Insulin and Glucagon

INSULIN
Insulin

Alpha cells o usually on peripheral o release glucagon Beta cells o Most of Islets are composed of beta cells o secrete insulin

Insulin synthesis Product of cleavage of a bigger molecule to a smaller molecule Precursor: preproinsulin o Preproinsulin proinsulin insulin Along with the release of insulin would be the release of C peptide Can measure proinsulin, insulin and C peptides o Unstable and rapidly degraded Require special procedures and immediate processing Mechanism of Action Insulin receptor: two alpha subunit in the ECF and two beta subunit embedded in the cell membrane Attached to the insulin receptor would be the tyrosine kinase When insulin binds to receptor, there would be phosphorylation of enzymes of insulin receptors Enzymes bring about metabolic effects of insulin Effects of Insulin: Transport of glucose o insulin facilitates entry of sugar from circulation into the cells o translocation of glucose transporters when activated will move from the intracytoplasmic area into the cell membrane, will open up and facilitate transport of glucose inside o Glucose Transporters GLUT1 Widely distributed in fetal tissues In adults: found in erythrocytes, Blood brain barrier For low level of basal glucose uptake required to sustain respiration in all cells Decreased blood glucose: Increased GLUT1 in cell membranes Increased blood glucose: Decreased GLUT1 in cell membranes GLUT2 Bidirectional transporter, allows glucose to flow in 2 directions Renal tubular cells, liver cells, pancreatic beta cells
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Glucose, galactose and fructose are transported from intestinal mucosal cells to portal circulation by GLUT2 GLUT3 In neurons and in the placenta Able to transport even in low glucose concentrations GLUT4 In adipose tissues and striated muscles Is the insulin regulated glucose transporter Responsible for insulin-regulated glucose storage GLUT5 Fructose transporter In small intestines

Protein synthesis Fat synthesis Glycogen synthesis Growth and gene expression

Insulin Secretion Key Regulator: Glucose In presence of glucose, it will enter the beta cell by way of glucose transporters and will undergo glycolysis and broken down into ATP ATP would bind to ATP sensitive potassium channels and closing it, potassium is trapped inside beta cells Beta cell is in a state of depolarization Opening of voltage gated calcium channels
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Calcium stimulates release of insulin that are stored in the storage granules Insulin released through exocytosis

Phases of Insulin Secretion First phase o Occurs very rapidly but only for a very short period of time o Rapid because insulin released is preformed insulin, already stored in beta cells o 5-10 minutes Second phase o Occurs later, around 15-30 minutes after ingestion o Gradual in onset but action is more prolonged o 1-2 hours long o Gradual because insulin still has to be produced

**Basic pharmacokinetics of insulin preparations: different onset of action, different duration **In Diabetic patients, first sign is the loss of the first phase of insulin release Control of Insulin Secretion Glucose - key regulator Sulfonylureas Insulin resistance, obesity Investing effect

Increase Insulin Secretion

Increased blood glucose Increased blood free fatty acids GI hormones (gastrin, CCK, secretin, GIP) Glucagon, growth hormone, cortisol Parasympathetic stimulation, acetylcholine -adrenergic stimulation Insulin resistance, obesity Sulfonylurea drugs (glyburide, tolbutamide)

Decrease Insulin Secretion

Decreased blood glucose Fasting Somatostatin -adrenergic activity Leptin

Sulfonylureas insulin secretagogues- facilitate secretion of insulin Site of action of sulfonylureas: potassium channels, keeps it close Sulfonylureas can cause beta cell exhaustion after at least 5 years of continuous use fastest onset of action, most hypoglycemic Glipizide, Gliclazide, Glimepiride Incretin effect Intestinal secretion of insulin Intestines play a role in releasing insulin
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Insulin and Glucagon

o Insulin absorbed in intestines o L cells release a hormone, GLP1 (Glucagon Like Peptide 1) o GLP1 stimulates beta cells to release insulin Very short lived because GLP1 is rapidly degraded Impaired among diabetics Oral glucose has greater incretin effect than intravenous glucose Eg. Sitagliptin

Insulin resistance Very common among overweight and obese Most cases would be a problem on insulin receptor Hyperinsulinemia or normal insulin levels if body is chronically exposed to this state, eventually the beta cells would die High glucose levels would stimulate beta cells to release insulin, but there is insulin resistance thus blood glucose is still high, vicious cycle Metabolic syndrome/syndrome X Overweight Truncal obesity Hypertensive elevated lipid profiles Smoking Insulin and CHO metabolism insulin lowers blood sugar levels insulin facilitates glucose uptake into muscle cells and adipose cells sugar levels will go down Activity: o In a resting muscle, muscle will need insulin to transport glucose o During Exercise: glucose readily goes into cells, exercising muscle fibers become more permeable to glucose Fate of Glucose Used for energy Excess glucose: stored as glycogen (Glycogenesis) Hepatic uptake, storage and use of glucose conversion of excess glucose into fatty acids Insulin inhibits gluconeogenesis Does insulin have an effect on glucose uptake and usage by the brain? Insulin has little effect on uptake or use of glucose in the brain Most brain cells are permeable to glucose and can use glucose even without insulin

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Insulin and Glucagon

Insulin and Fat Metabolism Increased glucose transport into liver activation of acetyl-CoA carboxylase and lipoprotein lipase o acetyl CoA carboxylase: fatty acid synthesis, converts acetyl CoA to malonyl CoA o lipoprotein lipase: breaks down fats into glycerol and fatty acids Inhibition of hormone sensitive lipase in adipose tissue o So the stored fat will not be broken down into fatty acids and released into circulation Increased formation of acetyl CoA and glycerol o First part of glycolysis Insulin will facilitate Fat synthesis and storage o Insulin uses glucose for energy, automatically reducing the utilization of fat Insulin and Protein metabolism Protein synthesis is the major effect of insulin Every aspect of protein synthesis is enhanced by insulin Insulin prevents protein breakdown o Insulin is an anabolic hormone Increased amino acid transportation into cells increased translation of mrna Increased DNA transcription Depressed gluconeogenesis o Amino acids are stored as proteins and not used as carbohydrates Consequences of Insulin Deficiency

Glucose uptake and utilization inhibited Glycogen synthesis inhibited Gluconeogenesis enhanced Lipid synthesis inhibited Cholesterol and phospholipid synthesis enhanced Ketone body formation enhanced Protein catabolism enhanced

GLUCAGON
Glucagon Anti thesis of insulin Counter regulatory hormone of insulin
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Effects of glucagon Increases blood glucose o Increased glycogenolysis o Enhanced gluconeogenesis o Activation of adipose cell lipase/hormone sensitive lipase o Inhibits triglyceride storage in the liver Mechanism of action of glucagon Has a receptor that is controlled by GDP that bring about its action by way of cAMP o cAMP- second messenger Pyruvate to glucose -gluconeogenesis Regulation of glucagon secretion

blood glucose levels: hypoglycemia blood amino acid levels: increased amino acids will enhance glucagon secretion exercise: increased amino acids Glucagon has same effects with: o epinephrine o growth hormone o cortisol

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