Discuss the structure and actions of the Insulin REceptor?
Heterodimer w/ Alpha and Beta Subunits
Alpha - binds insulin
Beta - Tyrosine Kinase domain
Tetramer formation as they come together and 2 beta subunits phopshorylate eachother producing a cascade that signa;s IRS and results in GLUT4 glucose transporters traveling from sequestered sites to cell surface ...and transcription of other things like Glucokinase
Which Glucose transportrers are found where?
Glut 1 - in the brain always and doesn't need insuline for transport of glucose
GLUT2 reulgates insulin release in response to blood glucose
Glut4 - inserted into membrane in muscles and adipose cells from intracellular storage vesicles in response to insulin
IS it more efficent to store energy as fat or glycogen in muscles?
Fat TG bc glycogen needs H2O for storage vs fat does not
How long does reuglar insulin act?
How many ppm does insulin need to be to be "purified" in instances of allergenciity?
<10ppm then purified
What are the Ultra-Short acting insulins? How do they work?
Lispro, Aspart, Glulisine
Remain in monomer form in vial and don't form hexamers so immediate use and peak at 15 minutes
take right before meals
(regular insulin forms hexamers in vials and so inject it and have to dilute it in tissues to work so 30 minute lag)
What are the long acting insulins? What's differences between them?
Glargine and Detemir
Glargine - Beta insulin supplement that is 18-24 hours long lasting and no discrete peak
Detemir - goes into blood and binds serum albumin and slowly released from albumin; slight peak ~12 hours and lasts 18 hours
What are the different insulin delivery systems?
Insulin is a peptide and so will be degraded orally so has to be given enterally
POrtable Pen injectors
Continuous SQ insulin infusion device aka pumps - preffered in kids and recomended for people with difficulty obtaining target control - lower total insulin dose
Inhaled - Afrezza
What are the problems/contraindications in Inhaled insulins?
Short term release
CONTRAINDICATION in patients w/ chronic lung disease - smokers, COPD, ASthma
Problem if taking and get URI
Complications of Insulin therapY?
Hypoglycemia- TX is sugar/IV glucose
Lipodystrophy at injection site --> hypertrophy of Sq fat tissue from multiple injections at same site and liposuction corrects this
What are the different classes of oral antidiabetic drugs?
Insulin secretagogies - Sulfonylureas or Meglitinides
Glucagon-like polypeptide 1 (GLP1) Agonsistss
Sulfonylureas - mechanism of action, Important considerations, what drgs are they?
Second Generation - fewer side effects and less drug interactions but more potent so more likely to produce hypoglycemia - Glyburide, Glipizide, Glimepiride vs First generations - tolbutamide, chlorpropamide, tolazamide, acetohexamide
Mechanism: insulin release from beta cells independent of glucose!!! Activate SUR1 receptor assocaited w/ K6.2 channel
Condiseration: Pt needs functioning beta cells to make and release insulin
What are the Meglitinides? Mechanism? Cautions? Indications?
Mechanism: modulate beta cell insulin release, same site of action as Sulfonylureas but weaker affinity for receptors - shorter action
CAUTION - metebolized by liver so careful in pts w/ hepatic impairment
NO SULFER STRUCTURE - good for patients allergic to sulfonylureas!
What drug is a "Biguanide"? Mechanism of action? Uses?
Blood glucose lowering ability not dependent on function beta cells - Euglycemic
Mechanism - not completely known but increases insulin sensitivity of tissues and reduces insulin resistance, stimulates glycolysis in tissues, reduces hepatic gluconeogenesis, slows GI glucose absorption w/ increased glucose to lactate conversion, reduction in Glucagon levels
FIRSTLINE TREATMENT FOR T2DM
What are the side effects of metformin?
GI!! Anorexia, N/V, abdominal discomfort and diarrhea
Usually transient at begining of therapy
Absorption of B12 impaired!!!!
What are contraindicatios for Metformin?
Renal or Hepatic disease
Alcoholism or conditions predisposing to tissue anorexia (like chronic cardiopulmonary dysfunction)
Increased Risk of Lactic Acidosis induced by Biguanides!!!
What are other uses for Metformin?
Pts w/ refractory obesity
DB Prevention in PREDIABETES - obese middle aged person w/ impaired glucose tolerance
PCOS - can lead to reversal of anovulation
Gestational Diabetes- more effective in preventing hypoglycemia but higher changes of pre-term birth (compared to insulin)
Cancer - reduced risk of pancreatic cancer and used in cancer treatment (esp breast cancer)
What are the Thiazolidinediones? How do they work? Use? Side Effects/ problems?
Rosiglitazone and Plioglitazone - enhance target tissue insulin sensitivity
Mechanism: activation of genes of PPAR-gamma (genes of lipid and glucose metab - peroxisome proliferator activated receptor)
PPAR-gamma is TF to increase things for glucose uptake and metab in muscle and adipose
- weght gain and redistribution from visceral fat to Subq sites
- delayed effects from upregulating genes
- BLADDER CANCER
- P450 interactions
What are the Alpha-glucosidase inhibitors? How do they work/mechanism of action? side effects?
Acarbose and Miglitol - Prevent GI breakdown of starches into monosaccharides and so less sugars absorbed in GI
Mechnaism- competitive inhibition of Alpha-Glucosidase so reduction in post-prandial glucose levels
Side Effects: FARTS!!! diarrhea, abdominal pain bc unabsorbed carbs get fermented in colon
Contraindicated in IBD!
Don't work overtime bc ileum and colon can upreulgate glycosidases
Problem w/ taking Acarbose/Miglitol w/ other Anti-DB agents?
Taking sulfonylureas or Insulins can cause patients to get hypoglycemic and if they are also on Alpha-glucosidase inhibitors then can NOT give patient sucrose bc can't break it down so need to give Fructose/Glucose
What are the Incretin based therapies?
Incretins are GI hormones that regulate blood glucose along with insulin and include Glucagon-like-peptide 1 (GLP1)
They sensitize the pancrease to glucose and suppress post-prandial glucagon release - INCREASE INSULIN RELEASE
Slow gastric emptying and increase satieity - weight loss
Only for T2DM bc require endogenous insulin
FX: cause insulin release so can see hypoglycemia
the GLP-1 Agonists - how do they work? What are they?
T2DM - see reduction in post-prandial rise in GLP1
Synthetic GLP1 has different Alanine at 2 position so not broken down by DPP4 as quickly
Exenatide and Liraglutide
- improve glucose control and cause weight loss
What are the DDP inhibitors and how do they work
Block DDP4 degratation of endogenous incretin hormones (GLP1) which increase circulating levels of endogenous incretin to increase glucose mediated insulin secretion and decreased glucagon levels
Sitagliptic, Saxagliptin, Vildagliptin
What are the SGLT2 Inhibitors? restrictions/side effects? Mechanism?
SGLT2 inhibitors block reabsorption of glucose by the kidney and so more excretion of glucose
Side effects: osmotic diuresis and dehydration, rapid weight loss, tiredness, worse UTIs
REstrictions: Severe renal imairment or diabetics w/ increased ketones or CV risk
Invokana / Canaglifozin and Farxiga / Dapaglifozin
What is glucagon? Where is it made? What does it do? Affects?
Glucagon - Hyperglycemic hormone made by alpha cells and degrades by liver and kidney w/ short half life in blood
- Metabolic: binds receptors in liver cells --> increass cAMP --> catabolism of glycogen and increased gluconeogenesis and ketogenesis --> increase blood glucose at expsence of hepatic glycogen
- Cardiac: ionotropic and chronotropic effects bc cAMP
- SM - relaxation of intestine
What are the clinical uses of glucagon?
SEVERE HYPOGLYCEMIA!!!! unconciouss and can't eat sugar then use this but contraindicated in repeated hypoglycemia bc hepatic stores will be depleted
Endocrine diagnosis - give glucagon and should see insulin release or in suspected endocrine tumores bc can see increased calcitonon from medullary carcinoma or catecholamines from pheo
Beta Blocker Poisoning - increases cAMP
Radiology of bowel - relaxes it for XR visualization