14. Drug treatment of type 2 diabetes Flashcards
Insulin action
Affects all major metabolic pathways - carbohydrate, fat, protein
Major target tissues are liver, adipose and skeletal muscle
Insulin effects on hepatic cells
decreases gluconeogenesis, glycogenolysis, ketogenesis, (increases glycogen synthesis)
insulin effects 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
insulin effects on adipocytes
increase glucose uptake, increase triglyceride synthesis; decrease FFA and glycerol release
Net effect of insulin
causes hypoglycemia and increase fuel storage in muscle, fat tissue and liver
Treatments
Diet, exercise, treatments for obesity and dyslipidaemia
Metformin and TZDs for insulin resistance
SGLT-2 inhibitors to block renal glucose absorption
GLP-1 analogues and DDP-4 inhibitors for beta-cell dysfunction
insulin replacement for loss of beta-cell mass
Describe sulfonylureas
E.g. gliclazide, glipizide, glimepiride
All orally active
All bound to plasma protein (90-99%)
Cause release of insulin
Pharmacodynamics of sulfonylureas
Primary mechanism of action • stimulates endogenous insulin release • binding site on ATP-sensitive K-channel to inhibiting the opening of the channel similar to ATP Secondary mechanisms of actions Evidence these drugs : • Sensitize ß-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
Major side effect: Hypoglycaemia
What is the golden standard drug for type 2 diabetes?
Metformin
How are biguanides different from sulfonylureas?
Differ from sulfonylureas 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.
What is the primary mechanism of action of biguanide drugs (metformin)?
AMPK part of second messenger system of insulin. Metformin is bypassing insulin by activating AMPK directly or bypassing AMPK-independent insulin pathways in hepatocytes.
AMPK then increases expression of SHP, a nuclear transcription factor, which then turns off expression of PEPCK and G6Pase involved in hepatic gluconeogenesis
How does metformin enhance peripheral glucose uptake?
Increased GLUT 4 translocation through AMPK
Heart muscle metabolic changes by p38 MAPCK and PKC-dependent mechanisms and independent of AMPK
What are some other non-primary mechanisms of metformin?
Increases insulin sensitivity
(Possibly through improved insulin binding to insulin receptors)
Enhances peripheral glucose uptake
Increases fatty acid oxidation via decreasing insulin-induced suppression of fatty acid oxidation
Decreases glucose absorption from GI tract (minor)
What are the 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)
Contraindications for metformin
hepatic disease past history of lactic acidosis (any cause) cardiac failure chronic hypoxic lung disease causes metabolic acidosis
Describe thiazolidinediones
Troglitazone was first ‘glitazone’ approved for use in NIDDM; off the market now due to hepatic failures.
Rosiglitazone now off the market due to CVS damage
Pioglitazone now only one remaining approved
Activate peroxisome proliferator-activated receptor-g (PPARg)
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-diabetic medications
Adverse reactions and drug interactions of glitazone
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
- do not cause lactic acidosis, even in patients with renal impairment
- Liver damage may require regular blood tests
Pioglitazone subject to interactions due to liver metabolism.
-may lower oral contraceptives levels containing ethinyl estradiol and norethindrone
Effects/characteristics of GLP-1
Increase glucose-dependent insulin secretion
Decrease glucagon secretion and hepatic glucose output
Regulates gastric emptying
Decreases rate of nutrient absorption
Decrease food intake
Decrease plasma glucose acutely to near-normal levels
Not resistant to DPP-IV degradation
Short duration in plasma
Give an example of GLP-1 and when is it administered?
Exenatide for example administered s.c. injection 30 to 60 mins before last meal of day
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
How does exanatide facilitate glucose control?
Facilitates glucose control by;
- 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
What are the side effects of exanetide?
Side effects are mainly gastrointestinal in nature including acid or sour stomach, belching, diarrhea, heartburn etc.
Describe exanatide
High plasma concentration
Strong effects on receptors
Injectables only (so far)
New oral formulation in clinical trials-neutralizes the acid in local area protecting against breakdown while also enhancing absorption
Describe Dipeptidyl peptidase-4 (DPP-4) inhibitors
Class of oral hypoglycemic agents
Mechanism of action is via increased levels of Incretins GLP-1 and GIP
Drugs in this class include vildagliptin (reversible), sitagliptin (reversible) and saxagliptin (covalently bound)
What is the effect of increased incretins?
Increased Incretins:
- Inhibit glucagon release
- Increase glucose-induced insulin secretion
- Decrease gastric emptying
- Reduce hepatic glucose production
- Improved peripheral glucose utilisation
DDP IV inhibitors
Orally active
Few side effects
Modest elevations of incretins
Weight neutral no gastrointestinal side effects
Cancer risk?
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
Describe SGLTs
SGLT1 found in small intestine (to absorb glucose) and proximal straight tubule of the nephron
SGLT2 found in proximal convoluted tubule
100% of glucose has to be reabsorbed along the nephron, 90% by SGLT2.
Therefore blocking this transporter causes blood glucose to be eliminated through the kidney
SGLT2 inhibitors
Dapagliflozin-approved for use in Europe April 2012
IC50 for SGLT2 is less than 1/1000 of the IC50 for SGLT1
Canagliflozin-approved by FDA 10th January 2013 to treat Type 2 diabetes in adults
Effects of SGLT2 inhibitors
inhibition of renal tubular Na+-glucose cotransporters
This reverses hyperglycaemia
This reverses glucotoxicity
Increased insulin sensitivity in muscle results in increased GLUT4 translocation and increased insulin signalling
increased insulin sensitivty in liver due to decreased G6P
Decreased gluconeogenesis by decreasing Cori cycle and decreased PEP carboxykinase
Improved 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
