Insulin Action - UpToDate

Insulin action - UpToDate 10/6/20, 10(13 AM
Official reprint from UpToDate®

www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Insulin action
Authors: Christos Mantzoros, MD, DSc, Shanti Serdy, MD
Section Editor: David M Nathan, MD
Deputy Editor: Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2020. | This topic last updated: Jun 02, 2020.
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 "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-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. The biochemistry of insulin action is reviewed in detail separately.
https://www.uptodate.com/contents/insulin-action/print?search=resist…search_result&selectedTitle=2~150&usage_type=default&display_rank=2 Page 1 of 21
(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
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, 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.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of insulin
resistance. J Clin Invest 2000; 106:165.
2. Previs SF, Withers DJ, Ren JM, et al. Contrasting effects of IRS-1 versus IRS-2 gene
disruption on carbohydrate and lipid metabolism in vivo. J Biol Chem 2000; 275:38990.
3. Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the
mechanism. Lancet 2010; 375:2267.
4. Kido Y, Nakae J, Accili D. Clinical review 125: The insulin receptor and its cellular targets.
J Clin Endocrinol Metab 2001; 86:972.
5. Stumvoll M, Meyer C, Mitrakou A, et al. Renal glucose production and utilization: new
aspects in humans. Diabetologia 1997; 40:749.
6. Woerle HJ, Meyer C, Popa EM, et al. Renal compensation for impaired hepatic glucose
release during hypoglycemia in type 2 diabetes: further evidence for hepatorenal
reciprocity. Diabetes 2003; 52:1386.
7. Ramnanan CJ, Edgerton DS, Rivera N, et al. Molecular characterization of insulin-

mediated suppression of hepatic glucose production in vivo. Diabetes 2010; 59:1302.
8. Philippe J. Insulin regulation of the glucagon gene is mediated by an insulin-responsive

DNA element. Proc Natl Acad Sci U S A 1991; 88:7224.
9. Sindelar DK, Balcom JH, Chu CA, et al. A comparison of the effects of selective increases
in peripheral or portal insulin on hepatic glucose production in the conscious dog.
Diabetes 1996; 45:1594.
10. Edgerton DS, Lautz M, Scott M, et al. Insulin's direct effects on the liver dominate the
control of hepatic glucose production. J Clin Invest 2006; 116:521.
https://www.uptodate.com/contents/insulin-action/print?search=resis…search_result&selectedTitle=2~150&usage_type=default&display_rank=2 Page 10 of 21
11. Girard J. Insulin's effect on the liver: "direct or indirect?" continues to be the question. J
Clin Invest 2006; 116:302.
12. Kahn BB. Lilly lecture 1995. Glucose transport: pivotal step in insulin action. Diabetes
1996; 45:1644.
13. Burcelin R, Crivelli V, Perrin C, et al. GLUT4, AMP kinase, but not the insulin receptor, are
required for hepatoportal glucose sensor-stimulated muscle glucose utilization. J Clin
Invest 2003; 111:1555.
14. Mandarino LJ, Printz RL, Cusi KA, et al. Regulation of hexokinase II and glycogen
synthase mRNA, protein, and activity in human muscle. Am J Physiol 1995; 269:E701.
15. Hue L, Rider MH. Role of fructose 2,6-bisphosphate in the control of glycolysis in
mammalian tissues. Biochem J 1987; 245:313.
16. Farese RV Jr, Yost TJ, Eckel RH. Tissue-specific regulation of lipoprotein lipase activity by
insulin/glucose in normal-weight humans. Metabolism 1991; 40:214.
17. Fielding BA, Frayn KN. Lipoprotein lipase and the disposition of dietary fatty acids. Br J
Nutr 1998; 80:495.
18. Vaughan M, Steinberg D. Glyceride biosynthesis, glyceride breakdown, and glycogen br

eakdown in adipose tissue: Mechanism and regulation. In: Handbook of physiology: Adi
pose tissue, Renold AE, Cahill GF (Eds), American Physiological Society, Washington, DC
1965. Vol 24, p.239.
19. Strålfors P, Björgell P, Belfrage P. Hormonal regulation of hormone-sensitive lipase in

intact adipocytes: identification of phosphorylated sites and effects on the
phosphorylation by lipolytic hormones and insulin. Proc Natl Acad Sci U S A 1984;
81:3317.
20. Zimmermann R, Lass A, Haemmerle G, Zechner R. Fate of fat: the role of adipose
triglyceride lipase in lipolysis. Biochim Biophys Acta 2009; 1791:494.
21. Lass A, Zimmermann R, Oberer M, Zechner R. Lipolysis - a highly regulated multi-
enzyme complex mediates the catabolism of cellular fat stores. Prog Lipid Res 2011;
50:14.
22. Enoksson S, Degerman E, Hagström-Toft E, et al. Various phosphodiesterase subtypes

mediate the in vivo antilipolytic effect of insulin on adipose tissue and skeletal muscle in
man. Diabetologia 1998; 41:560.
23. Strålfors P, Honnor RC. Insulin-induced dephosphorylation of hormone-sensitive lipase.

Correlation with lipolysis and cAMP-dependent protein kinase activity. Eur J Biochem
1989; 182:379.
24. Duncan RE, Ahmadian M, Jaworski K, et al. Regulation of lipolysis in adipocytes. Annu
Rev Nutr 2007; 27:79.
25. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients
with diabetes. Diabetes Care 2009; 32:1335.
26. Keller U, Gerber PP, Stauffacher W. Fatty acid-independent inhibition of hepatic ketone
body production by insulin in humans. Am J Physiol 1988; 254:E694.
27. Keller U, Lustenberger M, Stauffacher W. Effect of insulin on ketone body clearance

studied by a ketone body "clamp" technique in normal man. Diabetologia 1988; 31:24.
28. Jefferson LS. Lilly Lecture 1979: role of insulin in the regulation of protein synthesis.
Diabetes 1980; 29:487.
29. Flakoll PJ, Kulaylat M, Frexes-Steed M, et al. Amino acids augment insulin's suppression
of whole body proteolysis. Am J Physiol 1989; 257:E839.
30. Rosenfield RL, Barnes RB, Cara JF, Lucky AW. Dysregulation of cytochrome P450c 17
alpha as the cause of polycystic ovarian syndrome. Fertil Steril 1990; 53:785.
31. Adashi EY, Hsueh AJ, Yen SS. Insulin enhancement of luteinizing hormone and follicle-
stimulating hormone release by cultured pituitary cells. Endocrinology 1981; 108:1441.
32. Adashi EY, Resnick CE, D'Ercole AJ, et al. Insulin-like growth factors as intraovarian
regulators of granulosa cell growth and function. Endocr Rev 1985; 6:400.
33. Veldhuis JD, Zhang G, Garmey JC. Troglitazone, an insulin-sensitizing thiazolidinedione,

represses combined stimulation by LH and insulin of de novo androgen biosynthesis by
thecal cells in vitro. J Clin Endocrinol Metab 2002; 87:1129.
34. Arslanian SA, Lewy V, Danadian K, Saad R. Metformin therapy in obese adolescents with
polycystic ovary syndrome and impaired glucose tolerance: amelioration of
exaggerated adrenal response to adrenocorticotropin with reduction of
insulinemia/insulin resistance. J Clin Endocrinol Metab 2002; 87:1555.
35. Book CB, Dunaif A. Selective insulin resistance in the polycystic ovary syndrome. J Clin
Endocrinol Metab 1999; 84:3110.
36. Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology,
pathogenesis and diagnosis. Nat Rev Endocrinol 2011; 7:219.
37. Abrahamson, DI, Schkloven, et al. Influence of massive doses of insulin on peripheral
blood flow in man. Am J Physiol 1939; 128:124.
38. Steinberg HO, Brechtel G, Johnson A, et al. Insulin-mediated skeletal muscle

vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide
release. J Clin Invest 1994; 94:1172.
39. Hartell NA, Archer HE, Bailey CJ. Insulin-stimulated endothelial nitric oxide release is
calcium independent and mediated via protein kinase B. Biochem Pharmacol 2005;
69:781.
40. Tabit CE, Chung WB, Hamburg NM, Vita JA. Endothelial dysfunction in diabetes mellitus:
molecular mechanisms and clinical implications. Rev Endocr Metab Disord 2010; 11:61.
41. Johnstone MT, Creager SJ, Scales KM, et al. Impaired endothelium-dependent
vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993;
88:2510.
42. Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the
human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest
1992; 90:2548.
43. Williams SB, Cusco JA, Roddy MA, et al. Impaired nitric oxide-mediated vasodilation in
patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996; 27:567.
44. McVeigh GE, Brennan GM, Johnston GD, et al. Impaired endothelium-dependent and
independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes
mellitus. Diabetologia 1992; 35:771.
45. Williams SB, Goldfine AB, Timimi FK, et al. Acute hyperglycemia attenuates
endothelium-dependent vasodilation in humans in vivo. Circulation 1998; 97:1695.
46. Davidson JA, Parkin CG. Is hyperglycemia a causal factor in cardiovascular disease? Does
proving this relationship really matter? Yes. Diabetes Care 2009; 32 Suppl 2:S331.
47. Banskota NK, Taub R, Zellner K, King GL. Insulin, insulin-like growth factor I and platelet-
derived growth factor interact additively in the induction of the protooncogene c-myc
and cellular proliferation in cultured bovine aortic smooth muscle cells. Mol Endocrinol
1989; 3:1183.
48. Juhan-Vague I, Alessi MC, Vague P. Thrombogenic and fibrinolytic factors and
cardiovascular risk in non-insulin-dependent diabetes mellitus. Ann Med 1996; 28:371.
49. Schneider DJ, Nordt TK, Sobel BE. Attenuated fibrinolysis and accelerated atherogenesis
in type II diabetic patients. Diabetes 1993; 42:1.
50. Nordt TK, Sawa H, Fujii S, Sobel BE. Induction of plasminogen activator inhibitor type-1
(PAI-1) by proinsulin and insulin in vivo. Circulation 1995; 91:764.
51. Calles-Escandon J, Mirza SA, Sobel BE, Schneider DJ. Induction of hyperinsulinemia
combined with hyperglycemia and hypertriglyceridemia increases plasminogen
activator inhibitor 1 in blood in normal human subjects. Diabetes 1998; 47:290.
52. Schneider DJ, Sobel BE. PAI-1 and diabetes: a journey from the bench to the bedside.
Diabetes Care 2012; 35:1961.
53. Del Giudice ME, Fantus IG, Ezzat S, et al. Insulin and related factors in premenopausal
breast cancer risk. Breast Cancer Res Treat 1998; 47:111.
54. Gunter MJ, Hoover DR, Yu H, et al. Insulin, insulin-like growth factor-I, and risk of breast
cancer in postmenopausal women. J Natl Cancer Inst 2009; 101:48.
55. Goodwin PJ, Ennis M, Pritchard KI, et al. Fasting insulin and outcome in early-stage
breast cancer: results of a prospective cohort study. J Clin Oncol 2002; 20:42.
56. Kaaks R, Toniolo P, Akhmedkhanov A, et al. Serum C-peptide, insulin-like growth factor
(IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst
2000; 92:1592.
57. Schoen RE, Tangen CM, Kuller LH, et al. Increased blood glucose and insulin, body size,
and incident colorectal cancer. J Natl Cancer Inst 1999; 91:1147.
58. Koohestani N, Tran TT, Lee W, et al. Insulin resistance and promotion of aberrant crypt
foci in the colons of rats on a high-fat diet. Nutr Cancer 1997; 29:69.
59. Watkins LF, Lewis LR, Levine AE. Characterization of the synergistic effect of insulin and
transferrin and the regulation of their receptors on a human colon carcinoma cell line.
Int J Cancer 1990; 45:372.
60. Sandhu MS, Dunger DB, Giovannucci EL. Insulin, insulin-like growth factor-I (IGF-I), IGF
binding proteins, their biologic interactions, and colorectal cancer. J Natl Cancer Inst
2002; 94:972.
61. Moschos SJ, Mantzoros CS. The role of the IGF system in cancer: from basic to clinical
studies and clinical applications. Oncology 2002; 63:317.
62. Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch

Physiol Biochem 2008; 114:63.
63. Chan MT, Lim GE, Skovsø S, et al. Effects of insulin on human pancreatic cancer
progression modeled in vitro. BMC Cancer 2014; 14:814.
64. Trajkovic-Arsic M, Kalideris E, Siveke JT. The role of insulin and IGF system in pancreatic
cancer. J Mol Endocrinol 2013; 50:R67.
65. Petridou E, Mantzoros C, Dessypris N, et al. Plasma adiponectin concentrations in

relation to endometrial cancer: a case-control study in Greece. J Clin Endocrinol Metab
2003; 88:993.
66. Mantzoros C, Petridou E, Dessypris N, et al. Adiponectin and breast cancer risk. J Clin
Endocrinol Metab 2004; 89:1102.
67. Dal Maso L, Augustin LS, Karalis A, et al. Circulating adiponectin and endometrial cancer
risk. J Clin Endocrinol Metab 2004; 89:1160.
68. Wei EK, Giovannucci E, Fuchs CS, et al. Low plasma adiponectin levels and risk of
colorectal cancer in men: a prospective study. J Natl Cancer Inst 2005; 97:1688.
69. Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review
of current evidence. Endocr Rev 2012; 33:547.
Topic 1789 Version 11.0
GRAPHICS
Regulation of insulin release
Factors that stimulate insulin release

Glucose, mannose
Leucine
Vagal stimulation
Sulfonylurea drugs
Factors that amplify glucose-induced insulin release

Enteric hormones
Glucagon-like peptide 1
Gastric inhibitory peptide
Cholecystokinin
Secretin
Gastrin
Neural amplifiers
Beta-adrenergic stimulation
Amino acids
Arginine
Prostaglandin E2
Inhibitors of insulin release

Neural
Alpha-adrenergic effect
Humoral
Somatostatin
Drugs
Diazoxide
Phenytoin
Vinblastine
Colchicine
Reproduced with permission from: Masharani U, Karam JH. Pancreatic hormones and diabetes mellitus. In: Basic and Clinical
Endocrinology, 6th ed, Greenspan, FS, Gardner, DC (eds), McGraw-Hill, 2001. p. 627. Copyright © 2001. McGraw-Hill Companies, Inc.
Graphic 53967 Version 2.0
Metabolic actions of insulin on lipid and protein metabolism
Glucose metabolism (see text)
Lipid metabolism
Inhibition of lipolysis in fat; decreased plasma fatty acid concentrations
Stimulation of fatty acid and triacylglycerol synthesis in fat and liver
Increased lipoprotein lipase activity in fat; increased triglyceride uptake into fat
Decreased fatty acid oxidation in muscle and liver
Increased rate of formation of very-low-density lipoproteins in liver
Protein metabolism
Increased transport of some amino acids into muscle, adipose tissue, liver and other cells
Increased rate of protein synthesis in muscle, adipose tissue, liver and other tissues
Decreased proteolysis in muscle
Decreased urea formation
Schem reg glucose metab
Reproduced with permission from: Cryer PE, Polonsky KS. Glucose homeostasis and hypoglycemia. In:
Williams Textbook of Endocrinology, 9th ed, Wilson, JD, Foster, DW, Kronenberg, HM, Larsen, PR (Eds), WB
Saunders Co., Philadelphia 1998. p.940. Copyright ©1998 Elsevier Science.
Glucose transporters
Intestine, kidney: energy-dependent sodium/glucose co-transporters
Other cells: diffusion via GLUTs 1 to 5
GLUT-1: All human tissues; high affinity; basal glucose uptake; central nervous system, vessels
GLUT-2: Beta cells, liver; low-affinity; post-prandial action
GLUT-3: All tissues; major transporter in neurons of central nervous system
GLUT-4: Skeletal muscle, fat cells; insulin stimulates translocation from cytosol to cell membranes
GLUT-5: Brush border of intestinal cells, liver, spermatozoa; primarily transports fructose
Contributor Disclosures
Christos Mantzoros, MD, DSc Equity Ownership/Stock Options: Coherus [Drug development company –
nothing is FDA approved and nothing in the pipeline is in relation to my topics]; Pangea [Meal delivery
company]. Grant/Research/Clinical Trial Support: Esai [Obesity]; Novo Nordisk [Diabetes and obesity];
Coherus [Diabetes]. Consultant/Advisory Boards: Novo Nordisk [Obesity]; Regeneron [Diagnostics]; Ansh
Labs [Diagnostics]. Shanti Serdy, MD Nothing to disclose David M Nathan, MD Grant/Research/Clinical
Trial Support: Abbott [Diabetes]. Jean E Mulder, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

Insulin Action - UpToDate

Uploaded by

Copyright:

Available Formats

You might also like

Insulin Action - UpToDate

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Insulin Action - UpToDate

Uploaded by

Copyright:

Available Formats

Insulin action - UpToDate 10/6/20, 10(13 AM

Official reprint from UpToDate®

(See "Structure and function of the insulin receptor".)

Through activation of these signaling pathways, insulin acts as a powerful regulator of

METABOLIC EFFECTS OF INSULIN

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

● Inhibition of glycogenolysis and gluconeogenesis

● Insulin inhibits lipolysis of stored triglycerides by inhibiting hormone-sensitive lipase, the

activates a protein phosphatase that subsequently dephosphorylates and inactivates

Insulin and ketone body metabolism — Under hypoinsulinemic conditions, such as

By inhibiting gluconeogenesis, insulin maintains the availability of amino acids as substrates

PARACRINE EFFECTS OF INSULIN

OTHER ACTIONS OF INSULIN

Steroidogenesis — Insulin resistance is common in women with the polycystic ovary

Fibrinolysis — Epidemiological studies suggest that decreased fibrinolysis is associated with

Hyperinsulinemia has been linked to an increased risk of pancreatic cancer in meta-analyses

Circulating levels of adiponectin, a hormone secreted by adipocytes that functions as an

carcinogenesis remains to be fully elucidated; hypotheses include a direct effect of

● Insulin has a number of effects on glucose metabolism, including inhibition of

● Insulin secretion occurs in close proximity to other hormone-secreting cells of the

Use of UpToDate is subject to the Subscription and License Agreement.

7. Ramnanan CJ, Edgerton DS, Rivera N, et al. Molecular characterization of insulin-

8. Philippe J. Insulin regulation of the glucagon gene is mediated by an insulin-responsive

18. Vaughan M, Steinberg D. Glyceride biosynthesis, glyceride breakdown, and glycogen br

19. Strålfors P, Björgell P, Belfrage P. Hormonal regulation of hormone-sensitive lipase in

21. Lass A, Zimmermann R, Oberer M, Zechner R. Lipolysis - a highly regulated multi-

22. Enoksson S, Degerman E, Hagström-Toft E, et al. Various phosphodiesterase subtypes

23. Strålfors P, Honnor RC. Insulin-induced dephosphorylation of hormone-sensitive lipase.

27. Keller U, Lustenberger M, Stauffacher W. Effect of insulin on ketone body clearance

33. Veldhuis JD, Zhang G, Garmey JC. Troglitazone, an insulin-sensitizing thiazolidinedione,

38. Steinberg HO, Brechtel G, Johnson A, et al. Insulin-mediated skeletal muscle

62. Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch

65. Petridou E, Mantzoros C, Dessypris N, et al. Plasma adiponectin concentrations in

Topic 1789 Version 11.0

Regulation of insulin release

Factors that stimulate insulin release

Factors that amplify glucose-induced insulin release

Gastric inhibitory peptide

Inhibitors of insulin release

Graphic 53967 Version 2.0

Metabolic actions of insulin on lipid and protein metabolism

Glucose metabolism (see text)

Stimulation of fatty acid and triacylglycerol synthesis in fat and liver

Decreased fatty acid oxidation in muscle and liver

Increased rate of formation of very-low-density lipoproteins in liver

Decreased proteolysis in muscle

Decreased urea formation

Graphic 63558 Version 2.0

Schem reg glucose metab

Graphic 82039 Version 2.0

Intestine, kidney: energy-dependent sodium/glucose co-transporters

Other cells: diffusion via GLUTs 1 to 5

GLUT-2: Beta cells, liver; low-affinity; post-prandial action

GLUT-3: All tissues; major transporter in neurons of central nervous system

Graphic 67470 Version 1.0

Conflict of interest policy

You might also like