Insulin action

INTRODUCTION — Insulin is a 51-amino acid peptide hormone that is synthesized and secreted by pancreatic beta cells (table 1). This topic will review the metabolic actions of insulin. The details of insulin secretion are reviewed separately. (See "Pancreatic beta cell function".)

INSULIN SIGNALING — Insulin action begins with the binding of insulin to a heterotetrameric receptor on the cell membrane of the target cells. Insulin receptors are membrane glycoproteins composed of two separate insulin-binding (alpha-subunits) and two signal transduction (beta-subunits) domains (figure 1). Binding of insulin to the receptor results in conformational change of the alpha-subunits that enables adenosine triphosphate (ATP) binding to the beta-subunit's intracellular domain. ATP binding leads to activation of a tyrosine kinase in the beta-subunit that autophosphorylates the receptor. The phosphorylated receptor in turn phosphorylates other protein substrates beginning with insulin receptor substrate (IRS) 1 and 2 [1-4]. The insulin signal is further propagated through a phosphorylation network involving other intracellular substances.

Through activation of these signaling pathways, insulin acts as a powerful regulator of metabolic function. Furthermore, insulin receptor-mediated activation of the mitogen-activated protein (MAP) kinase pathway has been implicated in insulin's effects on growth and proliferation [4].

Of clinical relevance, defects in insulin signaling have been demonstrated in several of the insulin resistance syndromes. (See "Insulin resistance: Definition and clinical spectrum".)

METABOLIC EFFECTS OF INSULIN — Insulin directly or indirectly affects the function of virtually every tissue in the body. However, in this brief overview, we will focus on insulin's metabolic effects on the three tissues most responsible for energy storage: liver, muscle, and adipose tissue (table 2).

Insulin and glucose metabolism — Glucose is obtained from three sources: intestinal absorption of food, glycogenolysis (breakdown of glycogen [the storage form of glucose]), and gluconeogenesis (synthesis of glucose from precursors derived from carbohydrate, protein, and fat metabolism).

Once transported into cells, glucose can be stored as glycogen, or it can undergo glycolysis to pyruvate. Pyruvate can be reduced to lactate, transaminated to form alanine, or converted to acetyl coenzyme A (CoA). Acetyl CoA can be oxidized in the tricarboxylic acid cycle to carbon dioxide and water, converted to fatty acids for storage as triglyceride, or used for ketone body or cholesterol synthesis (figure 2).

Insulin has a number of effects on glucose metabolism, including:

●Inhibition of glycogenolysis and gluconeogenesis

●Increased glucose transport into fat and muscle

●Increased glycolysis in fat and muscle

●Stimulation of glycogen synthesis

Glucose production — Although glycogenolysis can occur in most tissues in the body, only liver and kidneys express the enzyme glucose-6-phosphatase, which is required for release of glucose into the bloodstream. The liver and kidneys also contain the enzymes required for gluconeogenesis. Of the two organs, the liver is responsible for the bulk of glucose output. In tracer studies, the kidney supplied only 10 to 20 percent of glucose production following an overnight fast [5]. Thus, the liver is a principal target for insulin action in the regulation of glucose production. However, in patients with type 2 diabetes, renal glucose release increases to compensate partially for reduced hepatic glucose release during counterregulation of hypoglycemia [6].

Insulin acts directly to limit hepatic glucose output by inhibiting glycogen phosphorylase, the glycogenolytic enzyme. Insulin also acts indirectly to decrease hepatic gluconeogenesis [7]. Indirect actions of insulin involve several pathways: decrease in the flow of gluconeogenic precursors and free fatty acids to the liver; inhibition of glucagon secretion, in part by direct inhibition of the glucagon gene in the pancreatic alpha cells [8]; and change in neural input to the liver. Infusion of insulin into the portal vein or into peripheral veins in studies in dogs have demonstrated that the direct effect of insulin on hepatic glucose production predominates [9,10], although with larger increases in insulin secretion, the indirect effect becomes more apparent [9,11].

Glucose utilization — Insulin stimulates glucose uptake by skeletal muscle and fat. In these tissues, glucose transport across cell membranes is mediated by glucose transporter 4 (GLUT-4) (table 3). This glucose transporter appears to reside in the cytoplasm of these cells; a signal from insulin results in translocation of GLUT-4 to the cell membrane, where it facilitates glucose entry into these tissues (eg, after a meal) [12]. Some studies in mice have demonstrated the complexity in the control of glucose homeostasis, suggesting that glucose uptake in skeletal muscle can also occur through an insulin independent increase in GLUT-4 and adenosine monophosphate (AMP)-activated protein kinase (AMPK) activity [13].

Under euglycemic conditions, most insulin-mediated glucose uptake occurs in muscle, and uptake by adipose tissue contributes <10 percent to a given increase in glucose uptake. However, adipose tissue also indirectly promotes glucose utilization via insulin-mediated inhibition of lipolysis. This occurs through the mechanism of competing substrates because decreased availability of free fatty acids as a fuel source favors increased glucose uptake and metabolism in muscle.

Insulin also promotes glucose disposal within cells through its effects on glycogen synthesis and glucose breakdown (glycolysis).

Insulin increases the activity of glycogen synthase in several tissues, including adipose tissue, muscle, and liver. However, this action of insulin does not result in net glycogen synthesis unless glycogen phosphorylase is strongly inhibited. In fact, the catalytic capacity of glycogen phosphorylase in human skeletal muscle is 50-fold greater than that of glycogen synthase.

Insulin stimulates the rate of glycolysis in skeletal muscle and adipose tissue by increasing the activity of two key enzymes in the glycolytic pathway, hexokinase and 6-phosphofructokinase [14,15].

Insulin and fat metabolism — Insulin serves to coordinate the use of alternative fuels (glucose and free fatty acids) to meet the energy demands of the organism during cycles of feeding and fasting and in response to exercise. In the postprandial state (when glucose is abundantly available), insulin secretion is increased, which promotes storage of triglyceride in fat cells. This is accomplished via several mechanisms:

●Insulin increases the clearance of triglyceride-rich chylomicrons (eg, those formed after a mixed meal) from the circulation via stimulation of lipoprotein lipase. This enzyme, which is located on the endothelium of capillaries in muscle and fat, hydrolyzes triglycerides in circulating lipoproteins. The fatty acids generated are then taken up by muscle or fat, in which they are oxidized or stored, respectively. Insulin activates adipose tissue lipoprotein lipase, but inhibits the same enzyme in skeletal muscle [16]. This tissue-specific effect on lipoprotein lipase results in diversion of triglycerides from muscle to adipose tissue for storage [17].

●Insulin stimulates re-esterification of free fatty acids into triglycerides within fat cells. This is accomplished indirectly via increased glucose transport into fat cells, an insulin-dependent process. Glycolytic activity within fat cells is increased, leading to increased levels of the glycolytic metabolite glycerol-3-phosphate, which is used in the esterification of free fatty acids into triglycerides [18].

●Insulin inhibits lipolysis of stored triglycerides by inhibiting hormone-sensitive lipase, the enzyme that catalyzes the rate-limiting step in lipolysis. Studies suggest that insulin activates a protein phosphatase that subsequently dephosphorylates and inactivates hormone-sensitive lipase [19-21]. A second mechanism involves an insulin-sensitive phosphodiesterase [22] that lowers intracellular cyclic AMP (cAMP) levels, thus inhibiting the cAMP-dependent protein kinase responsible for phosphorylating and activating hormone-sensitive lipase [23,24].

The overall effect of increased triglyceride storage and decreased lipolysis is decreased flux of free fatty acids to the liver. Although indirect, this appears to be a potent regulatory action of insulin in reducing hepatic gluconeogenesis and hepatic glucose output.

Insulin and ketone body metabolism — Under hypoinsulinemic conditions, such as prolonged fasting or uncontrolled diabetes mellitus, fat mobilization is greatly accelerated, resulting in an oversupply of free fatty acids to the liver. In this situation, the liver synthesizes ketone bodies from the abundant supply of acetyl CoA, a by-product of incomplete beta-oxidation of long-chain fatty acids. These ketoacids (acetoacetate, beta-hydroxybutyrate, and acetone) can be utilized as fuel by extrahepatic tissues, primarily skeletal muscle and the heart. Under extreme conditions, the brain also utilizes ketone bodies for fuel [25].

Insulin potently reduces circulating ketone body concentrations via several mechanisms. As noted above, insulin inhibits lipolysis, decreasing the supply of free fatty acids to the liver for ketogenesis. In addition, insulin directly inhibits ketogenesis in the liver [26], which may explain the resistance to ketosis that occurs in obese subjects and patients with type 2 diabetes mellitus, despite their high plasma free fatty acid concentrations. Lastly, hyperinsulinemia is associated with increased peripheral clearance of ketone bodies [27].

Insulin and protein metabolism — Insulin increases nitrogen retention and protein accretion.

Insulin facilitates transport of amino acids into hepatocytes, skeletal muscle, and fibroblasts, and it increases the number and translational efficiency of ribosomes. Overall, these actions result in an increase in protein synthesis [28].

Insulin also inhibits protein breakdown. In humans studied using the hyperinsulinemic-euglycemic clamp technique, physiologic increments in serum insulin concentrations blunt whole-body proteolysis in a dose-dependent manner [29]. The maximal effect is to reduce proteolysis by 40 percent, indicating that other regulatory factors also regulate proteolysis.

By inhibiting gluconeogenesis, insulin maintains the availability of amino acids as substrates for protein synthesis. Thus, insulin supports protein synthesis through direct and indirect mechanisms.

PARACRINE EFFECTS OF INSULIN — Insulin does not exert its effects in a hormonal vacuum. Insulin secretion occurs in close proximity to other hormone-secreting cells of the pancreatic islets, namely alpha and delta cells, which secrete glucagon and somatostatin, respectively. Insulin has paracrine effects on these neighboring cells. In addition, stimuli of insulin secretion, such as high serum glucose and amino acid concentrations, can directly alter the secretion of these other hormones. These alterations can in turn modulate the endocrine effects of insulin.

For example, the first target cells to be reached by insulin are the alpha cells, situated at the periphery of each pancreatic islet. Insulin decreases alpha cell secretion of glucagon, which in turn increases many of insulin's metabolic effects. In addition, hyperglycemia itself stimulates secretion of somatostatin, which acts upon alpha cells to decrease glucagon secretion. Conversely, amino acids increase glucagon secretion as well as insulin secretion. Thus, the type and amounts of islet hormones secreted in response to a meal depend upon the ratio of ingested carbohydrate to protein.

OTHER ACTIONS OF INSULIN — It has become increasingly clear that insulin has actions beyond the realm of energy metabolism, including actions on steroidogenesis, vascular function, fibrinolysis, and growth. From the clinical perspective, abnormal responses to insulin have been implicated in the pathogenesis of the polycystic ovary syndrome, cardiovascular disease and thrombosis, and certain cancers.

Steroidogenesis — Insulin resistance is common in women with the polycystic ovary syndrome, a condition characterized by hyperandrogenism and chronic anovulation. The resulting hyperinsulinemia stimulates ovarian androgen secretion both directly [30] and indirectly, by stimulating luteinizing hormone (LH) release [31] or increasing ovarian LH receptors [32]. In vitro and in vivo studies using insulin-sensitizing drugs support the above findings [33,34]. The paradoxical resistance to insulin's metabolic effects and concomitant sensitivity to its steroidogenic effects may be explained by a selective defect in insulin action affecting the metabolic (but sparing the mitogenic) insulin-signaling pathways in these women [35,36].

Vascular function — Insulin has vasodilatory properties [37], probably exerted via activation of nitric oxide production in endothelium [38]. Insulin-stimulated endothelial nitric oxide release occurs in a calcium-independent way and is mediated via protein kinase B [39,40]. Nitric oxide-mediated vasodilatation is impaired in patients with both type 1 and type 2 diabetes mellitus [41-44], which may contribute to the development of atherosclerosis in these patients. The association with insulin may be indirect, in that hyperglycemia itself impairs endothelium-dependent vasodilation [45,46]. However, concomitant with its vasoprotective effects via nitric oxide production, hyperinsulinemia may also have deleterious vascular effects via activation of the mitogen-activated protein (MAP) kinase pathway, which stimulates the proliferation and migration of vascular smooth muscle cells [47]. (See "Coronary endothelial dysfunction: Clinical aspects".)

Fibrinolysis — Epidemiological studies suggest that decreased fibrinolysis is associated with hyperinsulinemia and hypertriglyceridemia, the typical findings in patients with uncontrolled type 2 diabetes mellitus [48]. In both in vitro and in vivo animal studies, insulin in concentrations similar to those found in the serum of patients with type 2 diabetes stimulates vascular smooth muscle cells to produce plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis [49,50]. In humans, acute hyperinsulinemia in patients with hyperglycemia and hypertriglyceridemia causes an increase in plasma concentration levels of PAI-1 [51]. Insulin alone does not have a comparable effect in normal subjects. Together, these findings implicate hyperinsulinemia in the atherogenic process via its effects on fibrinolytic activity [52]. Common disorders associated with hyperinsulinemia are discussed further separately. (See "Insulin resistance: Definition and clinical spectrum" and "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)

Growth and cancer — Normal insulin secretion and action is critical to normal growth. Through both its anabolic effects on protein and lipid metabolism and its interactions with other mediators of growth (such as insulin-like growth factor [IGF]-1 and -2) and their receptors, insulin plays an important role in growth regulation. From the pathologic standpoint, it has been suggested that insulin, at high supraphysiologic levels, may possibly contribute to the development of a number of cancers including colorectal, ovarian, breast, and pancreatic cancer, but this remains to be fully elucidated.

Insulin and IGF-1 receptors are frequently overexpressed in breast cancer epithelial cells, with reported insulin receptor levels up to 10 times normal. This overexpression may confer a selective growth advantage to breast cancer cells, especially in the presence of hyperinsulinemia. Cross-sectional and prospective studies have found an association between higher fasting serum insulin concentrations and increased risk of breast cancer [53,54] and also poorer outcome in women with early breast cancer, independent of body mass index [55].

Epidemiological studies have also found an association between colorectal cancer and hyperinsulinemia [56,57]. These observations are consistent with in vivo and in vitro studies indicating that insulin stimulates the growth of colon epithelial and carcinoma cells [58,59]. Several models have been proposed for the role of insulin in colorectal carcinogenesis, including increased IGF-1 bioavailability via insulin-mediated changes in serum IGF-binding protein concentrations [60,61].

Hyperinsulinemia has been linked to an increased risk of pancreatic cancer in meta-analyses of epidemiological studies [62]. In vitro studies suggest that excessive insulin signaling may contribute to proliferation and survival in human immortalized pancreatic ductal cells and metastatic pancreatic cancer cells [63,64].

These epidemiology studies and observations cannot prove causality, however, and may indicate the presence of confounding and/or the presence of an underlying common factor.

Circulating levels of adiponectin, a hormone secreted by adipocytes that functions as an endogenous insulin sensitizer and lies upstream of insulin in the pathway linking central obesity with its comorbidities, have been inversely associated with risk for cancers of the endometrium, breast, and colon [65-68]. The mechanism by which adiponectin affects carcinogenesis remains to be fully elucidated; hypotheses include a direct effect of adiponectin on malignant cells and/or an indirect effect through low adiponectin increasing circulating insulin and IGF-1 levels as well as inflammation [69].

SUMMARY

●The initial step in insulin action is binding to the insulin receptor (figure 1), a transmembrane, multi-subunit glycoprotein that contains insulin-stimulated tyrosine kinase activity. (See 'Insulin signaling' above.)

●Insulin has a number of effects on glucose metabolism, including inhibition of glycogenolysis and gluconeogenesis, increased glucose transport into fat and muscle, increased glycolysis in fat and muscle, and stimulation of glycogen synthesis. (See 'Insulin and glucose metabolism' above.)

●Insulin serves to coordinate the use of alternative fuels (glucose and free fatty acids) to meet the energy demands of the organism during cycles of feeding and fasting and in response to exercise. In addition, insulin facilitates transport of amino acids into hepatocytes, skeletal muscle, and fibroblasts, which results in an increase in protein synthesis. (See 'Insulin and fat metabolism' above and 'Insulin and protein metabolism' above.)

●Insulin secretion occurs in close proximity to other hormone-secreting cells of the pancreatic islets, namely alpha and delta cells, which secrete glucagon and somatostatin, respectively. Insulin has paracrine effects on these neighboring cells. In addition, stimuli of insulin secretion, such as high serum glucose and amino acid concentrations, can directly alter the secretion of these other hormones. These alterations can in turn modulate the endocrine effects of insulin. (See 'Paracrine effects of insulin' above.)

●Insulin has actions beyond the realm of energy metabolism, including actions on steroidogenesis, vascular function, fibrinolysis, and growth. (See 'Other actions of insulin' above.)