The Aetiology and Treatment of Type 2 Diabetes Mellitus Flashcards
What tests are performed to diagnose diabetes and what are the defining values?
Fasting Blood Glucose: Normal < 6 Impaired Fasting Glucose = 6-7 Diabetes > 7 Glucose Tolerance Test (2 hr measurement) Normal < 7.8 Impaired Glucose Tolerance = 7.8-11.1 Diabetes > 11.1
State 3 factors that influence the pathophysiology of T2DM.
Genetics
Intrauterine environment
Adult environment
How is the intrauterine environment important in the pathogenesis of T2DM?
Epigenetic changes take place in utero which affect blood glucose control in the future
What is MODY?
Mature onset diabetes of the young (8 types)
Autosomal dominant
Ineffective pancreatic B cell insulin production
Caused by mutations of transcription factor genes (glucokinase gene)
Positive family history with NO obesity
What can modulate insulin resistance through adult life before someone develops diabetes?
Adipocytokines
What type of babies are more likely to develop T2DM in later life?
Small babies (low birth weight) Due to intrauterine growth restriction
How does insulin resistance lead to hypertension?
Insulin resistance leads to a compensatory hyperinsulinaemia
Though the insulin doesn’t affect the glycaemic control pathway, it stimulates the mitogenic pathway causing smooth muscle hypertrophy causing high BP
What eventually happens to the beta cells in T2DM?
Insulin resistance damages the B cells, eventually results in B cell failure
Describe how beta cell potential for insulin secretion and insulin resistance change with age.
Potential for insulin secretion decreases with age
Insulin resistance increases with age
Describe the metabolism + presentation of a typical patient with T2DM.
Heterogeneous Obese (80%) Insulin resistance + insulin secretion deficit Hyperglycaemia + dyslipidaemia Acute + chronic complications
What dietary changes can someone with T2DM make to reduce the effect of the missing first phase insulin release?
Complex carbohydrates: release glucose more slowly
Describe glucose clearance and hepatic glucose output in T2DM.
Glucose clearance is decreased (less able to enter muscle + less stored as glycogen)
HGO is increased
What normally happens to insulin secretion as insulin resistance increases?
Insulin secretion increases to compensate for the increased insulin resistance
Which adipocytes are particularly marked for breakdown of triglycerides?
Omental adipocytes (thus, omental fat correlates with risk of heart disease)
What happens to fatty acids when they go into the liver?
Can’t be used to make glucose so are converted to VLDL’s which are highly atherogenic
Describe how gut microbiota is implicated in T2DM.
May alter host signalling: they ferment lipopolysaccharides to short chain fatty acids, which enter the circulation + modulate bile acids (so affect host metabolism)
Associated with inflammation + adipocytokine pathways
What is a very common side effect of diabetes treatment?
Weight gain
Which diabetes treatment does not cause weight gain?
Metformin
What are the management strategies for T2DM?
Education
Diet
Pharmacological treatment
Complication screening
What dietary measures are recommended for someone with T2DM?
Decreased fat (particularly sat. fats) + refined carbs
Increased complex carbs + soluble fibre
Control total calories + increase exercise
Reduce salt
What is orlistat and why is it sometimes used in T2DM?
Pancreatic Lipase Inhibitor
Reduces break down of fats in the intestines thus reducing absorption of fats
More is excreted
State 7 classes of drugs that are used to treat T2DM and state how they work.
Insulin: reduces HGO
Metformin: insulin sensitiser
Sulphonylureas: makes existing pancreas produce more insulin
Alpha-glucosidase inhibitors: prolongs absorption of glucose from the intestine
Thiazolidinediones: act on insulin resistance (central + peripheral)
GLP-1 agonists + DPP4 inhibitors: increase insulin secretion + have anti-glucagon effect
SGLT2 inhibitors: act on PCT to increase glycosuria
When should you NOT use metformin?
Severe liver failure
Severe cardiac failure
Mild renal failure
Name one sulphonylurea.
Glibenclamide
Given to lean patients with T2DM (as causes weight gain)
Explain how sulphonylureas work.
Bind to receptors + block the ATP-sensitive K+ channel
Leads to Ca2+ influx, which causes insulin release
Name one alpha-glucosidase inhibitor. Explain how it works and state 1 side effect.
Acarbose
Prolongs absorption of oligosaccharides + allows the body to cope with the loss of 1st phase insulin
Side effect: flatus
Name a thiazolidinedione. What are its effects?
Pioglitazone
=PPAR agonist
Insulin sensitises mainly in peripheral tissues (leads to peripheral weight gain)
What does GLP-1 do?
Responsible for the incretin effect (where oral glucose stimulates more insulin than IV glucose)
Stimulates insulin + suppresses glucagon
What breaks down GLP-1?
Dipeptidyl peptidase-4 (DPP4)
How do gliptins work?
Inhibit DPP4 (increase half life of GLP1) Increases [GLP1] Decreases [glucagon] Decreases [glucose] Neutral on weight
Name a GLP1 agonist. Describe the action of GLP1 agonists
Exenatide. Injectable, long acting Decrease [glucagon] Decrease [glucose] Cause weight loss
Name an SGLT2 inhibitor and describe its mechanism of action
Empaglifozin
Inhibits Na-Glu transporter
Increases glycosuria
What can occur during pregnancy to identify women who are at high risk of getting diabetes in the future?
Gestational diabetes
Define Diabetes Mellitus
State of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues e.g. retina, kidney, nerves + arteries
Is T2DM ketosis prone?
No
What 3 clinical signs and symptoms indicate T2DM?
Osmotic symptoms
Infections
Presentation of complication e.g. hyperosmolar coma, ischaemic heart disease, retinopathy
List 3 microvascular complications of T2DM
Retinopathy
Nephropathy
Neuropathy
List 2 metabolic complications of T2DM
Lactic acidosis
Hyperosmolar coma
List 4 macrovascular complications of T2DM
Ischameic heart disease
Cerebrovascular disease
Renal artery stenosis
Peripheral vascular disease
What treatment complications may arise in T2DM?
Hypoglycaemia
Weight gain
What 4 elements must be targeted in treatment of T2DM?
Weight
Glycaemia
Blood pressure
Dyslipideamia
What weight loss treatment may cause T2DM to go into remission?
Gastric bypass surgery
By what mechanisms does metformin reduce insulin resistance?
Reduced HGO
Increases peripheral glucose disposal
What intervention is most effective at reducing incidence of T2DM?
Lifestyle changes
