Diabetes Flashcards
What is Diabetes Mellitus?
•Collection of diseases of glucose homeostasis
- Type 1 Diabetes (T1DM)
- Type 2 Diabetes (T2DM)
- Type 3c
- MODY
- Gestational Diabetes
- T2DMY
- Others
- Accounts for 10% of NHS budget
- Associated with serious complications
- Shortens lifespan/accelerates ageing
Diabetes Diagnosis – FBG/OGTT
Diabetes Diagnosis – HbA1c
Glucose binds irreversibly to Hb in
erythrocytes, forming HbA1c
- The higher the glucose, the higher the HbA1c
- HbA1c reflects the prevailing blood glucose
over the preceding 2-3 months
- Diagnosis:
- HbA1c mmol/mol
- Normal <42 mmol/mol
- ‘Prediabetes’ 42 to 47 mmol/mol
- Diabetes 48 mmol/mol or >
History of Diabetes
•First described in Ebers Papyrus
- One of only a few diseases mentioned
- Notes 3 types of healers (physicians, surgeons and Sorcerers)!
- No mention of glucose
Treatment was: a measuring glass filled with water from the bird
pond, elderberry, fibres from the asit plant,
fresh milk, beer swill, flower of the cucumber and
green dates’
Describe normal glucose homeostasis post prandially
Insulin is key hormone (glucagon and somatostatin also)
Post-prandially (fed)
- Glucose comes from GI tract via SGLT1
- Glucose stimulates insulin release from pancreatic-β cells (islets)
- Insulin promotes glucose uptake in hepatocytes (minor), skeletal muscle (major) and adipocytes and inhibits release of glucose from stores
- Glucose is stored as metabolites – anabolism occurs )
Describe normal glucose homeostasis in the fasting state
- Glucose drops – lowering insulin
- Insulin repression of glucose release lessens - catabolism occurs
Describe insulin production
•Insulin is produced by pancreatic beta-cells
- 51aa peptide comprising 2 chains (A and B)
- Synthesised on RER as pre-proinsulin
- Signal peptide removed before transfer to Golgi
- Cleaved by PC1/3 to form mature insulin
- Stored in secretory granules
Describe insulin release
- Nutrient response (glucose primarily) – biphasic pattern
- Large role for incretins???
- Basal secretion does occur (<1.5U/h)
What is insulin secretion increased by?
Draw a graph of insulin secretion
What are inretins?
- Gut hormones that regulate insulin secretion
- GLP-1 thought to be responsible for >60% of insulin response to glucose
- Short half life (2-3 minutes) due to DPP-IV
- New classes of drugs
GLP-1 analogues
DPP-IV inhibitors
•Recent research
Combined GLP-1 and GIP (LY3298176) may be best ever treatment
Effects of intecrins
T1DM
- <10% of cases
- Primarily children and adolescents
- Cause not understood
- Almost absolute insulin deficiency – T-cell
mediated autoimmune destruction of pancreatic β-cells
- Incidence varies dramatically
- Genetic factors – HLA class II DR-3/-4
(95% of European T1DM)
•GWAS studies – INS promoter, PTPN2, IL2Ra
Presentation of T1DM:
- Short illness (1-4 weeks)
- Classical diabetes symptoms (polyurea, polydipsia, fatigue weight loss)
What is the risk of developing type 1 diabetes for relatives of people with type 1 diabetes
Describe type 2 diabetes (T2DM)
•The commonest form of diabetes
- 300 million people worldwide (3 million in UK)
- Heterogeneous
- Interaction between genetic predisposition and environment
- Combination of insulin resistance and pancreatic β-cell dysfunction
- Traditionally found in older adults
- Lifetime risk of 1/10
- In some parts of USA, T2DM as common
- as T1DM in teenagers
TRUE or FALSE: T2DM has greater heritability than T1DM
- Approx. 40-80% of susceptibility
- More maternal than paternal
- Several gene polymorphisms identified as increasing risk (see box)
What are the key environmental factors of T2DM?
- Obesity – 80% of new cases
- Physical inactivity
- Foetal development
- Ageing
- These factors drive insulin resistance
What is the key cause of T2DM?
Insulin resistance
Defined as the inability of insulin to produce its usual biological effects
↓ inhibition of hepatic glucose output
↓ ability to stimulate glucose uptake in muscle and adipose tissue
↓ suppression of lipolysis →
•Potential mechanisms
- ↓ number of insulin receptors
- Abnormal insulin receptors
- Abnormal post-receptor signalling
- Abnormal GLUT-4 translocation
Lipotoxicity is the key mechanism
Define Β-cell Dysfunction
- Loss of β-cell function is the KEY DIAGNOSTIC EVENT
- Insulin resistance cannot explain the whole story!
Most T2DM are no more insulin resistant that most insulin resistant quartile of general population
Only 20% of insulin resistant people get T2DM
•Causes
Glucolipotoxicty
Genetics
Hormonal – incretins
Obesity
Describe the natural history of Diabetes
What is the main treatment for T1DM?
Insulin
What is the lifestyle changes help with T2DM?
- Diet
- VLCD
- Exercise
T2DM treatments: Oral antidiabetics
- Secretagogues
- Sensitisers
- Inhibitors of glucose absorption
- Incretin therapies
T2DM treatment: Insulin analogues
Long/short acting insulins
T2DM treatments: Novel drugs
- SGLT2 inhibitors
- GLP-1 analogues
- DPP4 inhibitors
- GLP-1-GIP combined therapies
Dsecribe microvascular complications
- Affect 80% of people with diabetes
- Already present in 20-50% of newly diagnosed T2DM
- Causes – hyperglycaemia (AGEs, sorbitol pathway etc)
- Retinopathy, nephropathy, neuropathy, diabetic foot
Describe macrovascular complications
- Large blood vessels (coronary arteries, aorta, larger arteries in brain/limbs)
- Commonly – heart disease, cerebrovascular disease, peripheral vascular disease
- Normally atherosclerosis
- Diabetes = 4-fold ↑ risk of MI in men, 10-fold in women
- Causes 65% of all deaths in diabetes.
Symptoms of T2DM
Retinopathy
- Most common cause of blindnes in people of working age
Nephropathy
- 20-44% of all new patients needing renal replacement therapy have diabetes
Erectile dysfunction
- May affect up to 50% of men ith long-standng diabetes
Macrovascular disease
- 2-3 fold increase risk of coronary heart disease and stroke
Foot problems
- 15% of people with diabetes develop foot ulcers; 5-15% of people with diabetic foot ulcers need amputations
TRUE or FALSE: T1DM can be prevented
FALSE
How can T2DM be prevented?
- Screening and aggressive treatment of IGT
- Increase physical activity
- Reduce carb/fat load
- Fasting?
- Drugs
Lifestyle changes that help with T2DM
Pharmacological T2DM prevention
