Hyperosmolar hyperglycemic state pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

The exact pathogenesis of [disease name] is not fully understood.

OR

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

OR

[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

OR

[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

OR

The progression to [disease name] usually involves the [molecular pathway].

OR

The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

Glucose homeostasis

Anabolic state during meals

• During fed state, high glycemic levels cause increased insulin release from pancreatic beta cells.
• Increased insulin levels inhibit glucagon from pancreatic alpha cells which lead to increase insulin-to-glucagon ratio.
• High insulin-to-glucagon ratio favors anabolic state during which insulin mediated uptake of glucose occurs in liver and muscle which is stored as glycogen.
• Insulin dependent uptake of glucose also drives potassium into the cells.
• The high insulin-to-glucagon ratio also favors uptake of amino acids by muscle.

Catabolic state between meals

• Between meals, the decrease in insulin and rise in glucagon leads to low plasma insulin-to-glucagon ratio which favors the catabolic state.
• During catabolic state, the breakdown of glycogen in the liver and muscle and gluconeogenesis by the liver occurs.
• Both these processes maintain plasma glucose concentration in the normal range.
• The low insulin-to-glucagon ratio also favors lipolysis and ketone body formation.
• Several insulin-independent tissues like brain and kidneys use glucose regardless of the insulin-to-glucagon ratio.

Pathogenesis

The progression to hyperosmolar hyperglycemic state (HHS) can occur due to the reduction in the net effective concentration of insulin relative to glucagon and other counterregulatory stress hormones (catecholamines, cortisol, and growth hormone), which can be seen in a multitude of settings.

• In type 1 diabetics, there is an immune-associated destruction of insulin-producing pancreatic β cells, which leads to no or decreased levels of insulin in the body.
• In type 2 diabetics, although the major mechanism of hyperglycemia is peripheral insulin resistance and there is some basal production of insulin; patients may develop a failure of pancreatic β cells at late stages of the disease.
• Increased levels of counterregulatory stress hormones can also cause insulin resistance. The levels of counterregulatory stress hormones can increase during an acute illness (eg, infections like genitourinary or pulmonary, myocardial infarction [MI], or pancreatitis), stress (eg, surgery or injuries), when counterregulatory hormones are given as therapy (eg, dexamethasone), and as a result of their overproduction (eg, in Cushing syndrome).
• Some pharmacologic agents can also cause insulin resistance. The notable pharmacologic agents which cause insulin resistance include antipsychotics like clozapine, olanzapine, risperidone or the immunosuppressive agents, such as cyclosporine, interferon, pentamidine and sympathomimetic agents like albuterol, dobutamine, terbutaline.
• All these situations can cause decrease effective insulin-to-glucagon ratio which can lead to hyperosmolarity and hyperglycemia seen in the hyperosmolar hyperglycemic state (HHS).

Hyperglycemia in hyperosmolar hyperglycemic state (HHS)

Hyperglycemia in HHS develops as a result of three processes:

Increased gluconeogenesis

• Gluconeogenesis takes place in the liver and it increases in HHS due to:
  • Increased gluconeogenic precursors, such as:
    • Amino acids (alanine and glutamine), which are increased due to proteolysis and decreased protein synthesis.
    • Lactate, which comes from muscle glycogenolysis
    • Glycerol, which comes from lipolysis.
  • Increased activity of gluconeogenic enzymes, which are further stimulated by stress hormones; include:
    • Phosphoenolpyruvate carboxykinase (PEPCK)
    • Fructose-1,6-Biphosphatase
    • Pyruvate carboxylase
    • Glucose-6-phosphatase
• The low insulin-to-glucagon ratio also inhibits production of an important metabolic regulator, fructose-2,6-biphosphate by triggering the production of cyclic adenosine monophosphate (cAMP), which activates a cAMP-dependent protein kinase. This kinase phosphorylates the PFK-2and FBPase-2 enzymes. This causes activation of FBPase-2 activity and inhibition of PFK-2 activity, thereby decreasing the levels of fructose 2,6-bisphosphate in the cell. With decreasing amounts of fructose 2,6-bisphosphate, glycolysis is inhibited while gluconeogenesis is activated.
• Reduction of fructose-2,6-biphosphate stimulates the activity of fructose-1,6-bisphosphatase (an enzyme that converts fructose-1,6-biphosphate to fructose-6-phosphate) and inhibits phosphofructokinase, the rate-limiting enzyme in the glycolytic pathway.

Increased glycogenolysis

• The low insulin-to-glucagon ratio promotes glycogenolysis by stimulating glycogen phosphorylase, a key enzyme of glycogen breakdown.

Impaired glucose utilization by peripheral tissues

• The low insulin-to-glucagon ratio also decrease the insulin dependent uptake of glucose by peripheral tissues.

Lipid and ketone metabolism in hyperosmolar hyperglycemic state (HHS)

• The low insulin-to-glucagon ratio affects lipid metabolism and mobilization because insulin normally promotes triglycerides clearance from circulation and inhibits lipolysis.
• The low insulin-to-glucagon ratio stimulates lipolysis from adipose tissue by activating hormone sensitive lipase. This lipolysis leads to the abundant supply of free fatty acids (FFA) to the liver.
• The free fatty acid levels may be as high in the hyperosmolar hyperglycemic state (HHS) as in diabetic ketoacidosis (DKA).
• The increase in free fatty acids in the liver diverts the hepatic fatty acid metabolism toward the ketogenesis.
• The ketogenesis occurs in the hepatic mitochondria and the transport of free fatty acids across the mitochondrial membrane is enhanced by the glucagon-mediated decrease in the cytosolic malonyl-CoA, which removes inhibition of carnitine palmitoyltransferase 1 (CPT1).
• The activation of carnitine palmitoyltransferase I allow free fatty acids to cross the mitochondrial membrane in the form of CoA after their esterification with carnitine.
• The insulin-to-glucagon ratio in the hyperosmolar hyperglycemic state (HHS) does not decrease to a level where unrestrained ketoacidosis occurs.
• The hyperosmolar hyperglycemic state (HHS) was also named hyperosmolar hyperglycemia nonketotic state, but findings of moderated ketonemia in several patients lead to the current term.

Hyperosmolarity in hyperosmolar hyperglycemic state (HHS)

• The hyperosmolar state in HHS is a combination of a decrease in total body water, loss of electrolytes, dehydration, and hyperglycemia.
• The osmotic diuresis in HHS results when the glucose concentration reaches greater than 180-200mg/dl.
• The glucose concentration greater than 180-200 mg /dl saturates the reabsorbing capacity of the proximal tubular transport system in the kidneys.
• The saturation of glucose transport system prevents further reabsorption and glucose eventually starts losing in the urine along with water and electrolytes and causing a decrease in the total body water.
• The blood glucose concentration keeps on rising due to continued gluconeogenesis, glycogenolysis, and decrease in total body water which further increases the plasma osmolarity.
• The increase in plasma osmolarity and water loss stimulates antidiuretic hormone (ADH) secretion, which leads to increase water reabsorption through the collecting ducts in the kidney.
• The renal water loss in the hyperosmolar hyperglycemic state (HHS) leads to dehydration especially in the elderly and in the patients who are dependent on others for care as they have decreased oral water intake.
• The decrease in effective circulatory volume due to dehydration leads to activation of renal angiotensin aldosterone system (RAAS), which conserves water but further exacerbates hyperglycemia due to oliguria which decreases renal excretion of glucose.
• The decrease in effective circulatory volume or hypotension eventually leads to coma due to the decrease in tissue perfusion, and the massive activation of renal angiotensin aldosterone system eventually leads to a renal shutdown.

Genetics

• [Disease name] is transmitted in [mode of genetic transmission] pattern.
• Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
• The development of [disease name] is the result of multiple genetic mutations.

Gross Pathology

• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].