with the addition of hepatic gluconeogenesis. Recently, the ominous octet (addition of deranged adipocyte metabolism, incretin defect, increased glucagon secretion, increased renal glucose reabsorption, neurotransmitter dysfunction, and central appetite dysregulation) and later the dirty dozen (addition of dopamine, vitamin D, testosterone, and renin-angiotensin system) elaborated on the prior simplistic disease models. Furthermore, with the addition of the gut, the unlucky Thirteen suggests that the contributing factors towards T2D pathogenesis are still in the process of being identified (DeFronzo, Diabetes 37(6):667–687, 1988; DeFronzo, Diabetes Rev 5:177–269, 1997; DeFronzo, Diabetes 58(4):773–795, 2009; DeFronzo et al., Diabetes Spectr 27(2):100–112, 2014; Kalra, J Pak Med Assoc 63(2):277–280, 2013; Kalra et al., Indian J Endocrinol Metab 17(3):367, 2013; Somasundaram et al., Jacobs J Diabetes Endocrinol 2(1):12, 2016; Kahn et al., Lancet 383(9922):1068–1083, 2014; Nolan et al., Lancet 378(9786):169–181, 2011). In this chapter, we will explore the various factors that have been identified or are being proposed as the underlying contributors to the pathogenesis and pathophysiology of T2D.