Diabetes PATHO Flashcards
Type 1 DM
Prevalence
Canada has one of the highest prevalence’s in the world
Men = women
10% of all diabetes diagnoses
Most common chronic paediatric illness
Diagnosis 11-13 years (rare < 1 years, > 30 years)
White people 2x > than ethnic minorities
Type 1 DM
Risk Factors
- virus
- formulae feeding
- cow milk allergies
- genetics (family history, 50% twins)
- HLA-DR (autoimmune disorders: thyroid (graves, hashimoto), adrenal (addisons), ceilac disease)
Type 1 DM
Pathophysiology
- Auto-immune
- Idiopathic
Genetic predisposition x environment
- formation auto-antibodies against
1. Islet antigen 2 antibodies (IA-2A)
2. anti-glutamic acid decarboxylase (GADA) antibodies - Activation macrophages, cytotoxic T cells, humoral immune response (antibody production)
- Destruction of beta cells (insulin producing cells)
- No insulin released
- No GLUT4, no uptake of glucose in fat/muscle/liver
- No inhibition of glucagon
- No amylin release
- No inhibition glucagon, gastric emptying is not slowed, saiety is not supressed
- removed inhibition glucagon
- increase blood glucose (counter-regulatory hormone)
- liver breaks down glycogen, makes glucose from a.a and FFA
- adipose tissue breaks down fat
- muscle breaks down protein
Type I DM
Onset & Screening
Slow onset
80-90% beta cell destroyed before detected
No screening for T 1 DM
- cannot prevent / delay diagnosis
If diagnosed screen for other auto-immune diseases (HLA-DL)
- Thyroid (graves, hashimoto)
- Celiac
- Addison’s disease
Type 1 DM
Clinical Signs and Symptoms
Polyuria
- osmotic diuresis
- glucosuria pulls water out of body
Polydipsia
- Hyperosmolarity of blood
- low blood volume
- triggers hypothalamus thirst center
Polyphagia
- breakdown of glycogen, muscle, fat stores
Underweight
Diabetic ketoacidosis:
- ketones detected in urine, breath, and blood
- liver oxidizing FFA for energy produces ketone bodies
- metabolic acidosis (hyperventilation, lethargy, coma)
Electrolyte imbalances:
- hyponatremia
- hypokalemia
Cellular dehydration
- seizures
No C-Peptide
- no endogenous insulin production
+/-
- IA-2A antibodies
- GADA antibodies
Blurred vision
- hyperglycemia in lens of eye, pulls water in
Genital Pruritis
Infection, poor wound healing
- hyperglycemia
- micro/macrovasular damage from hyperglycemia
Cardiovascular complications
- parasethesias
- chest pain
- extremity pain
Type 1 DM
Etiology
- Idiopathic
- Auto-immune *HLADR
Type 2 DM
Prevalence
90% Type 2 DM
> 40 years of age
ethnic minorities > white
(indigenous > african, hispanic, asian)
Obesity * (and metabolic syndrome)
men > women
Type 2 DM
Risk Factors
Age
> 40 years
obesity* (primary driver)
metabolic syndrome (dylipidemia, hypertension, abdominal girth, hyperglycemia)
- BP > 130
- TG > 1.7
- Waist circumference > 102cm males, > 88cm females
pre-diabetes (impaired FG, impaired GTT, elevated A1C)
- IFG 6.1-6.9mmol/L
- IGTT 7.8-11.0mmol/L
- 6.0-6.4% A1C
ethnic minorities
Males > females
PCOS
Sleep apnea
NAFLD
neuropsychiatric medications
Insulin Receptor Sensitivity
Modulating factors
- age
- weight
- HTN
- dyslipidemia
- stress
- exercise
Type 2 DM
Clinical Signs and Symptoms
- Silent hyperglycemia
- hyperinsulinemia results in silent hyperglycemia - Symptomatic hyperglycemia (HHS)
- Polyuria (osmotic diuresis)
- polydipsia
- polyphagia
- fatigue
- glucosuria
- albuminuria
- hyperglycemia
- blurred vision
- hyperosmolarity blood
- cellular dehydration, seizures
- electrolyte imabalances: hypokalemia, hyponatremia
- infections, impaired wound healing, genital pruritis
- microvascular and macrovascular complications: CVE, MI, paraesthesias, retinopathy, nephropathy
Type 2 DM
Pathophysiology
- Obesity results in peripheral insulin resistance
- adipokines, pro-inflammatory cytokines
- increased insulin resistance
- increased demand on beta cells
- cytotoxic to beta cells - beta cells hyper secrete insulin (hyperinsulinemia)
- increase beta cell secretion insulin
- beta cell dysfunction
- adipokines are also cytotoxic to beta cells
- silent hyperglycemia
- microvascular and macrovascular damage continues - beta cells begin to dysfunction
- adipokines are cytotoxic
- increased demand, decreased function
- decrease 1. insulin 2. amylin
- decrease response to incretins (GLP1 and GIP) which results in decrease insulin secretion - Decreased insulin and amylin removes negative inhibition on glucagon
- increase gluconeogenesis, and breakdown of fat, protein and glycogen
- increases blood glucose - decreased function amylin
- no saeity
- increased GI motility
Type 2 DM
Screening
Everyone is screened at 40 years, every 3 years
Screen earlier if risk factors present and screen every 6-12 months
*CANRISK calculator
Gestational DM
Prevalence
3-20% of pregnancies
- all mothers screened at 24 weeks
Gestational DM
Risk Factors
80% have pre-diabetes
1. insulin resistance
2. beta cell dysfunction
at baseline prior to pregnancy
- advanced maternal age
- obesity
- ethnic minorities
- family history, personal history (genetics)
- PCOS
- pre-diabetes
Gestational DM
Clinical Manifestations
- Silent hyperglycemia
- asymptomatic
- all mothers screened at 24 weeks - Symptomatic
- polyuria, polydipsia, polyphagia, fatigue, hyperglycemia, weight loss
Gestational DM
Preferred vs. Alternate screening
50g OGTT
- 2 hour mark BG > 9.0mmol/L
then
75g OGTT
- 2 hour mark BG > 8.5mmol/L
*lower threshold as fetus eats the glucose
Gestational DM
Complications of hyperglycemia
- still birth
- spontaneous abortions
- teratogenic (congenital abnormalities)
- pre-eclampsia
- retinopathy
Tighter glycemic control
- A1C < 6.1%
- Hypoglycemia < 3.7mmol/L
Gestational DM
Pathophysiology
Placent causes insulin resistance
- estrogen, progesterone, cortisol, GH, lactogen
- increase maternal resistance to insulin
- increases glucose in blood for the baby
Maternal counter-regulatory hormones released
- glucagon increases blood glucose
beta cell hyperplasia and hypertrophy
- hyperinsulinemia
- increased fetal uptake of glucose
80% of GDM have beta cell dysfunction at baseline along with insulin resistance
Gestational DM
Patient Education Post-Partum
- breast feed
- immediately (prevent hypoglycemia)
- until 4 months (prevent DM in baby and mother) - Re-check FPG at 6 weeks and 6 months
- type 2DM? - montior thyroid dysfunction
- higher risk for post partum thyroiditis
Diabetes Mellitus
Immediate Complications
- Diabetic Ketoacidosis (DKA)
- diabetic coma syndrome
- Type I DM - Hyperosmolar Hyperglycemic Syndrome (HHS)
- Type 2 DM - Hypoglycemic shock
- Insulin shock
- Insulin reaction
- Type 1 or 2 DM
Diabetic Ketoacidosis (DKA)
Risk factors
- Undiagnosed Type 1 DM
- Trigger - Sick, Trauma, Drug reaction (cocaine, SGLT2, anti-psychotics), thyrotoxicosis
- release of counter-regulatory hormones (cortisol) - Missed Insulin
- Insulin antagonists
Diabetic Ketoacidosis
Laboratory Results
BG > 14mmol/L
anion gap
low bicarbonate
high lactate (low pH)
plasma and urine ketoacids (beta hydroxybutyrate, acetoacetone, acetone)
Diabetic Ketoacidosis
Pathophysiology
- No insulin (relative insulin deficiency)
- Activation counter-regulatory hormones
- rise in cortisol
- increase blood glucose
- site of action: 1. liver 2. muscle 3. fat
- Liver: breaks down glycogen, gluconeogenesis from oxidation fat
- Muscle: breakdown protein
- Fat: lipolysis, FFA - FFA oxidation by liver produces ketoacids
- beta hydroxybutyrate
- acetoacetate
- acetone - Reduction pH leads to metabolic acidosis
- bicarbonate low, anion gap formation
- kaussmaul respirations - Hyperglycemia -> clinical signs and symptoms
- polyuria - osmotic diuresis
- dehydration
- hyperosmolality and CNS dehydration
- polydipsia
- polyphagia
- electrolyte imbalances: hyponatremia, hypokalemia
- N/V/D, arrhythmias, abdominal pain etc.
Hyperosmolar Hyperglycemic non-ketotic Syndrome
Risk Factors
- Type 2 DM undiagnosed
- Insulin antagonists
- Illness, trauma, drugs (corticosteroids) - Pancreatitis
- no insulin released
Hyperosmolar Hyperglycemic (HHS)
Laboratory results
BG > 33.5mmol/L
Osmolality > 320mmol/L
BUN:Cr > 20:1
NO KETONES
Hyperosmolar Hyperglycemic Syndrome (HHS)
Pathophysiology
Absolute or relative decrease in insulin
Hyperglycemia
- reduced insulin, blood glucose remains in blood
Silent hyperglycemia
- onset slow
- body has insulin to take up glucose
- progresses silently
- level hyperglycemia much more severe than DKA
Clinical S&S
- polyuria
- polydipsia
- severe dehydration
- severe electrolyte imbalances (N/V/abdominal pain, weakness): hyponatremia, hypokalemia
- poor skin turgor, dry lips, mucous membranes
- hypotensive shock
- poor kidney perfusion leads to accumulation BUN:Cr
- hypothermia (CNS dysfunction), stupor, coma
Higher mortality rate
DKA or HHS?
HHS
Hypoglycemic Shock
Risk Factors
Iatrogenic
- too much insulin
- too much insulin secretagogues
- Combination therapy
- Impaired awareness hypoglycemia (IAH) multiple hypoglycemic episodes (rapidly fluctuating BG)
- Exercise
- To little food with insulin therapy
- Alcohol
- Medications
- beta blockers (mask hypoglycemia) - Decline in insulin need
- Chronic kidney disease (decrease insulin degredation)
- post partum period (gestational DM)
Individuals at high risk for
Hypoglycemic shock
- age
- longer duration diabetes
- more hypoglycemic episodes (threshold hypoglycemia lower)
- diabetic neuropathy (ANS not activated)
- preschool
- cognitive impairment
- low health literacy
Why are frequent hypoglycemic episodes bad
Re-set glucose counter-regulatory threshold
- lower BG required to stimulate SNS response
- Neuroglycopenic symptoms are the first signs (Level 3)
- too late and require assistance to treat
*very dangerous
When are Type 1 DM more likely to experience hypoglcyemic shock?
Night time
Decreased sympathoadrenal repsonse to hypoglycemia
Level 3
*somogyi
Clinical Signs and Symptoms
Hypoglycemia
Adrenergic (Autonomic)
- trembling
- sweating
- palpitations
- pale
- anxiety
- nausea
- tingling
- hunger
Clinical Signs and Symptoms
Hypoglycemia
Neuroglycopenic
- Fatigue
- confusion
- slurred speech
- blurred vision
- weakness
- sensory and motor changes
- HA
- dizziness
- coma
- death
Classifications of Hypoglycemia
Level 1
BG 3.0-3.9mmol/L (< 4.0mmol/L)
Autonomic symptoms
Level 2
BG < 3mmol/L
Neuroglycopenic symptoms (able to self treat)
Level 3
BG < 3mmmol/L
neuroglycopenic symptoms
unable to self treat
Hypoglycemia
Laboratory diagnostics
Normal blood glucose adult 4.0-7.0mmol/L
Neonate < 1.7mmol/L
Adult < 3.9mmol/L
Pregnant adult < 3.7mmol/L
Hypoglycemic Shock
Pathophysiology
Too much insulin
- Trigger: too much insulin, combination therapy, excerise, alcohol, not enough food, sleep
- uptake of BG into cells
Counter-regulatory hormones released
- Cortisol increases: gluconeogenesis, glycogenolysis, lipolysis, proteolysis
- SNS activated: adrenergic symptoms
Insufficient counter-regulatory response
- neuroglycopenic symptoms: CNS depression, confusion, HA, coma, death
Long term Hypoglycemia
Complications
Hypoglycemia is pro-inflammatory
- platelet aggregation
- fibrosis
Long term consequences of hypoglycemia
- Fear of hypoglycemia (keep blood glucose high increase micro and macrovascular complications)
- IAH (impaired awareness hypoglycemia)
- Scaring of the brain (intellectual development, alzheimer’s disease, pontine dysfunction, hemiparesis)
Treatment of Hypoglycemia
- switch from intermediate to long acting insulin
- degludec > glargine > detemir - check insulin regularly at night (impaired awareness hypoglycemia)
- continuous glucose monitoring and continuous subcutaneous insulin infusions
- Increase glucose target for 3 months
- re-sets the adrenergic hypoglycemic set point
- avoidance hypoglycemia for 2 days or 3 months - Avoid drinking
- Exercise
- reduce pre-prandial insulin
- reduce basal insulin at night
- increase carbohydrate intake before exercise
- weights before cardio
- sprints in between cardio - patient and family education
*prevention is easier than treatment
Laboratory Values
Predict what chronic complications
A1C
- CVD, CVE, progression to T2DM
FPG and OGTT
- microvascular complications
Chronic complications of DM
Microvascular complications (capillaries)
1. neuropathy
2. retinopathy
3. nephropathy
Macrovascular complications (major arteries, cerebral arteries)
1. Cardiovascular disease
2. Cerebrovascular disease
3. Peripheral vascular disease
Microvascular complications
Pathophysiology
Hyperglycemia -> glycation end products -> inflammation -> atheroscelerosis -> scaring, narrowing -> ischemia -> necrosis
Retinopathy & DM
DM leading cause of blindness world wide
- non-proliferative stage
- inflammation, increased premeability retina capillaries - pre-proliferative stage
- ischemia, infarcts - proliferative stage
- neovascularization, retinal detachment, blindness
Other:
- blurred vision (lens swelling)
- cataracts
- glaucoma
Nephropathy & DM
DM leading cause of ESRD
50% individuals with DM
- Glomeruloscelerosis
- hyperglycemia damages the glomerular membrane
- inflammation -> scaring -> loss of negative charge and filtration slits
- proteinuria - Acute tubular necrosis
- hyperglycemia damages the epithelium of the nephron tubulse
- cannot reabsorb or secrete (perform functions)
Neuropathy & DM
Most common complication of DM
DM leading cause of nephropathy in the west
demylination of nerves
slows conduction
- sensory nerves
- loss sensation, pain, temperature, vibration, pressure, etc. - motor nerves
- loss of motor funciton
- Charcot Arthropathy - degeneration joints in foot - Autonomic nerves
- gastric paresis
- insensible hypoglycemia
- silent MI
- etc.
Macrovascular Complications
DM
- Cerebrovascular disease (strokes)
- cardiovascular disease (CAD, MI, etc.)
- peripheral vascular disease (ex. gangrene and amputations)
Cardiovascular disease (CAD) and DM
- CAD
- HF
- CAD
Coronary Artery disease leading cause of morbidity and mortality in DM
Hyperglycemia –> glycated end products –> inflammation endothelial lining –> recruitment neutrophils and macrophages -> oxidative damage LDL –> engluphed –> fatty streak / atheroscelerotic plaque –> unstable plaque –> thrombosis
narrow lumen –> ischemia –> infarct –> necrosis
- HF
Atheroscelerosis increases BP
Increase pressure heart pumps against
L ventricular remodelling
Diastolic compliance decreases
HFpEF - heart failure preserved ejection fraction
Peripheral artery disease and DM
Hyperglycemia -> demylination nerves -> slow/no conduction -> injury -> ulceration -> infection -> amputation
Impaired fasting glucose
Pathophysiological changes
6.1-6.9mmol/L
Impaired fasting glucose
*Predicts microvascular complications
PRO
- fast
- easy
- predicts microvascular complications
CON
- variable
- one point in time
- fasting 8 hours
Impaired oral glucose tolerance
Pathophysiological changes
7.8-11.0mmol/L
*predicts microvascular complications
PRO
- fast
- easy
- measure any time of day
CON
- unpalitable
- high cost
- high variability
- one time point
Impaired A1C
Pathophysiology changes
A1C 6.1-6.4%
*predicts microvascular changes
*predicts type 2 DM
*predicts CVD and all cause mortality
PRO
- predictor micro and macrovascular changes
- Predictor type 2 DM advancement
- reflects 120 days glucose management
CON
- not for diagnosis in children or adolescents
- altered values in hemoglobinopathies, age, ethnicity, liver and kidney disease
Pre-Diabetes
Diagnostic Classification
Impaired fasting glucose 6.1-6.9mmol/L
impaired oral glucose tolerance 7.8-11.0mmol/L
impaired A1C 6.1-6.4%
Goal of Treatment
DM
Maintain A1C in target range
- Tight control is not recommended (<6.5%) as associated with higher mortality, no CV benefit (only microvascular benefit)
Individualized based on age: children, adolescent, adult, pregnant, elderly ; and health status
Minimize fluctuations in BG
Minimize hypoglycemic episodes
- more episodes = higher mortality, cardiovascular complications, and IAH
Multifactorial treatment
- BG
- HTN
- dyslipidemia
- exercise
- smoking cessation
Glycemic Targets
Adults
Fasting plasma glucose 4.0-7.0mmol/L
2 hour post prandial glucose 5.0-10mmol/L
A1C < 7%
Glycemic Targets
Pregnancy
A1C < 7% (at minimum)
A1C < 6.5% (goal)
A1C < 6.1% (third trimester)
Prevention
- miscarriage, still birth, spontaneous abortion
- congenital abnormalities
- pre-eclampsia
- retinopathy
Glycemic Targets
Children and Adolescents
A1C < 7.5%
- prevention hypoglycemia (inflammatory scarring of brain and negative impact congitive development and IQ)
- prevention IAH development
Fasting plasma glucose 4.0mmol/L - 8.0mmol/L
2 hour post prandial glucose 5.0mmol/L-10mmol/L
Glycemic Targets
Functional dependence, IAH, frailty, palliative care
A1C 7.1-8.5%
Functional dependence
- unable to notify S&S of hypoglycemia
- IAH and high risk death
Frailty and palliative care
- hypoglycemia = degredation of glycogen, muscle, fat stores
- decreased implication of CV and microvascular damage
IAH
- loosen glycemic control
- re-set counter-regulatory threshold
Laboratory screening
DM
- A1C
- urinalysis (nephropathy)
- retinopathy
- neuropathy
- dyslipidemia
- blood pressure
- vaccinations yearly (influenzae, COVID19)
- smoking, alcohol cessation
- pregnancy planning
- autoimmune disorders (thyroid, celiac, addisons)
Self Monitoring
DM
Blood glucose at minimum TID
A1C levels for glycemic control over 120 days
Ketone monitoring when sick, stressed, trauma
Initiation insulin therapy
Children T2 DM
A1C > 9 %
- insulin and metformin
9% > A1C > 7%
- metformin
- diet, exercise
Nonpharmacological Management
DM
- Exercise (weight loss)
- Diet
Dietary Considerations
DM
- portion control (40-60% carbs, 15-20% protein, 20-35% fat)
- DASH, Mediterranean, Nordic, Vegetarian diets
- whole wheat, nuts, legums/beans/pulses, omega fats, fish, vegetable proteins, vegetables, fruits, high fibre
- low glycemic index carbohydrates
- regular spacing of meals throughout the day
- physical activity
- weight loss
Physical activity
DM
150minutes per week moderate-high intensity aerobic exercise
3x per week resistance training
No more than 2 days rest
Physical exercise induced
Hypoglycemia vs. hyperglycemia
PE induced hypoglycemia
- reduce bolus insulin
- eat before exercise
- reduce basal insulin 20% (exercise long lasting effect)
- cardio before weights
- sprints between weights
PE induced hyperglycemia
- weights and sprints induce counter-regulatory hormones which breakdown lipids, muscle, and glycogen stores to raise glucose levels
