Diabetes and lipid disorders Flashcards
insulin receptors
acts on specific insulin receptors on the cell
triggers the addition of GLUT4 transporters, which transport glucose from the blood into the cell
effects of insulin
liver:
promotes glycogen synthesis and storage
synthesis of protein, triglycerides and VLDL
glycolysis
inhibits gluconeogenesis, glycogenolysis, ketogenesis, lipolysis
muscle:
protein synthesis - amino acid transport, ribosomal protein synthesis
glycogen synthesis
increased glucose entry into muscle cells (GLUT4)
adipose tissue:
triglyceride storage - increases lipoprotein lipase activity to hydrolyse triglycerides from lipoproteins
increased glucose entry
inhibits intracellular lipoprotein lipase
biguanides - metformin
inhibit hepatic gluconeogenesis
+
weight neutral/loss
low cost
provem track record
- nausea loose stool flatuence lactic acidosis in: renal impairment heart failure liver disease
sulphonylureas - gliclazide, glimepiride
increase insulin secretion
bind to sulfonylurea receptor on beta cell, opening K+ channel causing K+ efflux and the cell membrane to depolarize. this opens a Ca2+ channel, and Ca2+ enters the cell, which increases insulin release
+
cheap
track record
-
hypo’s
weight gain
thiazolidinediones - pioglitazone
enhance lipogenesis
decrease lipolysis
decrease plasma FFAs
+
insulin sensitisers
- fluid retention weight gain increased peripheral fracture rate ? bladder Ca
SGLT2 inhibitors - empagliflozin
…flozin
prevent renal glucose reabsorption by inhibiting SGLT2 in the proximal tubule
\+ weight loss ? reno-protective effect - UTIs uncertain long term effects expensive
also reduces death rate for CVD
may help delay the onset of diabetic neuropathy
incretins
secreted by intestinal endocrine cells in response to nutrient intake
eg GLP-1 (glucagon like peptide)
GLP-1:
promotes satiety and reduces appetite
slows rate of gastric emptying
reduces hepatic glucose output
enhances glucose dependent insulin secretion
suppresses post-prandial glucagon secretion
hgalf life 1-2mins
DDP-IV breaks down GLP-1
DDP-IV inhibitors - sitagliptin
inhibit DDP-IV and prolong half life of GLP-1
\+ oral no hypo's well tolerated some licensed in renal impairment
-
expensive
unknown long term effects
GLP-1 mimetics - exanetide
resistant to DDP-IV
enhanced incretin effects
+
no hypo
weight loss
-
sub cut injection
N&V
expensive
stepped approach
- lifestyle
- monotherapy - add metformin
- dual therapy - add sulfonylurea
- triple therapy - add on agent (GLP-1 enhancer/SGLT2 inhibitor)
- insulin, if not already used
statins
act directly by:
decreasing cholesterol biosynthesis
increasing uptake of cholesterol from the circulation into the liver
possibly indirectly by: improving endothelial function reducing inflammation plaque stabilisation inhibiting thrombus formation
statin side effects
hepatic: deranged LFTs, liver injury
myalgia and myositis - elevated CK levels
minor: rash, GI upset, sleep disturbance, aches and pains
v small increased risk of DM in non diabetic population
peripheral neuropathy
statin interaction
P450 metabolism (CYP3A4)
CYP3A4 inhibitors include:
ciclosporin, clarithromycin, erythromycin, grapefruit juice
Fibrates
peroxisome proliferator activated receptor alpha (PPARa) activators
reduces VLDL & LDL while increasing HDL
ezetimibe
NPC1L1 inhibition - reduces transport of cholesterol from intestinal lumen
as secondary prevention, reduces in CVD in combination with statins
