Diabetes Flashcards
What is diabetes mellitus?
Insufficiency of insulin signalling relative to the requirements of the tissues for this hormone
What are some symptoms of diabetes?
Polyuria, polydipsia, polyphagia
Elevated fasting blood sugar, ketosis, weight loss
What are the normal and diabetes serum glucose levels?
Normal: 4.4-6.1 mmol/L
Diabetes mellitus: >7.0 (fasting plasma glucose), >11.1 (plasma glucose 2 hours after 75g glucose)
What is type 1 diabetes?
Autoimmune destruction of beta cells of the pancreas (no insulin in body)
Insulin dependent diabetes, juvenile onset, thin or normal weight
What is type 2 diabetes?
Strong genetic link with insulin resistance or insulin deficiency (later on)
Non-insulin dependent diabetes, mature onset, obese
How is type 2 diabetes treated?
Healthy diet and increased exercise
Hypoglycemic tablets
Insulin injections
What are beta cells like in a resting state?
Normal glucose levels go through GLUT2 and are sensed by the mitochondria
ATP is used to open a K channel and let K out of the cell which hyperpolarized state to not open the voltage gated Ca channel and not release insulin
What are beta cells like in a glucose stimulated state?
High glucose levels outside of the cell goes through GLUT2 and is sensed and metabolized by the mitochondria to increase ATP and close the K channel which depolarizes the cell and opens the voltage gated Ca channel so it can rush in and allow for the release of insulin
What is GLUT4?
GLUT4 is the insulin dependent transporter.
GLUT2 is insulin independent
How does insulin affect GLUT4 and GLUT1/2?
GLUT4 has increase uptake of glucose in skeletal muscle, cardiac muscle, smooth muscle, mucosa, adipose tissue, leukocytes, pituitary
GLUT1/2 is not affected in the brain, kidney, intestines, liver, RBC, endothelium, pancreas
What are the defects in glucose levels in those with diabetes?
Increase in extracellular glucose
Decrease in intracellular glucose (tissues with GLUT4)
Increase in intracellular glucose (tissues with GLUT1/2)
What occurs in insulin resistance?
Receptor and post receptor defects
Increased glucose production by liver, insufficient glucose disposal in peripheral tissues and impaired insulin secretion (affects liver and peripheral tissue)
How can the insulin receptor become insensitive in type 2 diabetes?
Cytokines (phosphorylate IRS1/2) and fatty acids inhibit IR signalling by insulin to activate GLUT4
What are the effects of insulin on the liver and muscle?
Liver: Inhibits glycogenolysis, inhibits conversion of amino acids to glucose, promotes glucose storage as glycogen
Muscle: Increased protein and glycogen synthesis
What causes a coma from insulin signalling deficiency?
Decreased glucose uptake causes hyperglycemia, glucosuria
Increased protein catabolism causes increased nitrogen and amino acid loss in urine
Increased lipolysis causes increased free fatty acids, cholesterol and ketone bodies
All cause electrolyte depletion which causes dehydration and thus coma
What are the complications of diabetes?
Blood vessels (heart disease, stroke, hypertension) Retinopathy, nephropathy, neuropathy
How is insulin synthesized?
Preproinsulin is converted to proinsulin when the signal sequence is cut off, then proinsulin is converted to insulin when chain C is cut out, leaving chain A and B
What is an example of rapid acting insulin? How long does it take to work?
Insulin Lispro, Insulin Aspart
onset in 10-30 minutes lasts 3-5 hours
What is an example of short acting insulin? How long does it take to work?
Regular novolin R (crystalline Zn)
Onset in 30 minutes to 1 hours and lasts 4-12 hours
What is an example of intermediate insulin? How long does it take to work?
NPH/Humulin N
Onset is 1-2 hours and lasts 10-20 hours
What is an example of mixture insulin? How long does it take to work?
Humalog mix
Onset is 10-30 minutes and lasts 14-24 hours
What is an example of long acting insulin? How long does it take to work?
NPH/Regular, insulin glargine (no peak), insulin detemir (no peak)
Onset is 0.5-1 or 1-4 hours and lasts 18-24 hours
What are rapid acting insulins?
Analog of human insulin in which amino acids 28 and 29 in the beta chain are reveresed and reduces antiparallel dimer formation
More closely resembles insulin response to a meal
Pharmacokinetics differ from normal insulin
How should rapid acting insulin be taken?
Take 15 minutes prior to a meal
Can be used by both Type 1 and Type 2
What are the benefits of rapid acting insulin?
Tighter control of glucose with no adverse effect on HbA1c
Decreased incidents and risk of hypoglycemia
What are short acting insulins?
Recombinant insulin
Dimers form hexamers in the vial
Acts as a depot and delays absorption into bloodstream
Over time hexamers breakdown to release bioactive insulin monomers
How should short acting insulin be taken?
Taken 30-45 minutes before a meal
What are long acting insulins?
For basal control, it is a human long acting insulin that differs in 3 amino acids in beta chain
Clear in pH 4 solution, precipitates at neutral pH in subcutaneous tissue
How are long acting insulins taken?
One injection per day (2 sometimes), lasts 24 hours with no peak
Less nocturnal hypoglycemia
What are the adverse effects of long acting insulin?
Pain at site of injection, potentially tumor growth
Cannot be diluted or mixed with other insulins
What are the new preparations of insulin available?
Nasal sprays (erratic), inhalers (as effective as regular therapy), pumps combined with continuous glucose monitoring
What drugs can decrease hypoglycemia by insulin?
Glucocorticoids, glucagon, epinephrine, growth hormone, thyroid hormone
What drugs can increase hypoglycemia by insulin?
ACE inhibitors, alcohol, salicylate, beta blockers, MAOi
Avoid!
What are the adverse effects of insulin>
Hypoglycemia (hunger, sweating, blurred vision, fatigue, headache, coma, unawareness in elderly)
Lipoatrophy (fat changes at site of injection)
Allergy
What are some examples of sulfonylureas? How do they work?
Glimepiride, glyburide, glipizide
Release insulin from pancreatic beta cells, reduce glucagon levels and potentiate the action of insulin on its target tissues
A partial antagonist to SUR1 and gives no excitatory effect to MgATP and stops K channel opening
What are the adverse effects of sulfonylureas?
Hypoglycemia (glyburide is worse), weight gain, aggravation of MI
Contraindicated in hepatic impairment, renal insufficiency, CVD and elderly
What are some examples of meglitinide analogs? How do they work?
Repaglinide, nateglinide
Binds to SUR1 and K channel to stop channel opening and increase the release of insulin
How can meglitinide analogs be taken?
Take 15-30 min prior to meals, 1 hour peak
Can be combined with metformin
Reoaglinde can be used in patients with renal impairment and elderly
What is an example of biguanides? How does it work?
Metformin (1st line therapy)
Activates cyclic AMP-activated protein kinase (AMPK) by blocking ATP production, the regulator of liver glucose production and improves insulin resistance
Not metabolized
What are the effects of metformin?
Normalizes blood glucose (euglycemic rather than hypoglycemic)
Increase glycolysis and insulin binding, inhibit gluconeogenesis in liver and glucose absorption in gut
Reduces fat and weight (burning fat and blocking lipogenesis)
What are some adverse effects of metformin?
Lactic acidosis due to impaired liver metabolism of lactate
Range of GI effects, B12 deficiency
What are some examples of glitazones (peroxisome proliferator-activated receptor (PPAR)-gamma agonists)? How do they work?
Rosiglitazone, pioglitazone
Enhances insulin sensitivity and decreases insulin resistance by binding to nuclear receptors which regulate genes responsible for lipid metabolism
Decreases gluconeogensis, increases glucose uptake in tissues
No effect on insulin secretion
How are genes involved in PPAR-gamma agonists?
It binds to a promoter region of DNA and causes increased transcription of proteins to cause fatty acid uptake, fatty acid trafficking, fatty acid oxidation and glucose uptake
How should glitazones be taken?
Take with food (better absorption), metabolized by CYP 3A4
For type 2 diabetes who have HbA1c >8.5% and need more than 30 units insulin daily
Max effect takes 12 weeks
What are the benefits of glitazones?
Tighter control of glucose, no lactic acidosis, lowers triglycerides and increases HDL, HbA1c decreased
What are some adverse effects of glitazones?
Edema, macular edema, loss of bone density, weight gain
Contraindicated in heart failure, liver impairment
Rosiglitazone can cause MI
Pioglitazone can cause bladder cancer
What are some examples of glucosidase inhibitors? How do they work?
Acarbose, miglitol
Slows carbohydrate breakdown in gut by being a competitive inhibitor of alpha-glucosidase enzymes, lowers HbA1c levels and post-prandial rise in blood glucose
What are the side effects of glucosidase inhibitors?
Dose dependent abdominal bloating, flatulence will reduce in 3 months
What occurs in the gut after meal ingestion?
Leads to secretion of GLP-1 (glucagon like peptide-1) and gastric inhibitory peptide (GIP) from the gut
What are some examples of incretin-related molecules? How do they work?
DPP-4 inhibitors, GLP-1 analogues
Increase insulin synthesis and release and also decrease glucagon (from pancreas alpha-cells)
What are some examples of DPP-4 inhibitors? How do they work?
Sitagliptin-PO4, Saxagliptin
Stops formation of GLP-1?
What are some adverse effects of DPP-4 inhibitors?
Respiratory infections, may produce pancreatitis (sitagliptin), hypersensitivity
What are some examples of GLP-1 analogues? How do they work?
Exenatide, Liraglutide
Enhances glucose-dependent insulin secretion from beta cells to restore the first-phase insulin response, suppresses glucagon secretion and glucose output, reduces food intake, slows gastric emptying (timely nutrient absorption)
Euglycemic
How can exenatide be used?
It is a synthetic version of an intestinal hormone
Used with either metformin or sulfonylurea
Risks of pancreatitis, renal dysfunction and nausea
What is pramlintide?
A synthetic analog of amylin which is more soluble and doesn’t readily aggregate like amylin (hormone co-secreted with insulin)
Can be mixed with regular or NPH insulin just prior to injecting
How does pramlintide work?
Suppresses glucagon secretion and slows the rate of glucose absorption in the gut
What is used to test average glucose concentrations?
Fructosamine reflects average glucose concentrations over 2-3 weeks prior to testing
How should type 1 diabetes be treated?
Control blood glucose with insulin and diet as best as possible
How should type 2 diabetes be treated?
Exercise, weight reduction and diet control
Can add anti-diabetic agents if mild (oral combination therapy and diet)
Add insulin
Reduce hypertension
What are some considerations in treatment with oral agents?
Elderly people should use sulfonylureas with caution with risk of hypoglycemia
Initial doses should be half in younger people and increased more slowly
What are the goal serum glucose levels in diabetes treatment?
Fasting: 4-7
1-2 hours after meal: 5-11
What are the 2 enzymes that insulin works on?
Glucokinase (converts glucose to glucose-6-phosphate) Glycogen synthetase (converts glucose to glycogen)
