TSR Med Students' Society Part III

Uh, if you made me run a marathon I'm not entirely sure. Over the first four (I think) hours my glycogen liver stores would keep me going and then would I switch to fat metabolism, the breakdown of glycerol to glucose and fatty acids into acetyl CoA (probably leading to ketogenesis though)?

I know gluconeogenesis only occures in the liver (it's my standard default organ for anything in metabolism I get stuck on too ). So it stacks up enough ATP for it's own metabolic needs then any extra turns into glucose for other cells? Where would it come from though, excess breakdown of glucose in the first time? Glycerol? Why would it not make it into glycogen? Can only muscle tissues convert glycogen to glucose?

Bits and bobs. Somethings just confuse me further though. Our metabolism teaching is incredibly poor unfortunately. They don't put lecture slides up either but instead lecture "notes". Learning from somebody elses notes is not useful though.

Insulin is the next PBL. I know it's breif mechanics though.

Glucose in the blood enters liver via glut2, leads to glucolysis and rising ATP. ATP closes K+ channels, cell becomes negative, voltage gated channels open and Ca+ moves in. Ca+ leads to exocytosis of insulin. Insulin binds to insulin receptors on muscle and adipose tissues moving glut4 receptors to the surface and increasing uptake of glucose.

Glycagon causes breakdown of glycogen and fats to bring up blood glucose but my knowledge of that is a lot more sketchy. Have no idea about GH/cotrisol/adrenaline.

i see.. unfortunately learning the pathways in isolation from their regulation is going to make it very challenging for a bit. perhaps go back to each major substrate in turn (mainly glucose and fat) then look at how it's first regulated at a cellular level because otherwise it's going to be hard to build up mechanistic understanding when it comes to complex phenomena like starvation responses.

Yea you pretty much have insulin down, it does have other effects which are brought about by too many protein kinases.

Glucagon essentially increases cAMP and thus PKA concentrations, which then goes on to phosphorylate the enzymes involved in glycolysis and gluconeogenesis (where insulin would dephosphorylate them)

Inhibit glucagon synthesis by inhibiting glucokinase (preventing Gluc-6-phos formation) and inhibition of Glycogen synthase.

Activated glucagon breakdown by activating glycogen phosporylase and G6Pase.

Inhibits glycolysis through prosprylation of glucokinase and phosphofructokinase and pyruvate kinase.

Boron Medical physiology has a really good explanation with a nice diagram. (attached)


As for the other hormones they are also secreted at low blood glucose concentrations and have an impact in increasing it.

there are mistakes here but im busy writing an essay so will describe in detail tomorrow evening if we're still on the topic. notable ones are that G6Pase is not regulated by phosphorylation (think of where it is!), insulin doesn't always dephosphorylate (GSK3!), the most important part of insulin signalling is not GLUT4 insertion, otherwise it would be bloody useless in adipose which in humans has virtually no capabilities for lipogenesis so can't do anything with glucose, glucokinase is NOT regulated by phosphorylation directly and neither insulin nor glucagon regulate that particular enzyme - other peripheral hexokinases are not regulated at all etc etc...

not a criticism!

Glucagon, Acting Through cAMP, Promotes the Synthesis of Glucose by the Liver

Glucagon is an important regulator of hepatic glucose production and ketogenesis in the liver. As shown in Figure 51-12, glucagon binds to a receptor that activates the heterotrimeric G protein Gαs, which stimulates membrane-bound adenylyl cyclase (see Chapter 3). The cAMP formed by the cyclase, in turn, activates PKA, which phosphorylates numerous regulatory enzymes and other protein substrates, thus altering glucose and fat metabolism in the liver. Whereas insulin leads to the dephosphorylation of certain key enzymes (i.e., glycogen synthase, acetyl CoA carboxylase, phosphorylase), glucagon leads to their phosphorylation.

A particularly clear example of the opposing actions of insulin and glucagon involves the activation of glycogenolysis, which is discussed in Chapter 3 (see Fig 3-7). PKA phosphorylates the enzyme phosphorylase kinase (see Fig. 59-8), thus increasing the activity of phosphorylase kinase and allowing it to increase the phosphorylation of its substrate, glycogen phosphorylase b. The addition of a single phosphate residue to phosphorylase b converts it to phosphorylase a. Liver phosphorylase b has little activity in breaking the 1 to 4 glycosidic linkages of glycogen, but phosphorylase a is very active. In addition to converting phosphorylase b to the active phosphorylase a form, PKA also phosphorylates a peptide called inhibitor I. In its phosphorylated form, inhibitor I decreases the activity of protein phosphatase 1 (PP1) that otherwise would dephosphorylate both phosphorylase kinase and phosphorylase a (converting them to their inactive forms). PP1 also activates glycogen synthase. Thus, through inhibitor I, glucagon modulates several of the enzymes involved in hepatic glycogen metabolism to provoke net glycogen breakdown. As a result of similar actions on the pathways of gluconeogenesis and lipid oxidation, glucagon also stimulates these processes. Conversely, glucagon restrains glycogen synthesis, glycolysis, and lipid storage.

The effects of the glucagon-as well as the effect of glucocorticoids-to enhance gluconeogenesis involve activation of the transcription factor CBP as well as PGC-1 (PPAR-γ coactivator-1), which enhances the transcription factor PPAR-γ (see Chapter 4). The net effect is an increase in the synthesis of such key regulatory enzymes as G6Pase and PEPCK-both of which promote the release of glucose. Insulin restrains the transcription of these two enzymes in two ways, both through the PI3K/protein kinase B pathway (Fig. 51-6). First, insulin increases the release of the transcription factor domain of SREBP-1 (see Chapter 3), which antagonizes the transcription of mRNA encoding the two enzymes. Second, insulin increases the phosphorylation of several transcription factors of the Foxo family, thereby promoting their movement out of the nucleus and preventing them from binding to the promoter regions of the two enzymes.

These actions of glucagon can be integrated with our understanding of insulin's action on the liver in certain physiological circumstances. For example, after an overnight fast, when insulin concentrations are low, glucagon stimulates the liver to produce the glucose that is required by the brain and other tissues for their ongoing function. With ingestion of a protein meal, absorbed amino acids provoke insulin secretion, which can inhibit hepatic glucose production and promote glucose storage by liver and muscle (see earlier). If the meal lacked carbohydrate, the secreted insulin could cause hypoglycemia. However, glucagon secreted in response to a protein meal balances insulin's action on the liver and thus maintains glucose production and avoids hypoglycemia.

A big boy punched me and ran away but then the fuzz caught him and battered him. Instant karma except now I've got a scar on my cheek and I need to go to court as he was so sozzled he probably doesn't remember doing it.

Agreed! I oversimplified, and while the phosphorylation certainly does not occur directly to the enzymes you have identified.

However, my understanding was that while the enzymes may have not been directly phsporylated, regulatory enzymes and proteins were being phosphorylated to bring about these effects.

Mostly from Chapter 51 of MP

in the case of glycogen signalling that is generally true but it's only acting on hepatocytes which makes it easier for us, insulin signalling however acts far more broadly and is much less linear in terms of mechanism but it is equally important to understand. the B&B section you quote is grossly oversimplified in some bits(e.g. inhibition of PP1)and also there are factual inaccuracies (e.g. phosphorylations of GPase and activities) and plain misleading bits (PPAR gamma coactivator stuff). the metabolic section in boron is not very good at all.

Just because it's on my face. I quite liked the way my face was before, and as it'll be my second facial scar now.

Totally knocked my pulling confidence right off.

What would you suggest I use for Carbohydrate and Energy metabolism?

Did some management training recently, among the recognised forms of bad management are 1) the Pidgeon model - fly in, squawk, **** everywhere and leave again; and 2) The Mushroom model - bury in ****, keep in dark. Delightful. The NHS has this in bucketfuls...starting from the health secretary downwards...

amazing!

Day two of CR and already fallen asleep with a massive hangover (I'm old now ) but at least I turned up to PBL

Hahaha, well done!

We have exams in like 2 week's time and whenever I think about how much I have to learn by then I feel a bit sick. Overwhelmed is not the word. Arrrrgggghhhhh.

Hahaha, well done!

We have exams in like 2 week's time and whenever I think about how much I have to learn by then I feel a bit sick. Overwhelmed is not the word. Arrrrgggghhhhh.