THE PANCREAS AND ITS HORMONES
The human pancreas is a pale white organ weighing about sixty grams. It is about 12 -15 cms long and is situated in the epigastric and left hypochondriac regions. Anatomically it has a broad head, a body and a narrow tail. The head lies in the bend of the duodenum, the body lies behind the stomach, and the tail in the front of the kidney and almost reaches the spleen. The abdominal aorta and inferior vena cava lies behind the gland.
Blood supply is by the mesenetric and splenic arteries.
Nerve supply is by the parasympathetic and sympathetic. Parasympathetic is stimulatory and sympathetic is depressor in function.

The pancreas is both exocrine and endocrine in function.
Exocrine pancreas
The exocrine part is composed by the acinar cells, constituted by the alveoli, collected themselves into lobules, which drain by tiny ducts into the pancreatic duct. The pancreatic duct extends throughout the length of the gland, joins the common bile duct and opens into the duodenum at the ampulla of vater.
Secretes,
Pancreatic lipase
Pancreatic amylase
Trypsinogen
Chymotrypsinogen
Procarboxy peptidase
The above are inactive precursors of the corresponding enzymes and are activated by the enterokinase, secreted by the intestinal microvilli.

Endocrine pancreas
The endocrine pancreas is constituted by the islets of Langerhans composed by a vairety of cells.
Alpha cells secrete Glucagon
Beta cells secrete Insulin
Delta cells secrete Somatostatin
PP cells secrete Pancreatic poly peptide
Pancreatic polypeptide
This hormone is believed to play a role in control of various gastro intestinal functions.
Somatostatin
This hormone is chemically same as the growth hormone inhibitting factor. Somatostatin secretion occurs at times of
1. Increased blood glucose level
2. Increased blood aminoacid level
3. Increased blood fatty acid level
4. Increased concentration of various upper gastro intestinal trat hormones
Somatostatin slows down the assimilation of food from the gut, decreases utilization of absorbed nutrients and prevents exhaustion of food rapidly.

Insulin
Comes from Insula (Latin) means Island
Insulin is a compound of two aminoacid chains joined by two disulphide bonds. Insulin looses its property if these chains are split. It is produced in the Islets of langerhans within the beta cells in the form of a preprohormone, which is cleaved in the endoplasmic retinaculam into proinsulin, which is again cleaved by the golgi bodies to form insulin. Insulin is packed into granules and is secreted into the blood. The half-life of insulin in the blood is 5-6 minutes. It is rapidly cleared of the blood within 10 – 15 minutes. The unused part is cleared by the liver and partly excreted through the kidneys.

Functions of Insulin
Effect of insulin on carbohydrate metabolism
After a meal, glucose is absorbed into the blood. As the amount of glucose rises, insulin is secreted by the beta cells. This increased amount of glucose is transported into the liver and is converted to glycogen, therafter is stored. When the blood glucose falls, this stored glycogen is converted into glucose.

Insulin regulates this process by the following procedures:-
1.  Prevents splitting of glycogen: By inhibition of the enzyme phosphorylase, which splits glycogen to glucose.
2. Enhances glucose uptake by the liver. The activity of the enzyme glucokinase is enhanced. The process of phosphorylation traps phosphorylated glucose trapped in the liver cells, as it is unable to diffuse through the cell membrane.
3. Promotes glycogen synthesis by increasing the activity of enzymes,Phosphofructokinase: phosphorylation of glucose,Glycogen synthetase: monosaccharides are polymerised to form glycogen.

As the blood glucose level falls, there is reduction in insulin secretion. Liver uptake of glucose is reduced. Phophorylase splits glycogen to glucose. Glucose phosphatase splits phosphate radical from glucose phosphate and free glucose enters the blood. Thus as the blood glucose level falls there is release of glycogen from the liver.
Insulin promotes conversion of excess liver glucose in to fatty acids which arte taken to the adipose tissue and is deposited as fat.

Insulin reduces neoglucogenesis. Insulin reduces the availability of amino acids which are required for the synthesis of enzymes needed for neoglucogenesis.

Glucose metabolism in the muscle
The muscles usually depend upon fatty acids and not glucose for the purpose of energy liberation because resting muscle membrane is not permeable to glucose with out the presence of insulin. Exercise increases the permeability of muscle membrane to glucose. Even during first few hours after a meal the cell membranes of the muscle is permeable to glucose.

Storage of muscle glycogen
Glucose is transported in to the muscle and is stored as muscle glycogen this is used in anaerobic break down in to lactic acid at times of oxygen lack. Muscle glycogen cannot be converted in to free glucose because muscles do not contain glucose phosphatase.

Transport of glucose across muscle cell membrane [facilitated diffusion]
Glucose cannot pass through the muscle cell membrane. Instead a carrier protein attached to the cell membrane carries it. This carrier is activated by insulin. [Glucose+ carrier] enters the cell, glucose is released and the carrier is used again.

Effect of Glucose on the brain
Insulin has no effect on the glucose level of the brain. Glucose is freely permeable across the brain cells, which depend exclusively on glucose for the purpose of energy.

Effect of Insulin on Fat metabolism
Even though insulin is always related to carbohydrate metabolism it is usually the impairment of fat metabolism, which is responsible for the changes like acidosis and atherosclerosis, resulting in the death of the patient.
Insulin increases peripheral utilization of glucose and reduces utilization of fat. It also enhances synthesis of fat in the liver and adipose cells.
1. As the concentration of glucose in the liver reaches 5-6 times the normal, the additional glucose is converted into fatty acids. Glucose enters the glycolytic pathway and is split into pyruvate and is transformed into acetyl coenzyme A, which forms the substrate from which fatty acids are synthesized.
2. Increased utilization of glucose initiates citric acid cycle and citrate and isocitrate are formed. These activate acetyl coA carboxylase, which initiates first stage of fatty acid synthesis.
3. Fatty acids from the liver are transported via the blood into the adipose cells and are stored.
4. Fatty acids are used in the liver to synthesize triglycerides. These are released as lipoproteins. Insulin activates lipoprotein lipase, which splits triglycerides into fatty acids and is carried to the adipose tissue, converted back into triglycerides and is stored.
5. Insulin enhances fat synthesis in adipose tissue by
i) Inhibiting sensitive lipase, which hydrolyses tryglycerides in the fat cells. Thus release of fattyacids into the circulating blood is reduced.
ii) Insulin promotes glucose transport into fat cells. During glycolytic breakdown of glucose large quantities of alpha- glycero phosphate is formed. This supplies glycerol. Glycerol, along with fatty acids form triglycerides, which are stored in the adipose tissue.

Fat metabolism in the absence of insulin
Sensitive lipase is activated. Hydrolysis of triglycerides in the fat cells release fatty acids and glycerol.
Increased levels of circulating fatty acids results in production of increased amounts of triglycerides in the liver, there by producing fatty liver.
Increased fatty acids are converted into phospholipids and cholesterol. These along with triglycerides are discharged as lipoprotein leading to atherosclerosis.
Increased fatty acids enter the carnitine cycle and beta oxidation of fatty acids produce acetyl coenzyme A. acetyl coenzyme A is condensed to form acetoacetic acid some of which is converted into alpha hydroxy buteric acid and acetone. When these are formed in excess acidosis and death results.

Insulin on protein metabolism
Patients with prolonged diabetes have inability to synthesize proteins leading to wasting of tissues as well as suffer from many cellular functioning disorders.
Insulin increases uptake of aminoacids into the cells.
Enhances formation of new proteins by increasing translation by m- RNA.
Increases rate of production of new DNA.
Reduces catabolism of proteins by cellular lysosomes.
Depresses gluconeogenesis, where by many amino acids are conserved.
Acts synergistically with the growth hormone.

Lack of insulin brings aminoacids to the blood and is degraded. This increases urea excretion in urine. Loss of protein causes protein wasting.

Control of insulin secretion
a. Blood glucose level : The level of insulin is minimum when the blood glucose level is at the fasting level.
b. Blood aminoacid level: Increased levels of aminoacids especially argenine and lysine along withan increase inblood glucose level increases the level of insulin.
c. G.I.T. Hormones: Gastrin, secretin, cholecystokinin and mainly gastric inhibitory peptide increase the secretion of insulin.
d. Other hormones:
i. The growth hormone, glucagon, cortisol, progesterone, oetrogen etc, cause exhaustion of the beta cells of the Islets of Langerhans due to continuous stimulation.
ii. Growth hormone and cortisol : These reduce cellular utilization of glucose and promote fat utilization.
iii. Epinephrine: Promotes glycogenolysis in the liver and liberates large quantities of glucose into the blood. Epinephrine has a lipolytic effect by activating tissue lipase.

Glucagon
Functions of glucagon:-
1. Breakdown of liver glycogen by the enzyme cascade system.
2. Increases gluconeogenesis.
3. Activates adipose cell lipase: fatty acids are made available for energy liberation.
4. Inhibits storage of triglycerides in the liver.
5. Glucagon in large quantities enhances strength of heart increases bile secretion, and inhibits gastric acid secretion.

Regulation of glucagon secretion
1. Reduced blood glucose level enhances glucagon secretion.
2. Increased level of aminoacids like argenine and alanine initiates glucagon secretion.
3. Exercise increases the level of blood glucagon.

Importance of blood glucose regulation
Brain retina and the germinal epithelium of the gonads are exclusively dependent upon glucose for the purpose of energy.
If the blood glucose level is raised above normal,
1.Osmotic pressure of extracellular fluid is raised causing entry of fluid into extracellular space leading to cellular dehydration.
2. Glucose is lost in urine.
3. Loss of water and elelctrolytes in the urine.
The above can result in circulatory shock.

DIABETES MELLITUS
By Diabetes mellitus is meant a group of metabolic disorders characterized by impaired utilization of blood glucose level, inducing hyperglycemia, along with affection of fat and protein metabolism. It is generally classified into two types:-
1. Primary diabetes mellitus or Juvenile diabetes mellitus ( Insulin dependant diabetes mellitus)
2. Secondary diabetes mellitus or Maturity onset diabetes mellitus ( Non insulin dependant diabetes mellitus)
Secondary diabetes mellitus is found following conditions like  Pancreatitis, C/c pancreatic calculus, haemochromatosis, pancreatectomy, drugs like corticosteroids etc.

Primary diabetes mellitus Secondary diabetes mellitus
Age group <20yrs
Blood insulin level is low

Patients are lean thin
Associated with metabolic ketocidosis ( fainting attacks)
Associated with auto immunity.
The antibodies destroy the beta cells
Associated with insulitis, the inflammation of the Islets of Langerhans
Age group >30 yrs
Blood insulin level is normal or high
Patients obese
Ketoacidosis is rare

Peripheral target organs show resistance to the action of insulin
The Islets of Langerhans are intact

Pathogenesis of Diabetes mellitus
Type I
Diabetes develops in childhood or adolescence. There is marked reduction in the number of the beta cells. The patients are found to have a genetic susceptibility to have diabetes. Auto immunity against beta cells are also found to be responsible. Auto immunity develops either spontaneously or following a viral infection like measles, mumps etc.
Type II
An autosomal dominant gene transmits this type of diabetes. This type of diabetes is usually associated with obesity. The cells are less responsive to hyperglycemia, because obesity decreases the number of insulin receptors in the target cells. Controlling the diet and taking regular exercise could delay the onset of symptoms.

Pathology in diabetes mellitus
The metabolic effect in this type of diabetes is due either to
• Some derangement in insulin secretion or
• Due to insulin resistance frequently associated with obesity.
As a result of impairment in the metabolism, there is decreased utilization of glucose by the tissues. Renal threshold for glucose is  180 mgs/ dl. If the amount of circulating glucose exceeds this, the remainder is lost in urine resulting in glycosuria.

In the absence of insulin, fat utilization is increased. Thus the amount of ketone bodies also rises. Since these are highly acidic they are always excreted in combination with sodium ions. In order to replace sodium ions hydrogen ions are employed. This results in acidosis. Acidosis produces rapid and deep breathing called Kussmald’s respiration, excreting large amounts of carbon dioxide resulting in a marked decrease in bicarbonate content of extracellular fluids. Large amounts of chloride ions are lost in urine. Acidosis can progress leading to comma and death.
The secondary changes in the body are produced as a result of the persistent hyperglycemia, resulting in diabetic angiopathy and diabetic nephropathy.

The patients develop complications by 10 –15 yrs. The basement membranes of small blood vessels get thickened. In the small arteries the process is called arteriolosclerosis, and in the larger arteries it is called atherosclerosis. The latter is characterized by deposition of cholesterol plaques in the intima of the blood vessels resulting in narrowing of the lumen. Depending upon the vessel that is involved, the effects can vary.
Affection of the coronary arteries can result in ischaemic heart disease. Due to the presence of associated neuropathy, usually silent ischaemia is found.
If the cerebral vessels are affected, strokes are common.
Gangrene can result from affection of the peripheral vessels. Diabetic gangrene is usually of the wet type due to superadded infection.
Diffuse or nodular glomerular sclerosis can lead to proteinuria and chronic renal failure.
Necrotising pappilitis is found in the kidney in many patients.
Increased susceptibility to infections can produce pyelonephrites.

The changes in the eyes are generally denoted by retinopathy. Retinal aneurysms are formed which can rupture leading to retinal haemorrhage. Associated with this there is an increased incidence of cataract and glaucoma.
In the Islets of Langerhans there is gradual reduction in the number of cells. Associated with this there is infiltration with lymphocytes resulting in insulitis.
Hyperlipidemia can cause multiple florid atherosclerotic lesions like plaque formation, which undergoes ulceration and calcification leading to thrombosis and embolism.
Myelin degeneration and axonal degeneration can cause peripheral neuropathy. Even autonomic nervous system can be affected leading to impotence and loss of bowel and bladder control.
Due to glucose loaded circulation the patient becomes more prone to infections like tuberculosis, mycosis, other skin infections etc.

Diagnosis
Urinary glucose estimation
Blood glucose level estimation, fasting and post prandial.
Glucose tolerance test

Management
Diabetic diet
Control of hyperglycemia
Control of complications