Biochem Of Metabolism, Block 3, # 30 (Diabetes 4)

Front 1

describe the genetics of type 1 diabetes: what's attacked?

Back 1

IDDM:

most patients have detectible autoimmune response to islet cell cytoplasmic antigens and islet cell surface antigens (ICCA and ICSA).

this antigen is often on glutamic acid dehydrogenase, specifically GAD65 (a variant found specifically on B-cells).

Front 2

what can be used to tell type 1 from type 2?

Back 2

anti-Gad65 antibodies should be present only in type 1 diabetics.

Front 3

when does type 2 diabetes appear? as in, when do blood sugar readings go up?

Back 3

when the pancreas can't produce enough insulin to overcome the insensitivity - blood sugars begin to rise

Front 4

what's an SNP, and what does it have to do with diabetes?

Back 4

SNP is a polymorphism, distinct from a mutation based solely on how prevalent it is - anything that occurs more than 1% of the time. Below that, it's a mutation.

SNP analysis has been used to investigate the genetic role of type II diabetes, looking for genes which are weird in patients.

Front 5

what SNP's are we likely to be tested on?

Back 5

Glut -2

Glucokinase Regulatory Protein.

PPAR-gamma

Front 6

what's glucokinase regulatory protein, and why might messing with it have something to do with betus #2?

Back 6

proper activation of hexokinase-IV requires working glucokinase regulatory protein (GRP).

note that hexokinase is necessary for turning glucose into G-6-P so it can't leave the cell. If you can't do this, glucose might be able to leak back out into the blood and not be used.

also, it's related to high triglyceride levels.

Front 7

what's PPAR gamma?

Back 7

PPAR - we know it binds RXR to turn on genes, including those for adipocyte differentiation. Why messing with it causes type II diabetes isn't known, but there are drugs which enhance its activity used to fight type 2 betus.

these drugs are the thiazolidinedione

Front 8

who has the highest rate of Type 2 betus?

Back 8

Native americans.

Note that pima indians in the US have lots, pimas in mexicao have little - so something to do with lifestyle.

Front 9

what are the 6 classes of diabetes drugs we unfortunately need to know?

Back 9

ASM BTT

Alpha-glucosidase inhibitors

Sulfonureas

Meglitinides

Biguanides

Thiazolidinediones

Targeting glucagon-like-peptide 1

Front 10

going back for a second, aside from cell surface antigens/cytosomal antigens, what can be auto-targeted?

Back 10

insulin itself can be attacked by antibodies.

Front 11

Back to drugs - #1. what should we know?

Back 11

alpha-glucosidase inhibitors.

alpha glucosidase in the small intestine helps absorb and digest sugars. specifically, turning disaccharides into monosaccharides for metabolism.

if you interfere with this, sugars remain in the gut and/or aren't turned into glucose, so keep sugar low.

this can lead to bloating/farts because bacteria can digest these, and they'll go to town.

drug names: acarbose and miglitol.

Remember A: M, A?

Front 12

what's drug class 2?

Back 12

sulfonyureas:

idea here is to secrete more insulin from the pancreas.

remember, glucose oxidation makes more ATP which closes K+ channels, depolarizes, and opens Ca++ to make insulin release.

If you block the K channel on its own, you can artifically increase insulin secretion.

Drugs: glucotrol, amaryl, diabeta, micronase, glynase.

RISK - hypoglycemia!

Front 13

what's drug class 3?

Back 13

Meglitinides: these are just like sulfonureas, in that they're K+ channel blockers to make more insulin get released.

here, however, it's functional only when glucose is high (right after a meal) and acts very quickly (sulfonureas are long-acting).

good thing is that the risk of dangerous hypoglycemia is lower.

names include: starlix and prandin

mega-star-pra

Front 14

what's class 4?

Back 14

biguanides!

all about making you more insulin-sensitive.

works by increasing insulin-receptor tyrosine kinase (and up cAMP).

effects - suppress gluconeogenesis, use more glut 4 in muscle/fat (also works on liver), synthesize glycogen.

more likely to esterify (store) FA's.

risk of hypoglycemia is minimal, as you're not making more insulin.

Very, very common.

drugs: glucophage, glucovance

Front 15

what's class 5?

Back 15

thiazolidinones: this is our PPARgamma agonist. remember, mutations in that gene are found in type 2.

this enhances its activity. PPary binds at P{AR-responsive elements (PPRE).

TZD releases adiponectin, to decrease output of glucose by the liver and uptake more in muscles.

rezulin, avandia, actos.

Front 16

what's class 6?

Back 16

Targeting Glucagon-like-peptide-1:

Misnomer, don't want to kill GLP1 - it's a good thing.

GLP-1 made in intestines in response to fat/carb/sugar intake, it helps release insulin and suppress glucagon.

so, drugs are agonists for GLP-1 receptors.

problem - short acting, so need to inject regularly. dramatically lowers blood glucose. it's degraded by DPP4 - so can target Dpp4 for destruction to lower glucose.

Beta-yetta is from lizards, like GLP, resistant to cleavage by DPP4.

Januvia targets DPP4.