Diabetes Management Flashcards
Diabetes Mellitus
Glucose Homeostasis: insulin promotes uptake of glucose by cells
- reduces blood glucose
Glucagon promotes conversion of glycogen stores to glucose
- increases blood glucose
Stimulation of insulin release
- Glucose enters cell through GLUT transporter
- Glucose metabolized, increases ATP
- ATP inhibits Katp channel
- This leads to calcium entry through calcium channels
- Calcium entry leads to exocytosis of insulin
Diabetes Mellitus key feature
Sustained elevations in blood glucose
High blood glucose leads to these complications (5)
Circulatory disorder Neuropathy Nephropathy Retinopathy Cardiovascular disease
The two types of diabetes and how they are different
Type 1: insulin deficiency (reduced secretion)
Type 2: Insulin resistance and (then) reduced secretion
Type 1 characteristics
Low insulin
- due to destruction of pancreatic beta cells
- likely autoimmune
- also genetic component
- typically earlier onset but not always
Type 2 characteristics
Often associated with/or worsened by obesity
Typically later onset but that is changing
About 90% of DM cases are type 2
Treatment overview for type 1 and 2 diabetes
Type 1: manage with insulin
Type 2: lifestyle changes - diet, exercise, etc.
Manage initially with oral hypoglycaemic
May need to add insulin later as beta cells fail
Monitoring of glucose (acute)
- self-monitoring of blood glucose (glucometer)
- target fasting blood glucose (4-7 mmol/L)
- Post-prandial (2 hours): 5-10 mmol/L
Monitoring of glucose (chronic)
Hemoglobin A1c
- glycated hemoglobin
- Glucose attached to Hb in blood
- Considered a more stable measure of Glycemic control over time
Insulin
- a 51 amino acid protein
- consists of two peptide chains (A & B) joined by 2 disulphide bridges
Actions of Insulin
Promotes entry of glucose into the cells
- Insulin binds to tyrosine kinase receptor
- Prompts a cascade of intracellular signalling events (protein synthesis and glycogen synthesis)
- Prompts translocation of GLUT-4 transporters to cell membrane
Actions of insulin in the liver
- decreases glucose synthesis (Gbuconeogensis)
- increases conversion of glucose to glycogen (storage)
Actions of insulin in muscle
- Increase in glucose to glycogen
- increase in protein synthesis.
Actions of Insulin in Fat
- Increases in Lipogenesis
- decrease in Lipolysis
Insulins route of administration
Injected: Subcutaneous
- intravenous in emergencies
- absorption depends on site of injection: more rapid in abdomen, slower in thigh or buttocks and exercise, heat tend to increase absorption
Rapid acting insulins
Regular insulin: onset is 1/2 hour, peak around 2 hours, duration 8 hours
Aspart insulin: onset is 1/4 hour, peak in 1-1.5 hours, duration 4 hours
Intermediate/long acting insulins
NPH: onset 1-2 hours, peak 6-12, duration 18
- Neutral Protamine Hagedorn
Glargine insulin: onset 3-4 hours, duration 20-24 hours
SIde effects of Insulin
Hypoglycemia: symptoms include sweating, tachycardia, confusion
- can progress to coma/death
Treatment: SUGAR
Other side effects of Insulin
Weight gain
Immune reactions
Lipodystrophy
- atrophy of subcutaneous fat at injection site
Insulin secretagogues two classes
Sulfonylureas
Meglitinides
Sulfonylureas example
Glyburide
Sulfonylureas mechanism
- act on pancreatic beta cells
- bind to the sulfonylurea receptor-1 (SUR-1) and stimulate insulin release while inhibiting Katp channel
Risk of Sulfonylureas
Stimulates insulin regardless of blood glucose levels
Risk of hypoglycemia
Side effects of Sulfonylureas
Weight gain Rash (hypersensitivity to sulpha) Gastrointestinal Concern over cardiovascular effects: - receptors in the cardiovascular system
Meglitinide example
Repaglinide
Repaglinide mechanism
Bind to a different sire of SUR-1 and stimulate insulin release
More rapid onset and shorter duration of action
- may lower risk of hypoglycemia
- more flexibility with regards to food intake
- need to be taken more often
Biguanides example
Metformin
Biguanides mechanism
Increases activity of AMP-dependent protein kinase (AMPK)
- AMPK is normally activated when cellular energy stores reduced
- may have protective (anti-oxidant) effects on endothelial cells
Key effects of AMPK:
Enhanced glucose uptake/cell sensitivity to insulin
Reduced Glycogenolysis
Reduced Gluconeogenesis
Biguanides pharmacokinetics
Eliminated by kidneys
Avoid using in patients with impaired renal function
Biguanides Side effects
Gastrointestinal: Nausea, diarrhea
Rare - Lactic acidosis
Avoid using in patients with decompensated heart failure
First line drug for Type 2 Diabetes?
Biguanides: good efficacy
- not associated with weight gain
- does not stimulate insulin release (hypoglycemia unlikely)
- Good safety profile
Incretins mediate
Mediate communication between gut and brain
- potential target for weight loss drugs
Examples of Incretins
Glucagon-like Peptide-1 (GLP-1)
Glucose dependent insulinotropic peptide (GIP)
The two variations of Incretins
GLP-1 agonists
DPP-4 inhibitors
GLP-1 agonist example
Liraglutide
DPP-4 inhibitors example
Sitagliptin
Incretins mechanism of action
- Increase insulin secretion
- Inhibit glucagon secretion
- Delay gastric emptying
- Reduce appetite
Administration of GLP-1 agonists
All administered by subcutaneous injection
Administration of DDP-4 inhibitors
All administered Orally
Difference in GLP-1 agonists and DPP-4 inhibitors
- GLP-1 agonists have more pronounced effects on the GI tract than DDP-4 inhibitors
- May reduce gastric emptying enough to interfere with drugs needing rapid absorption
Side effects of Incretins
Hypoglycemia: less common than with insulin or the insulin secretagogues, Incretins response to bodies need for insulin
Rare AE: Pancreatic disease, pancreatitis, cancer
GLP-1 agonist side effects
Gastrointestinal: Nausea, vomiting, diarrhea (or constipation), gall stones
- incretins effect communication between gut and brain
- GLP-1 agonists have a greater effect on the GI tract than DPP-4 Inhibitors: more GI side effects but more weight loss, liraglutide approved as a weight loss drug
- increases heart rate, arrhythmia, possible link to thyroid cancer
DPP-4 inhibitors (dipeptidyl peptidase 4) side effects
- Gastrointestinal: less common than GLP-1 agonists
- Increased risk of infection: typically upper respiratory or urinary tract
- DPP-4 plays role in the immune system (lymphocytes)
Thiazolidinediones example
Pioglitazone
TZD facts
- Peroxisome proliferator-activated receptor-gamma (PPAR-y) agonists
- PPAR-y receptors regulate genes related to glucose and lipid metabolism
- because they work on gene expression, TXD effects tend to be delayed
TZD actions
- insulin sensitizer: increases uptake of glucose
- Enhances uptake of free fatty acids into adipose tissue
- less FFA available to enter other tissues
- higher adipose tissue levels tend to reduce sensitivity to insulin
TZD actions on blood glucose
Reduce hepatic production of glucose
- reduced gluconeogenesis
TZD actions on lipids
Reduce triglycerides, increase HDL
Thiazolidinediones problems
Consistent safety issues have limited their use
Hepatotoxicity, myocardial infarction, bladder cancer
TZD side effects
Cardiovascular: heart failure
Edema
Weight gain: reduces leptin levels
Fractures (women)
Alpha-glucosidase inhibitors
- Glucosidases break down carbohydrates to glucose
- AGIs inhibit breakdown of carbs, preventing absorption
AGI example
Acarbose
Side effects of AGI
Gastrointestinal: bloating, diarrhea, pain. Bacteria feed on undigested carbs, release gas
Low risk of hypoglycemia: if it does occur, need to use glucose because sucrose won’t be absorbed
SGLT2 inhibitors mechanism
- inhibit renal mechanism for reabsorbing glucose
- in non-diabetic individuals, all filtered glucose is reabsorbed
- 90% of glucose reabsorption occurs at the proximal tubule
SGLT2 inhibitor example
Empagliflozin
Empagliflozin mechanism
Acts at the proximal tubule
Inhibits sodium-glucose Co-transporter 2 (SGLT)
Inhibition of SGLT2 results in
- reduction in glucose reabsorption: osmotic diuresis, reduces blood glucose
- induces weight loss
May reduce blood pressure via osmotic diuresis
SGLT2 inhibitors adverse effects
- Increased glucose in the nephron increases risk of infections: urinary tract infections, genital infections
- Dizziness, hypotension
- Nausea
- Hyperkalemia
- Rare cases of diabetic ketoacidosis
Type 2 diabetes combinations
Metformin + anything
Benefits: adding drugs that cause weight gain lead to a neutral effect
Common examples: Metformin + insulin and Metformin + Sulfonylurea
These combinations also decrease the risk of Hypoglycemia
Other Drug combinations
Metformin + SGLT2 inhibitor + DPP-4 inhibitor
- addition of drugs with neutral effect on weight or weight loss can enhance the weight loss
Future direction of Insulin administration
- inhaled insulin, powdered form through mouth
Problems: cost, first device failed to catch on, concerns over bronchospasm - Patches: use micro needle technology, patches contain insulin or beta cells which then secrete insulin
- Stem cells: Islet cell transplants