Biochem Ii Regulation Of Metabolism

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glucagon

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The effects of insulin are countered by a second polypeptide hormone – GLUCAGON - that is made in and released by α-cells of the pancreas

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insulin

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C peptide

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essential for proper tertiary and quaternary folding of proinsulin

blood test for indication of insulin production

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insulin and C peptide

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c peptide gets released as same time as insulin into blood. stored in cytosol of pancreas

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insulin secretion from cells description

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- Blood glucose levels trigger insulin
- beta cells have GLUT2 transporter in plasma membranes
beta cells have glucokinase to put a phosphate on it to prevent from diffusing (makes G6P)
- Glucose sends signal to beta cell to synthesize (turn on transcription) of more insulin

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step 1 of synthesis of insulin from beta cells

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Elevated glucose enters β-cell through Glucose transporter (GLUT2)

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step 2 synthesis of insulin from beta cells

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Glucokinase puts a PO4 group onto glucose which keeps it localized and primes it for catabolism

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step 3 synthesis of insulin from beta cells

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Glucose-6-P enters into glycolysis and aerobic metabolism to make energy (ATPs)

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step 4 synthesis of insulin from beta cels

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A Tyrosine Kinase enzyme uses ATP to put a Phosphate residue on the ATP- dependent Potassium channel
* Na/K differences are critical in this process

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step 5 synthesis of insulin from beta cells

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Phosphorylation closes the potassium (K+) channel and causes the β-cell to depolarize
- creates charge imbalance across cell to stop K buildup

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step 6 synthesis of insulin from beta cells

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Calcium ions enter the cell to adjust to the depolarization

- K and Ca signaling drive this process

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step 7 synthesis of insulin from beta cells

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Higher intracellular Ca++ causes Insulin to be released.

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sulonylureas effects on insulin response

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- blocks K+- ATP channel of beta cells.
- increases secretion of insulin
- decreases blood sugar

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dioxazide -

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- keeps K+-ATP channel of beta cells open
- inhibits insulin secretion
- increases blood sugar

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3 amino acids that alter beta cells membrane potential like glucose

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alanine, glycine and arginine

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Also, Glutamate - α-ketoglutarate

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TCA cycle to increase ATP, alters phosphorylation pump of K+ creating depolarization

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GI hormones (incretins) effect on insulin

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These hormones are secreted by the small
intestine in response to oral glucose

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acetylcholine - effect on insulin

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Acetylcholine triggers insulin release through phospholipase C (recall, PL-C is an enzyme that cleaves the phospho-head group from a glycerol lipid)

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epinephrine (adrenaline) effect on insulin

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- down regulation of insulin
- sereted by arenal mediulla
- derived from tyrosine
- stress response to allow glucose in blood for fight/flight syndrome

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somatostatin effect on insulin

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inhibits release of insulin from beta cells

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biological effects of insulin (stimulation)

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- glucose uptake
- glycogen synthesis
- protein synthesis
- fat synthesis

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biological effects of insulin (reduction)

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- decreases gluconeogenesis
- dereases glycogenolysis
- dereases lipolysis

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biological ffects of insulin genetically

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alters gene expression (DNA to RNA to protein)

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insulin secretogogues

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sulfonuylureas, benzoic acid derivatives
- stimulate release of insulin from beta cells
(glipizide, glyburide, repaglinide)

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glucagon hormone

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polypeptide secreted by alpha cells in islets of langerhans
- acts like epinephrine and opposes insulin

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effects of glucagon (stimulation

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- glycogenolysis (break down glycogen)
- gluconeogenesis (make more glucose)
- ketogenesis
- lipolysis

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factors to trigger alpha cells to release glucagon

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- low blood glucose
- certain amino acids
- epi and norepi

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timing of insulin/glucagon in blood after meals

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- 15-30 minutes glucose levels go up and insulin goes up too/glucagon goes down
-

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how peripheral tissues react to insulin

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- insulin receptor has outside cell portion that binds to cell
- transmission of signal inside cell to tyrosine kinase activity in cell

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type 2 diabetes possible cell defects

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- insulin receptor defect on cell
- signaling pathway insulin receptor in cell

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insulin receptor characteristics

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- The receptor is synthesized as a single polypeptide chain which is glycoslyated, and then cleaved into α and β subunits
- subunits disfulide linked
- a chains have insulin binding site
- beta chains tyrosine kinase enzyme

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tyrosine binding cascade from insulin receptor

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When insulin binds, it triggers the tyrosine kinase to
autophosphorylate 2 tyrosine residues of the insulin receptor found on the cytoplasmic face of the membrane
- Tyrosine phosphorylase also adds phosphates to the tyrosine residue of other intracellular proteins

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kinase enzymes

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- add phosphates
- up regulate

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phosphatase enzymes

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- remove phosphates
- down regulates

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hydroxyl groups amino acids involved in phosphyorlyation process

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Both the K+-ATP Channel Receptor on Pancreatic β-cells and the Insulin Receptor on Peripheral Tissues are phosphorylated on specific tyrosine residues by Tyrosine Kinase enzymes. As long as these Receptors remain phosphorylated, their activities remain “on”
- Affecting either the Kinases or the Phosphatases (genetically or pharmacologically) will have an effect on the glucose utilization pathways

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PTP-1B (protein tyrosine phosphatases)

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- If one can inhibit the Protein Tyrosine Phosphorylase, the Insulin effect will be “prolonged”, making the peripheral tissues more sensitive to insulin
- keeps the process "on"

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insulin sensitizers

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drugs that affect way insulin works on cells
(Metformin, actos, avandia)
- secretagogue works as a sensitizer

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end result of triggering insulin receptors in muscle and fat

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-Increase glucose uptake by putting glucose transport proteins on cell surface (GLUT4)
-Stimulate hexokinase to phosphorylate glucose
-Stimulate glycolysis and oxidative metabolism
(to make energy)
-Stimulate storage of excess glucose

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The most important hormonal changes to combat hypoglycemia (<40 mg/dl)

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increased glucagon & epinephrine and decreased insulin

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glucose levels in diabetes after eating

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- elevated glucose levels and stays elevated longer
- insulin does not go up in correlation with glucose
- glycogen does not inversely correlate with insulin (stays elevated in presence of insulin)

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effects of hyperglycemia

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cell injury/apoptosis
inflammation
altered tissue reaction

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glucosidase inhibitors

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- decrease absorption of glucose from the gut and/or lower the synthesis of glucose by the liver
- block simple sugars

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biguanides

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Block the liver’s production of glucose (gluconeogenesis)

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4 ways to pharmacologically treat diabetes

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1. Selectively and potently influence the synthesis and release of insulin from the pancreas (make new drugs that are “Insulin Secretagogues”)
(or give direct injections of insulin as in Type I diabetes)
2. Selectively and potently increase the sensitivity of peripheral tissues to the actions of insulin (make new drugs that are “Insulin Sensitizers”)
3. Reduce the absorption of carbohydrates from the gut or
4, Reduce the production of glucose by the liver to lower the glucose load in the
bloodstream

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metabolic syndrome causes

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obesity/diet, inactivity, genetic

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Non-alcoholic Fatty Liver Disease (NAFLD);

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Non-alcoholic steatohepatitis (NASH) an extreme form of NAFLD, which is regarded as a major cause of cirrhosis of the liver of unknown cause

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AMP-activated protein kinase (AMPK) and malonyl coenzyme A (CoA) to the regulation of energy balance

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- Malonyl CoA is a key factor involved in Fatty acid Synthesis
- inhibits the transfer of a fatty acid into the inner matrix of the mitochondria so fatty
acids cannot be oxidized (aka: degraded, catabolized)
- lipid storage leading to obesity

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adinopectin
(molecule alters mal-coa/ampk activity)

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A protein hormone secreted by adipose tissue into blood. Regulates fatty acid catabolism. Blood levels inversely correlate with body fat
- Related in structure to C1q (collagen-like protein) and TNF-α

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leptin
(molecule alters mal-coa/ampk activity)

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A protein hormone also secreted by adipose tissue into blood. Acts on the hypothalamus to suppress appetite
- activates AMP kinase (AMPK) directly in skeletal muscle and indirectly through the hypothalamic-sympathetic nervous system.

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TZD/metformin
molecule alters mal-coa/ampk activity

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Drugs that decrease insulin resistance- can they get normal glucose/fat metabolism back to “normal

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type 2 diabetes

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manifest primarily by reduced secretion of insulin from β-cells of the pancreas and/or by increased resistance to “respond” to the insulin signal by peripheral tissues

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diagnosis of diabetes

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defined by a fasting blood glucose level of > 126 mg/dl

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mechanism of diabetes

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- The body tries to flood the blood with more glucose (by increased gluconeogenesis) to compensate for reduced efficiency of processing (primarily by adipocytes and muscle)
- becauase of hydroxyl groups - The added glucose (which is very hydroscopic – i.e. binds lots of water) causes a hyperosmolar state in the blood. Tissues get dehydrated. Microvessels are affected

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macrovascular complications of diabetes

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Altered Fatty acid processing leads to lipid deposition in macro vessels leading to cardiovascular disease (atherosclerosis) and stroke (rupture of brain vessels)

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glycated hemoglobin A1c

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- non-enzymatic chemical adduct formed by glucose and hemoglobin (on the N-terminal amino acid of the β-chain of hemoglobin (a Valine)
- reaction is driven by “mass action” – the more
glucose around, the more hemoglobin can be glycated. A diabetic (with hyperglycemia) will have a higher level of Hemoglobin A1c
- RBC half life of 120 days so Hb A1c measurement provides a 120 day “average “ of glucose concentration in the blood

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tests to measure hb A1c

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immmunassays (antibody screenings)

ex: avg daily 135 = 6%
avg daily 205 = 8%
etc.

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diabetes and liver, adipose tissues

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diminished effects of insulin on target tissues lead to decreased processing of fats/amino acids leading to hypertriglyceridemia,

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abnormal metabolism

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Since glucose metabolism is “off” shift the energy burden to lipids and fatty acids and Make ketone bodies (leading to Ketoacidosis)