NORMAL PHYSIOLOGY: CONTROL OF SUBSTRATE FLUX
Normal physiology depends on insulin mediated availability of glucose, amino acids, and fatty acids to cells as substrates for energy production and cell growth. Diabetes mellitus is the clinical condition of hyperglycemia accompanied by inadequate insulin effect (due to insulin deficiency or impaired insulin action). The metabolic abnormalities in diabetes mellitus are due to a pathologic shift in energy substrate control. Carbohydrates, amino acids, and lipids are all used as forms of energy that must be stored when there is abundance and released when needed. While energy flux is a complex, multifactorial process, it is largely regulated by a balance between insulin and counterregulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) during fasting or in the postprandial state. Insulin’s main functions in energy homeostasis are to promote uptake of glucose by muscle and adipose tissue, inhibit glucose production by the liver, and inhibit triglyceride release from adipose tissue. The counterregulatory hormones serve the opposite function during fasting or starvation. During a carbohydrate-containing meal, circulating insulin levels rise while glucagon secretion is suppressed by glucagon-like peptide-1 (GLP-1) and amylin. Although most cell types require insulin for optimal glucose uptake, glucose itself can drive some of its own uptake into cells such as muscle (termed “glucose-mediated glucose uptake”), and some tissues, such as the brain, take up glucose independently of insulin or other hormones. Glucose uptake into cells is mediated by specific glucose transporters (GLUTs) (Table 20-1). While glucose is the most important energy substrate, ketones generated from fat breakdown provide an important alternative cellular energy source when intracellular glucose availability is low; fasting, insulin deficiency, or impairment of insulin action result in decrease of intracellular glucose and an increase in ketone production.
TABLE 20-1Glucose Transporters ||Download (.pdf) TABLE 20-1 Glucose Transporters
|Glucose Transporter ||Tissue Distribution ||Primary Function |
|GLUT1 ||Widespread ||General basal glucose transport including across blood–brain barrier, insulin independent |
|GLUT2 || |
Pancreatic β cells
Renal proximal tubule
Glucose concentration–dependent regulation of insulin secretion
Control of glucose homeostasis
|GLUT3 ||Neurons ||Glucose uptake into brain |
|GLUT4 || |
|Insulin-stimulated glucose uptake |
|GLUT5 ||Intestinal mucosa ||Fructose absorption |
Insulin sensitivity and insulin resistance refer to the relative concentration of insulin required to achieve normal extracellular glucose levels. Excessive elevation of counterregulatory hormones as occurs with the stress response to severe illness is associated with insulin resistance. Exercise increases insulin-independent glucose uptake in skeletal muscle by increasing translocation of GLUT4 to the muscle cell membrane, and in this way induces a state of increased insulin sensitivity.
The liver is the primary storage site of carbohydrate as glycogen, with muscle storing a small amount of glycogen; adipose tissue stores lipid and muscle stores protein that can be liberated for gluconeogenesis.
The liver is primarily responsible for the exchange of these energy ...