14. Drug Treatment of Type 2 Diabetes

Question 1

insulin action

Answer 1

affects all major metabolic pathways

major target tissues: liver, adipose, skeletal muscle

Question 2

insulin effects in hepatic cells

Answer 2

decreases gluconeogenesis
decreases glycogenolysis
decreases ketogenesis
increases glycogen synthesis

Question 3

insulin effects in muscle cells

Answer 3

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

Question 4

insulin effects in adipocytes

Answer 4

increases glucose uptake
increases triglyceride synthesis
decreases free fatty acids and glycerol release

Question 5

treatment for type 2 diabetes

Answer 5

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

Question 6

sulfonylureas

Answer 6

gliclazide, gliplizide, glimepiride
orally active
bound to plasma protein (90-99%)

Question 7

sulfonylureas primary mechanism of action

Answer 7

stimulates endogenous insulin release
binding site on ATP sensitive K+ channel
inhibits opening of channel, similar to ATP

Question 8

sulfonylureas secondary mechanisms of action

Answer 8

sensitises beta cells to glucose
decrease lipolysis
decrease clearance of insulin by liver

Question 9

sulfonylurea therapeutic uses

Answer 9

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

Question 10

biguanides

Answer 10

metformin
oral anti hyperglycaemic agent
do not stimulate insulin release
appear to increase glucose uptake in muscle and decrease glucose production by the liver

Question 11

metformin mechanism of action

Answer 11

suppression of hepatic glucose production through gluconeogenesis
through AMP-activated protein kinase (AMPK) dependent and independent pathways

Question 12

what effect does AMPK have?

Answer 12

increases expression of nuclear transcription factor SHP

inhibits expression of hepatic gluconeogenic genes (glucose-6-phosphatase, PEPCK)

Question 13

metformin effects

Answer 13

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

Question 14

properties of metformin

Answer 14

orally active 
does not bind to plasma proteins
excreted in urine 
often combined with other anti-diabetic medications 
also used for PCOS

Question 15

metformin adverse effects and toxicity

Answer 15

lactic acidaemia (rarely)
nausea, abdo discomfort, diarrhoea, metallic taste, anorexia
decreased B12 and folate in chronic use
MI/septicaemia - stop immediately

Question 16

metformin contraindications

Answer 16

hepatic disease
past history of lactic academia
cardiac failure
chronic hypoxic lung disease

Question 17

thiazolidinediones

Answer 17

glitazones - pioglitazone
activate peroxisome proliferator-activated receptor-gamma (PPAR-gamma)
involved in transcription of insulin-responsive genes and in regulation of adipocyte lipid metabolism

Question 18

pioglitazone pharmacodynamics

Answer 18

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

Question 19

pioglitazone adverse effects and drug interactions

Answer 19

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

Question 20

glucagon-like peptide 1 analogs (GLP-1 analogs)

Answer 20

essentially a synthetic incretin

increases insulin secretion when glucose is absorbed in GI (as opposed to injection)

Question 21

how do GLP-1 analogs work?

Answer 21

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

Question 22

exenatide

Answer 22

strong effects on receptors
high plasma concentration
given iv
GLP-1 analog

Question 23

GLP-1 analogs side effects

Answer 23

mainly GI
acid/sour stomach 
belching 
diarrhoea
heartburn

Question 24

dipeptidyl peptidase-4 (DPP-4) inhibitors

Answer 24

oral hypoglycaemic agents
increase levels of incretins GLP-1 and GIP
vildagliptin, sitagliptin

Question 25

what is the effect on increase incretins?

Answer 25

inhibit glucagon release
increase glucose-induced insulin secretion
decrease gastric emptying
reduce hepatic glucose production

Question 26

DPP-4 inhibitors effects

Answer 26

few side effects
modest elevations of incretins
weight neutral
orally active

Question 27

sodium-glucose transporter (SGLT) proteins

Answer 27

SGLT1 found in small intestine and proximal straight tubule of nephron
SGLT2 found in proximal convoluted tubule - 90% glucose reabsorption

Question 28

SGLT2 inhibitors

Answer 28

cause blood glucose to be eliminated through the kidney

dapagliflozin, canagliflozin

Question 29

SGLT 2 inhibitors effects

Answer 29

increase insulin sensitivity in muscle (more GLUT4 translocation, insulin signalling)
increased insulin sensitivity in liver
decreased gluconeogenesis
improved beta cell function

Question 30

SGLT2 inhibitors side effects

Answer 30

rapid weight loss
tiredness
osmotic diuretic - dehydration
can worsen urinary tract infections/thrush