Hypoglycemia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2] Amandeep Singh M.D.[3]


The pathophysiology of hypoglycemia depends on the failure of physiological defense mechanisms and hormones such as insulinglucagon, and epinephrine to correct hypoglycemia. Most of these defense mechanisms are hormones that control glycogenolysis and gluconeogenesis. Insulinoma is a rare benign pancreatic neuroendocrine tumor that arises from β islet cells. It is mediated by a mutation in mTOR/P70S6K signaling pathway. Non-islet-cell tumors (NICTH) are large tumors of mesenchymal or epithelial cell types originate from the pancreas. Hypoglycemia due to NICTH appears to be related to increased glucose utilization and inhibition of glucose release from the liver. This happens as a result of tumor production of incompletely processed IGF-2. On gross pathology insulinomas have a gray to red-brown appearance, encapsulated and are usually small and solitary tumors. On microscopic histopathological analysis, patterns like trabecular, gyriform, lobular and solid structures, particularly with amyloid in a fibrovascular stroma, are characteristic findings of insulinoma. It is also evaluated for the mitotic index and immunohistochemistry staining by Chromogranin Asynaptophysin, and Ki-67 index.

Hypoglycemia pathophysiology

Physiological effect of insulin

  1. Insulin binds to its receptor which involves many protein activation cascades.[1]
  2. Binding of insulin to the α-subunit results in changes which activate tyrosine kinase domains on each β-subunit.
  3. The tyrosine kinase activity causes phosphorylation of intracellular enzymes.
  4. The phosphorylation of MAP-Kinase leads to induction of gene expression.
  5. Phosphorylation of PI-3K isolates the GLUT-4 Vesicle and sends the vesicles back to the cell membrane.
  6. The GLUT-4 vesicles fuse with the cellular membrane allowing glucose to be transported into the cell.
thumb: Insulin cellular effect, source: Wikipedia
thumb: Insulin cellular effect, source: Wikipedia

Insulin is involved in many aspects of metabolism including:[2]

Pathogenesis of hypoglycemia in diabetics

The pathophysiology of hypoglycemia mainly relies on the failure of physiological defense mechanisms and hormones such as insulin, glucagon and epinephrine to correct hypoglycemia. Most of these hormones control glycogenolysis and gluconeogenesis, including:

  • Insulin

The most important and the first mechanism to counter-regulate hypoglycemia is the ability to suppress insulin release. This happens early when blood glucose level is between 80–85 mmHg. This can not occur in patients with absolute beta-cell failure, type 1 diabetes mellitus, and long-standing type 2 diabetes.[3] High insulin levels inhibit hepatic glycogenolysis causing more hypoglycemia.

  • Glucagon

Hypoglycemia stimulates secretion of glucagon. This happens when blood glucose level falls between 65–70 mmHg. Failure to secrete glucagon may be the result of beta-cell failure and high insulin level that inhibits glucagon secretion.[4]

  • Epinephrine

Epinephrine response to hypoglycemia becomes suppressed in many patients.[5] This happens when blood glucose level falls between 65–70mmHg. A suppressed epinephrine response causes defective glucose counter-regulation and hypoglycemia unawareness occurs.[6] This may be due to shifting the glycemic threshold for the sympathoadrenal response to a lower plasma glucose concentration. The brain is the first organ to be affected by decreased blood glucose level. Impairment of judgment and Seizures may occur resulting in coma.

Pathogenesis of hypoglycemia in insulinoma:

Pathogenesis of hypoglycemia in non-islet-cell tumors hypoglycemia (NICTH):


Genes associated with diabetes include the following:[10][11]

Genetics associated with:[12]

Gross pathology

One of the causes of hypoglycemia is insulinoma. The gross pathology of insulinoma is described below:

Gross pathology of insulinoma, source: By Edward Alabraba et al. - Pancreatic insulinoma co-existing with gastric GIST in the absence of neurofibromatosis-1. World Journal of Surgical Oncology 2009, 7:18doi:10.1186/1477-7819-7-18, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=6686376

Microscopic pathology


  1. Ahmad K (2014). "Insulin sources and types: a review of insulin in terms of its mode on diabetes mellitus". J Tradit Chin Med. 34 (2): 234–7. PMID 24783939.
  2. Dunning BE, Gerich JE (2007). "The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications". Endocr Rev. 28 (3): 253–83. doi:10.1210/er.2006-0026. PMID 17409288.
  3. Raju B, Cryer PE (2005). "Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans". Diabetes. 54 (3): 757–64. PMID 15734853.
  4. Dagogo-Jack SE, Craft S, Cryer PE (1993). "Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia". J Clin Invest. 91 (3): 819–28. doi:10.1172/JCI116302. PMC 288033. PMID 8450063.
  5. Geddes J, Schopman JE, Zammitt NN, Frier BM (2008). "Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes". Diabet Med. 25 (4): 501–4. doi:10.1111/j.1464-5491.2008.02413.x. PMID 18387080.
  6. Rizza RA, Haymond MW, Verdonk CA, Mandarino LJ, Miles JM, Service FJ; et al. (1981). "Pathogenesis of hypoglycemia in insulinoma patients: suppression of hepatic glucose production by insulin". Diabetes. 30 (5): 377–81. PMID 6262168.
  7. Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER; et al. (2009). "Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 94 (3): 709–28. doi:10.1210/jc.2008-1410. PMID 19088155.
  8. 9.0 9.1 Dynkevich Y, Rother KI, Whitford I, Qureshi S, Galiveeti S, Szulc AL; et al. (2013). "Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive". Endocr Rev. 34 (6): 798–826. doi:10.1210/er.2012-1033. PMID 23671155.
  9. Pociot F, Lernmark Å (2016). "Genetic risk factors for type 1 diabetes". Lancet. 387 (10035): 2331–9. doi:10.1016/S0140-6736(16)30582-7. PMID 27302272.
  10. Højlund K, Hansen T, Lajer M, Henriksen JE, Levin K, Lindholm J; et al. (2004). "A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene". Diabetes. 53 (6): 1592–8. PMID 15161766.
  11. Weksberg R, Shuman C, Smith AC (2005). "Beckwith-Wiedemann syndrome". Am J Med Genet C Semin Med Genet. 137C (1): 12–23. doi:10.1002/ajmg.c.30058. PMID 16010676.
  12. Mittendorf EA, Liu YC, McHenry CR (2005). "Giant insulinoma: case report and review of the literature". J Clin Endocrinol Metab. 90 (1): 575–80. doi:10.1210/jc.2004-0825. PMID 15522939.
  13. Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y; et al. (2013). "Diagnosis and management of insulinoma". World J Gastroenterol. 19 (6): 829–37. doi:10.3748/wjg.v19.i6.829. PMC 3574879. PMID 23430217.
  14. de Herder WW, Niederle B, Scoazec JY, Pauwels S, Kloppel G, Falconi M; et al. (2006). "Well-differentiated pancreatic tumor/carcinoma: insulinoma". Neuroendocrinology. 84 (3): 183–8. doi:10.1159/000098010. PMID 17312378.
  15. Lloyd, Ricardo (2010). Endocrine pathology : differential diagnosis and molecular advances. New York London: Springer. ISBN 978-1441910684.
  16. de Herder, Wouter W.; Niederle, Bruno; Scoazec, Jean-Yves; Pauwels, Stanislas; Klöppel, Günter; Falconi, Massimo; Kwekkeboom, Dik J.; Öberg, Kjel; Eriksson, Barbro; Wiedenmann, Bertram; Rindi, Guido; O’Toole, Dermot; Ferone, Diego (2007). "Well-Differentiated Pancreatic Tumor/Carcinoma: Insulinoma". Neuroendocrinology. 84 (3): 183–188. doi:10.1159/000098010. ISSN 0028-3835.
  17. 18.0 18.1 18.2 Neuroendocrine tumor of the pancreas. Libre Pathology. http://librepathology.org/wiki/index.php/Neuroendocrine_tumour_of_the_pancreas