L14 - Drug treatment of type 2 diabetes Flashcards
Major target tissues of insulin
- Liver, adipose and skeletal muscle
Effect of insulin on hepatic cells
- Decreases gluconeogenesis, glycogenolysis, ketogenesis, (increases glycogen synthesis)
Effect of insulin on muscle cells
- Increases GLUT-4 translocation to the membrane and hence increase glucose uptake, glucose oxidation, glycogen synthesis, amino acid uptake, protein synthesis
- Decreases glycogenolysis, amino acid release
Effect of insulin on adipocytes
- Increase glucose uptake, increase triglyceride synthesis; decrease FFA and glycerol release
Net effects of insulin
- Cause hypoglycemia and increase fuel storage in muscle, fat tissue and liver
Drugs used to treat insulin resistance
- Metformin
- Thiazolidinediones
Class of drugs used to reduce renal glucose absorption in hyperglycaemia
- SGLT-2 inhibitors
Treatment for loss of beta-cell mass in diabetes
- Insulin replacement therapy
Drugs used to treat beta-cell dysfunction in diabetes
- Sulphonylureas
- GLP-1 analogues
- DDP-4 inhibitors
Examples of sulfonylureas
- Gliclazide, glipizide, glimepiride
Features of sulfonylureas
- All orally active
- All bound to plasma protein (90-99%)
Primary mechanism of action - sulfonylureas
- Stimulates endogenous insulin release
- Sulfonylureas bind to and close ATP-sensitive K+ (KATP) channels on the cell membrane of pancreatic beta cells, which depolarizes the cell by preventing potassium from exiting. This depolarization opens voltage-gated Ca2+ channels.
- The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of mature insulin
Secondary mechanisms of actions - sulfonylureas
- Sensitise beta-cells to glucose
- Decrease lipolysis
- Decrease clearance of insulin by the liver
Therapeutic uses of sulfonylureas
Useful in type-2 DM only
• best patient is
○ over 40 yrs. old
○ DM duration less than 10 yrs.
○ daily insulin (if taking) less than 40 units
• can be used in combination with other anti-diabetic drugs
What is a major side effect of sulfonylureas
- Hypoglycaemia
How do biguanide drugs(oral antihyperglycemic agents) differ from sulfonylureas and meglitinides
- Differ from sulfonylureas and meglitinides both chemically and in mechanism of action
- biguanides do not stimulate insulin release or cause hypoglycemia
- biguanides appear to increase glucose uptake in muscle and decrease glucose production by liver.
Biguanide drugs - mechanism of action
- Suppression of hepatic glucose production through gluconeogenesis through AMP-activated protein kinase (AMPK) dependent and independent pathways
- AMPK increases expression of the nuclear transcription factor SHP which in turn inhibits the expression of hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase
Effect of biguanide drugs on insulin sensitivity
- Increases insulin sensitivity
- Possibly through improved insulin binding to insulin receptors
Effect of biguanide drugs on peripheral glucose uptake
Enhances peripheral glucose uptake
- Increased GLUT 4 translocation through AMPK
- Heart muscle metabolic changes by p38 MAPCK and PKC-dependent mechanisms and independent of AMPK
Effect of biguanide drugs on fatty acid oxidation
- 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 plasma proteins
- excreted unchanged in urine
- half-life 1.3 - 4.5 h
- often combined in a single pill with other anti-diabetic medications
- also used for polycystic ovary syndrome
Adverse effects and toxicity of biguanides
- metformin produces lactic acidemia only rarely
- more frequent in patients with renal impairment
- nausea, abdominal discomfort, diarrhea, metallic taste, anorexia more common
- vitamin B12 and folate absorption decreased with chronic metformin
- myocardial infarction or septicemia mandate immediate stoppage (associated renal dysfunction)
Metformin contraindications
- hepatic disease
- past history of lactic acidosis (any cause)
- cardiac failure
- chronic hypoxic lung disease
- causes metabolic acidosis
First ‘glitazone’(thiazolidinediones) to be approved
- Troglitazone was first ‘glitazone’ approved for use in NIDDM; off the market now due to hepatic failures
Why is rosiglitazone (a glitazone) off the market
- Due to CVS damage
What is the only remaining approved glitazone
- Pioglitazone
Mechanism of action - glitazones
- Activate peroxisome proliferator-activated receptor-gamma (PPARgamma)
- PPARs involved in transcription of insulin-responsive genes and in regulation of adipocyte lipid metabolism
Glitazone pharmacodynamics
In presence of endogenous or exogenous insulin glitazones will:
- Decrease gluconeogenesis, glucose output, and triglyceride production in liver
- Increase glucose uptake and utilization in skeletal muscle
- Increase glucose uptake and decrease fatty acid output in adipose tissue
- Cause differentiation of adipocytes
(monotherapy or with other anti-diabeic medications)
Glitazone pharmacokinetics
- Pioglitazone - taken once or twice a day orally
- Plasma levels peak about 3 hr
- Plasma half-life is 3-7 hr; active metabolites(t1/2 = 16-24 h)
- Liver metabolism and excreted in feces (2/3) and urine (1/3)
Adverse effects and drug interactions - glitazones
- fluid retention (promotes amiloride-sensitive sodium ion reabsorption in renal collecting ducts) causing, edema, mild anemia
- dose-related weight gain
- safety in pregnancy and lactation not determined
- Liver damage may require regular blood tests
- Pioglitazone subject to interactions due to liver metabolism.
Can glitazones cause lactic acidosis
- Do not cause lactic acidosis, even in patients with renal impairment
Effect of glitazones on oral contraceptives
- May lower oral contraceptive levels containing ethinyl estradiol and norethindrone
What are incretins
Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood glucose-dependent mechanism.
Effect of incretins on glucagon release
Incretins also inhibit glucagon release from the alpha cells of the islets of Langerhans.
In addition, they slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake
Effects of glucagon-like peptide-1 analogs
- Increases glucose-dependent insulin secretion
- Decreases glucagon secretion and hepatic glucose output
- Regulates gastric emptying and decreases rate of nutrient absorption
- Decreases food intake
- Decreases plasma glucose acutely to near-normal levels
Duration of glucagon-like peptide-1 analogs in plasma
- Short
What is an example of a glucagon-like peptide-1 analog
- Exenatide
How is exenatide administered
- Administered s.c injection 30 to 60 mins before last meal of the day
How does exenatide facilitate glucose control
○ Augmenting pancreas response
○ Suppresses pancreatic release of glucagon helping stop the liver overproducing glucose
○ Slows down gastric emptying
○ Reduces appetite and promote satiety via hypothalamic receptors
○ Reduces liver fat content
Can exenatide be given in combination with other drugs
• Adjuvant therapy for type II diabetic on metformin, a sulfonylurea, thiazolidinediones, or a combination of these drugs who have not been able to achieve adequate control of blood glucose
Side effects of exenatide
• Side effects are mainly gastrointestinal in nature including acid or sour stomach, belching, diarrhea, heartburn etc.
Differences in the effects of exenatide and GLP-1
- GLP-1 is not resistant to DPP-IV degradation but exenatide is
- GLP-1 has a short duration but exenatide has a long duration
Features of exenatide
- High plasma concentration
- Strong effects on receptors
- Injectables only(so far)
- New oral formulation in clinical trials-neutralises the acid in local area protecting against breakdown while also enhancing absorption
What are dipeptidyl peptidase-4 (DPP-4) inhibitors
- Class of oral hypoglycemic agents
Mechanism of dipeptidyl peptidase-4 (DPP-4) inhibitors
- Mechanism of action is via increased levels of incretins GLP-1 and gip
Effects of increased incretins
- Inhibit glucagon release
- Increase glucose-induced insulin secretion
- Decrease gastric emptying
- Reduce hepatic glucose production
- Improved peripheral glucose utilisation
Examples of dipeptidyl peptidase-4 (DPP-4) inhibitors
- Vildagliptin (reversible)
- Sitagliptin (reversible)
- Saxagliptin (covalently bound)
Features of DPP IV inhibitors
- orally active
- Few side effects
- Modest elevations of incretins
- Weight neutral no gastrointestinal side effects
Link between DPP-IV and cancer
- DPP-IV enzyme known to be involved in suppression of certain malignancies as it functions as a tumor suppressor
- Not yet seen with drugs in long-term preclinical studies
Transporters responsible for reabsorption of glucose in a nephron
- 90% of glucose reabsorbed by SGLT-2
- 10% of glucose reabsorbed by SGLT-1
Where are SGLT1 proteins found
• SGLT1 found in small intestine (to absorb glucose) and proximal straight tubule of the nephron
Where re SGLT2 proteins found
- PCT
Effect of blocking SGLT2 proteins
- Causes blood glucose to be eliminated through the kidney
Examples of SGLT2 inhibitors
- Dapagliflozin
* Canagliflozin
Effects of SGLT2 inhibitors
Inhibition of renal tubular Na+ glucose cotransporter –> reversal of hyperglycemia –> reversal of ‘glucotoxicity’
Specific effect of SGLT2 inhibitors on insulin sensitivity in muscle
- Increases insulin sensitivity in muscle
- Increases GLUT4 translocation
- Increases insulin signalling
Specific effect of SGLT2 inhibitors on insulin sensitivity in liver
- Increases sensitivity in liver
- Decreases glucose-6-phosphatase
Specific effect of SGLT2 inhibitors on gluconeogenesis
- Decreases rate of gluconeogenesis
- Decreased cori cycle
- Decreases PEP carboxykinase activity
Specific effect of SGLT2 inhibitors on beta cell function
- Improves beta cell function
Side effects of SGLT2 inhibitors
- Rapid weight loss (due to glycosuria (up to 70 g/day)
- Tiredness
- Osmotic diuretic so dehydration
- Can worsen urinary tract infections and thrush
