8/28/2014 Insulin action

http://www.uptodate.com/contents/insulin-action?topicKey=ENDO%2F1789&elapsedTimeMs=0&source=search_result&searchTerm=insulin&selectedTitle=4% 1/5
Official reprint from UpToDate
www.uptodate.com 2014 UpToDate
Authors
Christos Mantzoros, MD, DSc
Shanti Serdy, MD
Section Editor
David M Nathan, MD
Deputy Editor
Jean E Mulder, MD
Insulin action
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2014. | This topic last updated: Aug 14, 2014.
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 structure and function of the insulin
receptor and details of insulin secretion are reviewed separately. (See "Structure and function of the insulin
receptor" and "Insulin secretion and 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. Binding of insulin to the receptor
results in conformational change of the alpha-subunits that enables adenosine triphosphate (ATP) binding to the
beta-subunits 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. The biochemistry of insulin action is reviewed in
detail separately. (See "Structure and function of the insulin receptor".)
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 1).
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
8/28/2014 Insulin action
http://www.uptodate.com/contents/insulin-action?topicKey=ENDO%2F1789&elapsedTimeMs=0&source=search_result&searchTerm=insulin&selectedTitle=4% 2/5
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 counter-regulation 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 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
8/28/2014 Insulin action
http://www.uptodate.com/contents/insulin-action?topicKey=ENDO%2F1789&elapsedTimeMs=0&source=search_result&searchTerm=insulin&selectedTitle=4% 3/5
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 extra-hepatic 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.
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 cAMP levels, thus inhibiting the
cyclic AMP-dependent protein kinase responsible for phosphorylating and activating hormone-sensitive lipase
[23,24].

8/28/2014 Insulin action

http://www.uptodate.com/contents/insulin-action?topicKey=ENDO%2F1789&elapsedTimeMs=0&source=search_result&searchTerm=insulin&selectedTitle=4% 4/5
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
ovarian 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
"Endothelial dysfunction".)
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. Common disorders associated with hyperinsulinemia are discussed
further separately. (See "Insulin resistance: Definition and clinical spectrum" and "The 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
pathological standpoint, there is considerable evidence that insulin contributes to the development of several
cancers including colorectal, ovarian, and breast cancer.
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 [52,53] and
also poorer outcome in women with early breast cancer, independent of body mass index [54].
Epidemiological studies have also found an association between colorectal cancer and hyperinsulinemia [55,56].
These observations are consistent with in vivo and in vitro studies indicating that insulin stimulates the growth of
colon epithelial and carcinoma cells [57,58]. 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 (for a review, see [59,60]).
Circulating levels of adiponectin, a hormone secreted by adipocytes that functions as an endogenous insulin
sensitizer, have been inversely associated with risk for cancers of the endometrium, breast, and colon [61-64]. The
8/28/2014 Insulin action
http://www.uptodate.com/contents/insulin-action?topicKey=ENDO%2F1789&elapsedTimeMs=0&source=search_result&searchTerm=insulin&selectedTitle=4% 5/5
mechanism by which adiponectin affects carcinogenesis is unknown; hypotheses include a direct effect of
adiponectin on malignant cells or an indirect effect through decreases in circulating insulin and IGF-1 levels [65].
SUMMARY
Use of UpToDate is subject to the Subscription and License Agreement.
Topic 1789 Version 6.0
The initial step in insulin action is binding to the insulin receptor, a transmembrane, multi-subunit glycoprotein
that contains insulin-stimulated tyrosine kinase activity. (See 'Insulin signaling' above and "Structure and
function of the insulin receptor".)

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.)