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Endocrine & Metabolism > Pathogenesis of Type 1 & 2 Diabetes Mellitus > Flashcards

Pathogenesis of Type 1 & 2 Diabetes Mellitus Flashcards

1
Q

What is Diabetes Mellitus?

A

Hyperglycemia due to defective insulin production or action.

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2
Q

What are symptoms of DM?

A

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

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3
Q

What is the cause of Type 1 DM?

A

Autoimmune destruction of beta-cells in pancreas.

–> cannot produce insulin

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4
Q

What is the first marker of Type 1 DM?

A 
Multiple Ab(+) due to immune attack on beta-cells.
This stage is subclinical so don't get symptoms yet.
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5
Q

What immune cells are involved in the pathogenesis of Type 1 DM? What is the mechanism?

A

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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6
Q

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

A

Type 1: > 50%

Type 2: > 90%

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7
Q

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

A

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

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8
Q

What is reason for use of Abatacept in Type 1 DM?

- what other disease is Abatacept used for?

A
  • 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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9
Q

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

A
  1. Glucose toxicity (& lipotoxicity)
  2. Proinflammatory cytokines
  3. Islet amyloid deposits
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10
Q

What is the mechanism for proinflammatory cytokines in Type 2 DM?

A

In T2 DM, there is an increased number of macrophages in islets and these produce proinflammatory cytokines (ex. IL-1beta)

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11
Q

What is MODY?

- what is it associated with?

A

Mature Onset Diabetes in the Young

  • associated with genes that regulate beta-cell mass or function
  • NOT associated with obesity
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12
Q

Approximately what is the prevalence of Diabetes Mellitus?

A

1/4 in North America

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13
Q

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

A

Diabetic ketoacidosis

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14
Q

What is the leading cause of death in diabetic patients?

A

Heart disease or stroke

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15
Q

List the different types of Diabetes Mellitus and briefly state what each one is.

A 
Type 1 (beta cell destruction)
Type 2 (insulin resistance)
Type 3 (Other - drug-induced, pancreatic, infectious)
Type 4 (Gestational)
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16
Q

Which type of diabetes mellitus is associated with HLA?

- which HLAs are these?

A

Type 1 DM is associated with DR3 & DR4

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17
Q

Describe the pathogenesis of Type 1 DM.

A

Environmental triggers

  • insulitis
  • beta cell sensitivity to injury
  • loss of first-phase insulin response
  • glc intolerance
  • absence of C-peptide
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18
Q

When should patients begin to get screened for DM?

A

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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19
Q

What puts a patient at higher risk for developing DM earlier in life?

A
  • 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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20
Q

What are some acute complications of DM?

A
  • DKA
  • HHS (Hyperglycemic Hyperosmolar State)
  • Hypoglycemia
  • MI
  • Infections
  • Stroke
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21
Q

What are some common symptoms of DM?

A
  • 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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22
Q

What are some neonatal complications of gestational diabetes?

A
  • macrosomia
  • hypoglycemia
  • hypocalcemia
  • respiratory distress syndrome
  • polycythemia
  • intrauterine death
  • congenital malformations
  • hyperbilirubinemia
  • may be at higher risk of developing diabetes
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23
Q

What does a high creatinine level suggest?

A

Pre-renal failure

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24
Q

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

A

Metabolic Acidosis

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25
Q

Briefly, what is the pathogenesis of DKA (diabetic ketoacidosis)?

A
  • low insulin:counterregulatory hormone ratio
  • increase in lipolysis, gluconeogenesis, glycogenolysis, proteinolysis
  • increase in ketogenesis
  • Results in hyperglycemia, ketones on breath, and acidemia
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26
Q

What are the two main reasons for diabetic coma?

- and another less common reason..

A

DKA & HHS

- & hypoglycemia

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27
Q

Why is polyphagia a symptom of diabetes?

A
  • hyperglycemia
  • -> glycosuria
  • -> loss of calories (also leads to weight loss)
  • -> hunger
  • -> polyphagia
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28
Q

What are the main elements of treatment for DKA?

A
  • rehydration (saline)
  • insulin
  • K+
  • HCO3- (only if pH < 7)
  • treat underlying problem, if applicable
  • Constant monitoring
29
Q

What is the most common group of patients presenting with HHS (Hyperglycemic Hyperosmolar State)?

A

Elderly diabetic (Type 2) patients living alone.

30
Q

What causes pre-renal failure?

A

Depletion of intravascular volume (from polyuria –> loss of electrolytes & water)

31
Q

Does good glc control reduce chronic complications?

A

Yes (by ~60%)

32
Q

What lab tests are used to monitor diabetic nephropathy?

A

Serum creatinine (to get eGFR)
Albumin excretion rate
(..or albumin:creatinine ratio)

33
Q

What is the method for monitoring glc?

A

Self-monitoring QID

HbA1c Q3months

34
Q

What physical exam tests should be done routinely to monitor patients with diabetes?

A
  • BP
  • cardiovascular assessment
  • opthalmological exam
  • neurological exam exam
    (also should check lipids)
35
Q

How is HbA1c formed?

A 
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)
36
Q

Other than Hb, what else can glycosylation affect?

A

Can affect any protein exposed to high glc levels:
ex. collagen, lens crystallin, bsmt membrane proteins.

May form AGEs (Advanced Glycosylation End-products)

37
Q

What is the leading cause of end-stage renal failure?

A

Diabetes

38
Q

What are the most important things to control in patients with diabetes?

A
  • Glucose levels
  • BP
  • lipids (LDL)
  • ACR, eGFR
39
Q

When do chronic complications of DM usually manifest?

A

10-15 years after onset of disease

40
Q

What are the 4 mechanisms of glucotoxicity?

A
  1. AGEs
  2. Activation of PKC
  3. Disturbances in polyol pathways
  4. Generation of F-6-P
41
Q

What is AGE?

What is the mechanism of how AGE works?

A

AGE = Advanced Glycation End-products
AGE binds RAGE
–> release of cytokines & growth factors (TGF-beta, VEGF)

42
Q

What is diabetic microangiopathy?

A

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

43
Q

Atherosclerosis is accelerated in patients with diabetes. What are the main effects of this process and which organs are targeted?

A

Brain - Cerebrovascular disease (stroke)
Heart - CAD
Peripheral vasculature (amputations, impotence, poor wound healing).

44
Q

Why do disorders of fatty acid metabolism cause hypoglycemia?

A

Cannot produce ketones so body is dependent on glc, thus becomes hypoglycemic more easily

45
Q

Acanthosis nigricans is associated with what disease?

A

Type 2 Diabetes Mellitus

46
Q

With respect to insulin and glucagon secretion, what is the effect of the sympathetic nervous system?

A

Inhibits insulin secretion;

Stimulates glucagon secretion

47
Q

With respect to insulin and glucagon secretion, what is the effect of the parasympathetic nervous system?

A

Stimulates both glucagon and insulin secretion.

48
Q

What is the main cause for LOC in HHS?

A

Cerebral neuron dehydration

49
Q

What are the actions of metformin?

A

Increase insulin sensitivity
Inhibit glc absorption
Activate GLUT-4

50
Q

What does a deficiency in cortisol cause?

A

Difficulty excreting free water (leading to dilutional hyponatremia).

51
Q

What is Addison’s disease?

A

Autoimmune adrenal insufficiency

52
Q

What is carnitine used for?

A

Transports FAs into mitochondria for beta-oxidation

53
Q

What percent of the brain’s energy is derived from glc?

A

90%

54
Q

What is Whipple’s triad?

A
  • Pt shows signs of hypoglycemia
  • Blood glc < 2.5mmol/L
  • Symptoms improve with rapid dose of glc
55
Q

What are some neuroglycopenic symptoms?

A
  • tiredness
  • confusion
  • decreased LOC
  • blurred/double vision
  • behavioural changes
  • dizziness/uncoordination
  • paresthesias
  • slurred speech
  • headache/hunger
56
Q

What are some autonomic adrenergic symptoms of hypoglycemia?

A
  • increased HR
  • diaphoresis
  • tremors
  • anxiety
  • palpitations
  • nervousness
  • feeling cold
57
Q

How is the brain directly involved in glc homeostasis?

A

Pituitary secretes hormones (Cortisol & GH)

58
Q

Of the counter-regulatory hormones, which are slow-acting and which are fast-acting?

A

Glucagon & Epinephrine = fast-acting

Cortisol & GH = slow-acting

59
Q

What is the action of GH?

A

Lipolysis –> glycerol (to gluconeogenesis) and FFAs (alternate enrgy source)

60
Q

What is the action of Cortisol?

A

Gluconeogenesis, lipolysis, & protein catabolism

61
Q

What is the importance of lipolysis?

A
  • provides energy (ATP) for gluconeogenesis

- makes glycerol (can be used in gluconeogenesis)

62
Q

What are the specific actions of glucagon?

A

Increase gluconeogenesis

Increase glycogenolysis

63
Q

What are the specific actions of epinephrine?

A

Increase gluconeogenesis
Increase glycogenolysis

Inhibit peripheral glc use
Stimulates lipolysis

64
Q

What should be done for someone in an acute coma from hypoglycemia?

A

Administer 20-50 mL of 50% glc / 1-3 min

1 mg of glucagon IM or IV

65
Q

In a patient who appears ill/medicated, what are some causes of hypoglycemia?

A
  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)
66
Q

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

A
  1. Endogenous hyperinsulinemia (insulinoma, nesidioblastosis)
  2. Factitious insulin, sulfonylureas
  3. Ab to insulin receptor
67
Q

Use the ExPLAIN pneumonic to generate a list of causes for hypoglycemia.

A 
Exogenous
Pituitary failure
Liver failure
Adrenal insufficiency
Insulinoma
Neoplasm
68
Q

Directly how does alcohol affect glucose metabolism?

A

Alcohol inhibits gluconeogenesis

Endocrine & Metabolism (5 decks)

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