ReviewMolecular pathophysiology of hepatic glucose production
Introduction
Abnormal concentrations of glucose in plasma result in deleterious effects at the whole organism level. Glucose is the main energy source for the brain and decreased plasma glucose levels (hypoglycemia) can lead to impaired brain function and death. Conversely, increased plasma glucose levels (hyperglycemia), a major clinical symptom of diabetes, dramatically increase the risk of various macrovascular and microvascular complications.
Glucose homeostasis is balanced by nutrient sensing and hormonal signaling intracellular mechanisms that control tissue-specific rates of glucose utilization and production. Among the tissues contributing to the maintenance of normal ranges of blood glucose levels are the liver, skeletal and cardiac muscle, fat and brain. After a carbohydrate meal, ~33% of the glucose is taken up by the liver, another ~33% is taken up by muscle and adipose tissues, and the remaining glucose is taken up by the brain, kidney and red blood cells (RBC) (Moore et al., 2012). Insulin and glucagon are two central glucose-dependent counterregulatory hormones that orchestrate the peripheral tissues' responses to control rates of utilization and production of glucose to maintain glycemia within narrow ranges. Indeed, the resistance of these tissues to insulin is the major contributor to impaired glucose homeostasis leading to hyperglycemia and to the development of type 2 diabetes mellitus (T2DM) (Samuel and Shulman, 2012).
The liver plays a major role in maintaining glucose homeostasis, as it is the main organ for glucose storage, in the form of glycogen, as well as endogenous glucose production. When nutrients are available, insulin is secreted from pancreatic β cells and promotes hepatic glycogen synthesis and lipogenesis. When nutrients become scarce, insulin levels are decreased and glucagon is secreted from pancreatic α cells to promote hepatic glucose production (HGP) to meet brain and RBC energetic demands. HGP is achieved by glycogen breakdown (glycogenolysis) as well as by de novo glucose synthesis from available precursors (gluconeogenesis). Increased rates of HGP, as observed in patients with T2DM, significantly impair glucose homeostasis and significantly contribute to hyperglycemia (Lin and Accili, 2011). Therefore, controlling the rates of HGP is one of the major targets for the treatment of T2DM patients. In this review, we will focus on the molecular mechanisms underlying the nutrient and hormonal regulatory control of HGP.
Section snippets
Whole body glucose homeostasis
Blood glucose concentrations in normal healthy individuals are normally maintained at ~90 mg/dl. This is a result of an intricate balance between endogenous glucose production and glucose removal from the blood stream, which are dynamically regulated by hormonal and nutritional signals. The primary tissue source for endogenous glucose production is the liver and under some conditions the kidney. The clearance of glucose from the blood stream is the net consumption primarily by the brain,
Fed-fasting physiology
Maintaining relatively constant blood glucose levels is essential for the survival of the organism. This is specifically challenging in periods of reduced energy supply such as after prolonged fasting or exercise. In the fed state, circulating glucose is derived primarily from dietary sources and is distributed to the brain, the muscle and fat, and the liver. After an overnight fast (postabsorptive state) when dietary glucose supply is not available, glucose is produced primarily from
Molecular mechanisms that control hepatic glucose production
The molecular mechanisms determining whether the liver acts as a glucose producing organ or a glucose storage organ can be grossly divided into two categories: acute and long term. While the acute effects are brought about primarily by changes in metabolite flux controlled by protein modifications or allosteric effectors, the long term effects are brought about primarily by changes in the mRNA expression level of key enzymes in the glycolysis/gluconeogenesis pathways. Both the short and long
The liver is the major contributor to hyperglycemia observed in diabetes
T2DM has become a worldwide epidemic and is expected to affect almost one-third of adult Americans by 2050 (Boyle et al., 2010). The current increase in the prevalence of T2DM is believed to be a result of increases in energy consumption and in sedentary lifestyle in combination with genetic predisposition (Chen et al., 2012). T2DM is a multifactorial disease characterized by postprandial and postabsorptive hyperglycemia, insulin resistance and insulin deficiency (Rizza, 2010). As discussed
Conclusions
Glucose homeostasis in the liver is tightly controlled by nutritional and hormonal cues that regulate hepatic glucose production to meet whole body energy demands. The activity of numerous enzymes, transcription factors and coactivators is regulated by these nutritional and hormonal cues to control HGP both in the postprandial and postabsorptive states. Alteration in the mechanisms that control HGP can lead to hyperglycemia and to the development of T2DM. Although acquired late in the
Acknowledgements
This work was supported by NIH grants (R24 DK080261-06, RO1 DK081418, RO1 DK089883, RO1 DK069966) and American Diabetes Association grant to P.P. K.S is supported by the American Heart Association Postdoctoral Fellowship. A.K.R is supported by NIDDK grant F32DK102293-01.
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