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Insulin 

  • Author: Saranya Buppajarntham, MD; Chief Editor: Eric B Staros, MD  more...
 
Updated: Feb 14, 2014
 

Reference Range

Insulin is an anabolic hormone that promotes glucose uptake, glycogenesis, lipogenesis, and protein synthesis of skeletal muscle and fat tissue through the tyrosine kinase receptor pathway. In addition, insulin is the most important factor in the regulation of plasma glucose homeostasis, as it counteracts glucagon and other catabolic hormones—epinephrine, glucocorticoid, and growth hormone.

Table 1. Reference Range of Insulin Levels[1] (Open Table in a new window)

 Insulin Level Insulin Level (SI Units*)
Fasting< 25 mIU/L< 174 pmol/L
30 minutes after glucose administration30-230 mIU/L208-1597 pmol/L
1 hour after glucose administration18-276 mIU/L125-1917 pmol/L
2 hour after glucose administration16-166 mIU/L111-1153 pmol/L
≥3 hours after glucose administration< 25 mIU/L< 174 pmol/L
*SI unit: conversional units x 6.945
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Interpretation

A standard insulin test is positive for endogenous insulin and exogenous insulin. In addition, there is a minimal cross-reaction with proinsulin and insulinlike growth factors 1 and 2, with the degree of variability depending on the brand of the testing toolkit and technique used.

Insulin testing is used to assist in identifying causes of hypoglycemia (plasma glucose levels < 55 mg/dL), especially upon signs and symptoms of hypoglycemia (neurohypoglycopenic and autonomic symptoms). In this scenario, a 72-hour fasting test is performed.[2]

  • Insulinoma: High insulin and C-peptide levels
  • Non–beta cell tumors: Low insulin and C-peptide levels and high insulinlike growth factor 2 level[3]
  • Excessive insulin administration: High insulin levels and low C-peptide levels
  • Insulin secretagogue administration (sulfonylurea and glinides): High insulin and C-peptide levels
  • Congenital hyperinsulinism (mutation in insulin-secreting gene): High insulin and C-peptide levels
  • Autoimmunity to insulin or insulin receptor (common in patients receiving insulin or those who have autoimmune diseases such as systemic lupus erythematosus [SLE] or Hashimoto thyroiditis): Postprandial insulin is bound to antibodies and dissociated 1 hour later, resulting in an extremely elevated insulin level and high insulin–to–C-peptide ratio[4]

Table 2. Interpretation of 72-hour Fasting Test Results[2] (Open Table in a new window)

Condition Insulin C-Peptide Proinsulin Insulinlike Growth Factor 2 Sulfonylurea Glucose Level After Administration of Glucagon
Insulinoma
Non–beta cell tumors
Insulin injection
Sulfonylurea-induced

Conditions associated with elevated insulin levels

Conditions associated with increased insulin resistance[4, 5] (beta cell compensates via hypersecretion of insulin) include the following:

  • Obesity
  • Steroid administration
  • Acromegaly
  • Cushing syndrome
  • Insulin receptor mutation[4]
  • Type 2 diabetes (early stage)

Conditions associated with increased insulin secretion include the following:

  • Insulinoma (insulin or proinsulin secreting tumors)
  • Administration of insulin secretagogues

Excessive administration of insulin is associated with elevated insulin levels.

Conditions associated with decreased insulin excretion include the following[4] :

  • Severe liver disease
  • Severe heart failure (liver congestion)

Autoimmunity to insulin or insulin receptor is associated with elevated insulin levels.

Conditions associated with decreased insulin levels

Conditions associated with beta-cell destruction include the following:

  • Post pancreatectomy
  • Chronic pancreatitis
  • Autoimmune destruction
  • Type 1 diabetes

In type 2 diabetes (late stage), beta cells fail to secrete insulin for maintaining the blood glucose level, owing to insulin resistance and genetic defect.[6]

Increased insulinlike growth factor levels are associated with non–beta cell tumors.

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Collection and Panels

Method: Radioimmunoassay; enzyme-linked immunosorbent assay (ELISA)

Specifics for collection and panels are as follows:

  • Specimen type: Blood serum
  • Container: Vacutainer, red top
  • Collection method: Venipuncture
  • Specimen volume: 1 mL
  • Measure blood glucose and C-peptide level in same sample
  • An 8-hour fasting specimen required

Other instructions

A 72-hour fasting test is used to identify causes of postabsorptive hypoglycemia.[2] The patient is instructed to fast, and plasma glucose, insulin, proinsulin, and C-peptide levels are measured every 6 hours until the plasma glucose level is less than 65 mg/dL, after which the testing frequency is increased to every 1-2 hours. Fasting is ended when plasma glucose levels are less than 45 mg/dL accompanied by signs and symptoms of hypoglycemia. At the endpoint, a blood sample is collected and tested for glucose, insulin, proinsulin, C-peptide, beta-hydroxybutyrate, and sulfonylurea levels. The patient is given 1 mg of intravenous glucagon, and the response of the blood glucose level is measured.

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Background

Description

Biosynthesis[7, 4, 8]

Insulin is a peptide hormone that is secreted from beta cells of the islets of Langerhans in the pancreas. It is initially synthesized in endoplasmic reticulum and Golgi apparatus as proinsulin; it is then cleaved to insulin and C-peptide. Although insulin and C-peptide are cosecreted in equal molar proportions, the ratio of serum insulin to C-peptide is 1:5-15. Fifty to sixty percent of insulin is extracted by the liver before it reaches systemic circulation, and it has a half-life of only 4 minutes. In contrast, C-peptide and proinsulin are excreted via the kidney.[6]

Function

Insulin is an anabolic hormone that promotes glucose uptake, glycogenesis, lipogenesis, and protein synthesis of skeletal muscle and fat tissue through the tyrosine kinase receptor pathway. In addition, insulin is the most important factor in the regulation of plasma glucose homeostasis, as it counteracts glucagon and other catabolic hormones—epinephrine, glucocorticoid, and growth hormone.

Secretion

In normal physiology, insulin secretion is induced by elevated plasma glucose levels. Glucose diffuses to beta cells through glucose transporter 2 (GLUT2) and activates the glycolysis pathway, leading to elevated adenosine triphosphate (ATP) levels. Increasing ATP levels induce ATP-sensitive K+ channels to shut down and subsequently stimulate depolarization of the beta-cell membrane. Then, voltage-gate Ca2+ channels are opened to increase cytosolic Ca2+ and trigger insulin exocytosis.[6] However, high insulin levels in a hypoglycemic state have been found in a hypersecretory state; an example is insulinoma, in which insulin is secreted in at a high rate independent from the plasma glucose level.

Interestingly, oral administration of glucose is more effective in increasing insulin secretion than intravenous glucose (called "incretin effect"). Carbohydrate meals potentiate insulin secretion through multiple gastrointestinal hormones (incretin hormones), including cholecystokinin, glucagonlike peptide-1 (GLP-1), and gastric-inhibiting polypeptide (GIP).[6, 9]

Indications/Applications

Insulin testing is used to assist in identifying causes of hypoglycemia (plasma glucose levels < 55 mg/dL), especially upon signs and symptoms of hypoglycemia (neurohypoglycopenic and autonomic symptoms). In this scenario, a 72-hour fasting test is performed.[2]

Insulin testing is also used to assist in diagnosing early type 2 diabetes, in which there is a relatively increased production of insulin with a concurrent increase in blood glucose levels.

In addition, insulin testing is used to help differentiate type 1 and type 2 diabetes.

Considerations

Insulin levels may be falsely elevated by the following:

  • Amino acid (leucine, arginine, and lysine)
  • Steroid
  • Insulin secretagogue (sulfonylurea and glinide)
  • Estrogen[10]
  • Beta2 agonist

Insulin levels may be falsely decreased by the following:

  • Acarbose, metformin, octreotide, and beta-blocker
  • Hemolysis (insulin-degrading enzyme in red blood cell released)[4]
  • Hemodialysis
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Contributor Information and Disclosures
Author

Saranya Buppajarntham, MD Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center

Saranya Buppajarntham, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Coauthor(s)

Parichart Junpaparp, MD Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center

Parichart Junpaparp, MD is a member of the following medical societies: American College of Physicians, Medical Council of Thailand

Disclosure: Nothing to disclose.

Chief Editor

Eric B Staros, MD Associate Professor of Pathology, St Louis University School of Medicine; Director of Clinical Laboratories, Director of Cytopathology, Department of Pathology, St Louis University Hospital

Eric B Staros, MD is a member of the following medical societies: American Medical Association, American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology

Disclosure: Nothing to disclose.

Acknowledgements

Judy Lin, MD

Disclosure: Nothing to disclose.

References
  1. Melmed S, Polonsky KS, Larsen PR, Kronenberg HM. Williams Textbook of Endocrinology. 12th ed. Philadelphia: Elsevier Saunders; 2011.

  2. Wallach J. Interpretation of Diagnostic Tests. 6th ed. New York: Little, Brown; 1996.

  3. Rome DL. Insulin-like growth factors. N Engl J Med. 1997. 336:633-8.

  4. McPherson RA, Matthew R. Pincus MR. Henry's Clinical Diagnosis and Management by Laboratory Methods. 22nd ed. Philadelphia: Elsevier Saunders; 2011.

  5. Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, et al. Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008.

  6. Service FJ. Hypoglycemic disorders. N Engl J Med. 1995 Apr 27. 332(17):1144-52. [Medline].

  7. vanLeeuwen AM, Kranpitz TR, Smith LS. Davis’s Comprehensive Handbook of Laboratory and Diagnostic Tests-with Nursing Implications. 2nd ed. Philadelphia: F.A. Davis Company; 2006.

  8. Moller DE, Flier JS. Insulin resistance--mechanisms, syndromes, and implications. N Engl J Med. 1991 Sep 26. 325(13):938-48. [Medline].

  9. Burris CA, Ashwood ER, Burns DE. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 4th ed. St. Louis: Elsevier Saunders; 2006.

  10. Sharma G, Prossnitz ER. Mechanisms of estradiol-induced insulin secretion by the G protein-coupled estrogen receptor GPR30/GPER in pancreatic beta-cells. Endocrinology. 2011 Aug. 152(8):3030-9. [Medline]. [Full Text].

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Table 1. Reference Range of Insulin Levels[1]
 Insulin Level Insulin Level (SI Units*)
Fasting< 25 mIU/L< 174 pmol/L
30 minutes after glucose administration30-230 mIU/L208-1597 pmol/L
1 hour after glucose administration18-276 mIU/L125-1917 pmol/L
2 hour after glucose administration16-166 mIU/L111-1153 pmol/L
≥3 hours after glucose administration< 25 mIU/L< 174 pmol/L
*SI unit: conversional units x 6.945
Table 2. Interpretation of 72-hour Fasting Test Results[2]
Condition Insulin C-Peptide Proinsulin Insulinlike Growth Factor 2 Sulfonylurea Glucose Level After Administration of Glucagon
Insulinoma
Non–beta cell tumors
Insulin injection
Sulfonylurea-induced
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