Diabetic‑induced alterations in hepatic glucose and lipid metabolism: The role of type 1 and type 2 diabetes mellitus (Review)

Abstract

Diabetes mellitus (DM) is a growing health concern in society. Type 1 and type 2 DM are the two main types of diabetes; both types are chronic diseases that affect glucose metabolism in the body and the impaired regulation of glucose and lipid metabolism promotes the development and progression of DM. During the physiological metabolism process, the liver serves a unique role in glucose and lipid metabolism. The present article aimed to review the association between DM and glucose metabolism in the liver and discuss the changes of the following hepatic glucose fluxes: Gluconeogenesis, glucose/glucose 6‑phosphate cycling, glycogenolysis, glycogenesis and the pentose phosphate pathway. Moreover, the incidence of fatty liver in DM was also investigated.

Keywords: diabetes; sugar; insulin resistance; glucose metabolism; lipid metabolism.

Figure 1.

Metabolite cycle of glucose to glycogen. Under the regulation of insulin and glucagon, the liver aids the maintenance of blood glucose homeostasis. Insulin activates the uptake of glucose and the synthesis of glycogen, while inhibiting glycogenolysis and gluconeogenesis. Glucagon inhibits glycogenesis and promotes glycogenolysis. G6P is a key intermediate enzyme of the pathways and elevated G6P levels increases the activity of G6Pase, facilitating the production of glucose. GPa is the active form of GP and GPb is the inactive form. Conversely, GSb is the active form of GS and GSa is its inactive form. G6P, glucose 6-phosphate; GP, glycogen phosphorylase; GS, glycogen synthase; GK, glucokinase; G6Pase, glucose-6-phosphotase.

Figure 2.

Changes in hepatic glucose metabolic flux in DM. Thick arrows indicate increased flux, whereas thin arrows indicate reduced flux. T1DM: In T1DM, due to the lack of insulin, glycogen synthesis and glycolysis are decreased. The loss of insulin also causes the inactivation of the paracrine regulation of glucagon, which contributes to the development of hyperglucagonemia and to an increase in gluconeogenesis, which in turn leads to hyperglycemia. The changes in hepatic lipolysis in T1DM are not clear. T2DM: Insulin resistance exists in T2DM, leading to decreased glycogen synthesis and glucose metabolism via the TCA cycle, thereby increasing lipogenesis. Moreover, gluconeogenesis flux increases as a result of hyperglucagonemia. The changes in the PPP in both T1DM and T2DM are still not clear. T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TCA, tricarboxylic acid; PPP, pentose phosphate pathway; G6P, glucose 6-phosphate; ?, unclear.