Pharmacology of Type 2 Diabetes Mellitus

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  • Created by: LBCW0502
  • Created on: 22-10-19 10:25
The NHS spends how much money on complications relating to diabetes?
£14 billion
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What is the treatment for diabetes mellitus?
Diet (decrease intake of carbohydrate) and pharmacological treatment (if diet modifications alone is not effective)
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What is the treatment for type 1 diabetes?
Insulin
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What are the treatments for type 2 diabetes?
Biguanides (1st choice), incretins (GLP-1-agonists), dipeptidylpeptidase (DPP4) inhibitors, sodium glucose transporters 2 (SGLT) inhibitors, sulphonylureas, thiazolidinediones, meglitinides, alpha-glucosidase inhibitors, amylin analogues, insulin
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Describe features of biguanides - metformin (1)
Absorbed from SI, half life of 3 hours. Not protein bound, excreted unchanged in urine. Decreases blood glucose concentration by - decreased hepatic glucose production, potentiate insulin action in muscle/adipose tissue
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Describe features of biguanides - metformin (2)
Stimulation of glycolysis in tissues, stimulates glucose uptake, decrease carbohydrate absorption, stimulate lactate production, decreases LDL and VLDL, inhibit gene expression involved in gluconeogenesis
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Describe features of biguanides - metformin (3)
Not a very potent drug, large tablet size. Few interactions. Doesn't affect release of insulin/glucagon/GH/cortisol/somatostatin
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Describe features of biguanides - metformin (4)
May act through AMPK, increase AMP levels, inhibit AC/activate AMPK. mTOR. Inhibition of glycerophosphate dehydrogenase, decrease hepatic gluconeogenesis, increase GLP-1 release from intestines
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Describe features of biguanides - metformin (5)
Increases availability of GLUT-4 (also looked at as an anti-cancer drug due to MOA). Effects on - lipogenesis gene expression, gluconeogenesis gene expression, fatty acid/triglyceride synthesis, cholesterol biosynthesis
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Describe features of biguanides - metformin (6)
Advantages - don't cause: hypoglycaemia, stimulate appetite, cause weight gain. S/E - diarrhoea, nausea, metallic taste, rare lactate acidosis, decreases intestinal absorption of folate and Vit B12.
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Describe features of biguanides - metformin (7)
Drug of choice in obese patients who fail with diet alone. Given with incretins, DPP4 inhibitors, SGLT inhibitors, sulphonylureas, thiazolidenediones, insulin (but sulphonylureas, thiazolidenediones and insulin cause hypoglycaemia)
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Describe features of biguanides - metformin (8)
Reduces microvascular complications
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Which factors affect insulin release?
Oral glucose causes more insulin release than a glucose infusion due to release of gut peptides. Incretin - gut derived factor which increases insulin release
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What are the two main incretins?
GLP1 - glucagon like peptide. GIP - gastric inhibitory peptide or glucose dependent insulinotrophic polypeptide
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What are the cell types and secretory products in the pancreatic islets of Langerhans?
Alpha cells (glucagon, GLP1, GLP20. Beta cells (insulin, C-peptide, amylin/islet amyloid polypeptide). D/delta cells (somatostatin). F/PP cells (pancreatic polypeptide)
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What are the effects of somatostatin?
Inhibitory peptide, acts on alpha and beta cells (inhibits glucagon/insulin secretions). (GLP1 has an opposite effect of glucagon)
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Describe features of incretins (1)
Post-translational processing of preproglucagon. Encoding of proglucagon. In alpha cells, prohormone convertase 2 used (glucagon, GRPP, IP1, GLP1-IP2-GLP2)
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Describe features of incretins (2)
In intestinal cells (Psck 1/2 dominant) - GLP-1, GLP2, glucagon-IP1, IP2, GRPP-glucagon-IP1
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Describe features of incretins (3)
Compound stimulates insulin release. GIP from K cells in duodenum, GLP1 from L cells in distal ileum. Exendin-4. Acts on incretin receptor (GLP-1 receptor), gut specific
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Describe features of incretins (4)
Stimulate insulin release. Suppresses glucagon secretion. Reduces appetite and body weight. Slows gastric emptying. Stimulated beta cell number
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Describe features of incretins (5)
New version of Exendin-4 (GLP1 analogues), longer duration of action, reduce frequency of dosing (SC injection - once weekly, PO formulation - once daily)
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Describe features of incretins (6)
Active fragment, GLP1 7-36, inhibition of DPP-4, enhance activation of active fragment of GLP-1. Doesn’t cause hypoglycaemia due to being self-limiting
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Describe features of DPP-4 inhibitors (1)
Serine protease dipeptidyl peptidase 4 inhibitors (inhibits breakdown of incretins). Used as add on treatment, used with metformin. No effect on weight (no hypoglycaemia)
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Describe features of DPP-4 inhibitors (2)
GLP1 agonists preferred compared to DPP4 inhibitors. Examples of DPP4 inhibitors - Sitagliptin, Vildagliptin, Linagliptin (possible S/E - increase incidence of some cancers)
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Where is the majority of glucose re-uptake in the kidney (role of SGLT in glucose reabsorption in the kidney)?
PCT (SGLT1/2). SGLT2- glucose uptake with Na. SGLT1 - glucose uptake with 2Na. GLUT-1 - transfer glucose into the blood
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Describe features of SGLT2 inhibitors
Inhibit glucose re-uptake in kidney, up to 10% excretion of calorie intake. Can be used with metformin. E.g. dapagliflozin, canagliflozin, empagliflozin
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Describe the process of stimulus-secretion coupling in pancreatic beta cells
Glucose enters beta cell via GLUT2, metabolised in mitochondria, ATP synthesis, causes ATP dependent K channels to close, depolarisation of membrane, Ca influx, exocytosis of insulin
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Describe features of sulphonylureas (1)
Can cause hypoglycaemia in animals. Use of carbutamide in type 2 diabetes. Development of tolbutamide and chlorpropamide (devoid of antibacterial activity, long duration of action, lots of drug interactions, drug accumulation in renal impairment)
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Describe features of sulphonylureas (2)
Sulphonylureas - glibenclamide, glicazide, glimepiride, glipizide, gliquidone - less drug interactions, more potent
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Describe features of sulphonylureas (3)
MOA – bind to sulphonylurea site on ATP sensitive K channel, cause increase in insulin release due to cause depolarisation of beta cell membrane. Tolerance effect with increased use of sulphonylureas
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Describe features of K-ATP channels
Hetero-octamers, 2 inward K+ channel, 4 ABCC, family member of sulphonylurea (SUR1, SUR2A, SUR2B)
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What are the acute effects of sulphonylureas?
Increase insulin release, increase plasma insulin concentration, decrease hepatic clearance of insulin
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What are the chronic effects of sulphonylureas? (1)
No acute increase in insulin release but decreased plasma glucose concentration still remains. Chronic hyperglycaemia per se decreases insulin release. Down regulation of sulphonylurea receptor
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What are the chronic effects of sulphonylureas? (2)
Highly protein bound, drug interactions (NSAIDs, MAOBIs, some antibiotics etc.)
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Describe features of 1st and 2nd generation sulphonylureas
Excreted in urine, enhanced effect in elderly and renal disease. 1st generation - long half life (>24 hours). 2nd generation - short half life (7-10 hours), 100x more potent, last for 16-24h, less interactions
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What are the main adverse effects of sulphonylureas?
Neuroglycopenia, lack of glucose supply to the brain. Confusion and coma (take oral glucose). If severe give IV glucose, glucagon, adrenaline
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Describe features of meglitinides (1)
Repaglinide, nateglinide. Half life of 1h. More rapid, less sustained release, less potent than sulphonylureas, less hypoglycaemia. Take just before meal. Close K-ATP channels on beta cells
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Describe features of meglitinides (2)
Share 2 binding sites with sulphonylureas but have their own distinct binding site. More selective for beta cell than cardiac/vascular K-ATP channels, can be used as mono-therapy
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Describe features of thiazolidenediones (glitazones) - 1
Troglitazone, rosiglitazone, prioglizatone. Selective agonists for PPAR-gamma (nuclear-perosisome proliferator activated receptor). PPAR-gamma combines with RXR. Found mainly in adipose tissue but also in liver/muscle
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Describe features of thiazolidenediones (glitazones) - 2
Increases expression of various genes. Effects on adipogenesis, lipid metabolism, glucose homeostasis. Effective in type 2 diabetes (not type 1)
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Describe features of thiazolidenediones (glitazones) - 3
MOA - Activates insulin responsive genes that control carbohydrate/lipid metabolism, needs insulin to be effective, reduces insulin resistance in peripheral tissues, reduces glucose production by liver
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Describe features of thiazolidenediones (glitazones) - 4
Increases glucose uptake in muscle and adipose tissue potentiates actions of insulin. Increase adipocyte number & lipogenesis
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Describe features of thiazolidenediones (glitazones) - 5
Pioglitazone, protein bound, half life of 7 hours, half life of 24h for active metabolite. Takes 6-12 weeks for maximum effect to develop. Give with metformin, insulin or other hypoglycaemic drugs
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Describe features of thiazolidenediones (glitazones) - 6
Weight gain (1-4 kg) due to increased differentiation of adipocytes, fluid retention by stimulating amiloride sensitive Na absorption
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Describe features of alpha glucosidase inhibitors (1)
Acarbose, miglitol. Inhibits intestinal brush border alpha glucosidase. Inhibits carbohydrate breakdown, reduces postprandial increase in blood glucose levels. Effective in type and type 2 DM. Poorly absorbed, doesn't cause hypoglycaemia
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Describe features of alpha glucosidase inhibitors (2)
S/E - flatulence and diarrhoea
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Describe features of amylin analogues (1)
Main component of pancreatic amyloid related to calcitonin/CGRP. Decreases gastric emptying, inhibits glucagon release. Promotes satiety, decreases food intake, related to beta-amyloid (can aggregate)
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Describe features of amylin analogues (2)
Pramlintide. Analogue of human with pro replacement as in rat amylin (doesn't aggregate). Adjunct for both types 1 and 2 DM. Replace amino acids with 3 proline amino acids
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State features of monitoring (1)
Decision cycle for patient centred glycemic management in type 2 diabetes. Glucose lower medication in type 2 diabetes, overall approach. Measure HbA1c (target of <7%, depends on baseline). Combined therapy most appropriate
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State features of monitoring (2)
Most patients under glycaemic control from using metformin
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What are the treatments for obesity? (1)
Monoamine uptake inhibitor (sibutramine, withdrawn). Cannabinoid CB1 antagonist (rimonabant - withdrawn). Lipase inhibitor (orlistat). 5HT2C agonist (lorcaserin, phentermine/topiramate). GLP-1 agonist (liraglutide, naltrexone/bupropion)
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What are the treatments for obesity? (2)
In development. NPY agonists, Y2 agonist, Y2/Y4 agonist, Y5 antagonist. GLP-1 agonists (lixisenatide, albiglutide, taspoglutide, oxyntomodulin). Ghrelin antagonists and ghrelin vaccine. Melanocortin receptor (MC4R) agonists
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What are the treatments for obesity? (3)
Melanin-concentrating hormone antagonists. Metreleptin (leptin analogue). Pramlinitide (amylin analogue)
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Card 2

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What is the treatment for diabetes mellitus?

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Diet (decrease intake of carbohydrate) and pharmacological treatment (if diet modifications alone is not effective)

Card 3

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What is the treatment for type 1 diabetes?

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Card 4

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What are the treatments for type 2 diabetes?

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Card 5

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Describe features of biguanides - metformin (1)

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