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]

Overview

The pathophysiology of hypoglycemia depends on the failure of physiological defense mechanisms and hormones such as insulin, glucagon, 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 A, synaptophysin, and Ki-67 index.

Hypoglycemia pathophysiology

Physiological effect of insulin

1. Insulin binds to its receptor which involves many protein activation cascades.
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

Insulin is involved in many aspects of metabolism including:

• Insulin decreases blood glucose concentration by inducing uptake of the glucose by peripheral cells. This function is as a result of increased GLUT4 transporter insertion in the cell membrane of muscles and fat tissues which allows glucose to enter the cells.
• Increase of DNA replication and protein synthesis via control of amino acids uptake.
• Induction of glycogen synthesis when glucose levels are high.
• Increase of cellular potassium uptake.
• Decreased gluconeogenesis and glycogenolysis; decreased production of glucose from noncarbohydrate substrates, primarily in the liver (the vast majority of endogenous insulin arriving into the liver never leaves the liver).
• Increase of lipid synthesis: insulin forces fat cells to use blood glucose, which is converted into triglycerides; a decrease of insulin causes the reverse.
• Decrease in lipolysis: insulin forces reduction in conversion of fat cell lipid stores into blood fatty acids and glycerol; a decrease of insulin causes the reverse.
• Decrease in proteolysis: insulin decreases the breakdown of protein.
• Decrease of renal sodium excretion.

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. 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.

• Epinephrine

Epinephrine response to hypoglycemia becomes suppressed in many patients. This happens when blood glucose level falls between 65–70mmHg. A suppressed epinephrine response causes defective glucose counter-regulation and hypoglycemia unawareness occurs. 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:

• Insulinoma is a rare benign pancreatic neuroendocrine tumor that arises from β islet cells.^[1]
• It usually occurs sporadically but 10% are found to be associated with MEN 1 syndrome.^[2]
• It is thought that insulinoma is mediated by a mutation in mTOR/P70S6K signaling pathway. An oral mTOR inhibitor (Everolimus) may make better glycemic control in people having an insulinoma.^[4]
• Mitochondria plays a key role in glucose and insulin coupling to assure insulin secretion after glucose stimulation in pancreatic β cells. Coupling is impaired due to abnormal mitochondrial function in β cells causes the death of the cell.^[6]
• YY1 regulates this mitochondrial function.^[7] T372R mutation increases the transcription of YY1. The understanding of role and functions of YY1 in β cells in near future might prove to be therapeutic potentials.^[8]
• The progression to hypoglycemia is actually because of decreased glucose synthesis rather than increased use due to the direct effect of insulin on the liver.^[9]
• The neuroglycopenic symptoms appear eventually due to decreased blood glucose. Hypoglycemia stimulates catecholamine release which produces adrenergic symptoms.^[10]

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

• Non-islet-cell tumors are large tumors of mesenchymal or epithelial cell types originate from the pancreas.
• NICTH appears to be increased glucose utilization and inhibition of glucose release from the liver.
• This happens as a result of tumor production of incompletely processed IGF-2.
• Incompletely processed IGF-2 also suppresses glucagon and growth hormone release.
• The net result is continued glucose utilization by skeletal muscle and inhibition of glucose release, glycogenolysis, and gluconeogenesis in the liver.

Genetics

Genes associated with diabetes include the following:

• Currently, 58 genomic regions are found to be associated with type 1 diabetes mellitus (DM).
• The major susceptibility gene for type1 DM is located on HLA region of chromosome 6. It accounts for 40-50% of the genetic risk for type1 DM. This region encodes for class II major histocompatibility complex (MHC) molecules. Class II major histocompatibility complex (MHC) molecules play an important role in presenting antigen to helper T cells and initiating an immune response.
• Other major susceptibility genes which were associated with Type1 DM include polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin 2 receptor, CTLA4, and PTPN22.
• Presence of certain genes confers protection against the development of the disease. Haplotypes DQA1*0102, DQB1*0602 are extremely rare in individuals with type1 DM (<1%) and appears to provide protection from type1 DM.

Genetics associated with:

• Deregulation of imprinted gene expression in the chromosome 11p15.5 region can result in the BWS phenotype.
• The critical BWS genes in that region include insulin-like growth factor 2 (IGF2), H19, cyclin-dependent kinase inhibitor 1C (CDKN1C), potassium channel voltage-gated KQT-like subfamily member 1 (KCNQ1), and KCNQ1-overlapping transcript 1 (KCNQ1OT1, or long QT intronic transcript 1).

Gross pathology

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

• On gross pathology, insulinomas have a grey to red-brown appearance, encapsulated and are usually small and solitary tumors.
• Insulinoma is firm, homogeneous, pedunculated and rarely weighing more than 100g.

• Almost all insulinomas arises from pancreas, extrapancreatic ones causing hypoglycemia are rare.
• Tumors may have a cystic component.
• Lipid-rich insulinomas mimic adrenal cortical neoplasia.
• Features of malignancy: Large size, invasion to fibro-adipose tissue, invasion to adjacent organs, and invasion to large vessels.

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

• 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 (mitosis per 10 high-power fields) and immunohistochemistry staining by Chromogranin A, synaptophysin, and Ki-67 index.
• The structure of tumor cells observed under electron microscopy as group A characterized by abundant well-granulated typical B cells with the trabecular arrangement and group B as scarce well-granulated typical B cells and a medullary arrangement.

• 
  Histopathology of a pancreatic endocrine tumor (insulinoma). Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas
• 
  Histopathology of a pancreatic endocrine tumor (insulinoma). Chromogranin A immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas
• 
  Histopathology of a pancreatic endocrine tumor (insulinoma). Insulin immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas