Pharmacology-Diabetes Flashcards
What is the sequence of insulin production in the cell?
DNA -> RNA -> proinsulin (ER & golgi) -> secretory vesicle -> C-peptide
What factors stimulate the release of insulin?
Glucose (most important), amino acids, glucagon, ACh, GLP-1 and beta-2 stimulation
What factors inhibit the release of insulin
Somatostatin and alpha-2 stimulation
How does glucose mediate insulin release from the beta cells of the pancreas?
Glucose metabolism -> ATP -> Closes K+ channels -> Depolarizes cell -> Ca VGCs open -> Insulin release
What tissues are most susceptible to damage in patients with diabetes?
Those where insulin does not regulate glucose uptake: CNS, peripheral neurons (neruopathies), renal medullary cells (renal failure), endothelial cells (athero/arteriolosclerosis) and hepatocytes.
What are the hormones that counter the effects of insulin?
Cortisol, EPI/NE, Glucagon and GH
What are the effects of insulin on muscle, liver and adipose tissue?
Muscle = increased glucose/AA uptake, glycogen synthesis and protein synthesis. Liver: Increased glycogen synthesis. Fat: increased glucose uptake and fatty acid synthesis.
How does insulin bring about all of the intracellular changes it does?
Insulin receptor activation -> phosphorylation of IRS-1 on tyrosine residues -> IRS-1 activates PI-3 kinase -> GLUT4 moves to the membrane in fat and muscle. IRS-1 also phosphorylates a lot of other things to stimulate protein, triglyceride and glycogen synthesis.
What happens to metabolism as a result of lack of insulin in patients with type 1 diabetes?
Unopposed effects of cortisol, EPI/NE, glucagon and GH: glycogenolysis, protein depredation, gluconeogenesis, FFA release, ketone body generation and increased blood glucose.
What insulin preparations have a delay in their onset of action?
Regular insulin (hours), isophane insulin (NPH, a day), insulin zinc extended and insulin glargine
What insulin preparations pretty much take effect immediately?
Insulin lispro (reverse of insulin Lys and Pro)
Which insulin preparations have a lasting onset?
Insulin glargine (precipitates after injection and lasts 24 hours) has a “peakless basal replacement” and insulin zinc extended (crystal structure retards insulin absorption)
1st option for treatment of type II diabetes? 2nd option?
Diet and exercise. If this doesn’t work try oral hypoglycemics and euglycemics
What drugs are the oral hypoglycemics used to treat type II diabetes? Which ones are more and less potent?
Sulfonylureas: tolbutamide (low potency short duration), glyburide (high potency long duration) and glipizide (long-acting 2nd generation). Note that sulfonylureas bind to ATP-sensitive K channels. This causes depolarization of the beta cell and release of insulin. Metformin: a biguanide that inhibits gluconeogenesis. Acarbose: an alpha-glucosidase inhibitor that inhibits carbohydrate breakdown in the intestine. Thiazolidinediones: increase insulin sensitivity by increasing GLUT4 in muscle and fat and by decreasing gluconeogenesis in the liver. Sitagliptin: prevents breakdown of endogenous GLP-1. Canagliflozin: SGLT2 inhibitor.
What adverse effects do you need to be aware of with sulfonylureas?
Prolonged and severe hypoglycemia (sweating, hunger, parenthesis, tremor and anxiety)
What drug is not a sulfonylurea but acts just like one?
Repaglinide: binds to and blocks K+ channels on beta cells
What adverse effects do you need to be aware of in patients taking metformin?
Lactic acidosis in patients with renal failure or CHF. Note that you do not see hypoglycemia because it inhibits gluconeogenesis.
A patient is taking acarbose and tolbutamide. He begins to experience hypoglycemia. How do you correct his hypoglycemia?
Glucose. Note that you cannot give sucrose because acarbose is an alpha-glucosidase inhibitor and it would prevent the breakdown of sucrose to glucose.
Why do thiazolidinediones need some insulin to be present in order to work? What is the name of the drug?
Pioglitazone: is a PPAR-gamma agonist. In order to activate this nuclear receptor some insulin must be present.
Drug isolated from gila monster saliva that is used to treat diabetes
Exenatide. It mimics GLP-1, which travels to pancreatic beta cells and stimulates insulin release and inhibits glucagon release
What drug is orally active in treating type II diabetes?
Sitagliptin and saxagliptin, prevents breakdown of GLP-1 by inhibiting DPP-4.
What drug used to treat type II diabetes will make their urine even sweeter? What adverse effects do you need to be aware of with this drug?
Canagliflozin: SGLT2 (sodium-glucose cotransporter) inhibitor that prevents reabsorption of glucose back into the blood at the proximal tubules. Because of increased urine glucose mycotic infections, UTIs, volume depletion and electrolyte imbalances concerns.
Drugs to be used that can lessen the degree of kidney failure in diabetics?
Captopril (ACE-I) and irbesartan/losartan (ARBs)
What evidence is there that type I diabetes is an autoimmune disease?
Newly diagnosed type I diabetics have had beta cell antibodies in their blood for months to years and have CD8+ T-cells infiltrating the pancreas. Early treatment with cyclosporin A and imatinib (suppressed T-cell response) causes symptoms to subside.
Why is coxsackie virus a suspect in the pathogenesis of type I diabetes?
A region of the virus is similar to glutamic acid decarboxylase (GAD) expressed on beta cells. Note that injection of GAD into the thymus of mice prevents diabetes.
