Diabetes and Metabolism (Week 3) Flashcards

Question

Slow mechanisms to regulate metabolism (long-term changes)

Answer 1

Genetic regulation Response to diet and other environmental factors Hormonal effects on gene expression

Answer 2

Substrate concentration at which the reaction rate is half of Vmax (**lower** Km means **higher** **affinity**; lower Km means **slower rate** of reaction)

Answer 3

GLUT2: in the liver and pancreas beta cells, highest Km (lowest affinity); linear concentration in physiological range means will take up glucose proportional to how much in blood GLUT1: mid-range Km GLUT3: in the brain; lower Km (higher affinity) and flatter curve in physiological range means uptake in brain independent of plasma concentration (constant, steady supply of glucose to brain)

Answer 4

Insulin binds its receptor on cell surface --\> signals through PI3 kinase, etc --\> GLUT4 that exists in vesicles translocates to cell membrane --\> lets glucose in Whenno insulin (fasting state), GLUT4 transporters internalized again (this happens in muscle and adipose tissue)

Answer 5

Glucokinase: high Km, glucose sensor, present in liver and pancreatic beta cells Hexokinase: low Km, saturated at low glucose concentration, present in most cells

Answer 6

When lots of **glucose** in cytoplasm (let in by GLUT2), GK comes out to phosphorylate it to **G6P** --\> as glucose converted to G6P, MORE glucose enters cell --\> as G6P then **F6P** builds up, F6P tells GK to go back to nucleus (**negative feedback**)

Answer 7

Apparently not... Ex: 6 steps of glycolysis are reversible so are not regulated

Answer 8

1) **Phosphofructokinase** (PFK-1) (turns F6P --\> F1,6BP); Stimulated by **F2,6BP** and AMP; Inhibited by ATP, citrate, H+ 2) **Pyruvate** **kinase** (turns phosphoenolpyruvate (PEP)--\> pyruvate); Stimulated by F1,6BP; Inhibited by ATP, alanine; last step in glycolysis

Answer 9

Because end product G6P has many functions! Starts **glycolysis** but also **glycogen** **synthesis**, **pentose phosphate pathway** PFK-1 (phosphofructokinase-1) catalyzes first unique and irreversible reaction in glycolysis so that is the first regulated step

Answer 10

F2,6BP activates PFK-1 F2,6BP is made by **taking a little F6P** from the chain and **using PFK-2** (kinase activity) to phosphorylate it to **F2,6BP** F2,6BP is not part of the pathway, it is created solely to be a regulating molecule

Answer 11

**Bifunctional enzyme** that can be kinase (PFK2) or phosphatase (FBPase-2) **Kinase PFK2**: F6P --\> F2,6BP; when **NOT phosphorylated**; during **fed** state; increased **insulin**; stimulates PFK1 to do **glycolysis** **Phosphatase FBPase-2**: F2,6BP --\> F6P; when **phosphorylated**; during **fasting** state; increased **glucagon**; does NOT stimulate PFK1 so does **gluconeogenesis** Want PFK2 NOT phosphorylated so it WILL phosphorylate F6P to make F2,6P to activate PFK1 to do glycolysis

Answer 12

Complicated pathway --\> **dephosphorylates PFK-2** --\> high levels of F2,6BP --\> activate PFK-1 to continue glycolysis --\> **more glycolysis!**

Answer 13

Glucagon binds cell surface glucagon receptor --\> G-protein coupled response --\> increased cAMP --\> PKA --\> PKA **phosphorylates PFK-2** --\> phosphatase activity increases --\> lower levels of F2,6BP (so won't stimlate PFK-1) --\> **inhibit glycolysis**

Answer 14

Increased PKA phosphorylates an ISOFORM of the PFK-2 enzyme --\> in this case, phosphorylation actually increases kinase activity of this bifunctional enzyme --\> i**ncreased level of F2,6BP** --\> stimulate **PFK-1** --\> **increased glycolysis** This is good because when HR up, maybe running from a lion and want to have glycolysis in that case! Remember, muscle bifunctional enzyme works opposite way of liver bifunctional enzyme (if it worked like liver's bifunctional enzyme, we'd get decreased glycolysis when running from lion--would be bad news!)

Answer 15

Yes, has a bifunctional enzyme but it is not phosphorylated by PKA Skeletal muscle's bifunctional enzyme is regulated only by **levels of substrate (F6P)**

Answer 16

Turns phosphoenolpyruvate (PEP) --\> pyruvate Last step in glycolysis! Inactivated by glucagon in the liver: **glucagon** binds receptor on cell membrane --\> increase cAMP --\> PKA --\> PKA phosphorylates and thus **inactivates** pyruvate kinase

Answer 17

Pyruvate --\> lactate (by lactate dehydrogenase) instead of going through TCA cycle Cool side note: cancer cells do glycolysis then to lactate instead of TCA cycle even when there is O2 around and this can be used as a target for therapy

Answer 18

After glycolysis, pyruvate --\> acetyl CoA (by pyruvate dehydrogenase (PDH)) PDH is a multi-enzyme complex that is inhibited by NADH, acetyl CoA and ATP PDH active when NOT phosphorylated (Ca2+ during muscle contraction stimulates phosphatase) When phosphorylated, PDH inactive

Answer 19

1) **Pyruvate dehydrogenase** (PDH): turns pyruvate --\> acetyl CoA; Inhibited by ATP, acetyl CoA, NADH; first step in TCA cycle 2) **Isocitrate dehydrogenase**: turns isocitrate --\> alpha ketoglutarate; Stimulated by ADP; Inhibitied by ATP and NADH 3) **alpha-ketoglutarate dehydrogenase**: turns alpha-ketoglutarate --\> succinyl CoA; Inhibited by ATP, succinyl CoA, NADH

Answer 20

TCA cycle takes place in **mitochondria** and phosphorylation signals (via hormones) start on cell surface and go to cytosol! Instead, TCA cycle regulated by immediate (NADH) and eventual (ATP) **end products** (**allosteric** regulation)

Answer 21

NO! Uses unique enzymes, and must go from pyruvate through **oxaloacetate** to get back to phosphoenolpyruvate Also, requires 6 ATP (whereas glucose makes 2 ATP)

Answer 22

1) **Phosphoenol-pyruvate carboxykinase (PEPCK)**: turns oxaloacetate --\> phosphoenolpyruvate; Regulated by **transcription** (has very complex promoter), so more slowly; Tx **decreased** (activity inhibited) by **insulin**; Tx **increased** (activity stimulated) by **fasting, glucagon, glucocorticoids, thyroid hormone** 2) **Fructose 1,6-bisphosphatase**: turns fructose 1,6-bisphosphate --\> F6P; Stimulated by citrate; Inhibited by F2,6BP, AMP 3) **Glucose-6-phosphatase**: turns G-6P --\> glucose

Answer 23

Fructose-6-phosphate \<--\> Fructose-1,6-bisphosphate Citrate stimulates **fructose 1,6-bisphosphatsase** (to make F6P) and inhibits **PFK-1** AMP and F2,6BP inhibit fructose 1,6-bisphosphatsase and stimulate PFK-1 (to make F1,6BP)

Answer 24

This happens in the **liver** and kidney in order to provide glucose to other tissues (cannot happen anywhere else, this is why the liver has to be nice/altruistic and give glucose to everyone!) G-6-P enters the ER through **G-6-P transporter** --\> SP is a **Ca-binding stabilizing protein** that stabilizes glucose-6-phosphatase enzyme --\> **glucose-6-phosphatase** enzyme turns G6P to glucose --\> Pi is transported out **Pi transporter** and glucose is transported out **glucose transporter** back into cytoplasm

Answer 25

Liver can't produce glucose for the rest of the body and get severe **hypoglycemia** during fasting **Glucose-6-phosphate deficiency**; glycogen storage disease (can either have messed up **G6P transporter** or messed up **G-6-Pase**) Treatment: IV glucose (necessary for nighttime) or just can eat uncooked starch!

Answer 26

Alanine, lactate, glycerol (more?) Come from peripheral tissues (muscle, RBCs, renal medulla, adipose tissue)

Answer 27

Glycogen --\> glucose-1-phosphate (by glycogen phosphorylase-P) UDP-glucose --\> glycogen (by glycogen synthase) **Glycogen phosphorylase** is active when **phosphorylated** Glycogen synthase is active when NOT phosphorylated Phosphorylation stimulated by **glucagon** and **epi** (during **fasting** state) Dephosphorylation catalyzed by protein phosphatase 1 and stimulated by insulin (during fed state)

Answer 28

Synthesis of glycogen (glycogenesis): G6P, ATP, glucose (in liver) Breakdown of glycogen (glycogenolysis): Ca2+, AMP (in muscle) (Makes sense because you want glucose (do glycogenolysis) only when you need it, not when you have plenty of G6P, ATP and glucose!)

Answer 29

Lipogenesis Acetyl CoA --\> Malonyl CoA (by **Acetyl CoA carboxylase**) **Allosteric** regulation of ACC: Acetyl CoA carboxylase exists in inactive dimers --\> **citrate** stimulates formation into acetyl CoA carboxylase polymers (OR --\> **long-chain fatty acyl CoA** inhibits formation into active polymer (just negative feedback??)) Regulation of ACC by **hormones** and phos/dephosphorylation: **Insulin** stimulates protein phosphatase to dephosphorylate acetyl CoA carboxylate and **activate** it; **Glucagon** and **epi** stimulate cAMP-dependent protein kinase to phosphorylate acetyl CoA carboxylate and inactivate it Want to make fatty acids (which then you make into triglycerides to store) when you've just eaten

Answer 30

First enzyme of lipolysis (breaking down TGs to free fatty acids + glycerol so you can oxidize them to ketones and acetyl CoA to get more energy when you can't do glycolysis!) **Glucagon** binds receptor --\> cAMP activates protein kinase that phosphorylates and activates **HSL** --\> HSL turns fat (triglycerides) into fatty acids and glycerol When glucose is low, **glycerol** is released into circulation and can be sent to **liver** and made back into **glucose** Fatty acids released, bind to albumin and are taken up by tissues for activation to acyl CoA and then beta-oxidation ("fatty acid degradation") HSL active during fasting Want to break down fat (triglycerides) into fatty acids and glycerol when fasting to give you more energy!

Answer 31

**Phosphorylate** enzymes! Via cAMP and PKA

Answer 32

**Dephosphorylate** enzymes! Via protein phosphatase?

Answer 33

Phosphatase domain of PFK-2 (actually called FBPase2) Glycogen phosphorylase Hormone sensitive lipase These are all phosphorylated by glucagon or epi, and are active during fasting (want to decrease glycolysis, break down glycogen (give glucose to rest of body?) and break down fat when fasting)

Answer 34

Kinase domain of PFK-2 Pyruvate kinase Glycogen synthase Acetyl CoA carboxylase These are all dephosphorylated by insulin (want to break down glucose (do glycolysis), synthesize glycogen and synthesize fat when fed)

Answer 35

Defect in glycogen synthesis or breakdown If can't break down glycogen stored in liver, it accumulates and damages cells, can get enlarged liver If can't get glucose out into blood, get low blood sugar

Answer 36

Glucose-6-phosphatase converts G6P --\> glucose **Liver** (and kidney) ONLY produce glucose to send out to other tissues Muscle does NOT have this enzyme so they can't create their own glucose!

Answer 37

Because liver can no longer put glucose into blood (remember muscles can't put glucose into blood)

Answer 38

Converted to glucose: lactate, amino acids, glycerol Cannot be converted to glucose: fatty acids (bc chopped into 2 carbon chains and need 3 carbon chains to do gluconeogenesis)

Answer 39

Eventually (I think), but at the beginning of the disease, some beta cells destroyed and others still surviving

Answer 40

Body is getting bigger, growing a lot but not much beta cell growth so don't have enough insulin?

Answer 41

Used to distinguish between Type 1 and Type 2 Diabetes C peptide connects the A and B chains of proinsulin and gets **cleaved when insulin is formed**, so level of C peptide tells you how much insulin **you yourself are producing** Type 1 diabetes: low C peptide because not secreting much insulin on your own Type 2 diabetes: high C peptide because when you secrete insulin you secrete same amt C peptide

Answer 42

**C peptide**: will be **low** **Anti-GAD antibodies** or **insulin autoantibodies**: positive

Answer 43

Insulin usually signals the liver to stop glycogenolysis, to stop gluconeogenesis, and to inhibit the release of glucose from the liver, but now insulin not there so liver **puts out a ton of glucose into blood!** Lots of **glycogenolysis** so glycogen stores depleted Lots of **gluconeogenesis** so lots of glucose made and dumped out into circulation Lots of **proteolysis** and **lipolysis** to get more glucose made for rest of the body

Answer 44

Insulin usually tells muscle cells to take up glucose from blood, but now no insulin around Glucose can't get into muscle cells because GLUT4 transporters not on cell surface --\> cell **deprived of energy** --\> **Na/K ATPase pump fails** with no ATP around --\> K+ leaks out into blood --\> K+ excreted in urine --\> hypokalemia (whole body **K+ depletion**) Also, **muscle is broken down** for energy since muscle can't uptake glucose --\> AAs used to make glucose instead and get negative nitrogen balance Remember: Type 1 Diabetes used to be a WASTING disease

Answer 45

Renal threshold is **180**, and after this point, glucose cannot all be reabsorbed and is passed through kidney tubules with the rest of filtrate Glucose in filtrate in loop of henle causes water and other ions to be secreted to maintain osmotic pressure **Lose water** (polyuria thus polydipsia, dehydration), **lose salts** (NaCl, K), lose energy because losing glucose

Answer 46

Beta cells **don't function well** in high glucose environment So even if you have beta cells left, they won't be secreting insulin well because glucose toxicity caused them to not function well

Answer 47

Brain **downregulates** (to 10% of normal) glucose transporters to prevent glucose toxicity Important when treating patient, because when you decrease blood glucose, brain thinks there's not enough glucose around since it now has fewer transporters

Answer 48

Usually, insulin inhibits breakdown of triglycerides to free fatty acid and glycerol (lipolysis and ketogenesis) Fat is all **broken down** into **FFA** and **glycerol** (lipolysis) --\> also have no insulin, so presenting liver with lots of FFAs --\> liver converts FFAs to **ketones** if no insulin around --\> **diabetic ketoacidosis**

Answer 49

**Polyuria** and **polydipsia** **Volume depletion** (postural hypertension, tachycardia) **Loss of body fat and muscle** (weight loss and muscle weakness) **Deep shallow breathing**, breath of acetone (DKA) **Unexplained abdominal pain** Labs: high blood glucose, low bicarb (DKA, buffering acids), low pH, normal or high K+ even though **hypokalemia**

Answer 50

Give insulin!! Now have insulin pumps, or shots that don't hurt Must test glucose level ~6 times per day

Answer 51

30,000,000

Answer 52

Most common cause of early death (heart attack, stroke), blindness, kidney disease, leg amputation Greatest cost to health care system in USA

Answer 53

**Genetics** (Asian, AA, Latina, Pacific Islander, Native American) **Obesity** (or any other cause of insulin resistance) Low birth weight/fetal malnutrition Sleep disturbance

Answer 54

The **fatter** you are (higher BMI), the **more** **insulin** you need per day Because fat people not very sensitive to insulin, so need a lot of it to suppress hepatic glucose release

Answer 55

Have lots of **adipocytes** and these recruit inflammatory cells that release **cytokines** Cytokines contribute to insulin resistance. Interleukins (ILs) **oppose action of insulin** Note: because of this, can measure **C-reactive protein (increased in inflammation)** to predict risk for type 2 diabetes

Answer 56

Want baby to grow more than mother Placenta makes hormones to tell glucose not to go to mother but to go to baby instead (placental lactogen)

Answer 57

They just **increase insulin secretion** to ensure that glucose is not released from liver too much and is taken up by muscles enough (**don't get diabetes** even if they're really obese) Other 20% of those who become insulin resistant actually decrease insulin secretion (get Type 2 Diabetes)

Answer 58

We have baseline of glucagon in our blood (probably), but **glucose suppresses glucagon** so after we eat, glucagon decreases

Answer 59

High glucose Low insulin No drop in glucagon

Answer 60

If you have a hereditary component you'll **start losing beta cells** early in life so can create less insulin. Then as you get older and/or more **obese**, you become **insulin resistant** and need more insulin. But you can't make any more! Get Type 2 Diabetes.

Answer 61

Education Lifestyle (diet and exercise) Insulin and other medications Prevent complications

Answer 62

**Metformin**: makes liver **more sensitive** to insulin (enhances how insulin causes liver to inhibit gluconeogenesis and glycogenolysis); causes people to lose weight; decreases risk of cancer **Sulphonylurea**: lower blood sugar by making beta cells secrete **more insulin** **GLP-1**: also lower blood sugar by making beta cells secrete **more insulin** (secrete this naturally from bowel when you eat); increases risk of pancreatic cancer **Glitazones**: act on muscle to **enhance** how insulin causes muscle to bring glucose into muscle cell **Insulin**

Answer 63

1,500,000 people (half as many as Type 2) Not as heritable as Type 2, but more in caucasians

Answer 64

Tiny blood vessels exposed to high sugar causes damage to endothelium (glycosylation) Diabetic nephropathy (renal failure) Diabetic retinopathy (blindness) Diabetic neuropathy (amputations, impotence, severe hypoglycemia)

Answer 65

Coronary artery disease (MI) Cerebrovascular disease (CVA/stroke) Peripheral vascular disease (amputations)

Answer 66

Most diabetics die of cardiovascular disease (80%)! Control **cholesterol** (use statins) Control **triglycerides** Use anti-platelet drugs to prevent clots (**aspirin**) Keep **BP low** to prevent athreosclerotic complications Keep **blood sugar normal/low** to prevent micro- and macro-vascular disease Type 2 must **lose weight**--might even not need medications this way

Answer 67

Roundabout way! Glucose enters the cell because insulin is around now --\> glucose does **glycolysis** and TCA and electron transport to **create ATP** --\> now have ATP for **Na/K ATPase** that wasn't working before --\> pump works to bring K+ into the cell Note that you should still **give K+** IV too!