Hyperosmolar hyperglycemic state pathophysiology: Difference between revisions
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====Anabolic state during meals==== | ====Anabolic state during meals==== | ||
*During fed state, high glycemic levels cause increased insulin release from pancreatic beta cells. | *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. | *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. | *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. | *Insulin dependent uptake of glucose also drives potassium into the cells. | ||
| Line 44: | Line 44: | ||
*Both these processes maintain plasma glucose concentration in the normal range. | *Both these processes maintain plasma glucose concentration in the normal range. | ||
*The low insulin-to-glucagon ratio also favors lipolysis and ketone body formation. | *The low insulin-to-glucagon ratio also favors lipolysis and ketone body formation. | ||
*Several insulin-independent tissues like brain and | *Several insulin-independent tissues like brain and kidneys use glucose regardless of the insulin-to-glucagon ratio. | ||
===Pathogenesis=== | ===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. | 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 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. | *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. | ||
*The levels of counterregulatory stress hormones can increase during an acute illness (eg, genitourinary or pulmonary | *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 | *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 | *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 HHS==== | ====Hyperglycemia in HHS==== | ||
*Hyperglycemia in HHS develops as a result of three processes: | *Hyperglycemia in HHS develops as a result of three processes: | ||
| Line 71: | Line 71: | ||
=====Increased glycogenolysis===== | =====Increased glycogenolysis===== | ||
=====Impaired glucose utilization by peripheral tissues===== | =====Impaired glucose utilization by peripheral tissues===== | ||
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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 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
- Increased gluconeogenic precursors, such as:
- High glucagon-to-insulin ratio inhibits production of an important metabolic regulator, fructose-2,6-biphosphate.
- 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
Impaired glucose utilization by peripheral tissues
Hyperosmolarity
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.
Associated Conditions
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].