Week 1 - DM Flashcards
Intro, Pathogenesis, Clinical Pathology, New Developments
True or False?
DM = most common lifestyle/NCD
True
-in Aus = 7th leading cause of death
What is the definition of DM?
-disorder of metabolism (protein, carb, fat) due to lack of insulin:
T1DM - deficiency
T2DM - resistance * most common
What are the characteristic features of DM?
- polyuria
- polydypsia
- polyphagia
- HYPERGLYCEMIA (decr. insulin)
What are the 2 key consequences of lack of insulin in DM?
- decreased glucose inside cells
- cell starving, fatigue, damage and degeneration - increased glucose in blood
- BV damage (angiopathy) due to oxidation + tissue damage –> insulin = v. oxidative –> kidneys, CNS, eyes
- immunosuppression (infections increased)
Which hormones are involved in blood glucose control?
insulin (anabolic) –> decreased glucose (ONLY ONE)
glucagon, glucocorticoids, GH, epinephrine –> increased glucose
What is the normal BGL range?
3.5-5.5 mmol/L
How does glucose enter cells without insulin?
-via GLUT2 receptors into B-cells (insulin-independent)
Outline insulin secretion from B cells in pancreas?
- glucose enters B cells via GLUT2
- metabolism in mitochondria
- ATP production results in membrane depol. via K+ secretion
- Calcium influx results in insulin secretion
True or False?
Liver only has GLUT4 receptors
False
-also have GLUT2
Which tissues do insulin act on and what are the functions at each?
- adipose tissue
- increased glucose uptake
- increased lipogenesis
- decreased lipolysis - skeletal muscle
- increased glucose uptake
- increased glycogen synthesis
- increased protein synthesis - liver
- increased glycogenesis
- decreased gluconeogenesis
- increased lipogenesis
*insulin = ANABOLIC HORMONE
What % of cells in islets of langerhans are B cells?
80%
-insulin producing cells
What are the clinical features of DM?
- microangiopathy –> cerebral vascular infarcts, haemorrhage
- HTN, MI
- atherosclerosis
- nephrosclerosis –> glomerulosclerosis, arteriosclerosis, pyelonephritis
- peripheral vascular atherosclerosis –> gangrene/infarctions
- peripheral/autonomic neuropathy
Outline primary DM classification
- T1DM (IDDM/juvenile): 5-10%
- T2DM (NIDDM/adult onset): 90-95%
- MODY: 5% Maturity Onset Diabetes of Youth
- LADA: Latent Autoimmune Diabetes in Adults
- GDM: Gestational Diabetes Mellitus
- Other: - neonatal diabetes, insulin gene defects
Outline secondary DM classification
Excess hyperglycemic stimulus:
- cushings
- acromegaly
- pheochromocytoma
- steroid Tx.
B cell destruction:
- pancreatitis/tumours/hemochromatosis (bronze diabetes)
- infections –> CRS, CMV, TB
- endocrinopathy, Downs Synd.
What are increased infections in DM attributed to?
- BV damage (macro/microangiopathy)
- glycosylation of chemical mediators
- ischaemia of tissues
- lack of inflammatory response
- increased glucose?
What are the 3 etiological factors for T1DM?
- genetics (HLA DR3/4)
- environmental: - virus ?
- autoimmunity: - GAD65, ICA512 (against B cells –> insulitis)
Outline pathogenesis for T2DM
- genetic predisposition + obesity/lifestyle factors
- insulin resistance due to adipokines, FFA, inflamm mediators
- compensatory B cell hyperplasia –> normoglycemia
- initial increased insulin
- early B cell failure –> decreased insulin
- late B cell failure –> DIABETES
Why is there an initial increase in insulin in T2DM pathogenesis?
due to compensatory B cell hyperplasia from insulin resisitance
True or False?
late stage of T2DM can result in becoming IDDM
True
- total B cell loss can occur
- normal islets totally replaced by AMYLOID protein
- pts need to be put on insulin
What is proinsulin and what is it broken down to?
- what is released when B cells are stimulated
- broken into C-protein (remains in islets) and mature insulin (secreted)
What is the difference between T1DM and T2DM with regards to onset of presentation?
T1DM:
- sudden/acute presentation
- acute attack of hyperglycemia once B cell count falls low enough
T2DM:
- slow, gradual progression of increased BGLs
- chronic (yrs)
- early stages –> asymptomatic
Which type of diabetes are metabolic complications commonest in?
T1DM
What are the chemical mediators of insulin resistance in T2DM?
- adipokines
- inflammatory mediators
- FFA
What is the microscopic feature of islets in T1DM?
insulitis –> lymphocytes
What is MODY and which is the commonest subtype?
Maturity Onset Diabetes in Youth –> monogenic
- resembles T2DM but in young pts.
- 1-6 subtypes
- MODY2 (glucokinase mutation) = commonest
What is type A insulin resistance?
- monogenic
- hyperglycemia, hyperinsulinemia and insulin resistance
- insulin receptor mutations
- acanthosis nigricans
- females may have PCOS
What is LADA?
Latent Autoimmune Diabetes in Adults
- AKA: - 1.5 DM/ Type 3 DM
- rapid onset, no obesity, difficult control, lack of response to oral Tx.
- T1DM occuring in late age/adults
- opposite to MODY
Compare T1DM vs. T2DM
T1DM:
- autoimmune dis (gen + env + autoimmune)
- children <25yrs*
- IDDM - acute onset
- acute metabolic complications
- autoantibody –> YES (GAD65/ICA512)
- FHx –> no/yes
- 50% in twins
T2DM:
- genetic + lifestyle
- adults >25yrs*
- NIDDM - slow/chronic
- chronic vascular complications
- autoantibody –> NO
- FHx –> yes
- 90% in twins
What is microscopy of T1DM + T2DM?
T1DM:
-islets –> insulitis (lymphocyte infiltrate within islets)
T2DM:
-normal/amyloid (only in late stage)
What is the pathogenesis of polyphagia in DM?
- decreased anabolism (decreased insulin)
- increased catabolism (glucagon, GH, epinephrine) –> increased proteolysis/lipolysis
- INTRACELLULAR STARVING –> decreased insulin = decreased intracellular glucose –> polyphagia
What is the pathogenesis of polyuria and polydypsia in DM?
- decreased insulin/insulin resistance –> hyperglycemia
- excess glucose filtered in urine (glycosuria) –> takes away increased water in urine with glucose –> polyuria
- polyuria –> vol. depletion –> polydypsia
What are the 3 acute metabolic complications of Diabetes?
- DKA
- increase in type 1 - HHS/HONK
- severe hypoglycemia
- excess/OD of drugs or insulin OR lack of eating
What is DKA and its features?
- increase in T1DM –> acute metabolic complication
- severe hyperglycemia (increased glucagon/epi)
- osmotic diuresis and severe dehydration
- lipolysis, FFA –> ketonemia + ketonuria –> metabolic acidosis + dehydration
- fatigue, nausea/vomiting (acidosis), Kussmaul breathing (deep + laboured)
What is Hyperosmolar Hyperosmotic Synd. (HHS/HONK) and its features?
- severe hyperglycemia (osmotic diuresis + lack of hydration)
- severe dehydration ONLY (non - ketotic)
- no acidosis –> therefore no nausea/vomiting/kussmaul breathing
- common in elderly pts. w DM
Why can you get severe hypoglycemia in DM and what are the Sx.?
- excess/OD on drugs or too much insulin
- lack of eating
Sx: - sweating, palpitations, tachycardia, dizziness/confusion
Why do pts. begin losing weight once they develop diabetes?
-excess catabolism (lipolysis/proteolysis) + decreased anabolism (decreased insulin)
Why are skeletal/striated muscle, adipose tissue and the liver all insulin-dependent tissues?
They have GLUT4 receptors on surface which require insulin to transport glucose into cells
*liver also has GLUT2 receptors
What are the chronic vascular complications of DM in insulin-dependent tissues?
- striated muscle, fat, liver*
- decreased glucose inside cell –> decreased cell metabolism –> cell starvation
What are the chronic vascular complications of DM in insulin independent tissues?
BVs, Nerves, Eyes, CNS
-increased glucose in cytoplasm/BVs (hyperglycemia)*
Glucose polymerisation in cytoplasm
-polyols (sorbitol) –> osmotic damage + cell swelling (intracellular)
Activation of protein kinase C
-inflammation, angiogensis, fibrosis –> retinal damage
Glycosylation (glucose combines w body proteins and denatures it)
- Advanced Glycosylation End products (AGE)
- AGE deposition in BV wall –> damage –> protein leakage –> thickening (artereosclerosis) –> ischaemia (microangiopathy)
Atherosclerosis (macroangiopathy)
What is AGE and what results from it?
Advanced Glycosylation End products
- glycosylation of glucose with body proteins forms AGE (proteins become denatured)
- AGE deposits in BV wall causing damage, protein leakage, thickening (artereolosclerosis) –> ischaemia (microangiopathy)
What is the pathogenesis of microangipathy in Diabetes?
- hyperglycemia
- glycosylation of BM proteins
- AGE deposition –> BV wall damage –> protein leakage
- increased BM protein deposition (compensatory)
- thickening –> hyaline artereolosclerosis from increased AGE deposition
- narrowing of lumen –> ischaemia –> BV + organ damage
*microangiopathy = commonest cause of diabetic damage
Outline the 2 forms of retinopathy in DM
- Non-proliferative
- microaneurysms
- dots (aneurysms)
- blots - haemorrhage
- hard exudates
- soft/cotton wool –> infarcts - Proliferative
- neovascularisation
- larger haemorrhages
- retinal detachment (geographic areas of haemorrhage + total blindness) :(
What is the characteristic damage in DM neuropathy?
loss of myelin sheath
True or False?
longest nerves are first affected in DM neuropathy
True
-distal parts of hand + feet are first affected areas (pins/needles)
What are the Sx. of peripheral and visceral neuropathy?
Peripheral:
- bilateral, distal, pins + needles (glove & sock)
- progressive, irreversible
- parasthesia, pain
- muscle atrophy –> late manifestation
Visceral:
- cranial nerve –> diplopia, Bells palsy (VII)
- GIT –> constipation/diarrhoea
- CVS –> orthostatic hypotension
What are the features of neuropathic ulcers?
- at pressure points
- painless
- surrounded by callus (hyperkeratosis)
- ‘caved in’/punched out ulcer
- blood flow NOT affected
What is the major cause of morbidity/mortality in DM?
Nephropathy
What is the pathogenesis of nephropathy in DM?
- hyperglycemia
- glomerular capillary damage due to protein leakage (microalbuminuria)
- deposition of AGE in glomerulus –> as a nodule inside loops of capillaries
- Nodular Glomerulosclerosis (KW lesion) –> compression of capillaries –> decreased blood flow –> eventually diffuse glomerulosclerosis –> End Stage Renal Failure
What is nodular glomerulosclerosis AKA?
KW lesions
-Kimmelstiel-Wilson Lesions
What are diabetic xanthomas?
- reddish/yellow, pruritic, painful lesions/vesicles
- hyperglycemia + hyperlipidemia
- subcut. fat necrosis, foamy macrophages + free lipids
- eruptive xanthoma –> sudden crop of xanthomas (severe)
What is the pathogenesis of infections in DM?
MULTIFACTORIAL:
- impaired inflamm. response –> BV sclerosis
- WBC/endothelial damage by glycosylation
- glycosylation of chemical mediators of inflammation
- decreased metabolism (cell starving)
- tissue ischaemia + infarctions –> BV damage (anuerysms/haemorrhage)
- increased glucose (alone is NOT the cause)
What is the mechanism of cellular damage in insulin-dependent tissues?
cell starvation due to decreased glucose entering cells
What is the standard first drug of choice for T2DM and what is tis known MOA?
Metformin
-decreases hepatic gluconeogenesis
What are incretins?
GIP –> Glucose dependent Insulinotrophic Polypeptide
GLP-1 –> Glucagon-Like Polypeptide
*function to increase insulin and decrease glucagon
What are incretins destroyed by?
Dipeptidyl Peptidase (DPP4)
What are some new drug therapies used to target incretins?
Exenatide –> GLP-1 recpetor agonist (increased incretin function)
…gliptins –> DPP4 inhibitors (decreased destruction of incretins)
Which cells secrete incretin hormones?
intestinal endocrine cells
What are the gross kidney features of a pt. with ESRD following extensive PMHx of T2DM?
- atrophic small kidney
- cortical atrophy (increased hilar fat)
- multiple haemorrhagic necrosis areas at renal papillary tips
Why is there nodular glomerulosclerosis in glomerulus and not normal arteriolosclerosis?
- foot processes on glomerular capillary surface make it impermeable
- therefore NO protein leakage possible –> AGE protein deposition remaining inside capillary loop (capillaries pushed to peripheries) –> NODULAR HYALINE GLOMERULOSCLEROSIS
What lab. finding is siggestive of initial renal damage in diabetic pts.?
microalbuminuria
What is the diagnostic microscopic feature of diabetic renal damage?
nodular glomerulosclerosis
True or False?
epithelial casts in urine is suggestive of tubular damage
True
