Pathogenesis of Type 1 & 2 Diabetes Mellitus Flashcards
What is Diabetes Mellitus?
Hyperglycemia due to defective insulin production or action.
What are symptoms of DM?
hunger (polyphagia), thirst (polydipsia), increased urination (polyuria), weight loss
What is the cause of Type 1 DM?
Autoimmune destruction of beta-cells in pancreas.
–> cannot produce insulin
What is the first marker of Type 1 DM?
Multiple Ab(+) due to immune attack on beta-cells. This stage is subclinical so don't get symptoms yet.
What immune cells are involved in the pathogenesis of Type 1 DM? What is the mechanism?
T-cells (infiltrate the islet) - both CD4 & CD8
- direct interaction with beta-cells
- release cytokines (TNF, IL-1)
Final killers of beta-cells are CD8 (CTL) cells
What are the genetic concordance rates in identical twins for each Type 1 and Type 2 DM?
Type 1: > 50%
Type 2: > 90%
What acts as a marker for beta-cell destruction in Type 1 DM?
Islet cell auto-antibodies (ex. GAD, insulin)
What is reason for use of Abatacept in Type 1 DM?
- what other disease is Abatacept used for?
- may protect surviving beta-cells from auto-immune attack near the onset of disease
- also used in RA when DMARDs fail
What are the causes of loss of insulin secretion in Type 2 DM?
- Glucose toxicity (& lipotoxicity)
- Proinflammatory cytokines
- Islet amyloid deposits
What is the mechanism for proinflammatory cytokines in Type 2 DM?
In T2 DM, there is an increased number of macrophages in islets and these produce proinflammatory cytokines (ex. IL-1beta)
What is MODY?
- what is it associated with?
Mature Onset Diabetes in the Young
- associated with genes that regulate beta-cell mass or function
- NOT associated with obesity
Approximately what is the prevalence of Diabetes Mellitus?
1/4 in North America
Before insulin was created as a treatment option, what was the major cause of death in diabetics?
Diabetic ketoacidosis
What is the leading cause of death in diabetic patients?
Heart disease or stroke
List the different types of Diabetes Mellitus and briefly state what each one is.
Type 1 (beta cell destruction) Type 2 (insulin resistance) Type 3 (Other - drug-induced, pancreatic, infectious) Type 4 (Gestational)
Which type of diabetes mellitus is associated with HLA?
- which HLAs are these?
Type 1 DM is associated with DR3 & DR4
Describe the pathogenesis of Type 1 DM.
Environmental triggers
- insulitis
- beta cell sensitivity to injury
- loss of first-phase insulin response
- glc intolerance
- absence of C-peptide
When should patients begin to get screened for DM?
Should be considered in patients over age 40 and reassessed every 3 years.
May start screening younger if patient is at higher risk.
What puts a patient at higher risk for developing DM earlier in life?
- fam hx
- microvascular/macrovascular complications
- other related diseases (PCOS, acanthos nigricans)
- high risk ethnic group (hispanic, aboriginal, african)
- had gestational DM
- have pre-diabetes
- have cardiovascular risk factors
- use drugs a/w diabetes (glucocorticoids, atypical antipsychotics, HIV retrovirals)
What are some acute complications of DM?
- DKA
- HHS (Hyperglycemic Hyperosmolar State)
- Hypoglycemia
- MI
- Infections
- Stroke
What are some common symptoms of DM?
- polyuria
- polydipsia
- polyphagia
- weight gain/loss
- more bruising/takes longer to heal
- extreme fatigue
- blurred vision
- neuropathies/tingling
- frequent infections
- ED
What are some neonatal complications of gestational diabetes?
- macrosomia
- hypoglycemia
- hypocalcemia
- respiratory distress syndrome
- polycythemia
- intrauterine death
- congenital malformations
- hyperbilirubinemia
- may be at higher risk of developing diabetes
What does a high creatinine level suggest?
Pre-renal failure
If pt has low pH and low HCO3-, what does that suggest?
Metabolic Acidosis
Briefly, what is the pathogenesis of DKA (diabetic ketoacidosis)?
- low insulin:counterregulatory hormone ratio
- increase in lipolysis, gluconeogenesis, glycogenolysis, proteinolysis
- increase in ketogenesis
- Results in hyperglycemia, ketones on breath, and acidemia
What are the two main reasons for diabetic coma?
- and another less common reason..
DKA & HHS
- & hypoglycemia
Why is polyphagia a symptom of diabetes?
- hyperglycemia
- -> glycosuria
- -> loss of calories (also leads to weight loss)
- -> hunger
- -> polyphagia
What are the main elements of treatment for DKA?
- rehydration (saline)
- insulin
- K+
- HCO3- (only if pH < 7)
- treat underlying problem, if applicable
- Constant monitoring
What is the most common group of patients presenting with HHS (Hyperglycemic Hyperosmolar State)?
Elderly diabetic (Type 2) patients living alone.
What causes pre-renal failure?
Depletion of intravascular volume (from polyuria –> loss of electrolytes & water)
Does good glc control reduce chronic complications?
Yes (by ~60%)
What lab tests are used to monitor diabetic nephropathy?
Serum creatinine (to get eGFR)
Albumin excretion rate
(..or albumin:creatinine ratio)
What is the method for monitoring glc?
Self-monitoring QID
HbA1c Q3months
What physical exam tests should be done routinely to monitor patients with diabetes?
- BP
- cardiovascular assessment
- opthalmological exam
- neurological exam exam
(also should check lipids)
How is HbA1c formed?
Irreversible modification (Non-enzymatic glycosylation) of beta-chain of HbA. More blood glucose = more glycosylation (accumulates over life-span of RBC, thus reflects average blood glc over 3-4mo)
Other than Hb, what else can glycosylation affect?
Can affect any protein exposed to high glc levels:
ex. collagen, lens crystallin, bsmt membrane proteins.
May form AGEs (Advanced Glycosylation End-products)
What is the leading cause of end-stage renal failure?
Diabetes
What are the most important things to control in patients with diabetes?
- Glucose levels
- BP
- lipids (LDL)
- ACR, eGFR
When do chronic complications of DM usually manifest?
10-15 years after onset of disease
What are the 4 mechanisms of glucotoxicity?
- AGEs
- Activation of PKC
- Disturbances in polyol pathways
- Generation of F-6-P
What is AGE?
What is the mechanism of how AGE works?
AGE = Advanced Glycation End-products
AGE binds RAGE
–> release of cytokines & growth factors (TGF-beta, VEGF)
What is diabetic microangiopathy?
Vascular complication of DM:
=Hyaline arteriolosclerosis (affects small arterioles)
- diffuse thickening of bsmt membrane and arteriole walls
- rigid vessels; narrow lumen
- leaky vessels or microaneurysms
Atherosclerosis is accelerated in patients with diabetes. What are the main effects of this process and which organs are targeted?
Brain - Cerebrovascular disease (stroke)
Heart - CAD
Peripheral vasculature (amputations, impotence, poor wound healing).
Why do disorders of fatty acid metabolism cause hypoglycemia?
Cannot produce ketones so body is dependent on glc, thus becomes hypoglycemic more easily
Acanthosis nigricans is associated with what disease?
Type 2 Diabetes Mellitus
With respect to insulin and glucagon secretion, what is the effect of the sympathetic nervous system?
Inhibits insulin secretion;
Stimulates glucagon secretion
With respect to insulin and glucagon secretion, what is the effect of the parasympathetic nervous system?
Stimulates both glucagon and insulin secretion.
What is the main cause for LOC in HHS?
Cerebral neuron dehydration
What are the actions of metformin?
Increase insulin sensitivity
Inhibit glc absorption
Activate GLUT-4
What does a deficiency in cortisol cause?
Difficulty excreting free water (leading to dilutional hyponatremia).
What is Addison’s disease?
Autoimmune adrenal insufficiency
What is carnitine used for?
Transports FAs into mitochondria for beta-oxidation
What percent of the brain’s energy is derived from glc?
90%
What is Whipple’s triad?
- Pt shows signs of hypoglycemia
- Blood glc < 2.5mmol/L
- Symptoms improve with rapid dose of glc
What are some neuroglycopenic symptoms?
- tiredness
- confusion
- decreased LOC
- blurred/double vision
- behavioural changes
- dizziness/uncoordination
- paresthesias
- slurred speech
- headache/hunger
What are some autonomic adrenergic symptoms of hypoglycemia?
- increased HR
- diaphoresis
- tremors
- anxiety
- palpitations
- nervousness
- feeling cold
How is the brain directly involved in glc homeostasis?
Pituitary secretes hormones (Cortisol & GH)
Of the counter-regulatory hormones, which are slow-acting and which are fast-acting?
Glucagon & Epinephrine = fast-acting
Cortisol & GH = slow-acting
What is the action of GH?
Lipolysis –> glycerol (to gluconeogenesis) and FFAs (alternate enrgy source)
What is the action of Cortisol?
Gluconeogenesis, lipolysis, & protein catabolism
What is the importance of lipolysis?
- provides energy (ATP) for gluconeogenesis
- makes glycerol (can be used in gluconeogenesis)
What are the specific actions of glucagon?
Increase gluconeogenesis
Increase glycogenolysis
What are the specific actions of epinephrine?
Increase gluconeogenesis
Increase glycogenolysis
Inhibit peripheral glc use
Stimulates lipolysis
What should be done for someone in an acute coma from hypoglycemia?
Administer 20-50 mL of 50% glc / 1-3 min
1 mg of glucagon IM or IV
In a patient who appears ill/medicated, what are some causes of hypoglycemia?
- Drugs (ex. insulin, alcohol)
- Critical illness (ex. hepatic, renal, cardiac failure, sepsis)
- Hormone deficiencies (ex. cortisol)
- Non-islet cell tumour (ex. mesenchymal IGFII)
In patients who are otherwise well, what are some causes of hypoglycemia?
- Endogenous hyperinsulinemia (insulinoma, nesidioblastosis)
- Factitious insulin, sulfonylureas
- Ab to insulin receptor
Use the ExPLAIN pneumonic to generate a list of causes for hypoglycemia.
Exogenous Pituitary failure Liver failure Adrenal insufficiency Insulinoma Neoplasm
Directly how does alcohol affect glucose metabolism?
Alcohol inhibits gluconeogenesis
