Physiology of Insulin Secretion and Action
Insulin is secreted by the beta calls of the islets of langerhans which are located in the pancreas. It consists of two polypeptide chains, cx and P consisting of 21 and 30 amino-acids respectively. The two chains are linked to each other by two disulfide bonds.
Insulin is secreted by the beta calls of the islets of langerhans which are located in the pancreas. It consists of two polypeptide chains, cx and P consisting of 21 and 30 amino-acids respectively. The two chains are linked to each other by two disulfide bonds.
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| Schematic Representation of Insulin |
The two chains when initially produced in the beta cell are connected by a third polypeptide chain, the connecting peptide or the, C-peptide. The three chain complex is known as pro-insulin. The C-peptide is cleaved before insulin leaves the Beta cell.
Insulin Secretion from the Beta Cell
The amount of insulin secreted by the beta cell is closely regulated by the prevailing blood glucose level, with the aim that the glucose levels are kept within very narrow limits. Glucose diffuses into the beta cell, then undergoes phosphorylation facilitated by an enzyme glucokinase. This rise in glucose concentration in the beta cell enhances electrical activity in the cell membrane and closes ATP dependent K+ channels; this results in opening of Ca" channels and an influx of calcium ions occurs. This results in release of preformed insulin which is stored in the cytoplasm of the beta cell.
Insulin Secretion from the Beta Cell
The amount of insulin secreted by the beta cell is closely regulated by the prevailing blood glucose level, with the aim that the glucose levels are kept within very narrow limits. Glucose diffuses into the beta cell, then undergoes phosphorylation facilitated by an enzyme glucokinase. This rise in glucose concentration in the beta cell enhances electrical activity in the cell membrane and closes ATP dependent K+ channels; this results in opening of Ca" channels and an influx of calcium ions occurs. This results in release of preformed insulin which is stored in the cytoplasm of the beta cell.
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| Schematic Beta Cell Showing K+ and Ca++ Channels |
Pattern of Insulin Secretion in a 24 Hour Day
Some amount of insulin is secreted continuously throughout the 24 hours in order to carry on the basal metabolic functions of the body. This is the basal secretion. In response to meals, there is a sharp increase in insulin secretion, the purpose being to store the nutrients absorbed and clamp down the glucose levels. This meal-stimulated release of insulin has an initial rapid first phase, followed by a slower and lower peak level of insulin. The total amount of insulin secreted by the pancreas is estimated as 18 to 32 units per 24 hours. Humans need energy constantly but can eat only intermittellfly. Hence meals provide nutrients and calories which are in excess of the immediate needs. The excess calories are stored in liver and muscle as glycogen, and in adipose tissue as triglyceride. This happens under the influence of insulin whose secretion is triggered by the rising glucose level.
As the time interval after the meal increases and glucose level falls, insulin level declines, and glucagon secretion begins from the alpha cells of the islet of langerhans,The effect of this shift from a "high insulin-low glucagons" state, to a "high Diabetes MellitusCardiovasculnr Related Disorders glucagon-low insulin" state, results in release of glucose and free fatty acids which are the principal fuels required for metabolic activities, froin stores in the liver and adipose tissue.The hallmark of diabetes is hyperglycemia. This is due to a deficiency of insulin.There are two major types of diabetes mellitus, Type I and Type 11.
Type I Diabetes Mellitus
This is also known as IDDM for Insulin Dependent Diabetes mellitus, Juvenile ketosis prone diabetes. This is characterized by absolute deficiency of insulin due to destruction of p-cells by an auto-immune process. It is believed that viruses, cow's inilk antigen, etc., may be the etiologic agents which trigger anti-body formation in people with certain types of HLA ahtigens on chromosome 6; these are HLA-DR 3 and/or DR4. Though this type of diabetes starts more commonly in children, it may manifest for the first time in adults. Characleristically, there is an abrupt onset of thirst, polyuria and polyphagia, rapidly followed by dehydration and coma and death if medical attention is not sought. The patient requires daily insulin twice or thrice a day for survival; any stoppage of insulin for more than 24 hours results in rapid development of symptoms of hyperglycemia, followed by keto-acidotic coma and death. A history of this type of onset, or such symptoms occurring on stopping insulin,is very suggestive of type one diabetes.
Type II Diabetes Mellitus
Also known as NIDDM (Non-insulin Dependent Diabetes Mellitus), type two diabetes is the most common type comprising 85 per cent to 95 per cent of any diabetes cohort. It is characterised by resistance of cells to the action of insulin,particularly the cells in the liver, adipose tissue and skeletal muscle. This resistance is due to insensitivity of the insulin receptor on the cell membrane, as well as due to "post-receptor" events concerned with intracellular pathways of insulin action. If the pancreas were able to overcoine this resistance by increasing insuliil production,hyperglycemia and diabetes would not occur. However, in diabetics the beta cells of the pancreas are unable to do this. Thus this dual defect of insulin resistance and relative insulin deficiency is the cause of the metabolic abnormality in type two diabetes. It is not clear which defect appears first.
Obese individuals also have insulin resistance but because their beta cells can compensate by increasing insulin output, they do not have high blood sugars. It is clear from this that Type two diabetes and obesity are closely related.Epidemiological and twin studies have shown that there is a familial clustering of Type two diabetes, suggesting a genetic factor. However, no specific gene defect has been identified. It is thought that both genetic and environmental factors are responsible for full manifestation of the diabetic phenotype.
MQDU Diabetes
Maturity Onset Diabetes of the Young (MODY) is a specific subgroup of Type two diabetes in which a definite genetic defect has been identified. This subgroup comprises patients who develop Type'II diabetes in the 2nd or 3rd decade, and in whom at least one parent is diabetic, as well as a large number of diabetic siblings.This is consistent with an autosomal doininant mode of inheritance. It has been found that they have a mutation in the glucokinase gene.
Syndrome X
The metabolic syi~droine is a term given to a collection of clinical and biochemicalabnoimalities often seen in type two diabetics.The components of this syndrome are as follows:
Obesity, Diabetes, Hypertension, Dyslipdemia and Hyperinsulinemia.
The combination of problems makes them at high risk for atherosclerosis, and in particular ischemic heart disease.A part fonn type one and type two diabetes there are other clinical tyges of patients with hyperglycernia.
When diabetes is detected for the first time in a pregnant state, it is termed Gestational diabetes. The diabetic stale disappears once the woinan del.ivers. This term does not include known diabetics who become pregnant. It is possible that undetected Type 11 diabetes could be first detected during pregnancy and masquerade as gestational diabetes. In these patients the diabetes does not disappear once pregnancy is over.
Secondary Diabetes.
This term refers lo diabetes that develops in associati011 with disorders other than Qpe I, Q p e I1 and gestational diabetes. A brief classification of sccondary diabetes is given below: (a more comp>rehensive list of uncolnnlon disorders may be fouild in standard textbooks)
As the time interval after the meal increases and glucose level falls, insulin level declines, and glucagon secretion begins from the alpha cells of the islet of langerhans,The effect of this shift from a "high insulin-low glucagons" state, to a "high Diabetes MellitusCardiovasculnr Related Disorders glucagon-low insulin" state, results in release of glucose and free fatty acids which are the principal fuels required for metabolic activities, froin stores in the liver and adipose tissue.The hallmark of diabetes is hyperglycemia. This is due to a deficiency of insulin.There are two major types of diabetes mellitus, Type I and Type 11.
Type I Diabetes Mellitus
This is also known as IDDM for Insulin Dependent Diabetes mellitus, Juvenile ketosis prone diabetes. This is characterized by absolute deficiency of insulin due to destruction of p-cells by an auto-immune process. It is believed that viruses, cow's inilk antigen, etc., may be the etiologic agents which trigger anti-body formation in people with certain types of HLA ahtigens on chromosome 6; these are HLA-DR 3 and/or DR4. Though this type of diabetes starts more commonly in children, it may manifest for the first time in adults. Characleristically, there is an abrupt onset of thirst, polyuria and polyphagia, rapidly followed by dehydration and coma and death if medical attention is not sought. The patient requires daily insulin twice or thrice a day for survival; any stoppage of insulin for more than 24 hours results in rapid development of symptoms of hyperglycemia, followed by keto-acidotic coma and death. A history of this type of onset, or such symptoms occurring on stopping insulin,is very suggestive of type one diabetes.
Type II Diabetes Mellitus
Also known as NIDDM (Non-insulin Dependent Diabetes Mellitus), type two diabetes is the most common type comprising 85 per cent to 95 per cent of any diabetes cohort. It is characterised by resistance of cells to the action of insulin,particularly the cells in the liver, adipose tissue and skeletal muscle. This resistance is due to insensitivity of the insulin receptor on the cell membrane, as well as due to "post-receptor" events concerned with intracellular pathways of insulin action. If the pancreas were able to overcoine this resistance by increasing insuliil production,hyperglycemia and diabetes would not occur. However, in diabetics the beta cells of the pancreas are unable to do this. Thus this dual defect of insulin resistance and relative insulin deficiency is the cause of the metabolic abnormality in type two diabetes. It is not clear which defect appears first.
Obese individuals also have insulin resistance but because their beta cells can compensate by increasing insulin output, they do not have high blood sugars. It is clear from this that Type two diabetes and obesity are closely related.Epidemiological and twin studies have shown that there is a familial clustering of Type two diabetes, suggesting a genetic factor. However, no specific gene defect has been identified. It is thought that both genetic and environmental factors are responsible for full manifestation of the diabetic phenotype.
MQDU Diabetes
Maturity Onset Diabetes of the Young (MODY) is a specific subgroup of Type two diabetes in which a definite genetic defect has been identified. This subgroup comprises patients who develop Type'II diabetes in the 2nd or 3rd decade, and in whom at least one parent is diabetic, as well as a large number of diabetic siblings.This is consistent with an autosomal doininant mode of inheritance. It has been found that they have a mutation in the glucokinase gene.
Syndrome X
The metabolic syi~droine is a term given to a collection of clinical and biochemicalabnoimalities often seen in type two diabetics.The components of this syndrome are as follows:
Obesity, Diabetes, Hypertension, Dyslipdemia and Hyperinsulinemia.
The combination of problems makes them at high risk for atherosclerosis, and in particular ischemic heart disease.A part fonn type one and type two diabetes there are other clinical tyges of patients with hyperglycernia.
When diabetes is detected for the first time in a pregnant state, it is termed Gestational diabetes. The diabetic stale disappears once the woinan del.ivers. This term does not include known diabetics who become pregnant. It is possible that undetected Type 11 diabetes could be first detected during pregnancy and masquerade as gestational diabetes. In these patients the diabetes does not disappear once pregnancy is over.
Secondary Diabetes.
This term refers lo diabetes that develops in associati011 with disorders other than Qpe I, Q p e I1 and gestational diabetes. A brief classification of sccondary diabetes is given below: (a more comp>rehensive list of uncolnnlon disorders may be fouild in standard textbooks)
A) Pancreatic disorders:
a) Pancreatectoiny
b) Pancreatitis
C )Malnutrition-related diabetes
a) Pancreatectoiny
b) Pancreatitis
C )Malnutrition-related diabetes
B) Endocrinopathies
a) Acromagaly
b) Cushings syndrome, exogenous steroid
c) Hyperthyroidism etc.
C) Drugs, chemical agents, toxins:
b) Cushings syndrome, exogenous steroid
c) Hyperthyroidism etc.
C) Drugs, chemical agents, toxins:
a) Diuretics ..... Thiazides, loop diuretics,
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b) Anti-hypertensives: Clonidine, diazoxide,B. blockers
C )Horlnones: Steroids, growth honnone etc.
d) Anticonvulsants: Phenytoin
e) Antimitotics: Streptozotocin, mithrarnycin etc.
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b) Anti-hypertensives: Clonidine, diazoxide,B. blockers
C )Horlnones: Steroids, growth honnone etc.
d) Anticonvulsants: Phenytoin
e) Antimitotics: Streptozotocin, mithrarnycin etc.
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