Type 2 DM Flashcards
1
Q
What is Diabetes Mellitus?
- meaning and
- diagnostic terms
A
- a condition where the blood glucose is above an internationally accepted levels
- Usual Clinical diagnosis of blood-
- Glucose: = or > 11.1mmol/l + symptoms
- Glucose = or > 11.1 mmol/l x 2
- HbA1c = or > 48mmol/mol (6.5%)
- this is Glycohaemoglobin or glycated haemoglobin: a measure of how well-controlled haemoglobin is in the long terms (over a 3 month period). normal levels should be below 5%
2
Q
Explain the Glucose Tolerance test
A
- 75 g Glucose Tolerance test
- Diabetes Mellitus indicated when
- Fasting plasma glucose = / > 7 mmol/l
- 2 hour plasma glucose = / > 11.1 mmol/l
- Impaired Glucose Tolerance indicated when
- 2-hour glucose between 7 -11 mmol/l
- Impaired Fasting Glucose indicated when
- Fasting glucose between 6 – 6.9 mmol/l
- Diabetes Mellitus indicated when
3
Q
What is Type 2 Diabetes Mellitus from a physiological perspective?
A
- insulin resistance +
- abnormal beta-cells
which cannot produce enough insulin to keep the blood glucose normal
4
Q
What damages the Islet cell in T2DM?
A
- Islet amylin polypeptide polymers secreted from pancreatic islet beta-cells and converted to amyloid deposits
- seen as green staining in histological samples of T2DM Islet cells
- there is a deficit in Beta-cells
- increased beta-cell apoptosis
- therefore less insulin is produced
5
Q
What are some aetiological causes of Type 2 diabetes?
A
- Genetic
- polygenic
- Sox5 regulates beta-cell phenotype and is reduced in T2DM
- Fetal Programming (epigenetic)
- maternal hyperglycaemia
- Intrauterine growth retardation
- Old age
- Change in gut microbiota
- Glucotoxity and Lipotoxicity
- later effects
6
Q
What fat is associated with T2DM?
A
- Visceral Fat
- Epicardial Fat
- a strong risk for vascular disease
- Excess fat in the pancreas
- this is specific to T2DM & is important in preventing normal insulin production
- Ectopic Fat
7
Q
What is Ectopic Fat, its effect?
A
And endocrine organ producing
- Free fatty acids
- causing insulin resistance
- these are atherogenic lipids
- Cytokines
- causing insulin resistance
- Inflammation
- Procoagulant factors (PAI1)
8
Q
What are the side effects/ morbidities that accompany T2DM?
A
- Hyperglycaemia
- Dysregulation of lipid metabolism
- high levels of proinflammatory cytokines
- high levels of free radicals
- increased susceptibility to infection
9
Q
What is the pathogenesis of retinopathies?
A
induced by the following
- impaired autoregulation of retinal blood flow
- maintaining constant blood flow within the relative range is impaired in hyperglycaemia
- results in increased retinal blood flow –> shear stress in blood vessels
- causing increased vascular leakage and the production of vasoactive substances
- accumulation of sorbitol within the retinal cells
- glucose – (aldose reductase)–> sorbitol
- consumption of NADPH in the process of NADPH can result in oxidative stress
- sorbitol accumulation –> alterations in the activity of pkC
- Protein Kinase C may regulate vascular endothelial growth and regulate vascular permeability
- accumulation of advanced glycosylation end products (AGEs) in the extracellular fluid
- AGEs may cross-link with collagen and initiate microvascular complications
- interaction between AGEs and their receptor RAGE may generate new ROS and cause vascular inflammation
10
Q
Cataracts in T2DM
A
- caused by increased generation of polyols from glucose
- the AR pathway is the initiating factor in diabetic cataract formation
- leads o osmotic stress in the ens –> apoptosis + increased ROS
- 1% reduction in HBA1c reduces cataract risk by 19%
11
Q
the pathological evolution of Diabetic Nephropathy
A
- Within the first years after the onset of diabetes
- glomerular hyperperfusion
- increased glomerular filtration
- renal hypertrophy
- Microalbuminuria (30-300mg per day) of albumin in the urine
- predictor of progression of proteinuria –> decline of GFR
- patients are at an increased risk of end-stage renal disease and premature CVD
- predictor of progression of proteinuria –> decline of GFR
- Hyperglycemia results in increased ROS and AGEs
12
Q
Explain the pathogenesis of diabetic neuropathy
- Metabolic and Vascular risk factors
A
Metabolic and Vascular risk factors contribute to the pathogenesis of diabetic neuropathy
-
Metabolic risk factors
- Advanced Glycosylation End-products (AGEs): advanced glycosylation of essential nerve proteins is implicated in this pathology
- Sorbitol: accumulation of intracellular sorbitol –> increased cell osmolality, decreased intracellular myoinositol and Na-K-ATPase activity, and slowing in nerve conduction velocity
- Oxidative stress__: hyperglycemia –> accumulation and stabilization of ROS which damages peripheral nerves
-
Vascular risk factors
- potentially associated with CVD risk factors i.e increased triglyceride, increased BMI, smoking, hypertension
- Thrombodium and tissue plasminogen activator levels are reduced in peripheral nerve microvessels from diabetic patients
13
Q
Treating/Preventing T2DM from a Lifestyle perspective
A
- Diet
- Eat well plate
- Mediterranian diet
- Excercise
- walking the dog (manageable to patient)
- Education
- education programmes e.g Desmond
- Quit smoking
14
Q
What medical treatments can be used to treat the following factors within T2DM?
- Dyslipidaemia
- Hypertension
A
- Dyslipidaemia
- statins
- Hypertension
- use of Aspirin
15
Q
What screens for T2DM complications are there?
- eyes
- kidneys
- feet
A
- Eyes
- Retinal Photography
- Laser treatment when required
- Kidneys
- Measure urine albumin ( EMU)
- Control Blood Pressure
- ACE inhibitors & ARBs
- Feet
- Screen for neuropathy & Vascular disease
16
Q
Clinical features need to be assessed in a diabetic foot?
A
- Neuropathy
- Ischemia
- Bony deformity
- Callus
- Swelling
- Skin integrity/breakdown
- between toes and under metatarsal heads
- Infection
- Necrosis
17
Q
What is the effect of Insulin in Hepatic cells?
A
- decrease gluconeogenesis
- decrease glycogenolysis
- decrease ketogenesis
- increases glycogen synthesis
18
Q
What is the effect of Insulin in muscle cells?
A
- increase GLUT-4 translocation to the membrane
- increase in glucose uptake
- increase in glucose oxidation
- increase in glycogen synthesis
- increases in amino acid uptake and protein synthesisis
- decrease in glycogenolysis, and amino acid release
19
Q
What is the effect of Insulin in adipocytes?
A
- increase glucose uptake
- increase triglyceride synthesis
- decrease lipolysis
20
Q
What are the various treatment options for T2DM?
- what do they specifically target
A
- Metformin and TZds
- for Insulin resistance
- SGLT-2 inhibitors
- Renal glucose absorption
- Insulin replacement
- loss of beta-cell mass
- Sulphonylureas | GLP-1 analogues | DDP-4 inhibitors
- beta-cell dysfunction
- Diet and exercise
- treats obesity and dyslipidaemia
overall treating hyperglycaemia
21
Q
When is Sulphonylureas indicated as a treatment for T2DM?
- examples
- mechanism
A
- patients who cannot tolerate metformin or ar not a candidate for it
- if metformin alone is not controlling the glycaemia
- shorting examples - Glipizide, Gliclazide, are preferred in elderly patients
Action
- bind to and inhibit the ATP dependant K+ channel in pancreatic beta cells
- causes depolarization of cell membrane
- Ca2+ influx –> stimulation of insulin secretion
- sensitizes B-cells to glucose, decreases lipolysis
- decreases clearance of insulin the liver
22
Q
What are the side-effects of Sulphonylureas?
A
- Hypoglycaemia
- more common with long-acting sulphonylureas
- glyburide, chlorpropamide
- more common with long-acting sulphonylureas
- most likely to happen after
- exercise or a missed meal
- high drug dose,
- malnourishment
- alcohol abuse
- impaired renal or cardiac function, GI disease
- concurrent treatment with salicylates, sulphonamides, fibrates or warfarin, after leaving hospital
23
Q
What is the action of Biguanide drugs in T2DM?
(metformin)
A
- they do not stimulate insulin release or cause hypoglycemia
- biguanides increase glucose uptake in muscle and decrease glucose production by the liver
- decrease hepatic liver production through AMP-activated protein kinase (AMPK) dependent and independent pathways
24
Q
Go over the mechanism of action of Biguanide drugs
A
- Suppression of hepatic glucose production through AMPK pathways
- AMPK increases expression of nuclear transcription factor SHP
- inhibits the expression of hepatic gluconeogenesis genes PEPCK and G-6-P
- Increases insulin sensitivity
- Possibly through improved insulin binding to insulin receptors
- Enhances peripheral glucose uptake
- Increased GLUT 4 translocation through AMPK
- Heart muscle metabolic changes via p38 MAPCK and PKC-dependent mechanisms and independent of AMPK
- Increases fatty acid oxidation via decreasing insulin-induced suppression of fatty acid oxidation
- Decreases glucose absorption from GI tract
25
What are the pharmacological properties of metformin?
* orally active
* doesn't bind to plasma proteins
* excreted unchanged in urine
* half-life 1.3-4.5h
26
What are the indications/ uses of Metformin?
* first line treatment for T2DM unless otherwise contraindicated
* dose gradually titrated until maximum effective dose reached
* combined with other anti-diabetic mediation in a single drug
* also used for polycystic ovary syndrome
27
What are the side-effects and contraindications of Metformin?
* GI side effects
* nausea, anorexia, abdominal discomfort, diarrhoea, metallic taste in the mouth
* Lactic acidosis (rare)
* more frequent in a patient with renal impairment also _contraindicated in those with_
* reduced tissue perfusion, infection,
* cardiac failure, chronic hypoxic lung disease
* liver disease, or alcohol abuse
* individuals with a past history of lactic acidosis
* vit B12 and folate absorption decreased with chronic metformin
an **MI** or **septicemia** mandate immediate stoppage
28
What is the mechanism of action of Thiazolidinediones?
* increases insulin sensitivity and the peripheral uptake and utilization of glucose in muscle and fat
* _bind to and activate PPARs which regulate gene expression and regulation of adipocyte lipid metabolism_
* Peroxisome proliferator-activated receptor-gamma
* may facilitate glucose transport in skeletal muscle
* may work in regulating the expression of adipose tissue adipokines
* may reduce hepatic glucose production and improve pancreatic beta-cell dysfunction
29
When are Thiazolidinediones (Glitazones) indicated?
* May be considered when sulphonylureas is contraindicated or when hypoglycaemia is particularly undesirable
* used when potentially aiming to reduce HbA1c levels
* *pioglitazone* may be added to metformin and/ or sulphonylureas in individuals without risk for heart failure or fracture
30
What are the pharmacokinetics of Glitazones (thiazolidinediones)?
* Pioglitazone: taken once or twice a day orally
* plasma levels peak about 3hr
* the plasma half-life is 3-7hr; active metabolites (16-24h)
* metabolised in the liver
* excreted in faeces (2/3) and urine (1/3)
31
What are the side effects of Glitazones?
- drug interactions/ contraindications
* cause fluid retention causing oedema and mild anaemia
* increase the risk of heart failure
* dose-related weight gain
* safety in pregnancy and lactation not determined
* increased incidence of fractures in females treated with *rosiglitazone*
* *Pioglitazone* has many drug interactions as it is metabolised in the liver
* may lower levels of oral contraceptive drugs containing Ethinyl estradiol and norethindrone
32
What is the effect of Glucagon-Like peptide (GLP-1) analogues
* increase glucose-dependent insulin secretion
* decrease glucagon secretion and hepatic glucose output
* regulates gastric emptying and decreases the rate of nutrient absorption
* decreases food intake
* decreases plasma glucose acutely to near normal levels
* has a short duration in plasma
33
Give an example of a GLP-1 and describe it's the mechanism of action
*Exanatide*
* administered s.c. injection 30 to 60 mins before last meal of day
* 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
* has a longer duration in plasma than actual GLP-1
34
What are the side effects of GLP-1 analogues?
* Mainly GI problems
* acid or sour stomach
* belching
* diarrhoea
* heartburn
35
What are Dipeptidyl peptidase-4 (DPP-4) inhibitors?
* Class of oral hypoglycemic agents
* Mechanism of action is via increased levels of Incretins GLP-1 and GIP
* Increased Incretins
* Inhibit glucagon release
* Increase glucose-induced insulin secretion
* Decrease gastric emptying
* Reduce hepatic glucose production
* Improved peripheral glucose utilisation
* Drugs in this class include *vildagliptin* (reversible), *sitagliptin* (reversible) and *saxagliptin* (covalently bound)
36
What are Sodium-glucose transport (SGLT) protein inhibitors?
- examples
* drugs that inhibit the reabsorption of glucose from the proximal convoluted tubule in the nephron
* SGLT-2 proteins transport glucose against a concentration gradient and the inhibitors blocks this process
* *Dapagliflozin*
* *Canagliflozin*
37
What are the effects of SGLT2 inhibitors?
reversal of hyperglycaemia by inhibitors Na+-Glu cotransporter --\> the reversal of glucotoxicity, so these effects are seen
* increases insulin sensitivity in muscle
* increased GLUT4 translocation
* increased insulin signalling
* Increased Insulin sensitivity in the liver
* decreased action of glucose-6-phosphatase
* Decreased Gluconeogenesis
* decreased Cori cycle
* decreased PEP carboxykinase
* Improved beta cell fuction
38
What are the side effects of SGLT2 Inhibitors?
* Rapid weight loss
* Tiredness
* Osmotic diuretic --\> dehydration
* _Can worsen urinary tract infections and thrush_
39
Review the available treatments for T2DM
