Diabetes mellitus

PHRM 304

Insulin
Insulin is a hormone that is central to regulating energy and glucose metabolism in the body. It is produced by beta () cells in the islets of Langerhans (one million) in the pancreas. The pancreas is a dual-function gland, having features of both endocrine and exocrine glands.

Insulin
First protein for which an amino acid sequence was determined. Insulin is a polypeptide hormone composed of 51 amino acids and has a molecular weight of 5808 Da. 2 chains (A chain 21 amino acid and B chain 30 amino acid) linked by two disulphide bonds.

21 amino acid

30 amino acid

Fig: Polypeptide chain of insulin

Insulin
Functions glucose uptake glycogen synthesis glycolysis gluconeogenesis glycogenolysis Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle.

Insulin secretion
The main factor controlling the synthesis and secretion of insulin is the blood glucose concentration. Beta cells respond both to the absolute glucose concentration and to the rate of change of blood glucose.

Insulin secretion
Other stimuli to insulin release include amino acids, fatty acids, the parasympathetic nervous system, peptide hormones for the gut and drugs that act on sulfonylurea receptors.

Insulin secretion
Steps: Glucose enters beta cells via a membrane transporter called Glut-2. Glucose metabolized via glucokinase (the ratelimiting enzyme that acts as the 'glucose sensor' linking insulin secretion to extracellular glucose) and glycolysis increases intracellular ATP.

Insulin secretion
This blocks ATP sensitive KATP channels, causing membrane depolarisation and opening of voltage-dependent calcium channels, leading to Ca2+ influx. The resulting increase in cytoplasmic Ca2+ triggers insulin secretion to blood.

Diabetes mellitus
Diabetes mellitus-is a group of metabolic diseases in which a person has high blood sugar. Normal blood glucose level 80 mg/dl-110 mg/dl (3.6-5.8 mmol/lit) Major causes: i) the body does not produce enough insulin, or ii) because cells do not respond to the insulin that is produced.

Diabetes mellitus
Symptoms: Symptoms are secondary to hyperglycemia: Polyuria (frequent urination) Polydipsia (increased thirst) and Polyphagia (increased hunger)
The proximal tubule can only reabsorb a limited amount of glucose. When the blood glucose level exceeds about 160 180 mg/dl, the proximal tubule becomes overwhelmed and begins to excrete glucose in the urine. This point is called the renal threshold of glucose (RTG).

Diabetes mellitus: Types

Type I (IDDM) Early onset (before age 30) Body weight: normal or low Insulin resistance: Occasional Treatment: Diet + Insulin Oral agent Genetic reason is absent: due to birth defect, infection Type II (NIDDM) Adult onset (after age 40) Body weight: obese (high) Insulin resistance: common Treatment: Diet + Oral agent Insulin Genetic reason is common: Family history

Gestational diabetes
A high blood glucose level during pregnancy Never had diabetes before May precede development of type 2 DM

Diabetes insipidus
Large amounts of urine are produced (polyuria) Which is not sweet (insipidus meaning "without taste" in Latin) production of antidiuretic hormone (ADH)

Effect of insulin on glucose uptake and metabolism

Through acetyl-CoA

Glycolysis Energy to living cells through the citric acid cycle (Krebs cycle/TCA cycle)

Advanced glycation end-products (AGEs)

Due to hyperglycemia in patients with diabetes Responsible for pathogenic conditions of diabetes Has inflammatory property Diabetes-related chronic inflammatory diseases such as myocardial infarction, nephropathy, retinopathy, neuropathy, feet ulcer.

Insulin receptor
Insulin receptor is a transmembrane receptor It belongs to the large class of tyrosine kinase receptors Two alpha subunits and two beta subunits make up the insulin receptor.

Insulin resistance
Defective insulin Obesity

Fig: Insulin receptor

A Protein Kinase Receptor

The mammalian hormone insulin does not enter the cell, but is bound by the extracellular domain of a receptor protein with four subunits (two and two ).

A Protein Kinase Receptor

Binding to the subunit causes a conformational change in the cytoplasmic domain of the subunits, exposing a protein kinase active site. This protein kinase activity phosphorylates insulin response substrate proteins, triggering further responses within the cell and eventually resulting in the transport of glucose across the membrane into the cell.

Drugs
Sulfonylureas: Stimulate beta cells to release more insulin. 30% beta cell should remain active for activity. Used for type II diabetics. Meglitinides: Nonsulfonylurea insulinotropic agent. Biguanides: No effects on beta cells. 3 sites for work: peripheral tissue, liver, intestine.

Drugs
Thiazolidinediones: Decrease insulin resistance in peripheral target tissue. -glucosidase inhibitor: delay carbohydrate absorption from GI tract.