Diabetes Flashcards
How is proinsulin converted to active insulin
C peptide is cleaved off (hence presence of c peptide indicates endogenous synthesis of insulin)
Active insulin is a and b peptide chains connected by disulphide bond
How are insulin receptors downregulated
Internalization of insulin receptor complex. Metabolised at lysosome and recycled to plasma membrane
What is type 1 diabetes
Immune mediated B cell destruction, absolute insulin deficiency
What is type 2 diabetes
Insulin resistance with relative insulin deficiency or predominant secretory defect with resistance
How is type 2 diabetes treated
Start from lifestyle modification, then hypoglycemia agents, then insulin therapy
Insulin therapy used when glycemic target not reached with 2 or more oral hypogycemic agents
How to test for type 2 diabetes
Casual non fasting plasma glucose ≥ 11.1mmol/L
Fasting glucose ≥ 7mmol/L
6.1-6.9mmol/L means prediabetic. Undergo glucose tolerance test to see if 2 hour post challenge plasma glucose ≥11.1mmol/L
How can insulin be administered
Subcutaneously
What is prandial insulin
Insulin replacement to get rid of glucose post meal
What is basic insulin
Background insulin to suppress hepatic glucose production overnight and in between meals
How is rapid acting insulin made
Substitute or add amino acids to change charge/conformation of insulin at physiological pH. This weakens propensity to self associate/dimerise via charge repulsion, allowing for rapid absorption
Examples fo rapid acting insulin
Lispro, glulisine, aspartame’s
When should rapid acting insulin be administered
Right before meal to reduce risk of hypoglycemia
What is the duration of action of rapid acting insulin
2-4h
Why is rapid acting insulin more able to reduce post prandial glucose to a greater extent than human insulin
Higher concentration after subcutaneous injection
Appearance of lispro
Rapid acting insulin, clear appearance
What is the appearance of short acting/regular insulin
Clear appearance
Why does short acting insulin have delayed onset
Self aggregate in subcutaneous tissue hence should inject 20-30min before meal
When is short acting insulin given intravenously
During hyperglycemia crisis in the hospital
What kind of insulin is neutral protamine hagedorn insulin
Intermediate acting insulin (human insulin + protamine)
What is the appearance of NPH insulin
Cloudy
Risk of taking NPH insulin
High risk of hypoglycemia due to high intra and inter patient variability and long peak effect (patient must eat meal when insulin is peaking)
Name some long acting insulin
Glargine and determir
Duration of action of glargine
18-24h, virtually no plasma peak
What is long acting insulin used for
Basal glucose levels, background insulin
What is the hypoglycemia risk of long acting insulin
Low because lower intra subject variation
How do glargine and detemir have long action
Glargine has acidic ph of 4, aggregate and slowly release over time
Determir has fatty acid side chain that increases a self association or aggregation into hexamer and has reversible albumin binding
How can NPH be combine with other insulin’s
Can combine with rapid acting, regular
Why is degludec ultra long acting
Forms large multi hexamer at physiological pH
Large molecular size allow for continued slow release doa>42j
What can degludec be mixed with
Aspart
Why might you not want to give degludec to pt with renal or hepatic impairment
Decreased ability to make day to day adjustments due to long doa. This risk is more pronounced in patients with hepatitic or renal impairment
Factors affecting absorption of insulin
Site of injection. Abdomen faster due to increased blood flow
Depth of injection. Directly into muscles = greater absorption as there is greater vascularisation
Increased volume delays absorption
Exercising muscle group before injection increases absorption rate
Heat/massage of the injection site increases absorption rate
Adverse effects of insulin injection
Hypoglycemia — dizziness, tremor, shaky hands
Lipodystrphy at side of injection due to accumulation of fate (insulin lipogenesis action
Name the insulin snesitisers
Biguanide (metformin)
Thiazoldinedione (pioglitazone, rosiglitazone)
What is first line oral hypoglycemia agent
Metformin
Action of metformin
Insulin sensitiser, does not affect insulin secretion
Decrease hepatic glucose production
Increase density of insulin receptors
Decrease intestinal glucose absorption
Increase muscular glucose absorption
Side effects of metformin
Git issues eg flatulence, diarrhea (take with or after meals to reduce side effects)
Increase risk of vitamin b12 malabsorption hence b12 deficiency
Use with caution in patients with renal problems or lactic acidosis
No hyperinsulinemia or hypoglycemia
Weight loss
Mechanism of action of thiazoldinedione
Activate nuclear transcription factor PPAR-gamma whose ligands regulate glucose metabolism, adipogenesis to increase insulin dependent glucose disposal
Improve insulin sensitivity at tissue
Side effects of thiazoldinedione
PCHEFB
Pioglitazone induces CYP450 enzyme activity —> reduce serum concentration of drugs
Increased risk of heart failure due to fluid retention
Peripheral edema
Fat/weight gain
Bone fracture
What is sulfonylurea
Insulin secretagogue, second line oha
First gen tolbutamide
Second gen glibenclamide, glipizide, glicazide, glimepiride [more potent]
Which sulfonylureas have lower ris of hypoglycemia
Glipizide and glicazide
Mechanism of action of glibenclamide
Sulfonylurea urea, insulin secretagogie
Stimulate release of insulin from pancreas by beta cells in pancreatic islets
Target pancreatic B cell atp sensitive potassium channel —> bind to Su receptor protein at k-atp channel
Inhibit k-atp channel mediated K+ efflux
Depolarisation
Voltage sensitive ca2+ channel opens and ca2+ influx
Calcium dependent exocytosis of insulin granules from pancreatic B cells
Which sulfonylurea has high risk of hypoglycemia
Gibenclamide
Side effects of sulfonylureas
Weight gain (1-4kg) Hypoglycemia risk esp elderly, those with renal/hepatic impairment
Meglitinide mechanism of action
Bind and close atp dependent potassium channel in glucose dependent manner. Similar to sulfonyl urea —> less k+ efflux —> depolarisation —> ca2+ —> calcium dependent exocytosis of insulin
Difference being it binds to SUR1 site instead of SU receptor protein
And also glucose dependent manner hence only augmenting action of glucose dependent insulin release, reducing risk of hypoglycemia
Name egs of meglitinide
Repaglinide, netaglinide
Name examples of alpha glucosidase inhibitor
Acarbose, miglitol
Mechanism of action og miglitol
Alpha glucosidase inhibitor. Irreversibly inhibits membrane bound alpha glucosidase at intestinal brush borders, slowing down hydrolysis of oligosaccharide to glucose and other sugars (carb digestion). This slows down rise in glucose levels after meal, inhibiting post prandial hyperglycemia
Inhibitor has strong affinity to alpha glucosidase than dietary carbohydrates
How much acarbose be administered
Alpha glucosidase inhibitor administer with food
Why may alpha glucosidase inhibitors be poor tolerated by patients
Carbohydrates remain at gut and broken down by bacteria, leading to flatulence, gastric distension
A glucosidase inhibitors contraindicated in
Patients with GI diseases, patients with severe renal or hepatic disease (not related to excretion)
What o dipeptidyl peptidase 4 inhibitors do
Bind and inhibit dpp4 which breaks down incretin
Prolongs action of endogenous incretin which stimulate B cell to secrete insulin in glucose dependent manner, and suppress a-cell mediated glucagon release and hepatic glucose production
Vildagliptin cannot be used in
Patients with hepatic impairment
Can patient with chronic kidney disease take linagliptin
Yes, no dose adjustment needed
Side effects of linagliptin
Dpp4 inhibitor
GI problems eg diarrhea, flue like symptoms eg headache, runny nose
Use with caution in patients with pancreatitis history
Expensive
What are exenatide, liraglutide
Glucagon like peptide 1 receptor agonist
How are glp 1 receptor agonists administered
Subcutaneous injection
Mechanism of action of liraglutide
Active glp-1 receptor in beta cells, resulting in initial rapid release of endogenous insulin in presence of elevated glucose.
Suppress glucagon release by pancreas
Delay gastric emptying and reduce appetite hence weight loss `
Side effects of glp 1 receptor agonist
GI problems Cannot use inpatient with pancreatitis Expensive Low risk of hypoglycemia Weight loss Reduce major adverse cardiovascular events
Name sodium glucose co transporter 2 inhibitors
Empagliflozin, canagliflozin, dapagliflozin
Mechanism of sglt2 inhibitors
Reduce reabsorption of filtered glucose at pct, increase urinary glucose excretion
Effects of sglt2 inhibitors
Reduce risk for major cardiac event in patient with atherosclerotic cvs Reduce hospitalisation for heart failure Reduce progression of renal disease UTI Increased urination Yeast infection Canagliflozin increases risk of lower limb amputation Diabetic ketoacidosis
