Diabetes Pathophysiology

Diabetes occurs when there is a dis-balance between the demand and production of the hormone insulin.

Control of blood sugar

When food is taken, it is broken down into smaller components. Sugars and carbohydrates are thus broken down into glucose for the body to utilize them as an energy source. The liver is also able to manufacture glucose.

In normal persons the hormone insulin, which is made by the beta cells of the pancreas, regulates how much glucose is in the blood. When there is excess of glucose in blood, insulin stimulates cells to absorb enough glucose from the blood for the energy that they need.

Insulin also stimulates the liver to absorb and STORE any excess glucose that is in the blood. Insulin release is triggered after a meal when there is a rise in blood glucose. When blood glucose levels fall, during exercise for example, insulin levels fall too.

High insulin will PROMOTE glucose uptake, Glycolysis (break down of glucose), and Glycogenesis (formation of storage form of glucose called glycogen), as well as uptake and synthesis of amino acids, proteins, and fat.

Low insulin will promote Gluconeogenesis (breakdown of various substrates to release glucose), Glycogenolysis (breakdown of Glycogen to release Gluose), Lipolysis (breakdown of lipids to release glucose), and Proteolysis (breakdown of proteins to release glucose). Insulin acts via insulin receptors.

	Liver	Adipose or fat Tissue	Muscle
High insulin	Glycolysis Glycogenesis	Triglyceride synthesis	Amino acid uptake Protein synthesis
Low insulin	Gluconeogenesis Glycogenolysis	Lipolysis	Proteolysis

Normal Responses to Eating and Fasting

1. In a fed state: there is increased insulin secretion, causing glycolysis, glycogen storage, fatty acid synthesis/storage, and protein synthesis.
2. After an overnight fast:  there is low insulin and high glucagon that can cause glycogen breakdown, hepatic gluconeogenesis, and lipolysis.
3. After a prolonged fast:  there is extremely low insulin and low glucagon, this causes lipolysis to take over.  Lipids are the main fuel source.  Gluconeogenesis is minimized, as it causes nitrogen wasting, ammonia build-up, and loss of muscle mass.

Hormones

Hormones that raise blood sugar include glucagon, epinephrine and norepinephrine, cortisol, Growth hormone etc. These hormones are released due to stress.  Thus during phases of stress like an infection, surgery or pregnancy diabetes control worsens and blood sugar rises.

Pathophysiology of type 1 diabetes

In this condition the immune system attacks and destroys the insulin producing beta cells of the pancreas. There is beta cell deficiency leading to complete insulin deficiency. Thus is it termed an autoimmune disease where there are anti insulin or anti-islet cell antibodies present in blood. These cause lymphocytic infiltration and destruction of the pancreas islets. The destruction may take time but the onset of the disease is rapid and may occur over a few days to weeks.

There may be other autoimmune conditions associated with type 1 diabetes including vitiligo and hypothyroidism. Type 1 diabetes always requires insulin therapy, and will not respond to insulin-stimulating oral drugs.

Pathophysiology of type 2 diabetes

This condition is caused by a relative deficiency of insulin and not an absolute deficiency. This means that the body is unable to produce adequate insulin to meet the needs. There is Beta cell deficiency coupled with peripheral insulin resistance.

Peripheral insulin resistance means that although blood levels of insulin are high there is no hypoglycaemia or low blood sugar. This may be due to changes in the insulin receptors that bring about the actions of the insulin.

Obesity is the main cause of insulin resistance. In most cases over time the patients need to take insulin when oral drugs fail to stimulate adequate insulin release.

	Type 1 Diabetes	Type 2 Diabetes
Etiology	Autoimmune	Peripheral insulin resistance
Formerly known as	IDDM	NIDDM or “adult onset” diabetes
Age of onset	Younger	Older
Obesity	Rare	Common
Family History	Rare	Common
HLA association/Genetic association	Yes	No
Ketosis	Yes	No
Insulin resistance	No	Yes
Presence of body’s own insulin	No	Yes
Respond to Oral Agents	No	Yes

Pathophysiology of gestational diabetes

Gestational diabetes is caused when there are excessive counter-insulin hormones of pregnancy. This leads to a state of insulin resistance and high blood sugar in the mother. There may be defective insulin receptors.

Pathophysiology behind symptoms and complications of diabetes

• Polydipsia or increased thirst is due to high blood glucose that raises the osmolarity of blood and makes it more concentrated.
• Polyuria or increased frequency of urination is due to excess fluid intake and glucose-induced urination.
• Weight loss occurs due to loss of calories in urine.
• Polyphagia or increased hunger due to loss or excess glucose in urine that leads the body to crave for more glucose.
• Poor wound healing, gum and other infections due to increased blood glucose providing a good source of nutrition to microbes and due to a diminished immunity.
• Heart disease – this occurs due to changes in the large blood vessels leading to coronary, cerebral, and peripheral artery diseases, atherosclerosis, dyslipidemia etc.
• Eye damage – this is termed diabetic retinopathy and occurs due to damage of the fine blood vessels of the retina in the eye due to long term exposure to high blood sugar.
• Kidney damage – similar damage to small and large blood vessels of the kidneys. Initially there is proteinuria or increased outflow of protein and may lead to end stage renal disease (ESRD).
• Nerve damage – this can affect the arms and legs and is called stocking-glove numbness/tingling. It can also affect autonomic functions leading to impotence,ERECTILE DYSFUNCTION, difficulty in digestion or gastroparesis etc.
• Diabetic foot – this occurs due to peripheral nerve damage as well as blood vessel affliction due to long term diabetes. Little trauma, sores and blisters go unnoticed due to lack of sensation and peripheral vascular disease impairs healing and allows infection.
• Diabetic Ketoacidosis is caused in type 1 diabetes where there is complete lack of insulin and reliance on fatty acids for energy. This uncontrolled lipid breakdown leads to formation of ketones and causes acidosis and ketonemia. This is a medical emergency.
• Non-Ketotic Hyperosmolarity – this is caused due to extreme rise of blood sugar. This is seen in type 2 diabetics. There is just enough insulin to suppress ketone synthesis. The high blood sugar leads to excessive concentration or osmolarity of blood which in turn leads to dieresis and collapse of the blood vessels and cardiovascular shock. This is a medical emergency.

By Dr Ananya Mandal, MD

Sources

1. www.diabetes.org.uk/
2. www.bbc.co.uk/.../aboutdiabetes_what.shtml
3. http://www.nhs.uk/Conditions/Diabetes/Pages/Diabetes.aspx
4. http://www.patient.co.uk/doctor/diabetes-mellitus
5. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002194/
6. http://www.diabeteswellness.net/Portals/0/files/DRWFUSdiabetes.pdf
7. http://www.cdc.gov/chronicdisease/resources/publications/AAG/ddt.htm
8. http://www.news-medical.net/health/Diabetes-Pathophysiology.aspx