Insulin, Glucagon and Diabetes melitus

Key Actions of Insulin on Adipose tissue

- Increases glucose uptake - Increases free fatty acid uptake - Increases lipogenesis (lipid synthesis) - Decreases lipid breakdown

Key Actions of Insulin on Muscle

- Increases glucose uptake - Increases glycogenesis - Increases amino acid uptake - Increases protein synthesis

Key Actions of Insulin on Liver

- Increases glucose uptake - Increases glycogenesis (glycogen synthesis) - Decreases gluconeogenesis (glucose synthesis) - Decreases glycogenolysis (glycogen breakdown) - Increases lipogenesis (fatty acids synthesis)

Insulin Secretagogues = Sulfonylureas

-Binds to & closes ATP-sensitive K channels -Increases insulin release from beta cells -Treatment for Type II diabetes Sulfonylureas also -Sensitize β-cells to glucose -Limit glucose production in liver -Decrease degradation of insulin

Mechanism of Glucose-Induced Insulin Secretion

1- Glucose enter the β cell via GLUT-2 Transporters 2- Glucose stimulates the Krebs Cycle, generating ATP (Glucokinase catalyzes the conversion of Glucose to G6P, the critical first step in the Krebs Cycle) 3- ATP displaces ADP from open ATP-sensitive K channels 4- Bound ATP causes channels to close 5- Depolarization of cells 6- Depolarlization opens voltage-gated Ca channels 7- Influx of Ca activates release of insulin from insulin-containing vesicles

Incretins

A hormone that stimulates insulin secretion in response to meals. The two most important incretin hormones are called glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP)

Which of the following increase the secretion of insulin, growth hormone, and glucagon? A. A protein meal B. A carbohydrate meal C. A fat meal D. Fasting

A. A protein meal

Cortisol and glucagon have similar effects on which of the following? A. Blood glucose concentration B. Protein synthesis in muscle C. Glycogenolysis D. Glucose uptake in peripheral tissues

A. Blood glucose concentration

Which of the following are incorrectly paired? A. Epinephrine : increased glycogenolysis in skeletal muscle B. Glucagon : increased glycogenolysis in skeletal muscle C. Glucagon : increased gluconeogenesis D. Growth hormone : increased plasma glucose concentration E. Cortisol : increased plasma glucose concentration

B. Glucagon : increased glycogenolysis in skeletal muscle

Which of the following would most likely occur in the earliest stages of type II diabetes? A. Increased insulin sensitivity B. High circulating levels of C-peptide C. Decreased hepatic glucose output D. Metabolic acidosis E. Hypovolemia

B. High circulating levels of C-peptide

Which of the following are incorrectly paired? A. Glucagon: increased glycogenolysis in liver B. Insulin: increased gluconeogenesis in liver C. Epinephrine: increased glycogenolysis in liver D. Epinephrine: increased glycogenolysis in muscle E. Cortisol: decreased glucose uptake in muscle

B. Insulin: increased gluconeogenesis in liver Insulin increase glucose uptake -> increase glycogenesis

Which of the following would produce opposite directional changes in insulin and glucagon secretion? A. Amino acids B. Somatostatin C. Glucose D. beta-adrenergic stimulation

B. Somatostatin In the pancreas, somatostatin is produced by the delta cells of the islets of Langerhans, where it serves to block the secretion of both insulin and glucagon from adjacent cells Somatostatin also inhibits the release of growth hormone from the pituitary gland

A 60-year-old man comes to the physician's office complaining of recent onset of fatigue and the need to urinate several times each night. He is 6' tall and weighs 300 lbs. His blood pressure is 140/90. Laboratory data reveal a fasting blood glucose concentration of 270 mg/dL. Urinalysis reveals high urine glucose but no ketones. What is the most likely cause of this man's symptoms? A. Type 1 diabetes mellitus B. Type 2 diabetes mellitus C. Addison's disease D. Cushing's disease E. Diabetes insipidus

B. Type 2 diabetes mellitus More often Diabetic ketoacidosis (DKA) = presence of ketone bodies in urine are found in Type 1 diabetes

DPP-4 Inhibitors

Both GLP-1 & GIP are inactivated by dipeptidyl peptidase-4 (DPP-4) DPP-4 inhibitors block degradation of incretins & increase insulin secretion

Which of the following does not play a role in the secretion of insulin from B-cells when plasma glucose concentration increases? A. Glucose influx into B cells via GLUT2 transporters B. Oxidation of glucose and the generation of ATP C. Opening of ATP-sensitive potassium channels D. Depolarization of the cell membrane E. Opening of voltage gated calcium channels

C. Opening of ATP-sensitive potassium channels Potassium channels are closed

A patient has uncontrolled type I diabetes. Which of the following is likely to be present? A. Decreased plasma osmolality B. Increased plasma volume C. Increased plasma pH D. Increased release of glucose from the liver E. Decreased rate of lipolysis

D. Increased release of glucose from the liver

Which of the following conditions result in stimulation of glucagon secretion? A. Decreased plasma amino acid concentration B. Increased somatostatin secretion within the islets C. Intravenous infusion of glucose D. Intravenous infusion of insulin

D. Intravenous infusion of insulin Rapid increasing of insulin in blood -> decrease blood glucose level - > stimuli glucagon secretion

Diabetic Nephropathy

During hypoxia, oxygen supply is substantially decreased, especially in tubular segments of the inner medulla, through a multitude of mechanisms. (1) The number of peritubular capillaries is decreased. The postglomerular peritubular blood flow is reduced (2) by angiotensin II and nitric oxide, and (3) by anemia. (4) Oxygen demand is also increased in the tubule of the outer medulla of the diabetic kidney due to compensation for the tubular loss of nephrons.

GLP-1 agonists (peptides)

Exenatide BYETTA®: b.i.d. subQ injection BYDUREON®: once a week, subQ injection Liraglutide VICTOZA®: q.d., subQ injection

Glucagon

Glucagon is secreted by the alpha cells

Pacreas

Has both exocrine (gastric digestive enzyme)and endocrine cells( alpha- glucagon, beta- insulin)

Which of the following metabolic responses would be expected during the postabsorptive period, compared to the postprandial state?

Increase glucagon secretion Increase hormone-sensitive lipase Decrease adipocyte alpha-glycerol phosphate

A large dose of insulin is administered intravenously. Which of the following sets of hormonal changes would be expected to occur in the plasma in response to the insulin injection?

Increase growth hormone Increase glucagon Increase epinephrine

Which of the following metabolic responses would be expected during the postprandial period (fed state), compared to the postabsorptive state (fasted state)?

Increase lipoprotein lipase Deacrease hormone-sensitive lipase Decrease glycogen phophorylase

Insulin: chemistry (cont.)

Insulin A & B chains (51 amino acids) Plasma T½ = 6 minutes Degraded by insulinase in liver Insulinase (aka insulin-degrading enzyme (IDE), insulysin, insulin protease) also can degrade the Aβ protein in Alzheimer's disease

Lipidemia in Diabetes (seen in severe T1DM)

Ketonuria: loss of ketone in urine

Hyperglycemia in Diabetes

Polyuria : high volume of urine Polydipsia: abnormal great thirst as a symptom of disease. Osmotic diuretic: inhibition of water and sodium reabsorption

Insulin: chemistry

Synthesized as preproinsulin Cleaved in ER to form proinsulin Cleaved in Golgi to form insulin + C peptide

Poor circulation in diabetes

increase blood glucose level increase the hardening of the arteries

Insulin receptor

insulin receptor is • a Receptor Tyrosine Kinase (RTK) • a Homodimer (each monomer has one α & β subunit) Binding of insulin to receptor • activates tyrosine kinase activity • causes phosphorylation of many intracellular enzymes (insulin receptor substrates) • activates other enzymes, changes gene expression

Glucagon receptor

is a G-protein coupled receptor - Activates adenylyl cyclase - Increases cyclic AMP - Activates protein kinase A

T1DM (type I diabetes mellitus)

• 5-10% of all diabetes patients • Selective destruction of β cells - Autoimmune disorder - Environment factor unknown - likely viral infection • Usual onset in US = 14 yo, but can occur in any age • Management - No preventive strategy - Basal & bolus insulin administration - Blood glucose monitoring - Diet The response to insulin is normal. The response of muscle to glucose uptake is normal

T2DM (type 2 diabetes mellitus)

• 90-95% of all diabetes patients • Reduced response to insulin (insulin resistance) - Associated with overweight & obesity (esp. accumulation of abdominal fat) - Mechanism of etiology not fully understood • Fewer insulin receptors • Abnormalities in insulin receptor signaling pathway • Usual onset in US > 30 yo, often 50-60 yo • Management (Mayo Clinic Recommendation) - Lifelong commitment • Blood sugar monitoring • Healthy diet • Regular exercise • If necessary, medication & insulin therapy The response to insulin is under normal. The response of muscles to glucose uptake is below normal

Metformin

• Biguanides, such as - Metformin (Glucaphage®) • First-line medication for T2DM • *******Metformin is the only oral anti-hyperglycemic medication proven to reduce risk of total mortality in T2DM******** • Pharmacological actions - Increase sensitivity to insulin - Suppresses gluconeogenesis in liver - Increases peripheral glucose uptake - Molecular mechanism of action unclear

Toxic effects of glucose

• Chemical Interaction with proteins − Changes protein functions • Formation of Advanced Glycation End Products (AGE) - Causes oxidative damage to most cells - Changes vessel permeability & functions - Pro-inflammatory - Others Note: the glucose that enters the neurons are not regulated by the increase or decrease of insulin -> more glucose -> more glycation to neurons • Formation of polyols via aldose reductase - Produces reactive oxygen species - Causes oxidative damage Polyols are sugar-free sweeteners. Polyols are carbohydrates but they are not sugars.

Diabetes Mellitus

• Etiology - Lack of insulin secretion • Type I diabetes - T1DM, IDDM (insulin-dependent diabetes mellitus), juvenile diabetes - Reduced sensitivity of target tissues to insulin • Type II diabetes - T2DM, NIDDM (non-insulin-dependent DM), adult-onset diabetes • Gestational diabetes (20-50% develops T2DM later) • Syndrome - Impaired carbohydrate, fat, & protein metabolism

Regulation of Glucagon

• Hypoglycemia stimulates secretion • High blood amino acid levels stimulate secretion • Exercise stimulates secretion ATTENTION: high blood amino acid levels is the only case where both insulin and glucagon secretions are activated. Insulin - increase protein synthesis Glucagon - increase gluconeogenesis from amino acids in liver

Key Actions of Insulin

• Lowers blood glucose levels - Increases uptake of glucose by muscle, adipose, and many tissues *****(except neurons)**** - Increases glycogen synthesis in liver - Inhibits glucose production in liver • Increases synthesis & storage of fat - Increases synthesis of fatty acid in liver - Inhibits breakdown of lipid in adipose tissue • Increases synthesis of proteins ATTENTION : nerves cells always function on glucose. Lacking of glucose will cause neuropathies.

Key actions of glucagon

• Major target is the liver, where it promotes - Glycogenolysis—breakdown of glycogen to glucose - Gluconeogenesis—synthesis of glucose from lactic acid and non-carbohydrates - Release of glucose to the blood • In liver and adipose tissue, it stimulates lipolysis NOTE: glucagon does not stimulate the metabolism of protein. that's the difference with insulin

Diabetic Neuropathies

• Nerve damage can be throughout the body - Typically legs, feet, toes, arms, hands, fingers - Numbness, tingling, or pain • Mechanism of Pathogenesis - Poor circulation - Protein catabolism - Toxic effects of glucose