Diabetes Mellitus Flashcards
What is Diabetes Mellitus (DM)? (+associated problems)
A group of metabolic diseases charcaterised by hyperglycemia resulting from defects in:
= insulin secretion / action / or both
Chronic hyperglycemia associated with long-term damage, dysfunction and failure of:
= eyes
= kidneys
= nerves
= heart
= blood vessels
What makes up the ominous octet of hyperglycaemia?
- Increased glucagon secretion (islet alpha cell)
- Impaired insulin secretion (islet beta cell)
- Decreased incretin effect
- Increased lipopolysis
- Increased glucose reabsoption
- Decreased glucose uptake
- Neurotransmitter
- Increased hepatic glucose production
What is insulin?
= 51 a.a. peptide
= α and β chains linked by disulphide bonds
= produced in β cells of islets of langerhans in the pancreas
= synthesised as pre-proinsulin cleaved to proinsulin
= cleaved from C-peptide to release
What are the action of insulin in different organs?
Brain
= ↑ hunger
= ↓ hepatic glucose production
= ↓ lipoprotein production
Peripheral Muscle
= ↑ glucose metabolism
= ↑ glycogen synthesis
= ↑ muscle mass
= ↑ mitochondrial dysfunction
Adipose Tissues
= ↑ inflammation
= ↑ M2 to M1 macrophage switch
= ↑ glucose metabolism
= ↑ lypogenesis
= ↓ lippolysis
Livers
= ↓ glucose synthesis
= ↑ glycogen synthesis
= ↑ lipid accumulation
= ↑ inflammation
How does insulin act as an anabolic hormone?
= leads to glucose transport into muscle and fat cells
= promotes glycogen synthesis
= inhibits gluconeogenesis
= inhibits lipolysis
= promotes formation of triglycerides
= activates membrane sodium-potassium ATPases promoting K flux into cells
= stimulates cell growth
What is the pathophysiology of DM?
Healthy
= insulin released and insulin receptor on surface of cell
Type 1
= pancreas fails to produce insulin
Type 2
= insulin produced
= BUT cells fail to respond to insulin properly (i.e. receptor)
What are some symptoms of DM?
= always tired
= frequent urination
= sudden weight loss
= wounds that don’t heal
= always hungry
= sexual problems
= blurry vision
= vaginal infections
= numb or tingling hands or feet
= always thirsty
How does endocrine control of glucose work?
INSULIN
Stimulation:
= glucose
= amino acids
= gastric inhibitory polypeptide (released from K cells of duodenum and jejunum)
= parasympathetic stimulation
Inhibition:
= glucagon
= sympathetic stimulation
GLUCAGON
Stimulation:
= low glucose
= amino acids
= sympathetic stimulation
= adrenaline
Inhibition
= insulin
= gastric inhibitory polypeptide (GIP)
What are some diagnostic tests for DM?
A1C
Fasting plasma glucose
2-hr plasma glucose during OGTT
Random plasma glucose
What are some stats about DM in the UK?
6% of adults (3.2 million) diagnosed with DM in UK
Type 1 DM
= 10% of total
= prevalence in <19 y.o = 1 in 430-450
= prevalence in <14 y.o = 24.5 in 100,000
= peak diagnosing age = 10-14 years
What are the different classifications of DM?
Type 1
= autoimmune
= rapidly develops
= mostly diagnosed in young children
= insulin needed immediately
Type 2
= not autoimmune
= develops slowly
= diagnosed mostly in adults
= insulin not needed immediately - other medications
Gestational
= diabetes during pregnancy (2nd/3rd trimester)
= goes away after pregnancy
= treated through diet and exercise, sometime insulin
= increases risk of type 2 later in life
MODY
= maturity onset diabetes of the young
= mimics type 2 (but in young people)
= strong genetic risk factor
= insulin not always needed
LADA
= latent autoimmune diabetes of adulthood
= form of type 1 but in adulthood
= can be misdiagnosed
(Type 3)
= controversial
= suggests alzheimers could be called type 3 sue to insulin resistance seen
EXTRA READING - Type 3
= insuline resistance and insulin-degrading enzyme deficiency in brain of AD patients
= unable to use glucose effectively = leads to amyloid-plaques
= not widely accepted
Summarise the causes of T1DM.
Immune / Autoimmune
Environmental
= intrauterine
= early life
= geography
Genetics
= HLA /MHC
What are the genetics of T1DM?
85 % of T1DM patients have no affected 1st degree family relatives
Risk among 1st degree relatives of T1DM is approx 15x greater than general population
EXTRA READING
= HLA (human leukocyte antigen) = chromosome 6
= also genes that regulated immune function (e.g. CTLA-4, PTPN22, INS =)
What are some environmental risk factors for T1DM?
Viruses
= coxsackie B
= cytomegalovirus
= echo
= epstein-barr
= mumps
Diet
= cow’s milk
= caffeine
= nitrates
Lifestyle
= exposire to toxins
= stress
What is the geographical variation and incidence of T1DM?
Incidence varies worldwide
= risk increases with distance from equator
Relocating from region of low to high incidence
= increases risk of T1DM
= suggests environmental factors
= BUT still variations in incidence between neighbouring areas of similar latititude
= suggests other contributing factors
What is the pathophysiology of T1DM?
= cellular mediated autoimmune destruction of insulin producing β cells in pancreatic islets of langerhans
= autoantibodies
to GAD, islet cell, IA-2 and zinc transporter 8 found in 96% of patients at diagnosis
What is T2DM?
= usually presents in middle age / eldely
= often with a family history
= strong links with obesity and hypertension
= associated insulin resistance at cellular level
= inadequate insulin produced to overcome resistance
What is the aetiology of insulin resistance?
= defective insulin mediated glucose uptake
Genetics
= islet cell development
= insulin release
= abnormal insulin receptor
= abnormal signalling proteins
Environment
= obesity
= diet
= ageing
= medication
Leads to T2DM
= hyperglycaemia
= lipolysis
= lipid abnormalities
How is obesity linked to T2DM?
Weight gain of 7-11kg over 18 years
= 2-fold increase in risk of diabetes
= prevalence in adults is rising = global burden
As obesity increases
= so does insulin resistance and hyperinsulinaemia
= linked to inflammation
What is the evidence for inflammation being a link between obesity and T2DM?
ADIPONECTIN (adipocyte-derived cytokine)
= improved lipid profiles, better glycaemic control
= reduced markers of inflammation in diabetic patients
= inversely associated with risk for diabetes in nondiabetic population
TNF-α (pro-inflammatory cytokine)
= TNF-α mRNA adipose tissue positively correlated obesity and hyperinsulinaemia
= blocking TNF-α antibodies improves glucose utilisation in obese rodents
= patients with rheumatoid arthritis treated with anti-inflammatory TNF inhibitors have lower incidence of diabetes
CXCL5 (pro-inflammatory, expressed in macrophage fraction white adipose tissue)
=binding to receptor CXCR2 reduces insulin-stimulated glucose uptake in muscle
= serum level CXCL5 higher in obese individuals / insulin-resistant obese compared to non-insulin-resistant obese individuals
= CXCL5 concentrations decrease with weight loss
What are the core defects in T2DM?
Insulin Resistance
(+ hyperinsulinaemia with normal glucose tolerance)
Impaired β-cell function
= both lead to insulin resistance and declining insulin levels with impaired glucose tolerance
= T2DM
What is the progression of DM?
Start with normal glucose tolerance
Then impaired glucose regulation
Then DM:
- can be non insulin requiring
- insulin requiring for control
- insulin requiring for survival (only T1DM)
What are some comparisons between T1DM and T2DM?
What is DKA?
= Diabetic Ketoacidosis
D = hyperglycaemia or normoglycaemia in known diabetics (>11mmol)
K = ketosis (>3 mmol/L / known diabetic)
A = metabolic acidosis (HCO3 <15 or pH <7.3)
= dehydration (fluid deficit 100ml/kg)
What is Diabetic Retinopathy?
= diabetic eye disease
= most common cause of blindness ages 30-69
= 20% of T2DM patients have retinopathy at diagnosis
= after 15 years, 2/3 have background retinopathy
What are some examples of drug treatments (+what do they affect)?
Metformin
Alphaglucosidase inhibitors
= glucose absorption
Thiazolidinediones
= glucose uptake and utilisation
Sulfonylureas / Meglitinides
= pancreas, insulin production
