Insulin, Glucagon, and Diabetes Mellitus

Insulin and Glucagon are synthesized and metabolised like most peptide hormones.

1. Large Preprohormones.
2. Golgi apparatus Prohormones are packed in granules and then cleaved into free hormone plus a peptide fragmet (Insulin and the C-Peptide)
3. Circulate unbound and therefore have a Short Half Life - 5 to 10 minutes
4.  50% of Insulin and Glucagon are secreted into the portal circulation where it exerts its effect on the Liver, and eliminated on first pass by liver.

Insulin and its metabolic effects

1. Insulin is a hormone associated with energy abundance
1. Insulin is used for energy and anabolic processes and storage of nutrients for later use when energy supplies are low
2. Stores of carbohydrates, protein, and fats are increased in the presence of insulin
3. Insulin has 
1. rapid - seconds - (increase glucose and amino acid uptake into the cells),
2. intermediate - minutes - (stimulation of protein synthesis, inhibition of protein degradation, activation and deactivation of enzymes), and 
3. delayed - hours - (increased transcription) actions on carbohydrate, fat and protein
2. Most of the actions of insulin are achieved through autophosphorylation of receptors
1. Insulin does not use second messenger system
2. Signal transduction is achieved through autophophorylation of the intracellular domains of its own receptor.
3. Insulin receptor has two alpha subunits on the outside of the cell and two beta subunits that protrude into the cytoplasm
4. Binding of Insulin to the alpha subunits - stimulates tyrosine kinase - 
3. Effects of Insulin on Carbohydrate Metabolism
1. In muscle, insulin promotes the uptake and metabolism of glucose
1. facilitates glucose diffusion from blood into the cells by increasing the number of glucose transporters in the cell membrane.
2. Increased glucose transported into the muscle cells undergoes glycolysis and oxidation and is stored as glycogen.
3. Glucose is insulin dependent and uptake is restricted to postprandial period when insulin is secreted and in period of exercise when glucose transport is noninsulin dependent
4. In the liver, insulin promotes glucose uptake and storage, and inhibits glucose production.
1. Increase the flux of glucose into the cells
1. Inducing glucokinase which increase the phophoralation of glucose to glucose -6 phosphate (not increasing glucose transporters)
2. Increase glycogen systhesis by activating glycogen syntatase - as well as increasing glucose uptake
3. Direct the flow of glucose through glycolysis by increasing the activity of key glycolytic enzymes (phosphofructokinase and pyruvate kinase)
4. Decrease the hepatic output of glucose in several ways 
1. Impairs glycogenolysis by inhibiting glycogen phophorylase
2. Decreases the exit of glucose from the liver by inhibiting glucose-6-phosphatase
3. Inhibits gluconeogenesis by decreasing the amino acid uptake into the the liver
4. Decreases the activity of gluconeogenic enzymes:
1. pyruvate carboxylase and 
2. fructose-1,6-diphosphatase
5. Enhance synthesis of fatty acids in two ways:
1. Insulin increases the flow of glucose to pyruvate (glycolysis) and conversion to Acetyl-CoA
2. Insulin stimulates acetyl-CoA carboxylase which converts actyl-CoA to malonyl-CoA - this is a rate limiting step in the synthesis of fatty acids.
5. In adipose tissue, insulin facilitates glucose entry into cells
1. by increasing glucose transporters in the cell membranes
2. Subsequently, the metabolism of glucose to alpha-glycerol phosphate provides the glycerol that is needed for esterification of fatty acids for storage as triglycerides.
6. Insulin has little effect on glucose uptake and use by the brain
7. Effects of insulin on fat metabolim
1. In adipose tissue, insulin enhances storage and inhibits mobilization of fatty acids. 
1. Insulin inhibits hormone sensitive lipase
1. this decreases the rate of lipolysis of triglicerides and the release of stored fatty acids into the circulation
2. Insulin increases glucose transport. The subsequent metabolism of glucose to alpha-glycerol phosphate - increases the rate of esterification of fatty acids for storage as triglycerides.
3. Insulin induces lipoprotein lipase. This enzym is present in the capillary wall and splits circulation triglycerides into fatty acids, which is necessary for their transport into fat cells.
8. In the liver, insulin promotes the synthesis and inhibits the oxidation of fatty acids

1. promotes the synthesis of fatty acid from glucose in the liver
2. increase availability of alpha-glycerol phosphate from glycolysis, fatty acids are esterified to form triglycerides. 
3. Oxidation of fatty acids is impaired because of the increase in conversion of acetyl-CoA to malonyl-CoA by acetyl-CoA carboxylase. Melonyl-CoA inhibits carnitine acytranferase, which is responsible for shuttling fatty acids from the cytoplams into the mitochondria for beta oxidation and conversion to keto acids, insulin is antiketogenic
9. EFFECTS OF INSULIN IF PROTEIN METABOLISM
1. Insulin is an anabolic hormone
1. increases amino acid uptake into cells by stimulating transporters across cell membrane - limiting increase in plasma amino acid levels after a protein meal.
2. Stimulates gene transcription and translation of mRNA
3. Inhibits catabolism of proteins and decreases the release of amino acids from muscle
4. Insulin is essential for growth - diabetic animals fail to grow. Insulin and growth hormone are synergistic.
10. Control of Insulin Secretion
1. Glucose is the most important controller of insulin secretion
2. Multiple stimuli other than hypoglycemia increase insulin secretion
1. amino acids 
2. Gastrointestinal hormones
1. Gastrin inhibitory hormone and glucagon-like polypeptide 1
3. Cortisol and Growth Hormone
1. Increase insulin secretion as they antagonise the effects of insulin on glucose uptake in peripheral tissues, leading to increased blood glucose concentration.
2. Cushing syndrome (Cortisol excess) and Acromegaly (Growth Hormone Excess) leat to hypertrophy and exhaustion of beta cells of teh pencrease and thereby cause Diabetes Mellitus

Glucogon

Most of the actions of Glucagon are acheived by activation of Adenylyl cyclase

1. Adenylate cyclase (EC 4.6.1.1, also known as adenylyl cyclase, adenyl cyclase or AC) is a lyase enzyme. It is a part of the cAMP-dependent pathway
2. 
   



G protein signal transduction (epinephrin pathway)

Epinephrine binds its receptor, that associates with an heterotrimeric G protein. The G protein associates with adenylate cyclase, which converts ATP to cAMP, spreading the signal 




Stimulates the cAMP second messenger system, activating protein kinase A




1. Protein kinase A (PKA) refers to a family of enzymes whose activity is dependent on the level of cyclic AMP (cAMP) in the cell, in cell biology. PKA is also known as cAMP-dependent protein kinase EC 2.7.11.11). Protein kinase A has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism.

Glycogon promotes hyperglycemia in several ways:

1. Glycogon stimulates glycogenolysis:
1. activation of glycogen phosphorylase and 
2. inhibition of glycogen synthase
2. Glucagon Inhibits Glycolysis: 
1. Inhibits phosphofructokinase and pyruvate kinase. Consequently glucose-6-phosphate levels rise, leading to increased glucose release from the liver
3. Glucagon stimulates gluconeogenesis - Glucagon increases the hepatic excretion of amino acids from the plasma and increases in the activities of key gluconeogenic enzymes:
1. Pyruvate carboxylase, and 
2. Fructose 1,6-diphosphotase

Glucagon is ketogenic. Because Glucagon inhibits acetyl-CoA carboxylase, there is a decrease malonyl-CoA, an inhibitor of carnitine acetyltranferase. Consequently, fatty acids are directed into the mitochondria for beta oxidation and ketogenesis.

Control of Glycogon Secretion

1. Glucose is the most important controller of glucagon sectretion
1. Hypoglycemia increases glucagon secretion 
2. Hyperglycemia inhibits glucagon secretion
2. Amino acids, especially arganine and alanine, stimulate glucagon secretion 
1. after a protein meal, both insulin and glucagon secretion are stimulated, but the glucagon response is depressed if glucose is digested simultaneously
2. Without the glycogon response to a protein meal, the increased insulin would result in hypoglycemia
3. Fasting and exercise stimulate glucagon secretion. 
1. Glucagon helps prevent hypoglucemia

Somatostatin - its effect to inhibit Glucagon and Insulin Sectretion

1. Synthesized by the delta cells in the pancreas, as well as the gut and the hypothalamus, where it is a hypophysiotropic hormone
2. Pancreatic somatostatin is stimulated by:
1. Ingestion of food
2. Increase blood levels of glucose, amino acids and fatty acids and
3. a number of GIT hormones
3. Inhibits GIT motility, secretion and absorption and delays the assimilation of nutrients from the GI tract and utilisation of absorbed nutrients by the liver and the peripheral tissue.

Diabetes Mellitus

1. carbohydrate, fat and protein metabolism are impaired because of a deficient response to insulin
2. Type I Diabetes Mellitus - IDDM - impaired secretion of insulin
1. Impaired secretion of insulin by the beta cells of the pancreas
2. Autoimmune destruction of beta cells due to viral infections
3. Juvenile diabetes - occurs in childhood
4. Pathophysiology
1. Hyperglycemia - impaired glucose uptake into the tissue and increased glucose production by the liver (increased gluconeogenesis)
2. Depletion of proteins - due to decrease synthesis and increased catabolism
3. Depletion of fat stores and increased ketogenesis.
5. Results in
1. Glucoseuria, osmotic diuresis, hypovolemia, and hypotension
2. Hyperosmolality of the blood, dehydration, and polydipsia
3. Hyperphagia but weight loss; lack of energy
4. Acidosis progressing to diabetic coma, rapid and deep breathing
5. Hypercholestrolemia and atherosclerosic vascular disease.
3. Typre II Diabetes Mellitus - NIDDM - resistance to the metabolic effects of insulin in target tissues
1. Associated with obesity
2. Insulin resistance 
3. adult onset Diabetes Mellitus
4. Accelerated lypolysis and ketogenesis do not occur
5. Calorie restriction and weight reduction usually improves insulin resistance in target tissue.