Hyperosmolar hyperglycemic state pathophysiology

Hyperosmolar hyperglycemic state Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Hyperosmolar hyperglycemic state from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic study of choice
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X-ray
Echocardiography and Ultrasound
CT scan
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Hyperosmolar hyperglycemic state pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hyperosmolar hyperglycemic state pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hyperosmolar hyperglycemic state pathophysiology
CDC on Hyperosmolar hyperglycemic state pathophysiology
Hyperosmolar hyperglycemic state pathophysiology in the news
Blogs on Hyperosmolar hyperglycemic state pathophysiology
Directions to Hospitals Treating Psoriasis
Risk calculators and risk factors for Hyperosmolar hyperglycemic state pathophysiology

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
• 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.

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].