Pathogenesis of Type 1 & 2 Diabetes Mellitus Flashcards by Chelsea V

What is Diabetes Mellitus?

Hyperglycemia due to defective insulin production or action.

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What are symptoms of DM?

hunger (polyphagia), thirst (polydipsia), increased urination (polyuria), weight loss

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What is the cause of Type 1 DM?

Autoimmune destruction of beta-cells in pancreas.

–> cannot produce insulin

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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.

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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

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What are the genetic concordance rates in identical twins for each Type 1 and Type 2 DM?

Type 1: > 50%

Type 2: > 90%

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What acts as a marker for beta-cell destruction in Type 1 DM?

Islet cell auto-antibodies (ex. GAD, insulin)

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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

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What are the causes of loss of insulin secretion in Type 2 DM?

Glucose toxicity (& lipotoxicity)
Proinflammatory cytokines
Islet amyloid deposits

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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)

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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

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Approximately what is the prevalence of Diabetes Mellitus?

1/4 in North America

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Before insulin was created as a treatment option, what was the major cause of death in diabetics?

Diabetic ketoacidosis

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What is the leading cause of death in diabetic patients?

Heart disease or stroke

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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)

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Which type of diabetes mellitus is associated with HLA?

- which HLAs are these?

Type 1 DM is associated with DR3 & DR4

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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

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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.

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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)

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What are some acute complications of DM?

DKA
HHS (Hyperglycemic Hyperosmolar State)
Hypoglycemia
MI
Infections
Stroke

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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

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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

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What does a high creatinine level suggest?

Pre-renal failure

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If pt has low pH and low HCO3-, what does that suggest?

Metabolic Acidosis

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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?

1. AGEs 2. Activation of PKC 3. Disturbances in polyol pathways 4. 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?

1. Drugs (ex. insulin, alcohol) 2. Critical illness (ex. hepatic, renal, cardiac failure, sepsis) 3. Hormone deficiencies (ex. cortisol) 4. Non-islet cell tumour (ex. mesenchymal IGFII)

In patients who are otherwise well, what are some causes of hypoglycemia?

1. Endogenous hyperinsulinemia (insulinoma, nesidioblastosis) 2. Factitious insulin, sulfonylureas 3. 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

Pathogenesis of Type 1 & 2 Diabetes Mellitus Flashcards

(68 cards)