Pancreas has dual functions, endocrine function and exocrine function.

Endocrine function is concerned with production of hormones.

Exocrine function is concerned with secretion of digestive juice called pancreatic juice.

Endocrine function of pancreas is performed by islets of Langerhans.

Human pancreas contains about 1 to 2 million islets of Langerhans.

Types of Cells in Islets of Langerhans

1. A cells or α-cells → secrete glucagon.
2. B cells or β-cells → secrete insulin.
3. D cells or δ-cells → secrete somatostatin.
4. F cells or PP cells → secrete pancreatic polypeptide.

General Information

Source of Secretion

Insulin is secreted by B cells or β-cells in islets of Langerhans of pancreas.

Chemistry of Insulin

Insulin is a polypeptide with 51 amino acids and molecular weight of 5,808.

It has two amino acid chains called α-chain and β-chain, which are linked by disulfide bridges.

The α-chain of insulin contains 21 amino acids and β-chain contains 30 amino acids.

Half-life and Plasma Level of Insulin

• Half-life → 5 minutes.
• Plasma level → 10 μU/mL.

Synthesis of Insulin

Insulin is synthesized in rough endoplasmic reticulum of β-cells in islets of Langerhans.

Sequence of Events

1. Initially, the precursor pre-proinsulin is formed by translation of mRNA in ribosomes attached to rough endoplasmic reticulum.
2. Pre-proinsulin moves into rough endoplasmic reticulum where it is converted into proinsulin.
3. Proinsulin consists of one α-chain, one β-chain and one connecting peptide called C-peptide.
4. Proinsulin is converted into insulin by endopeptidases. The α and β chains of insulin are linked by disulfide linkages.
5. Insulin, C-peptide and a little quantity of proinsulin are packed into secretory granules by Golgi apparatus.

Storage of Insulin

Insulin is stored in cytoplasm of β-cells in the form of secretory granules. It is released from β-cells when required.

Release of Insulin

When blood glucose level increases after a meal, insulin is released from β-cells by exocytosis.

C-Peptide Test

Measurement of concentration of C-peptide in blood is useful to evaluate insulin synthesis by pancreas and to determine mode of treatment of diabetic patients.

The β-cells of islets of Langerhans synthesize and release equal molar quantities of insulin and C-peptide into blood.

Since insulin has a short biological half-life of 5 minutes, it is cleared by metabolism rapidly. But C-peptide has a longer half-life than insulin, so it remains in the blood for a little longer period.

Thus, measurement of C-peptide concentration in blood may be a reliable indicator of insulin production by pancreas.

Metabolism of Insulin

Insulin is degraded in liver and kidney by insulin protease or insulin-degrading enzyme.

Insulin is the important hormone concerned with regulation of carbohydrate metabolism and blood sugar level. It is also concerned with metabolism of proteins and fats.

Action on Carbohydrate Metabolism

Insulin is the only antidiabetic hormone secreted in the body, i.e. it is the only hormone in the body that reduces blood sugar level.

Insulin reduces blood sugar level by the following actions on carbohydrate metabolism.

1. Facilitating Transport and Uptake of Glucose by the Cells

Insulin facilitates transport of glucose from blood into cells by increasing the permeability of cell membrane to glucose.

Insulin stimulates rapid uptake of glucose by all the tissues, particularly muscle and adipose tissues.

However, insulin is not required for glucose uptake in some tissues such as brain (except hypothalamus), renal tubules, mucous membrane of intestine and RBCs.

Insulin also increases the number of glucose transporters called GLUT in cell membrane.

2. Increasing Peripheral Utilization of Glucose

Insulin promotes peripheral utilization of glucose. In the presence of insulin, glucose which enters the cell is oxidized immediately. Rate of utilization of glucose depends upon intake of glucose.

3. Increasing Storage of Glucose: Glycogenesis

Insulin promotes rapid conversion of glucose into glycogen (glycogenesis), which is stored in muscle and liver. Thus, glucose is stored in these two organs in the form of glycogen. Insulin activates the enzymes necessary for glycogenesis.

4. Inhibiting Glycogenolysis

Insulin inhibits glycogenolysis, i.e. the breakdown of glycogen into glucose in muscle and liver.

5. Inhibiting Gluconeogenesis

Insulin inhibits gluconeogenesis, i.e. the formation of glucose from proteins.

Action on Protein Metabolism

Insulin facilitates synthesis and storage of proteins and inhibits cellular utilization of proteins by:

1. Facilitating transport of amino acids into cells from blood. Insulin increases the permeability of cell membrane for amino acids.
2. Accelerating synthesis of proteins by influencing transcription of DNA and by increasing the translation of mRNA.
3. Preventing catabolism of proteins by decreasing the activity of cellular enzymes which act on proteins.
4. Preventing conversion of proteins into glucose.

Action on Fat Metabolism

Insulin stimulates synthesis of fat. It also increases storage of fat in adipose tissue.

1. Synthesis of Fatty Acids and Triglycerides

Insulin promotes transport of excess glucose into cells, particularly the liver cells. This glucose is utilized for synthesis of fatty acids and triglycerides.

Insulin promotes synthesis of lipids by activating the enzymes which convert:

1. Glucose into fatty acids.
2. Fatty acids into triglycerides.

2. Transport of Fatty Acids into Adipose Tissue

Insulin facilitates transport of fatty acids into the adipose tissue.

3. Storage of Fat

Insulin promotes storage of fat in adipose tissue by inhibiting the enzymes which degrade triglycerides.

Action on Growth

Along with growth hormone, insulin promotes growth of body by its anabolic action on proteins.

It enhances transport of amino acids to the cell and synthesis of proteins in the cells.

It also has the protein-sparing effect, increasing glucose utilization by the tissues.

Houssay Animal

Houssay animal is one in which both anterior pituitaries are removed. This animal is used to demonstrate the importance of insulin and growth hormone in the growth of the body.

Administration of either insulin or growth hormone alone does not induce growth in this animal. Administration of both hormones stimulates growth. This proves the synergistic action of insulin and growth hormone on growth.

Mode of Action of Insulin

On the target cells, insulin binds with insulin receptors and forms an insulin-receptor complex. This receptor complex activates the action by activating intracellular enzyme systems.

Insulin Receptor

Insulin receptor is a glycoprotein and is present on almost all the cells of the body.

Subunits of Insulin Receptor

Insulin receptor is a tetramer, formed by four protein subunits (two α-subunits and two β-subunits).

The α-subunits protrude out of the cell and the β-subunits protrude inside the cell. Both subunits are linked to each other by disulfide bonds.

Intracellular surfaces of β-subunits have the enzyme activity, protein kinase (tyrosine kinase) activity.

When insulin binds with α-subunits of the receptor, tyrosine kinase at the β-subunit is activated by means of autophosphorylation.

Activated tyrosine kinase acts on many intracellular enzymes by phosphorylating or dephosphorylating the enzymes, so that some of the enzymes are activated while others are inactivated. Thus, insulin exerts its action on target cells by activating or inactivating other enzymes.

Insulin secretion is mainly regulated by blood glucose level. In addition, other factors like amino acids, lipid derivatives, gastrointestinal and endocrine hormones, and autonomic nerve fibers also stimulate insulin secretion.

1. Role of Blood Glucose Level

When blood glucose level is normal (80 mg to 100 mg/dL), the rate of insulin secretion is low (up to 10 μU/min).

When blood glucose level increases between 100 mg and 120 mg/dL, the rate of insulin secretion rises rapidly to 50 μU/min.

When blood glucose level rises above 200 mg/dL, the rate of insulin secretion also rises very rapidly up to 400 μU/min.

2. Role of Proteins

Excess amino acids in blood stimulate insulin secretion.

3. Role of Lipid Derivatives

The β-ketoacids such as acetoacetate also stimulate insulin secretion.

4. Role of Gastrointestinal Hormones

Insulin secretion is increased by gastrointestinal hormones such as gastrin, secretin, cholecystokinin and gastric inhibitory peptide (GIP).

5. Role of Endocrine Hormones

Diabetogenic hormones such as glucagon, growth hormone and cortisol increase the blood sugar level which, in turn, stimulates insulin secretion indirectly.

Prolonged hypersecretion of these hormones causes exhaustion of β-cells resulting in diabetes mellitus.

6. Role of Autonomic Nerves

Stimulation of parasympathetic nerve (right vagus) to pancreas increases insulin secretion by secreting acetylcholine.

Stimulation of sympathetic nerves inhibits the secretion of insulin by noradrenaline.

However, role of these nerves on regulation of insulin secretion under physiological conditions is not clear.

General Information

Source of Secretion

Glucagon is secreted from A cells or α-cells in the islets of Langerhans of pancreas.

It is also secreted from A cells of stomach and L cells of intestine.

Chemistry of Glucagon

Glucagon is a polypeptide with 29 amino acids. Its molecular weight is 3,485.

Half-life

Half-life of glucagon is 3 to 6 minutes.

Synthesis of Glucagon

Glucagon is synthesized from the precursor called pre-proglucagon in α-cells of islets.

Pre-proglucagon is converted into proglucagon, which gives rise to glucagon.

Metabolism of Glucagon

About 30% of glucagon is degraded in liver and 20% in kidney.

The cleaved glucagon fragments are excreted through urine.

About 50% of the circulating glucagon is degraded in blood itself by enzymes such as serine and cysteine proteases.

Actions of Glucagon

Actions of glucagon are antagonistic to insulin actions. It increases blood sugar level and facilitates the conversion of proteins into glucose.

1. Action on Carbohydrate Metabolism

Glucagon increases blood glucose level by increasing glycogenolysis and gluconeogenesis in liver and releasing glucose into the blood.

2. Action on Protein Metabolism

Glucagon increases transport of amino acids into liver cells. Amino acids are utilized for gluconeogenesis.

3. Action on Fat Metabolism

Glucagon shows lipolytic and ketogenic actions. It increases lipolysis by increasing the release of free fatty acids from adipose tissue and making them available for peripheral utilization.

Lipolytic activity of glucagon, in turn, promotes ketogenesis (formation of ketone bodies) in liver.

4. Other Actions of Glucagon

1. Glucagon inhibits secretion of gastric juice.
2. It also increases secretion of bile from liver.

Mode of Action of Glucagon

On target cells, glucagon causes formation of cyclic AMP which brings out the actions of glucagon.

Regulation of Secretion of Glucagon

Secretion of glucagon is controlled mainly by blood glucose and amino acid levels in the blood.

1. Role of Blood Glucose Level

When blood glucose level decreases below 80 mg/dL, α-cells of islets of Langerhans are stimulated and more glucagon is released. Glucagon in turn increases the blood glucose level.

On the other hand, when blood sugar level increases, α-cells are inhibited and secretion of glucagon decreases.

2. Role of Amino Acid Level in Blood

Increase in amino acid level in blood stimulates secretion of glucagon. Glucagon, in turn, converts the amino acids into glucose.

3. Role of Other Factors

Factors increasing glucagon secretion:

1. Exercise.
2. Stress.
3. Gastrin.
4. Cholecystokinin.
5. Cortisol.

Factors inhibiting glucagon secretion:

1. Somatostatin.
2. Insulin.
3. Free fatty acids.
4. Ketones.

Differences Between Insulin and Glucagon

General Information

Source of Secretion

Somatostatin is secreted from D cells (δ-cells) in islets of Langerhans of pancreas.

It is also secreted from D cells in stomach and upper part of small intestine.

Chemistry of Somatostatin

Somatostatin is a polypeptide. It is synthesized in two forms:

1. Somatostatin-14 with 14 amino acids.
2. Somatostatin-28 with 28 amino acids.

Both forms have similar actions.

Half-life

Half-life of somatostatin is 2 to 4 minutes.

Synthesis of Somatostatin

Somatostatin is synthesized from the precursor prosomatostatin.

Prosomatostatin is converted mostly into somatostatin-14 in the D cells of islets.

In the intestine, a large amount of somatostatin-28 is produced from prosomatostatin.

Metabolism of Somatostatin

Somatostatin is degraded in liver and kidney.

Actions of Somatostatin

1. Somatostatin acts within islets of Langerhans and inhibits α- and β-cells, i.e. it inhibits the secretion of glucagon and insulin.
2. It decreases the motility of stomach, duodenum and large intestine.
3. Somatostatin reduces the secretion of gastrointestinal hormones gastrin, cholecystokinin, gastric inhibitory peptide and vasoactive intestinal polypeptide.
4. Hypothalamic somatostatin inhibits secretion of GH and TSH from anterior pituitary. It is also called growth hormone inhibitory hormone (GHIH).

Mode of Action of Somatostatin

Somatostatin brings out its actions through cAMP.

Regulation of Secretion of Somatostatin

Pancreatic Somatostatin

Secretion of pancreatic somatostatin is stimulated by glucose, amino acids and CCK.

Tumor of D cells of islets of Langerhans causes hypersecretion of somatostatin. It leads to hyperglycemia and other symptoms of diabetes mellitus.

Gastrointestinal Tract Somatostatin

Secretion of somatostatin in GI tract is increased by presence of chyme containing glucose and proteins in stomach and small intestine.

General Information

Source of Secretion

Pancreatic polypeptide is secreted by F cells or PP cells in the islets of Langerhans.

It is also found in small intestine.

Chemistry

Pancreatic polypeptide is a polypeptide with 36 amino acids.

Half-life

Half-life of pancreatic polypeptide is 5 minutes.

Synthesis

Pancreatic polypeptide is synthesized from preprohormone precursor called pre-propancreatic polypeptide in the PP cells of islets.

Metabolism

It is degraded and removed from circulation, mainly in kidney.

Actions of Pancreatic Polypeptide

Exact physiological action of pancreatic polypeptide is not known. It is believed to suppress the secretion of glucagon from α-cells in islets of Langerhans.

Mode of Action

Pancreatic polypeptide brings out its actions through cAMP.

Regulation of Secretion

Secretion of pancreatic polypeptide is stimulated by the presence of chyme containing more proteins in small intestine.

Normal Blood Sugar Level

In normal persons, blood sugar level is controlled within a narrow range.

In early morning after overnight fasting, the fasting blood sugar level is low, ranging between 70 and 110 mg/dL.

Between 1st and 2nd hour after meals, postprandial blood sugar level rises from 100 to 140 mg/dL.

Sugar level in the blood is brought back to normal at the end of 2nd hour after the meals.

Blood sugar-regulating mechanism is operated through liver and muscle by means of pancreatic hormones insulin and glucagon. Many other hormones are also involved in regulation of blood sugar level.

Hormones which increase blood sugar level are called diabetogenic hormones or anti-insulin hormones.

Necessity of Regulation of Blood Glucose Level

Regulation of blood sugar (glucose) level is very essential, because glucose is the only nutrient that is utilized for energy by many tissues including brain tissues, retina and germinal epithelium of the gonads.

Role of Liver

Liver serves as an important glucose buffer system.

When blood sugar level increases after a meal, the excess glucose is converted into glycogen and stored in liver.

Afterwards, when blood sugar level falls, the glycogen in liver is converted into glucose and released into the blood.

Storage of glycogen and release of glucose from liver are mainly regulated by insulin and glucagon.

Role of Insulin

Insulin decreases blood sugar level and it is the only antidiabetic hormone available in the body.

Role of Glucagon

Glucagon increases the blood sugar level.

Role of Other Hormones

Other hormones increasing blood sugar level include:

1. Growth hormone.
2. Thyroxine.
3. Cortisol.
4. Adrenaline.

Thus, liver helps to maintain the blood glucose level after meals by storing glycogen and by releasing glucose when blood sugar level is low after 2 hours of food intake.

Insulin and glucagon help to control blood sugar level, especially after meals. Glucagon and other hormones help to maintain the blood sugar level by raising it in between the meals.

Hypoactivity: Diabetes Mellitus

Diabetes mellitus is a metabolic disorder characterized by high blood sugar (glucose) level associated with other manifestations. In most of the cases, diabetes mellitus develops due to deficiency of insulin.

Diabetes mellitus is of two types:

1. Type I diabetes mellitus.
2. Type II diabetes mellitus.

There is also secondary diabetes mellitus.

Type I Diabetes Mellitus

Type I diabetes mellitus is due to deficiency of insulin. So, it is also called insulin-dependent diabetes mellitus (IDDM).

Type I diabetes mellitus may occur at any age. But it usually occurs before 40 years of age. When it occurs at infancy, it is called infantile diabetes mellitus or, in childhood, it is called juvenile diabetes.

Causes of Type I Diabetes Mellitus

1. Degeneration of β-cells in the islets of Langerhans of pancreas.
2. Destruction of β-cells by viral infection.
3. Congenital disorder of β-cells.
4. Destruction of β-cells during autoimmune diseases.

Other Forms of Type I Diabetes Mellitus

1. Latent Autoimmune Diabetes in Adults (LADA)

LADA or slow onset diabetes has IDDM type but it progresses slowly and occurs in later years after 35 years.

It may be difficult to distinguish it from type II diabetes mellitus, since pancreas lasts longer period to stop secreting insulin.

2. Maturity Onset Diabetes in Young Individuals (MODY)

It is a rare inherited form of diabetes mellitus that occurs before 25 years. It is due to hereditary defects in insulin secretion.

Type II Diabetes Mellitus

It is due to the absence or deficiency of insulin receptors. It usually occurs after 40 years; hence it is called maturity onset diabetes mellitus.

This type of diabetes mellitus is also called non-insulin-dependent diabetes mellitus (NIDDM).

Differences Between Type I and Type II Diabetes Mellitus

Causes for Type II Diabetes Mellitus

In this type of diabetes, structure and function of β-cells and blood level of insulin are normal. But insulin receptors may be less, absent or abnormal, resulting in insulin resistance.

Common Causes of Insulin Resistance

1. Genetic disorders → significant factors causing type II diabetes mellitus.
2. Lifestyle changes such as bad eating habits and physical inactivity, leading to obesity.
3. Stress.

Diabetes Mellitus Associated with Other Endocrine Disorders

Diabetes is very common in some of the endocrine disorders such as gigantism, acromegaly and Cushing’s syndrome.

Hyperglycemia in these conditions causes excessive stimulation of β-cells. Constant and excessive stimulation, in turn, causes burning out and degeneration of β-cells. Exhaustion of β-cells leads to permanent diabetes mellitus.

This type of diabetes mellitus is called secondary diabetes.

Signs and Symptoms of Diabetes Mellitus

Various manifestations of diabetes mellitus develop because of three major setbacks of insulin deficiency:

1. Increased blood sugar level (300 to 400 mg/dL) due to reduced utilization by the tissues.
2. Mobilization of fats from adipose tissue for energy purpose, leading to elevated fatty acid content in blood. This causes deposition of fat on the wall of arteries and development of atherosclerosis.
3. Depletion of proteins from the tissues.

1. Glucosuria

Loss of glucose in urine is known as glucosuria. Normally glucose does not appear in urine.

When glucose level rises above 180 mg/dL in blood, glucose appears in urine. It is the renal threshold level for glucose.

2. Osmotic Diuresis

Diuresis due to osmotic effects is called osmotic diuresis.

Excess glucose in the renal tubules develops osmotic effect. Osmotic effect decreases the reabsorption of water from renal tubules resulting in diuresis. It leads to polyuria and polydipsia.

3. Polyuria

Excess urine formation with increase in frequency of voiding urine is called polyuria. It is due to osmotic diuresis caused by increase in blood sugar level.

4. Polydipsia

Polydipsia is the increase in water intake. Excess loss of water decreases water content and increases salt content in the body. This stimulates the thirst center in hypothalamus. Thirst center in turn induces water intake.

5. Polyphagia

Polyphagia means the intake of excess food. It is very common in diabetes mellitus.

6. Asthenia

Asthenia is the weakness, easy fatigability and slowness of muscles. Body becomes very weak. There is loss of energy. Asthenia is because of protein depletion which is caused by lack of insulin.

7. Acidosis

During insulin deficiency, glucose cannot be utilized by the peripheral tissues for energy. So, a large amount of fat is broken down to release energy. It causes formation of excess ketoacids leading to acidosis.

8. Acetone Breathing

In cases of severe ketoacidosis, acetone is expired in the expiratory air, giving the characteristic acetone breath or fruity breath. It is a life-threatening condition of severe diabetes.

9. Kussmaul Breathing

Kussmaul breathing is the increase in rate and depth of respiration caused by ketoacidosis.

10. Circulatory Shock

Osmotic diuresis leads to dehydration, which causes circulatory shock. It occurs only in severe diabetes.

11. Coma

Due to Kussmaul breathing, large amount of carbon dioxide is lost during expiration. This leads to drastic reduction in the concentration of bicarbonate ions causing severe acidosis and coma. It occurs in severe cases of diabetes mellitus.

Increase in blood sugar level develops hyperosmolarity of plasma which also leads to coma. It is called hyperosmolar coma.

Complications of Diabetes Mellitus

Prolonged hyperglycemia in diabetes mellitus causes dysfunction and injury of many tissues resulting in complications such as:

1. Cardiovascular complications such as hypertension and myocardial infarction.
2. Degenerative changes in retina called diabetic retinopathy.
3. Degenerative changes in kidney known as diabetic nephropathy.
4. Degeneration of autonomic and peripheral nerves called diabetic neuropathy.

Diagnostic Tests for Diabetes Mellitus

Diagnosis of diabetes mellitus includes determination of the following:

1. Fasting blood sugar.
2. Postprandial blood sugar.
3. Glucose tolerance test (GTT).
4. Hemoglobin A1c (HbA1c) or glycosylated (glycated) hemoglobin test.

Glycosylated Hemoglobin

Glycosylated hemoglobin is formed by reaction between hemoglobin and blood glucose.

HbA1c test measures the average blood sugar level 2 to 3 months before the test. In normal conditions it is present in low percentage (< 5.7%).

Abnormal Response in Diagnostic Tests

Abnormal response in diagnostic tests occurs in conditions like prediabetes. There is increased fasting blood glucose level or impaired (decreased) glucose tolerance.

Treatment for Diabetes Mellitus

Type I Diabetes Mellitus

Type I diabetes mellitus is treated with exogenous insulin. Since insulin is a polypeptide, it is degraded in GI tract if taken orally. So, it is generally administered by subcutaneous injection.

Type II Diabetes Mellitus

Type II diabetes mellitus is treated by oral hypoglycemic drugs. Patients with longstanding severe diabetes mellitus may require a combination of oral hypoglycemic drugs with insulin to control hyperglycemia.

Oral Hypoglycemic Drugs

Oral hypoglycemic drugs are classified into three types:

1. Insulin secretagogues: These drugs decrease blood glucose level by stimulating insulin secretion from β-cells. Sulfonylureas (tolbutamide, glyburide, glipizide, etc.) are commonly available insulin secretagogues.
2. Insulin sensitizers: These drugs decrease blood glucose level by facilitating insulin action in the target tissues. Examples are biguanides (metformin) and thiazolidinediones (pioglitazone and rosiglitazone).
3. Alpha glucosidase inhibitors: These drugs decrease blood glucose level by inhibiting α-glucosidase enzymes for the conversion of complex and other monosaccharides for absorption from intestine. Examples of α-glucosidase inhibitors are acarbose and miglitol.

Physiological Basis of Treatment for Diabetes Mellitus

1. Regular monitoring of blood glucose level.
2. Regular measurement of HbA1c.
3. Lifestyle changes such as proper diet, regular exercise, stress management and weight control.

Hyperinsulinism is the hypersecretion of insulin.

Cause of Hyperinsulinism

Hyperinsulinism occurs due to the tumor of β-cells in the islets of Langerhans.

Signs and Symptoms of Hyperinsulinism

1. Hypoglycemia

Blood sugar level falls below 50 mg/dL.

2. Manifestations of Central Nervous System

Manifestations of central nervous system occur when the blood sugar level decreases. All the manifestations are together called neuroglycopenic symptoms.

Initially, activity of neurons increases resulting in nervousness, tremor all over the body and sweating.

If not treated immediately, it leads to clonic convulsions and unconsciousness.

Slowly, the convulsions cease and coma occurs due to damage of neurons.