T2 Diabetes mellitus & drug treatments Flashcards
Define T2DM
Biochemical results?
Condition of insulin resistance and beta cells cannot produce enough insulin to keep b/g normal
- Deficit in B cells/ increased b-cell apoptosis/ extracellular anyloid deposits derived from LADP
Glucuse ≥ 11.1 mmol/L + symptoms
Glucuse ≥ 11.1 mmol/L x2
HbA1c ≥ 48 mmol/mol (6.5%)
How would you diagnose T2DM if unsure (or in pregnant ladies)?
- 75g glucose tolerance test
DM if : fasting plasma glucose ≥ 7mmol/L; 2 hour plasma glucose ≥ 11/1 mmol/L - Impaired glucose tolerance
- 2 hour glucose 7-11 mmol/L - Impaired fasting glucose
- Fasting glucose between 6.6-9 mmol/L
- Excess fat in diabetic pancreas (as fat decreases, B cell function increases)
- Waist circumeference?
Consider the aetiology of T2DM
What could cause it
- Genetics contributing to reduced beta cell mass
- seen in high percentage of indentical co-twins
- polygenic
- fetal programming (epigenitic) - maternal hyperglycaemia, intrauterine growth retardation - B cell regression
- Old age
- Other pancreatic pathology
- Change in the gut microbiota
- Glucotoxicity and lipotoxicity
Which organs are disturbed due to the decrease in incretin?
Glucotoxicity and lipotoxicity leading to:
B cell in pancreas –> Insulin –> Fat, liver, muscle
Explain the link between epicardial fat and vascular disease
STRONG RISK FACTOR
- FFAs: atherogenic lipids, insulin resistance
- Cytokines: insulin resistance, inflammation
- Procoagulant factors (PAI1)
Discuss the epidemiology of T2DM
4.6 million plus a futhr 1.23 million at high risk
Related to obesity (which has increased in UK)- coprevalence is 70% of those ≥ 45
- Age group most likely to be obese 55-64 (however increasing in younger people)
What advice is given by healthcare professionals?
What are the side effects/ morbidity related to?
Keep a BMI<23, exercise, healthy diet
- Hyperglycaemia
- damages organs and nerves (cataracts )
- 1% decrease in HBA1c decreases cataracts risk by 19% - Dysregulation of lipid metabolism (bad for vaascular system)
- Maculopathy - Increased levels of proinflammatory cytokines
- Increased levels of free radicals
- Increased susceptibility to infection
** Can lead to haemodialysis for chronic renal failure
What is a neuropathic ulcer?
Nerve damage due to diabetes causes altered or complete loss of feeling in the foot and/or leg. This is known as peripheral neuropathy. Pressure from shoes, cuts, bruises, or any injury to the foot may go unnoticed. The loss of protective sensation stops the patient from being warned that the skin is being injured and may result in skin loss, blisters and ulcers.
Adverse side effects of T2DM
- Glycosylation of connective tissue e.g. Cheiroarthropathy
BONE
- mechanically weaker, doubles risk of farcture (in spite of normal bone density)
Neuropathis ulcer
State 4 consequences of dyslipidaemia and pro-inflammatory state
- CAD
- Lipoprotein classes and inflammation
- Atherosclerotic lesions
- Peripheral vascular disease
What lifestyle changes can be adopted to treat T2DM?
How can prevention and screening help?
Medications?
Diet, exercise, smoking cessation
Screen for complications and treat early
- Retinal photography –> laser treatment
- Measure kidney albumin (EMV), control BP, ACE inhibitors
- Screen for neuropathy and vascular disease
Reduces CV risk factors
Statins for hypertension caused by hyperglycaemia.
Biochemical goal of treatment?
LDL <2 mmol/; non- HDL chol <2.78
BP: 120-140/80
HbA1c 6.5-7.5% (48-58 mmol/mol)
- Must be indivually tailored: Strict adherance to guidelines for pregnant women and be cautious that giving elderly people ‘hypos’ –> falling
Outline the effects of insulin on
- hepatocytes
- myocytes
- adipocytes
- Decreased gluconeogenesis, glycogenolysis and ketogenesis
- Increased GLUT-4 translocation to membrane, glucose oxidation, glycogen synthesis, AA uptake, protein synthesis
- Decreased glycogenolysis, AA release - Increased glucose uptake, increased TG synthesis, decreased FFA’s and glycerol release
**NET EFFECT IS TO CAUSE HYPOGLYCAEMIA AND INCREASE FUEL STORAGE IN MUSCLE, FAT TISSUE AND LIVER
What can cause hyperglycaemia and which drug classification may exploit these mechanisms as therapetic sites?
- B- cell dysfunction
- Sulfunylureas, GLP-1 analogues, DDP-4 inhibitors - Loss of B-cell mass
- Insulin replacement - Diet/exercise
- Renal glucose absorption
- SGLT2 inhibitors - Peripheral insulin resistance
- Metformin, TZDs
CONSIDER THERAPUTIC TREATMENTS FOR T2DM
Sulfonylureas
- Examples?
- Route of administeration?
- Mechanism of action?
- Indication?
Gluclazide, glipizide, glimipinde
Orally active
Plasma protein bound
Cause the release of endogenous insulin in abscence of glucose by binding to ATP-sensitive K+ Channel (mimmicks effect of ATP)
Secondary MOA: Sensitize B-cells to glucose, decrease lipolysis, decreases clearance of insulin by the liver
Useful only in T2 DM
- Ideal patient (40+, DM for <10y, dailu insulin <40 units)
- Can be used in combination with other anti-diabetic drugs
CONSIDER THERAPUTIC TREATMENTS FOR T2DM
Biguanides
- Examples?
- Route of administeration?
- Mechanism of action?
- Excretion?
- Other indications?
Metformin (often coformulated with other anti-diabetic drugs)
Oral antihyperglycaemic agent
Doesnt bind plasma proteins (once had its effects, it doesnt need to remain in the blood)
Doesn’t stimulate insulin release and therefore doesnt cause hypoglycaemia
- Increases glucose uptake in muscle
- Decreased gluconeogenesis by liver through AMP-activated PK (AMPK) dependent and independent pathways
( AMPK increases expression of the nuclear transcription factor SHP, which in turn INHIBITS the expression of hepatic gluconeogenic genes PEPCK and G6Patase)
- Excreted unchanged in urine (1/2 life 1.5-4.5 hours)
- Polycystic ovary syndrome
CONSIDER THERAPUTIC TREATMENTS FOR T2DM
State the metabolic changes induced by metformin
- Increases insulin sensitivity
- Enhanced peripheral glucoses uptake (Glut 4 translocation through AMPK)
- Heart metabolic changes by p38 MAPCK and PKC-dependent mechanism and independent og AMPK
- Increased FA oxidation via low decreased insulin-induced suppression of FA oxidation
- Decreased glucose absorption from GI tract (causes GI disturbances- minor effect)
CONSIDER THERAPUTIC TREATMENTS FOR T2DM
What are side effects of metformin?
Contraindications?
- Lactic acidaemia (RARE), although frequent in those with kidney impairment
- Nausea, abdo discomfort, diarrhoea, metallic taste, anorexia
- Vit-B12 and folate malabosorption (not that bad as folate fortified foods)
- MI or septicaemia –> IMMEDIATELY STOP
Hepatic disease, PMHx of lactic acidosis, HF, Chronic hypoxic lung disease (causes metabolic acidosis)
CONSIDER THERAPUTIC TREATMENTS FOR T2DM
Thiazolidinediones
- Examples?
- Mechanism of action?
- Effects?
Pioglitazone
Activates peroxisome proliferatory - activated receptor y (PPARy) which is involved in transcription of insulin-response genes and regulation of adipocytes lipid metabolism
! Only works in the presence of insulin (either endogenous or exogenous) In absence of insulin, may be used in combination with other Anti-D drugs
- Decreases gluconeogenesis, glucose output and TG production in liver
- Increases glucose uptake and utilisation in skeletal m
- Increases glucose uptake and decreased FA output in adipose tissue ; also causes differentiation of adipocytes
CONSIDER THERAPUTIC TREATMENTS FOR T2DM
How is Pioglitazone (Thizolidinedione) taken and metabolised?
Side effects?
Taken 1/2x/day
- Plasma levels peak at 3 hours, 1/2 life= 3-7 hours
- Liver metabolised and excreted (2/3) and urine (1/3)
- Fluid retention (promotes amiloride- sensitive Na+ reabsorption in renal CD –> OEDEMA, mild anaemia)
- Dose related weight gain
- Safety in pregnancy/lactation?
- Liver damage
- Interaction with other drugs? May decrease efficacy of contraceptive drugs
CONSIDER THERAPUTIC TREATMENTS FOR T2DM
Glucagon-like peptide-1 ANALOGS
- Examples?
- Route of administeration?
- State 5 ways in which it facilitates glucose control
Exenatide
Administered IV 30-60 minutes before last meal of the day –> high plasma concentration
- Augmenting pancreatic response
- Suppressing 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
CONSIDER THERAPUTIC TREATMENTS FOR T2DM
Glucagon-like peptide-1 ANALOGS
Interactions with other drugs?
Side effects?
Used in adjuvant therapy for T2DM on metformin, thiazolidinediones, or a combination of these drugs who have not been able to achieve adequate control of b/g
Side effects: Mainly GI (acid/sour stomach, belching, diarrhoea, heartburn)
CONSIDER THERAPUTIC TREATMENTS FOR T2DM
Glucagon-like peptide-1 ANALOGS
How does GLP-1 compar to Exanatide (analog)?
GLP-1
- increases glucose dependent insulin secretion
- decreases glucagon secretion and hepatic glucose output
- regulates gastric emptying reducing rate of nutrient absorption
- reduces food intake
- reduces plasma glucose actutely (to normal)
- it is NOT resistant to DPP-VI degradation –> short duration in plasma
Exanaride is resistant to DPP-IV degradation
It also has a long duration in plasma following sc injection
CONSIDER THERAPUTIC TREATMENTS FOR T2DM
(DPP-4) Inhibitors
- Examples?
- Route of administeration?
- Mechanism of action?
- Side effects?
Vildagliptin (reversible), Sitagliptin (reversible), saxagliptin (covantly bound)
Oral hypoglycaemic agen
(Modestly) Increases levels of incretins GLP-1 and GIP
- increases glucagon release
- increases glucose-induced insulin secretion
- decreases gastric emptying
- decreases hepatic glucose production
- increases peripheral glucose utilisation
Few side effects, neutral weight, no GI symptoms. Cancer risk? (DPP-IV enzyme involved in tumour suppression)
CONSIDER THERAPUTIC TREATMENTS FOR T2DM
SGLT Protein inhibitors
- Which SGLT are preferentially targerted? Why?
- Mechanism of action?
- Side effects?
Dapagliflozin, Canagliflozin
SGLT2 (responsible for 90% of glucose reabosorption)
- Higher capacity, low affinity at proximal CT
SGLT1 (at d.LoH)- Low capacity, higher affinity
Inhibition of renal tubule Na+ glucose cotransporter –> reversal of hyperglycaemia –> reversal of “glucotoxicity”
- Increased insulin sensitivity in muscle (GLUT4 translocation and insulin signalling);
- and in liver (reduced G6Patase)–> reduced gluconeogenesis (decreased Cori cycle and PEP carboxykinase)
- Increases b-cell function
Rapid weight loss, tirednessm osmotic diuretic –> dehydration (ask patient to drink more)
CAN WORSEN UTI AND THRUSH (peeing glucose, yum)
