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Flashcards in Diabetes Deck (35):
1

Type 1 diabetes

Insulin dependent. Autoimmune destruction of beta-cells

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Type 2 diabetes

Non-insulin dependent. Insulin secretion is unable to match increasing insulin demands due to insulin resistance.

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What is insulin?

Peptide. T(1/2)=7 mins. Cleaved from pro-insulin in beta-cells. 2 insulin molecules can form a dimer and then a hexadimer around a Zn ion but must dissociate before binding to the insulin receptor.

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Insulin receptor

Dimer. Receptor tyrosine kinase. Upon binding undergoes mutual phosphorylation that recruits substrate proteins such as insulin receptor substrate.

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How is insulin secretion controlled?

Local intra-islet regulation. Also interactions between insulin and glucagon. Incretin effect.

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What is the incretin effect?

Glucose in the gut stimulates release of incretins. Bind to GPCRs on beta-cells and stimulate an increase in cAMP. Cause an increase in the gain of glucose evoked insulin release.

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How does glucose stimulate insulin release?

Taken up passively by GLUT-2 transporter into beta-cells. Phosphorylated to glucose-6-phosphate by glucokinase. Causes an increase in ATP/ADP ratio. Closes ATP-K+ channel. Causes depolarisation and opening of L-type calcium channels. Stimulates release of insulin containing vesicles

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2 main treatments for type 1 diabetes?

Insulin replacement therapy and islet transplantation.

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Islet transplantation.

Follow Edmonton protocol. Require immunosuppression by diclizumab.

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Insulin replacement therapy

Given subcutaneously to prolong action. Also given with zinc crystals.

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Factors affecting s/c absorption

Prep of dose. Injection site. Changes at injection site.

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Humulin S

Short acting insulin replacement therapy. 30 min onset. 2-4 hr peak. 8hr duration

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Insulatard

Medium acting insulin replacement therapy. 1-2hr onset, 4-12hr peak, 16-24 hr duration.

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Human ultratard

Long acting insulin replacement therapy. 1-2hr onset. 4-12 hr peak. 20-35 hr duration .

15

Levemir

Insulin analogue. 0-15 min onset, 1-2hr peak, 4-6 hr duration.

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Diabetes

Defective control of plasma glucose concentration by insulin

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What can cause type 2 diabetes?

Obesity. Receptor defect. Decrease in number of receptors. Beta-cell burnout - decrease in insulin sensitivity.

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What are the 5 main treatment options?

Lifestyle (alcohol, smoking). Diet/exercise. Oral monotherapy. Oral combination therapy. Insulin.

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4 main non-pharmacological treatments?

Statins. Fibrates. Resins. Orlistat.

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Statins

Inhibit HMG-CoA reductase. The RL enzyme in the melavonate pathway of cholesterol synthesis

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Fibrates

Fenofibrate. Increase HDL, decrease triglyceride levels and improve insulin resistance

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Resins

Bind cholesterol

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Orlistat

Inhibits pancreatic lipase and decreases triglyceride absorption from the gut by 30%.

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What does GLP-1 do?

Increases glucose evoked insulin secretion from beta-cells. Decreases postprandial glucagon production from alpha cells. Slows gastric emptying. Increases satiety and decreases appetite. Decreases hepatic output from liver.

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Liraglutide and exanatide

Long lasting GLP-1 analogues

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Januvia

DPP IV inhibitor, decreases metabolism of GLP-1 but can cause upper respiratory tract infection, sore throat and diarrhoea.

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Alpha glycosidase inhibitors
Acarbose
Moglitol
Voglibose

Reduce carbohydrate metabolism. Saccharides that act as competitive substrates for alpha-glucosidase enzymes in the brush border of the gut.

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Acarbose

Oligosaccharide. Alpha glucosidase inhibitor.

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Moglitol

Alpha glucosidase inhibitor. Monosaccharide.

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Voglibose

Alpha-glucosidase inhibitor. Fewer side effects but Acarbose has higher efficacy.

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Thiazolidinediones

Insulin sensitisers.

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Glitizones

Thiazodolinedione. Binds to PPAR(gamma) receptor that binds to retinoid X receptor and upregulates insulin sensitive genes. GLUT4, lipoprotein lipase, fatty acid transporter protein, fatty acid CoA synthase.

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Rosaglitizone

In combo with metformin - avandamet. In combo with glimepiride - avandaryl. Decreases excessive lipolysis and free fatty acid output. Decreases excessive hepatic glucose production. Directly decreases insulin resistance.

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Metformin

Biguanine. T(1/2)= 4-6 hrs. Decreases hepatic gluconeogenesis. Increases insulin sensitivity by increasing peripheral glucose uptake. Stimulates AMPK. Decreases glucose absorption from GI tract.

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Sulphonylureas

Increase insulin secretion. Bind to SUR1 region on ATP-k+ channels, stimulate depol, opening of L-type ca channels and release of insulin containing vesicles. Eg gliclazide.