14. Drug Treatment of Type 2 Diabetes Flashcards
insulin action
affects all major metabolic pathways
major target tissues: liver, adipose, skeletal muscle
insulin effects in hepatic cells
decreases gluconeogenesis
decreases glycogenolysis
decreases ketogenesis
increases glycogen synthesis
insulin effects in muscle cells
increases GLUT-4 translocation to the membrane
increases glucose uptake and oxidation
increases glycogen synthesis
increases amino acid uptake and protein synthesis
decreases glycogenolysis
decreases glycerol release
insulin effects in adipocytes
increases glucose uptake
increases triglyceride synthesis
decreases free fatty acids and glycerol release
treatment for type 2 diabetes
insulin resistance - metformin, TZDs
beta-cell dysfunction - sulphonylureas
loss of beta cell mass - insulin replacement
renal glucose absorption - SGLT-2 inhibitors
diet, exercise treatments for obesity and dyslipidaemia
sulfonylureas
gliclazide, gliplizide, glimepiride
orally active
bound to plasma protein (90-99%)
sulfonylureas primary mechanism of action
stimulates endogenous insulin release
binding site on ATP sensitive K+ channel
inhibits opening of channel, similar to ATP
sulfonylureas secondary mechanisms of action
sensitises beta cells to glucose
decrease lipolysis
decrease clearance of insulin by liver
sulfonylurea therapeutic uses
type 2 diabetes
best patient = over 40, has had diabetes <10 years, daily insulin less than 40 units
can be used in combination with other anti-diabetic drugs
biguanides
metformin
oral anti hyperglycaemic agent
do not stimulate insulin release
appear to increase glucose uptake in muscle and decrease glucose production by the liver
metformin mechanism of action
suppression of hepatic glucose production through gluconeogenesis
through AMP-activated protein kinase (AMPK) dependent and independent pathways
what effect does AMPK have?
increases expression of nuclear transcription factor SHP
inhibits expression of hepatic gluconeogenic genes (glucose-6-phosphatase, PEPCK)
metformin effects
increases insulin sensitivity
enhances peripheral glucose uptake
increases fatty acid oxidation, via decreasing insulin-induced suppression of fatty acid oxidation
decreases glucose absorption from GI tract
properties of metformin
orally active does not bind to plasma proteins excreted in urine often combined with other anti-diabetic medications also used for PCOS
metformin adverse effects and toxicity
lactic acidaemia (rarely)
nausea, abdo discomfort, diarrhoea, metallic taste, anorexia
decreased B12 and folate in chronic use
MI/septicaemia - stop immediately
metformin contraindications
hepatic disease
past history of lactic academia
cardiac failure
chronic hypoxic lung disease
thiazolidinediones
glitazones - pioglitazone
activate peroxisome proliferator-activated receptor-gamma (PPAR-gamma)
involved in transcription of insulin-responsive genes and in regulation of adipocyte lipid metabolism
pioglitazone pharmacodynamics
in presence of insulin:
decreases gluconeogenesis, glucose output and triglyceride production in the liver
increases glucose uptake and utilisation in skeletal muscle
increases glucose uptake and decrease fatty acid output in adipose tissue
causes differentiation of adipocytes
pioglitazone adverse effects and drug interactions
fluid retention
dose-related weight gain
safety in pregnancy and lactation unknown
liver damage - may require regular blood tests
subject to interactions, due to liver metabolism - may lower oral contraceptive levels containing ethinyl, oestradiol, norethindrone
glucagon-like peptide 1 analogs (GLP-1 analogs)
essentially a synthetic incretin
increases insulin secretion when glucose is absorbed in GI (as opposed to injection)
how do GLP-1 analogs work?
augment pancreas response
suppresses pancreatic release of glucagon - stops liver overproducing glucose
slows down gastric emptying
reduces appetite, promotes satiety via hypothalamus receptors
reduces liver fat content
exenatide
strong effects on receptors
high plasma concentration
given iv
GLP-1 analog
GLP-1 analogs side effects
mainly GI acid/sour stomach belching diarrhoea heartburn
dipeptidyl peptidase-4 (DPP-4) inhibitors
oral hypoglycaemic agents
increase levels of incretins GLP-1 and GIP
vildagliptin, sitagliptin
