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In this article we will discuss about:- 1. Chemistry of Insulin 2. Insulin Receptor 3. Secretion 4. Factors Stimulating Secretion 5. Factors Inhibiting Secretion 6. Metabolism 7. Functions 8. Pathophysiology 9. Abnormal Metabolism in Diabetic States 10. Antibodies in Insulin 11. Experimental Diabetes 12. Regulation of Secretion 13. Affect on Gene Expression.
Contents:
- Essay on the Chemistry of Insulin
- Essay on the Insulin Receptor
- Essay on the Insulin Secretion
- Essay on the Factors Stimulating Insulin Secretion
- Essay on the Factors Inhibiting Insulin Secretion
- Essay on the Metabolism of Insulin
- Essay on the Functions of Insulin
- Essay on the Pathophysiology of Insulin
- Essay on the Abnormal Metabolism in Diabetic States
- Essay on the Antibodies in Insulin
- Essay on the Experimental Diabetes
- Essay on the Regulation of Insulin Secretion
- Essay on the Affect of Insulin on Gene Expression
Essay # 1. Chemistry of Insulin:
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a. Insulin is a protein hormone secreted from the β-cells of the islet of Langerhans.
b. Traces of zinc are required for the crystallization of insulin.
c. It consists of 51 amino acids and contains two polypeptide chains (A and B) linked together by two disulphide bridges [one is 7-7 and another in 20-19 of A & B chains, respectively], A third intra-disulphide bridge between 6 and 11 amino acids of A chain also occurs.
d. It has a molecular weight of 5,734.
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e. Alkali or reducing agents can inactivate insulin by breaking the disulphide bonds.
f. Proteolytic enzymes digest the insulin protein and inactivates insulin. Hence, it cannot be given orally.
The structure of insulin is given (Fig. 31.13).
Essay # 2. Insulin Receptor:
a. Insulin acts on target tissues by binding to specific insulin receptors which are glycoproteins.
b. The human insulin receptor gene is found on chromosome 19. The insulin receptors are being constantly synthesized and degraded. Their half-life is 6 to 12 hours only.
c. It is synthesized as a single chain polypeptide, pro-receptor in the rough endoplasmic reticulum and is rapidly glycosylated in Golgi region.
d. The pro-receptor is cleaved to form mature α and β subunits (α2β2) which is heterodimer, linked by S- S bonds.
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e. Both subunits are extensively glycosylated and removal of sialic acid and galactose decreases insulin binding and insulin action.
f. Insulin receptors are found in target cell membrane.
g. Though insulin receptor is a heterodimer consisting of 2 subunits, designated α and β (α2β2) linked by disulphide bonds.
h. The α subunit is entirely extracellular and it binds insulin, probably via a cystinerich domain.
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i. The β subunit is a trans-membrane protein that performs the second major function of a receptor, i.e. signal transduction and insulin action.
j. Binding of insulin to the receptor stimulates its tyrosine kinase activity. Tyrosine kinase enzyme phosphorylates the phenolic -OH group of tyrosine residues in specific protein including that of a tyrosine in the chain of insulin receptor itself to modulate their activities, ATP + tyrosine protein → ADP + phosphotyrosine protein.
The cytoplasmic portion of p subunit has tyrosine kinase activity and an auto-phosphorylation site.
Essay # 3. Insulin Secretion:
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About 50 units of insulin are required per day. The human pancreas stores about 250 units.
Normal concentration of insulin (fasting) in plasma: 6-126 µU/ml.
Essay # 4. Factors Stimulating Insulin Secretion:
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a. Increased blood glucose level causes an increase in insulin secretion and decreased blood glucose level depresses insulin secretion.
b. The hyperglycemia produced by glucagon enhances insulin production.
c. Since the growth hormone and glucocorticoids cause hyperglycemia they also stimulate insulin secretion.
d. Sugars which are readily metabolized— e.g., mannose and fructose—can stimulate insulin release. But non-metabolised sugars such as glactose, L-arabinose and xylose do not stimulate.
e. Many agents, such as amino acids, fatty acids and some gastro—intestinal products can stimulate insulin release only in presence of glucose.
f. Insulin secretion is enhanced by cAMP, ACTH and thyrotropin.
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g. Amino acids particularly leucine and arginine can stimulate pancreas to produce insulin in both vivo and vitro. Proteins like casein also increases secretion of insulin.
h. Central nervous system indirectly influences the release of insulin. Vagal stimulation causes an increase in insulin secretion.
i. Sulfonylureas, the hypoglycemic agent, may act on insulin secretion by a different mechanism than that of glucose.
Essay # 5. Factors Inhibiting Insulin Secretion:
a. Epinephrine is the highly effective inhibitor of insulin secretion.
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b. Starvation reduces insulin secretion.
c. Magnesium also inhibits insulin secretion.
d. Vagotomy reduces insulin secretion.
Essay # 6. Metabolism of Insulin:
a. Insulin is degraded in liver and kidney by the enzyme glutathinone insulin trans-hydrogenase which brings about reductive cleavage of the S-S bonds that connect A and B chains of the insulin molecule. Reduced glutathione acts as a coenzyme.
b. The A and B chains are further degraded by proteolysis. But when insulin is bound to antibody, it is much less sensitive to enzymic degradation.
Essay # 7. Functions of Insulin:
a. Insulin is firmly bound to the highly specific receptor site present in the cell membrane. The receptor may probably be a glycoprotein. The biologic activities of insulin’s are proportionate to their binding affinities. Insulin, thus, may carry out most of its function without entering the cell. The number of receptors declines where insulin levels are high.
b. Insulin exhibits transport at the membrane site, RNA synthesis at the nuclear site, translation at the ribosome for protein synthesis, and influence on tissue levels of cAMP. It is active in skeletal and heart muscle, adipose tissue, liver, the lens of the eye and leukocytes. It is inactive in renal tissue, red blood cells and gastrointestinal tract. The most metabolic function is centered in the muscle, adipose tissue and liver.
c. It facilitates the transport of glucose and related monosaccharides, amino acids, potassium ion, nucleosides, inorganic phosphate, and calcium ion in muscle and adipose tissue.
d. In muscle for adipose tissue, insulin increases the entry of glucose and thus leads to increased glycogen deposition, stimulation of HMP shunt resulting in increased production of NADPH, increased glycolysis, increased oxidation (Increase in oxygen uptake and CO2 production), and increased fatty acid synthesis.
e. In adipose tissue, it increases lipid synthesis by means of fatty acid synthesis and glycerophosphate for triacylglycerol synthesis.
f. Insulin increases intracellular concentration of non-metabolized sugars such as galactose, L-arabinose, and xylose. The hormone facilitates the entry of those sugars having the same configuration at carbons, 1, 2, and 3 as D-glucose. Since fructose having a ketone group at position 2 is not transported by insulin. Intracellular transport of glucose is enhanced by anoxia indicating that glucose transport requires energy.
g. It also increases the uptake of nonmetabolizable amino acids such as alpha-aminoisobutyrate. It maintains muscle protein by decreasing protein degradation.
h. In adipose tissue, it quickly depresses the liberation of fatty acids caused by epinephrine or glucagon.
i. Insulin directly increases protein synthesis as the hormone promotes the incorporation of labelled intracellular amino acids into protein. At the ribosomal level, it increases the capacity of this organelle to translate information from messenger RNA to the protein-synthesizing machinery.
j. In the liver, it stimulates glycolysis by increasing the synthesis of glucokinase, phosphofructokinase. and pyruvate kinase. It also depresses the enzymes controlling gluconeogenesis such as pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-di-phosphatase, and glucose-6-phosphatase. Enzymes which are unimportant in the control of gluconeogenesis as well as glycolysis are not affected by insulin.
Essay # 8. Pathophysiology of Insulin:
a. About 90% of persons with diabetes have non-insulin dependent (Type II) diabetes mellitus (NIDDM). Such patients are usually obese, have elevated plasma insulin levels.
b. The other 10% have insulin dependent (Type 1) diabetes mellitus (IDDM).
c. A few individuals produce antibodies directed against their insulin receptors. These antibodies prevent insulin from binding to the receptor so that such persons develop a syndrome of severe insulin resistance.
d. Tumors of β-cell origin cause hyperinsulinism thereby hypoglycemia. Leprechaunism is caused by the role of insulin in organogenesis. The syndrome is characterized by low birth weight, decreased muscle mass, decreased subcutaneous fat, and early death.
Essay # 9. Abnormal Metabolism in Diabetic States:
a. In diabetes, hyperglycemia occurs due to the impaired transport and uptake of glucose into muscle and adipose tissue. Transport and uptake of amino acids are also depressed causing the raised level of amino acids into the blood, particularly, alanine, which supply fuel for gluconeogenesis in the liver. The amino acid breakdown during gluconeogenesis increases the production of urea nitrogen.
b. Lipid and fatty acid synthesis is decreased due to the decrease in acetyl-CoA, ATP, NADPH and glycerophosphate in all tissues. Stored lipids are hydrolysed by increased lipolysis and the liberated fatty acids interfere the carbohydrate phosphorylation in muscle and liver developing hyperglycemia.
c. Fatty acids in high concentration reaching the liver inhibit fatty acid synthesis by a feedback inhibition at the acetyl-CoA carboxylase step. Increased acetyl-CoA from fatty acids activates pyruvate carboxylase, stimulating gluconeogenic pathway for the conversion of amino acid carbon skeletons to glucose. Fatty acids also stimulate gluconeogenesis by entering the citric acid cycle and increasing production of citrate which is an inhibitor of glycolysis (at phosphofructokinase).
Thus, the fatty acid cycle at the level of citrate synthetase and pyruvate and isocitrate dehydrogenases. The acetyl CoA, which cannot enter the citric acid cycle or cannot be used for fatty acids synthesis, is utilized in the synthesis of cholesterol or ketones or both. The rise in ketone bodies concentration in body fluids and tissues leads to acidosis.
d. Glycogen synthesis is diminished due to decreased glycogen synthetase activity, increased phosphorylase activity and increased ADP: ATP ratio. The phosphorylase activity is stimulated by epinephrine or glucagon.
e. The insulin deficiency causes hormonal imbalance and favours the action of corticosteroids, growth hormone and glucagon which enhance gluconeogenesis, lipolysis, and decreased intracellular metabolism of glucose. The excess glucose in the urine requires water to be excreted out causing dehydration.
f. In the degradation in insulin, both liver and kidney are required. Therefore, in renal or hepatic disease, insulin requirement is decreased. This is observed in some diabetics with associated kidney or liver disease.
Essay # 10. Antibodies in Insulin:
a. The repeated injection of insulin produces low levels of an antibody to insulin in all subjects after 2 or 3 months of treatment.
b. The antibodies can produce lesions in the islet cells and severe diabetes.
c. Antibody-bound insulin is only slowly degraded; thus much of the insulin is actually wasted.
Essay # 11. Experimental Diabetes:
a. Experimental diabetes can be produced by total pancreatectomy or by a single injection of alloxan, a substance related to the pyrimidine’s or with streptozocin, an N-nitroso derivative of glucosamine.
b. Diabetes can also be produced by injection of diazoxide, a sulfonamide derivative which inhibits insulin secretion.
c. The injection of large amounts of antibodies to insulin is also considered to produce experimental diabetes.
d. Phlorhizin diabetes can be produced by the injection of the drug phlorhizin. This is actually a renal diabetes in which glycosuria is only produced by the failure of the reabsorption of glucose by the renal tubules.
Essay # 12. Regulation of Insulin Secretion:
40 to 50 units of insulin is daily secreted from human pancreas. This represents about 15 to 20 per cent of the hormone stored in the gland. Insulin secretion is an energy-requiring process. Different factors are involved in insulin release.
a. Glucose:
(a) The increased concentration of glucose is the best regulator of insulin secretion.
(b) Among two ideas, one idea suggests that glucose combines “with a receptor which” is located on the B cell membrane that activates the release mechanism. The second idea suggests that intracellular metabolites pass through a pathway .such as the HMP shunt, the TCA cycle, etc.
b. Hormonal Factors:
(a) Epinephrine inhibits insulin release.
(b) Beta adrenergic agonists stimulate insulin release by increasing intracellular cAMP.
(c) Cortisol, estrogens, and progestin’s also increase insulin secretion. Hence, insulin secretion is markedly increased during the later stages of pregnancy.
c. Pharmacologic Agents:
(a) Many drugs stimulate insulin secretion, but the sulfonyl urea compounds are used for therapy in humans.
(b) Drugs such as tolbutamide stimulate insulin release and effectively used in the treatment of type 11 (non-insulin-dependent) diabetes mellitus. This class of drug is binded by a receptor which has been derived from the pancreatic P cells.
Essay # 13. Affect of Insulin on Gene Expression:
(a) The actions of insulin are found to occur at the plasma membrane level or in the cytoplasm.
(b) The synthesis of phosphoenolpyruvate carboxykinase (PEPCK) which catalyses a rate-limiting step in gluconeogenesis is decreased by insulin and hence gluconeogenesis is decreased.
(c) Transcription is decreased due to the decreased amount of the primary transcript and of mature mRNA PEPCK which in turn is directly related to the decreased rate of PEPCK synthesis.
(d) More than 100 specific mRNAs are affected by insulin, and a number of mRNAs in liver, adipose tissue, skeletal muscle, and cardiac muscle. Some examples of the affect of insulin on gene transcription is noted (Table 31.1).
