Endocrinology 16 - Type 2 Diabetes Mellitus Flashcards
Define diabetes mellitus
Diabetes mellitus can be defined as a state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues, notably the retina, kidney, nerves, and arteries
List the main characteristics of T2DM
- Not ketosis prone
- Not mild
- Often involves weight, lipids and blood pressure
Describe the epidemiology of T2DM
- Diabetes 10% at 60 years (4-7% T2DM)
- Increasing age, but now seen in children
- Varies enormously, but is increasing
- Occurring and being diagnosed younger
- Greatest in ethnic groups that move from rural to urban lifestyle
Describe pathophysiology of T2DM
- MODY (uncommon but useful insights)
- Genes and intrauterine environment, as well as adult environment
- Insulin resistance and secretion defects
- Fatty acids important in pathogenesis and complications
What is maturity onset diabetes of the young?
- Several hereditary forms
- Autosomal dominant
- Ineffective pancreatic B cell insulin production
- Mutations of transcription factor genes, glucokinase gene
- Positive FH, no obesity
- Specific treatment for type
Describe the onset and progression of T2DM
- Genes (more insulin needs to be produced their whole life, low insulin in the fetus, obesity in the adult)
- Dyslipidaemia caused by insulin resistance adipocytokines
- Insulin resistance and eventual B cell failure and insulin secretion deficit
- Increased hyperglycaemia and dyslipidaemia due to B cell failure
- Acute and chronic complications. May eventually need insulin
How important is obesity in T2DM?
- More than a precipitant
- Fatty acids and adipocytokines important
- Central or omental particularly (drain directly to the liver)
- 80% T2DM obese at diagnosis
- Weight reduction is useful to adress in treatment
How do gut bacteria relate to T2DM?
- Fatty acids released by the biome could enter the circulation and alter liver metabolism. Local fermentation of fatty acids
- More important in obesity association than diabetes
- Alter our signalling
- Alter inflammation and metabolic pathways
(correlative not causative at the moment)
How does T2DM present?
- Heterogenous
- Obesity
- Insulin resistance and secretion deficit
- Hyperglycaemia and dyslipidaemia
- Osmotic symptoms
- Screening test
Acute and chronic complications
- Infections (due to high sugar)
- Hyperosmolar coma (acute complications)
- Ischaemic heart disease or retinopathy (chronic complications)
List the complications of T2DM
Microvascular
- Retinopathy
- Nephropathy
- Neuropathy
Metabolic
- Lactic acidosis
- Hyperosmolar
Macrovascular
- Ischaemic heart disease
- Cerebrovascular
- Renal artery stenosis
- PVD
- Hypoglycaemia
How is T2DM managed?
- Education
- Diet
- Pharmacological treatment
- Complication screening
Why does T2DM need to be treated?
- Symptoms
- Reduce chance of acute metabolic complications
- Reduce change of long term contributions
How do patients with T2DM need to eat?
- Control calories and increase exercise
- Reduce refined carbohydrate
- Increase complex carbohydrate
- Reduce fat as a proportion of calories
- Increase unsaturated fat as a proportion of fat
- Increase soluble fibre
- Address salt
How is T2DM treated and monitored?
- Weight
- Glycaemia
- Blood pressure
- Dyslipidaemia
- Gasric bypass
- Metformin
- Acarbose
- Thiazolidinediones
- GLP-1
- Empaglifoxin
What are the effects of metformin?
- Insulin sensitiser
- Used in overweight patients where diet has not succeeded
- Reduces insulin resistance
- GI side effects
- DO NOT USE if liver, cardiac or mild renal failure
What is acarbose, how does it work and are there any side effects?
- Alpha glucosidase inhibitor
- Prolongs absorption of oligosaccharides
- Allows insulin secretion to cope, following defective first phase insulin
- As effective as metformin
- Side effects flatus
What are thiazolidinediones? List the effects
- Peroxisome proliferator-actived receptor agonists (PPAR-γ)
- eg. Pioglitazone
- Insulin sensitizer, mainly peripheral
- Adipocyte differentiation modified, weight gain but peripheral not central
- Improvement in glycaemia and lipids
- Evidence base on vascular outcomes
What is GLP-1, and what are its actions?
- Secreted in response to gut nutrients
- Transcription product of proglucagon gene, mostly from L cell.
- Stimulates insulin, suppresses glucagon
- Increases satiety
- Restores B cell glucose sensitivity
- Short half life, rapid degredation from enzyme dipeptidyl peptidase-4 (DPPG-4 inhibitor)
List the GLP-1 agonists and their uses
- Exenatide and liraglutide
- Injectable
- Long acting GLP-1 agnosit
- Decrease glucagon
- Decrease glucose
- Weight loss
List the uses of Gliptins
- DPPG-4 inhibitor (oral)
- Increase half life of exogenous GLP-1
- Increase GLP-1
- Decrease glucagon and glucose
- Neutral effect on weight
What is empaglifozin? List its effects.
- Used in T2DM patients
- Inhibits Na-Glu transporter in the proximal convoluted tubule (SGLT-2)
- Increases glucosuria
- HbA1c lower
- 32% lower all cause mortality
- 35% lower risk heart failure
What should be controlled as well as weight in T2DM?
- Blood pressure
- Diabetic dyslipidaemia (high cholesterol and triglyceride, low HDL-cholesterol)
How does fetal and infant weight affect diabetes?
- Weight at one year less than 8kg increases risk of diabetes or impaired glucose tolerance
- Low protein intrauterine increases risk of diabetes due to impaired pancreatic development
What happens to insulin secretion and insulin resistance as we age?
- Insulin secretion decreases as we age
- Insulin resistance increases as we age
Why does dyslipidaemia occur in T2DM?
- Triglycerides broken down to glycerol and non esterified fatty acids
- NEFAs are converted to very low density lipoproteins
- Glycerol is used to produce more glucose in the liver (gluconeogenesis)
What is important in insulin resistance and decreased decretion?
- Exercise and diet
- Genes
- Split pro-insulin
- Microbiome
- Adiopocytokines
- Intrauterine enviroment
What is orlistat?
- Intestinal lipase inhibitor
- Fat we have eaten is not absorbed and passes into the faeces instead
- Used for weight loss
What is sibutramine?
- Reuptake noradrenaline to affect energy use
- Previously used for weight loss
- Not used anymore
How do sulphanylureas work?
- Stimulate release of insulin from B cells of the pancreas
- Does this by binding to and closing ATP sensitive potassium channels in the cell membrane (causes depolarisation by preventing K+ entering the cell, opening VGCCs)
- Requires presence of functional B cells
List the drugs used in diabetes treatment
- Suphanylureas (eg. glibenclamide)
- DPP4 inhibitors (gliptins)
- GLP-1 agonists
- Metformin
- Acarbose (glucosidase inhibitor
- Thisalidinediones (eg. pioglitazone)
- SGLT-2 inhibitors (empaglifozin)
What are the side effects of sulphonylureas?
- Hypoglycaemia
- Weight gain
