Diabetes Flashcards
Pancreatic islet innervation
PSNS: vagus, ACh mediated –> increase insulin release
SNS: Post-ganglionic fibers originating in celiac ganglion (foregut)
- NE mediated –> inhibit insulin secretion
- E from adrenal gland –> neurohormonal action to decrease insulin
Type 1 DM pathophys
Genetic + immune + environmental factors –> cell destruction
Strong genetic correlation with certain HLA loci, associated with other autoimmune diseases
- HLA-DR, HLA-DQ alleles
-Polygenic
- 50% concordance in identical twins
Viruses: coxsackie, mumps, rubella
Lymphocyte infiltration –> islet cell destruction
- islet cell Ab present in up to 60-85% of cases (best predictor of disease)
- up to 69% have Ab against insulin
Possibilities:
- molecular mimicry
- bystandar activation - nonspecific infection causes cytokine release into pancreas
- beta cell apoptosis
80% beta cell destruction –> symptomatic
Type 2 DM pathophys
Impaired insulin secretion AND peripheral insulin resistance
>90% concordance in identical twins - strong genetic component
1) Glucose tolerance normal, insulin resistance high - compensation by increased insulni secretion
2) Beta cells unable to maintain hyperinsulinemic state –> glucose intolerance, diabetes
Associated with obesity, particularly intraabdominal obesity
Resistance involves genetic and/or acquired post-receptor defects in insulin action
Rare (5%) , single gene mutation = “mature onset diabetes of the young”
genes that regultae beta cell mass or function - MODY2, glucokinase, impaired insulin secretion
Causes of progressive loss of insulin secretion in type 2 diabetes
glucose toxicity and lipotoxicity to beta cells
beta cell exhaustion/stress
pro-inflammatory cytokines: beta cells during hyperglycemic stress make pro-inflammatory cytokines
Islet myloid deposits: toxic amyloid deposits composed of islet amyloid polypeptide (IAPP) found in most T2D patients
Nesidioblastosis
= hyperinsulinemic hypoglycemia
excessive function of pancreatic beta cells with abnormal microscopic appearance
aka congenital hyperinsulinism
islet cell enlargement, islet cell dysplasia, beta cell hyperplasia/budding from ductal epithelium
Proliferation of islet cells from pancreatic ducts –> hypoglycemia and hyperinsulinemia in infants and newborns
Insulinoma
Tumour of the pancreas
Symptoms of hypoglycemia - improved by eating
tx surgery
Type 1 DM onset and epidemiology
<30 yrs old, acute
Caucasians
Rare in blacks, hispanics, asians
5-10% of DM
Type 2 DM onset and epidemiology
Usually >40, gradual
Black, hispanics, Asians, aboriginals
>90% of DM
5% of population, and increasing
Syndrome X
etiology of type 2 DM
central obesity, hyperlipidemia, hyperinsulinemia, HTN, diabetes
Type 1 DM clinical features
normal to wasted body
polydipsia
polyuria
hyperphagia
Type 2 DM clinical features
overweight with central obesity HONDA patient don't usually get ketosis often normal insulin levels acanthosis nigricans (dark pigmentation)
Acute complications of DM
Diabetic ketoacidosis (Type 1) Hyperglycemic hyperosmolar state (type 2, elderly) Hypoglycemia Myocardial infarction Stroke
Diabetic ketoacidosis pathophys
Hyperglycemia leading to:
- osmotic diuresis - loss of electrolytes
- ileus from electrolyte abnormalities - voimting
- polyuria, polydipsia, dehydration, hypotension, tachycardia and peripheral circulatory failure
- decrease intravascular volume –> aldosterone secretion via RAAS –> potassium loss
Upregulation of glucagon
- increased lipolysis and ketogenesis –> accumulation (beta-hydroxybutyrate)
- metabolic acidosis + compensatory hyperventilation
- acidosis –> K out of cells, then lost into urine
+ insulin treatment –> activates Na/K pump, K sequestered into cells
Hyperglycemic hyperosmolar state pathphys
Residual activity in patients –> lipolysis not activated, no ketoacidosis
Ppt factor = increased insulin resistance triggered by illness/drugs
Major problem = extreme dehydration secondary to osmotic diuresis
- glucose level >45
- contraction of blood volume - can become hypoxic - lactic acidosis may develop due to anaerobism
- sodium concentrations may become elevated secondary to diuresis
- confusion and lethargy as serum osmolality >300; coma >340
Chronic complications of DM (categories)
vascular renal eye neurologic skin infections
Chronic complications of DM - pathogenesis
Non-enzymatic glycosylation of proteins. 3 stages:
1) Schiff base formation (reversible)
2) Amadori product formation (reversible)
3) advanced glycosylation end product formation (AGEs) - irreversible
Pathology due to accumulation of AGEs in vessel walls
Intracellular hyperglycemia
- glucose accumulates in tissues that do not require insulin for entry: nerves, lens, kidneys, blood vessels
Metabolized to sorbitol and fructose –> osmotic load –> injury
DM vascular disease
Diabetic microangiopathy: diffuse tihckening of basement membrane, microaneurysm formation
Hyaline arteriolosclerosis: thickening of vessel walls –> HTN
Accelerated atherosclerosis: coronary arter, cerebrovascular, peripheral vascular
DM renal disease
DM most common cause of end-stage renal disease in north america
Glomerulosclerosis
Renal vascular lesion
Infections - acute/chronic pyelonephritis more common/severe in DM
Papillary necrosis - ischemic (type 1); sloughed papilla may cause obstruction
Autonomic neuropathy - urinary retention in bladder
Glomerulosclerosis (DM)
Microalbuminuria - earliest clinically detectable feature
Diffuse glomerulosclerosis:
- diffuse increase in the mesangial matrix in glomerulus
-not specific
Nodular glomerulosclerosis (Kimmelstiel-Wilson lesion)
- distinctive ball-like deposits of matrix in mesangial core of clomerulus
- tends to occur at periphery of glomerulus pushing capillaries aside
- presence of nodular glomerulosclerosis = DM
Renal vascular lesions (DM)
renal atherosclerosis - both large and small vessels
Renal arteriolosclerosis - afferent and efferent arteriole
Eye disease (DM)
diabetic retinopathy
cataracts - usually premature development of senile nuclear sclerosis and cortical cataract, not hyperglycemic cataract due to sorbitol (rare)
glaucoma - neovascularization may affect iris (rare); block drainage of aqueous fluid
ocular palsies- usually secondary to CNIII infarct; Argyll Robertson pupils and Horner’s syndrome
Diabetic retinopathy classifications
Background (non-proliferative)
Pre-proliferative (advanced non-proliferative)
Proliferative retinopathy
Background diabetic retinopathy
Increased vascular permeability and retinal ischemia (microangiopathy)
earliest features = microaneurysms (dots)
Intra-retinal hemorrhages (blots)
hemorrhage into nerve fibre layer (flame shape)
hard exudates (lipid deposits)
Pre-proliferative diabetic retinopathy
increased caliber and beading of retinal veins
cotton wool spots - microinfarcts of nerve fibre layer with fuzzy edges
arteriolar hyalinization (cytoid bodies)
large areas of capillary non-perfusion in absence of new vessels
Proliferative retinopathy
Ischemia and hypoxia of retina –> neovascularization
fragile new vessels rupture and bleed
fibrosis, then contraction causing increased traction on retina
possible retinal detachment
DM neurologic disease
distal symmetric sensori-motor polyneuropathy
Autonomic neuropathy
diabetic polyradiculopathy (diabetic amyotrophy)
mononeuropathy
Distal symmetric sensori-motor polyneuropathy
Most common neuropathy in diabetics, unknown etiology
Sensori-motor nerves affected (motor effects usually less pronounced)
decreased sensation in distal extremities
All sensory modalities affected
Autonomic neuropathy - DM
ED
bowel dysfunction
Diabetic polyradiculopathy
uncommon, usually males with type 2
axon loss at level of nerve root (L2-L4, maybe L5)
rapid development of pain, weakness of upper legs (esp. anterior thighs)
Mononeuropathy
single/mnultiple, peripheral or cranial nerves (compression/entrapment or infarction)
asymmetric
DM skin disease
necrobiosis lipoidica diabeticorum (non-scaling plaque on shi nwith yellow skin, telangiectasia)
granuloma annulare (lesion with raised annular border on dorsum of hand/arm)
injection site lipodystrophy
recurrent infections (esp Candida)
ulcers
DM - infection
malignant otitis externa (Pseudomonas)
rhinocerebral mucormycosis (increased risk if ketoacidotic)
emphysematous cholecystitis
emphysematous pyelonephritis/papillary necrosis
mucocutaneous candidal infections
soft tissue infection - diabetic foot
DM prevention/screening/diagnosis
Inial: fasting plasma glucose (<6.1)
oGTT - higher sensitivity
HbA1C (4-6%)
Insulin PK
based on diffusion time
Oral hypoglycemic agents
sulfonylureas meglitinides alpha-glucosidase inhibitors biguanides thiaxolindinediones incretin
Sulfonylurea MOA
Bind to SU receptors on beta cells
closure of K-ATP channels –> depolarization of cell –> CaV channels open –> Ca influx –> insulin release
Glucose-independent insulin release
Sulfonylurea PK
metabolized in liver
mostly excreted by the kidney
Sulfonylurea effects
improve hyperglycemia and glucotoxicity
reduces HbA1c by 1-2%
Sulfonylurea SEs
weight gain
hypoglycemia (esp in RF, liver failure and elderly)
SU prototype
-ide
Meglitinides MOA
insulin secretagogues
Bind to K-ATP channels on beta cells
Glucose-dependent insulin release
Meglitinide PKs
short-acting, take after meals
liver metabolism
90% fecal excretion
meglitinide suffix
-glinide
meglitinide effects
attenuate post-prandial hyperglycemia
reduces HbA1c by 1-2%
Alpha-glucosidase inhibitor suffix
-acarbose
Alpha-glucosidase inhibitor MOA
decreased conversion of complex CHO to monosaccharides
Alpha-glucosidase inhibitor PK
excreted in feces/urine
take with meals
Alpha-glucosidase inhibitor effect
reduce HbA1c by 0.4-1%
Alpha-glucosidase inhibitor SE
weight neutral
GI symptoms
hypoglycemia
Biguanide prototype
metformin
Biguanide MOA
reduce hepatic gluconeogenesis
increase insulin-stimulated glucose transport at muscle
decrease FA oxidation
Biguanide PK
onset within 1-2 hour
not metabolized
eliminated via urine
Biguanide effects
reduce HbA1c by 1-2%
reduces triglycerides and LDL cholesterol
increases HDL
reduction in MI
metformin SE
wt loss less hyperglycemia GI metallic taste lactic acidosis (rare)
Thiaxolindinedione suffix
-glitazone
Thiaxolindinedione MOA
enhance responsiveness and efficiency of beta cells
Thiaxolindinedione PK
durable monotherapy
requires 6-12 weeks for maximal effect
Thiaxolindinedione effects
Lowers HbA1c by 1-2% over 6-12 weeks
may increase HDL and LDL, reduce TAGs
may improve CV effects
Thiaxolindinedione SEs
weight gain
fluid retention (contraindicated in CHF)
rare risk of macular edema and fractures
hepatotoxicity with troglitazone (less wiht newer agents)
GLP1 agonist suffix
-tide
GLP1 agonist MOA
incretin Actions of endogeneous GLP1: -stimulates insulin secretion - suppresses glucagon secretion -slows gastric emptying -improves insulin sensitivity -reduces food intake
GLP1 agonist PK
injected
GLP1 agonist effect
lowers HbA1c by 0.4-0.8%
GLP1 SE
potential weight loss
nausea, vomiting, bloating
hypoglycemia rare
Dipeptidyl peptidase-IV inhibitor suffix
-sitagliptin
Dipeptidyl peptidase-IV inhibitor MOA
inhibition of DPP-IV (breaks down GLP1)
DDPIV inhibitor effects
lowers HbA1C by 0.4-0.8%
DDPIV inhibitor Se
potential weight loss
nausea vomiting bloating
hypoglycemia rare
PKC activation
Hyperglycemia causes PKC activation
(increased DAG –> PKC activated)
production of VEGF, TGFB and plasminogen activator inhibitor (procoagulant)
Polyol path
glucose –> sorbitol –> fructose
NADPH used up, required for glutathione production
oxidative stress
sorbitol –> cataracts
