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141 Cards in this Set
- Front
- Back
What catalyzes the rate limiting step of the glycolytic pathway?
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Phosphofructokinase (Fructose 6 phosphate -> Fructose 1,6-bisphosphate); Rxn also uses ATP
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Does vigorously exercising muscle have an increased or decreased conversion of pyruvate to lactate?
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Increased
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Low hemoglobin and low lactate levels could be associated with a deficiency of which enzyme?
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Pyruvate kinase
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A low NAD+/NADH ratio would increase or decrease the oxidation of acetyl CoA by the TCA cycle?
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Decrease. Low ATP/ADP or GTP/GDP would stimulate.
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What is biotin required for?
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The synthesis of glucose from pyruvate (specifically, it is a coenzyme for the conversion of pyruvate to OAA, with pyruvate carboxylase)
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Where does gluconeogenesis occur?
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Liver and Kidney
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When does gluconeogenesis occur?
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Overnight for maintaining blood glucose
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What rxns are unique to gluconeogenesis?
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OAA -> PEP (PEP carboxylase), Fructose 1,6-bisphosphate -> fructose 6-phosphate (fructose 1,6-bisphosphotase), glucose 6 phospahte -> glucose (glucose 6 phosphotase)
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What are the two main ways that gluconeogenesis is regulated?
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Glucagon and the availability of substrates.
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Which amount is higher, the Estimated Average Requirement (EAR) or the Recommended Dietary Allowance (RDA)?
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RDA
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What are the BMI cutoffs?
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Underweight <19
Acceptable 19-26 Overweight 26.1-29 Obese 30-40 Morbid Obesity >40 |
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What questions should you ask when using the WAVE dietary assessment?
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Weight, Activity, Variety, Excess
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Approximately what percentages of Resting energy expenditure, Thermic Efect of Food and Energy Expended in Physical Activity make up the daily expenditure of an average person?
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8% - TEF
60-75% - EEPA 17-32% - REE |
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By how much do patients underreport food intake?
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20-40%
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In what order do we burn foods?
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Protein, Carbs, Fat
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What are anabolic vs. catabolic pathways?
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Anabolic pathways occur when the body is in positive energy balance. Building polymers from monomers. Catabolic pathways occur during the phase of nutrient breakdown in order to meet the energy needs of the body.
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What constitutes a key step?
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Changing location, investing energy (adding phosphate group), using energy, rate limiting step
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What is invested in the Energy Investment phase of glycolysis?
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2 ATP
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What is gained in the Energy Payoff Phase of glycolysis?
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4 ATP, 2NADH
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Glucose -> Glucose 6-phosphate: enzyme? importance?
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Hexokinase or glucokinase; important because it is irreversible (traps glucose inside cell) and invests 1 ATP
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What is the difference between Hexokinase and Glucokinase?
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Hexokinase - present in all cells, useful at low glucose [ ], low Vmax
Glucokinase - present in liver and pancreatic beta cells (regulates insulin release), higher [ ] and high Vmax **inhibited by fructose 6-phosphate |
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Fructose-6-phosphate -> Fructose 1,6-bisphosphate: enzyme? importance
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Phosphofructokinase 1 (PFK 1), rate limiting and committed step
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What controls PFK 1?
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Most potent activator of PFK 1 = Fructose 2,6-bisphosphate. Inhibited by ATP/citrate. stimulated by AMP
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How do we get F 2,6-bisphosphate?
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Fructose 6-phosphate -> Fructose 2,6-bisphosphate
enzyme: PFK 2 |
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PFK 2 is bifunctional. What does what?
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Kinase favors F 2,6 BP. Phosphotase favors F 6-phosphate.
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Does F6P -> F 1,6 BP require energy?
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Yes. ATP > ADP
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2 Glyceraldehyde-3-phosphate -> 2 1,3-bisphosphoglygerate: energetics of rxn? enzyme?
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Gain of 2 NADH (beginning of energy payoff phase), glyceraldehyde-3-phosphate dehydrogenase
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1,3, bisphosphoglycerate -> 3 phosphoglycerate: energetics? enzyme?
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ATP gained; first substrate level phosphorylation. phosphoglycerate kinase.
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phosphoenol pyruvate -> pyruvate: energetics? enzyme?
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Gain 1 ATP; 2nd substrate level phosphorylation. pyruvate kinase. Irreversible
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In the presence of O2, what is pyruvate oxidized to?
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Acetyl CoA
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What happens to the lactate formed in exercising muscle?
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It travels to the liver where it is converted to glucose via glucogneogenesis.
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What does the pentose phosphate pathway produce from glucose 6-phosphate?
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NADPH, ribose 5-phosphate, glycolytic intermediates
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What catalyzes the first, committing and rate limiting step of the pentose phosphate pathway?
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Glucose-6-phosphate dehydrogenase
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Where is the pyruvate dehydrogenase complex?
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mitochondrial matrix
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What is the clinical consequence of a thiamine deficiency?
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Thiamine is required for the oxidation of pyruvate to Acetyl CoA. Neurologic deficiency.
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What inhibits/activates the pyruvate dehydrogenase complex(PDH)?
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Inhibited by ATP, Acetyl CoA, NADH, and fatty acids. Activated by AMP, NAD+.
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In the fasting state, PDH is inhibited, promoting what pathway?
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gluconeogenesis
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PDH is active or inactive in the phosphorylated state?
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inactive
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What inhibits the kinase that phosphorylates (and inactivates)PDH?
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ADP. ADP thus activates PDH and ATP inactivates PDH. Calcium stimulates the phosphatase, so it also activates PDH.
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Where do the rxns of the TCA cycle take place?
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mitochondria
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What is the source of the Carbons for CO2 and the electrons of NADH and FADH2 in the TCA cycle?
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Acetyl CoA
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The condensation between acetyl CoA and oxaloacetate yields what? Why is this step important?
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It yields citrate. It is important because it is irreversible.
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What enzyme is used in the following rxn: pyruvate > Acetyl CoA?
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pyruvate dehydrogenase
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Where does oxidative phosphorylation take place?
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The electron transport chain consists of four multiprotein complexes in the inner mitochonrial membrane.
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In the Islets of Langerhans, what cell types do we have and what hormones do they excrete?
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Beta - Insulin, Alpha - Glucagon, D - Somatostatin, F or PP - Pancreatic polypeptide
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What is the structure of insulin?
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A and B chains joined by disulfide bonds after cleavage of C chain
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What stimulates insulin secretion?
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Glucose, amino acids and drugs such as sulphonylureas. In the presence of glucose, glucagon, GI peptides, vasoactive intestinal peptide and acetylcholine also stimulate insulin secretion.
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What inhibits insulin secretion?
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Drugs: diazoxide, somatostatin, alpha-adrenergic agents. Maybe fatty acids.
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What effects do catecholamines (especially epinephrine) have on insulin secretion?
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Primarily inhibition, with long term stimulation in may stimulate
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How does metabolism of glucose lead to insulin release in beta cells?
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Metabolism > depolarization by closing ATP-regulated potassium channels > opening of voltage gated calcium channels > rise in intracellular calcium > exocytosis
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What does acetylcholine do for insulin release?
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Stimulates
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Where does insulin go first?
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Liver. 50% is extracted in the liver.
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What does insulin do in order to help make glycogen?
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It activates glycogen synthase.
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How does the insulin receptor transduce the signal?
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Insulin > PI-3 activation > activates PDK > activates PKB > glycogen synthase kinase > glycogen synthase > glycogen
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Insulin makes more GLUT-4 transporters insert where?
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muscle and adipose tissue > greater transport of glucose into muscle/adipose tissue
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Where does glucagon mainly act?
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liver
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How is the secretion of glucagon regulated?
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Inhibited by glucose in alpha cells, free fatty acids, somatostatin. Stimulated by epinephrine. Glucagon secretion can be inappropriately high if insulin is low (Type I DM).
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How does glucagon act?
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Interacts with G-protein to increase cAMP
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What pathways does glucagon promote?
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glycogenolysis, gluconeogenesis
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What effect does glucagon have on insulin production?
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stimulation
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What effect does somatostatin have in metabolism?
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It inhibits both insulin and glucagon
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Epinephrine and norepinephrine have effects that mimic those of what hormone?
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Glucagon - increase blood glucose
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What hormones promote lactate production in muscles, due to increased insulin resistance?
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catecholamines - norepi, epi; cortisol
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What effect does growth hormone have on insulin sensitivity?
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Decreases insulin sensitivity
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What happens in response to carbohydrate feeding?
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Increased insulin, decreased glucagon, glycogen storage in liver and muscle, decreased fatty acid mobilization from adipose tissue
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How long does it take for hepatic hepatic glycogen to be depleted?
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24-28 hrs
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After 7 days, what is fueling the brain?
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ketone bodies
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What situations cause gluconeogenesis to occur?
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Fasting, vigorous exercise, high protein diet, stress
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What does the Cori cycle do?
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Takes blood-borne glucose and makes lactate
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What are the enzymes of the irreversible rxns of glycolysis?
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pyruvate kinase, phosphofructokinase, hexokinase
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What enzymes are used in gluconeogenesis to bypass the irreversible steps of glycolysis?
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pyruvate carboxylase, phosphoenol pyruvate carboxykinase, fructose 1,6 bisphosphatase and glucose 6 phophatase
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What enzyme catalyzes the rxn of pyruvate > oxaloacetate?
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pyruvate carboxylase
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What enzyme catalyzes the rxn of OAA > PEP?
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PEP carboxykinase
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What enzyme catalyzes the rxn of fructose 1,6 bisphosphate to fructose 6 phosphate?
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Fructose 1,6 bisphosphatase ***RLS***
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What enzyme catalyzes the rxn on G6P > glucose? Where is it found?
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glucose 6 phosphphatase; in the membrane of the endoplasmic reticulum in hepatocytes and renal cells
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What effects does AMP have on fructose 1,6 bisphosphatase and PFK-1?
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AMP inhibits fructose 1,6 bisphosphatase and activates PFK1
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What are the 3 steps in glycogen degredation?
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1. release of glucose 1 phosphate from glycogen (glycogen phosphorylase **key regulatory enzyme**) 2. remodeling of glycogen substrate (debranching enzyme) 3. conversion of glucose 1-phosphate into glucose 6-phosphate
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In skeletal muscle, what pathway does the G6P enter to serve as a source of energy?
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glycolysis
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In liver, what happens to muscle glycogen?
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It is converted to glucose (glucose 6 phosphotase) to support blood glucose levels
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Where is glucose 6 phosphatase found?
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liver
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What does glycogen sythase do?
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It catalyzes the transfer of glucose from UDP-glucose to a growing chain.
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What kind of branches are formed by a branching enzyme?
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alpha 1,6 linkages
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Why is branching important?
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It increases the rate of glycogen synthesis and degredation
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How is glycogen metabolism regulated?
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insulin and glucogon
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How is glycogen synthase allosterically activated?
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Activated by glucose-6-phosphate
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What allosterically inhibits glycogen phosphorylase?
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glucose 6 phosphate
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How does calcium lay a role in glycogen phosphorylase regulation?
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Calcium release (active muscle) activates phosphorylase kinase which in turn phosphorylates glycogen phosphorylase making it active
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What does AMP do to glycogen phosphorylase?
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It binds to the inactive form and activates it
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How does the binding of glucagon or epinephrine lead to activation of glycogen phosphorylase?
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Glucagon/epinephrine activates PKA, which phosphorylates phosphorylase kinase which phosphorylates glycogen phosphorylase
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What inhibits glucagon?
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high blood glucose and insulin
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Glycogen synthase and pyruvate dehydrogenase are activated or inhibited by a high insulin:glucagon ratio?
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Activated
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What are the levels of basal glucose production rate for different ages?
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Neonate - 8-12 mg/kg/min
Infant - 6-8 mg/kg/min Child - 4-6 mg/kg/min Adult - 2-4 mg/kg/min |
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How low is too low (hypoglycemia)?
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Child - 45 mg/dL
Adult - 60 mg/dL |
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What is the treatment for hypoglycemia (child)?
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2.5mL/kg of D10
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What are the sites of microvascular disease?
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kidneys, eyes, nerves
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What levels define diabetes?
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Fasting glucose >126, 2hr glucose >200
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What are some of the symptoms of diabetes?
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polyuria, polydipsia, blurry vision, weight loss
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Which has more of a genetic component - type I or type II diabetes?
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type II
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What are the "stages" in the development of Type I diabetes?
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Genetic predisposition, precipitating event, overt immunologic abnormalities, progressive loss of insulin release, overt diabetes, no c peptide
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What are some of the autoantibodies against insulin/ islet cells?
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Islet cell autoantibody (ICA), GAD65, IA2, ZnT8
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What defines an impaired glucose tolerance?
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Fasting glucose 100-125, OGTT 140-199
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What percentage of the beta cell mass has to be destroyed for symptoms of diabetes to appear?
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~90%
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Microvascular risk is linked to which measure?
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fasting blood glucose
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Cardiovascular risk is linked to which measure?
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OGTT
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What are the criteria for the diagnosis of DM?
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Random plasma glucose >200 plus symptoms OR fasting blood glucose >125, OR OGTT >200
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In what ethnic groups is there a genetic predisposition to DM type II?
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African-Americans, hispanics, Pima Indians
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Is there monozygotic twin concordance with DM type II?
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Yes, 90-100%
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Which state is more affected in type II DM, the basal state or the first phase of insulin secretion?
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Acute/first phase - pretty much gone. The basal state and second phase are preserved. Eventually, all insulin secretion is seriously diminished.
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What are the signs and symptoms of the metabolic syndrome?
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abdominal obesity, glucose intolerance, hypertension, atherosclerosins, polycystic ovary syndrome, altered carbohydrate metabolism, dyslipidemia, procoagulant state
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What recombinant human insulins are available and what is their duration of action?
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(1) Short-acting Regular insulin: (30 min before meals) - Humulin R or Novolin R **can be SubQ or IV; (2) Intermediate Acting: NPH - peaks at 6-7 hours
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What insulin analogs are available?
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(1) Rapid acting (food is on the table) - Humalog, Novolog, Glulisine; (2) Long-acting - Glargine (24 hrs), Detemir (17 hours)
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What is the MOA of sulfonylureas?
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Close ATP sensitive potassium channels in beta cell membranes; depolarization allows calcium influx which stiumulates insulin secretion
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What are some sulfonylureas?
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Glyburide > glipizide > glimpiride (duration of action)
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What are pros/cons of sulfonylureas?
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Pros: cheap, can be used early in the course and in combination with other agents; Cons: weight gain, hypoglycemia, lose effectiveness (renal excretion)
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What is Metformin's MOA?
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It acts at the liver to help insulin suppress hepatic glucose production
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What are the pros and cons of Metformin?
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Pros: effective for insulin resistance, no hypoglycemia, no weight gain, can combo; Cons: GI side effects, risk of lactic acidosis, not good with CHF, renal insufficiency, alcohol, contrast media
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What is the MOA of the thiazolidinediones?
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Activation of peroxisome proliferator-activated receptor gamma. Insulin sensitizers, at the level of skeletal muscle and adipose tissue
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What are some of the thiazolidinediones?
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pioglizazone (actos) and rosiglitazone which is controversial
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What are the pros and cons of the thiazolidinediones?
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Pros: effective for insulin resistance Cons: $$$, edema, CHF, CV events
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How do the GLP-1 receptor agonists work (Byetta)?
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It amplifies glucose-stimulated insulin secretion, inhibits glucagon secretion and slows gastric emptying.
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How does the DPP-4 inhibitor, Sitagliptin, work?
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It increases the circulating levels of endogenous GLP-1 -> lowers fasting and postprandial glucose
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How does the amylin analog work?
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Inhibits gastric emptying, glucagon secretion and reduces short-term food intake.
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What is our goal for HgA1C in adults?
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<7%
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What is the limiting factor in HgA1C goal attainment?
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episodes of hypoglycemia
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What is the approximate energy expenditure per kg?
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25-35 kcal/kg/day
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What are the percentages of each macronutrient in the average diet?
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Protein 15%, Fat 35%, Carb 50%
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How many grams of carbs does the average diet have?
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262.5 g of carbs
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What is the energy density of carbohydrates?
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4kcal/gram
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What does the glycemic indedx tell you?
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With 100 grams of given food, what is the area under the blood glucose/time curve
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What does the epi data say about diets and diabetes?
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correlation between total carbs, high fructose corn syrup and diabetes
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What is the relationship between glycemic load, fiber and diabetes?
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low fiber, high glycemic load -> diabetes
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What is the long term intervention that best prevents diabetes?
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increase fiber, low fat, low sat fat, physical activity
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What are some complications (morbidity) from diabetes?
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CV disease, retinopathy, neuropathy, amputations
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A diabetic with a hx of heart attack has approximately what risk of having a MI in 10 years?
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~50%
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What is dyslipidemia?
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Small, dense LDL, decreased HDL, increased triglycerides
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Why treat cholesterol in diabetes?
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decrease plaque progression, CV events, mortality (Only done in 25% of patients)
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What is the BP goal in diabetes?
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120-130/80 (even lower w/ kidney failure)
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Patients with diabetes should be taking what for their procoagulant state?
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aspirin (+ statins, beta blockers, ACE inhibitors)
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Where do we have aldose reductase and why does it matter?
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eyes, nerves, kidneys. Glucose > sorbitol, toxicity
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What is the leading cause of renal failure?
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diabetes (46% of Type I, 35% of Type II)
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What is the progression of diabetic nephorpathy?
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basement membrane thickening, mesanglial expansion, glomerular fibrosis and tubulointerstitial scarring **need to detect microalbuminuria/proteinuria nephropathy in order to intervene - ACE inhibitor**
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