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SMP - APP Part 1 > Lecture 11 - Endocrine Pathophysiology I: Diabetes > Flashcards

Lecture 11 - Endocrine Pathophysiology I: Diabetes Flashcards

1
Q

2 most common complications of diabetes?

A
  1. Blindness

2. Kidney disease

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2
Q

Describe the insulin signaling cascade. 7 steps

A
  1. Binding of insulin to its receptor
  2. Autophosphorylation of the insulin receptor, which then itself acts as a tyrosine kinase that phosphorylates insulin receptor substrate 1 (IRS-1)
  3. Numerous target enzymes, such as protein kinase B and MAP kinase are activated and these enzymes have a multitude of effects on cell function
  4. GLUT4 is recruited to the plasma membrane, where it facilitates glucose entry into the cell
  5. Transport of amino acids, potassium, magnesium, and phosphate into the cell is also facilitated
  6. Synthesis of various enzymes is induced or suppressed
  7. Cell growth is regulated by signal molecules that modulate gene expression: mRNA and IREs (insulin responsive elements)
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3
Q

How to treat a patient that has high plasma [K+]?

A

Insulin and glucose because it increases ATP in the cells, which increases Na+/K+-ATPase and drives K+ into the cells

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4
Q

8 effects of insulin?

A

↓ Appetite
↓ Glucagon

↑ Glucose uptake by muscle, fat, etc.
↑ Glycolysis
↑ Glycogen synthesis
↑ Triglyceride (fat) synthesis

↑ Amino acid uptake
↑ Protein synthesis

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5
Q

10 effects of lack of insulin? What are these primarily mediated by?

A

Primarily mediated by glucagon

↑ Appetite
↑ Glucagon

↓ Glucose uptake by muscle, fat, etc.
↑ Blood glucose

↑ Gluconeogenesis
↑ Lipolysis → ↑ FFAs
↑ Protein breakdown
↑ Glycogenolysis
↑ Ketone body production → ketoacidosis

↓ Protein synthesis

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6
Q

What cells of the pancreas secrete glucagon?

A

α cells of the islets of Langerhans

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7
Q

What is insulin secretion by the pancreas stimulated by?

A

Glucose

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8
Q

What is glucagon secretion inhibited by?

A

Insulin

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9
Q

What happens in a patient when insulin is lacking?

A

Glucagon is always high, independent of the glucose level

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10
Q

How to make a clinical diagnosis of diabetes mellitus? What to note?

A
  1. Fasting plasma glucose level > 126mg/dL (7mmol/L) - NOT DEFINITIVE

OR

  1. Plasma glucose levels in excess > 200mg/dL (11mmol/L) after 2 hours during an OGTT - DEFINITIVE
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11
Q

What is a normal fasting blood glucose level?

A

< 100mg/dL (5.6mmol/L)

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12
Q

What is an OGTT?

A

Oral Glucose Tolerance Test

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13
Q

Why are hungry after a very sweet meal?

A

Because after glucose levels spike they decrease below normal due to high insulin

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14
Q

What is pre-diabetes? 2 types? Describe each. What to note?

A
  1. Impaired fasting glucose (IFG) = condition in which the blood glucose level is 100-125 mg/dL after an overnight fast: not high enough to be classified as diabetes
  2. Impaired glucose tolerance (IGT) = condition in which the blood glucose level is 140-199 mg/dL after a 2-hour oral glucose tolerance test: not high enough to be classified as diabetes

=> depending on the test used to diagnose it

Note: some people have both IFG and IGT

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15
Q

Prevalence of pre-diabetes?

A

~40 percent of U.S. adults ages 40 to 74 have pre-diabetes

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16
Q

What % of pre-diabetes patients become diabetics? What to note?

A

~10% each year

Note: but a lot can be done to prevent or delay diabetes

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17
Q

4 types of diabetes mellitus? Describe each and % of patients.

A
  1. Type 1 diabetes mellitus (IDDM) [~10%] => autoimmune destruction of β-cells
  2. Type 2 diabetes mellitus (NIDDM) [~90%] => insulin resistance

OTHER DIABETES [<1%]

  1. Maturity-onset diabetes of youth (MODY) => genetic defect in insulin production or release
    [~2% of young (i.e. < 15 yo) diabetics]
  2. Gestational diabetes mellitus (GDM) => any diabetes identified during pregnancy
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18
Q

How is the % of Type 1 and Type 2 diabetic patients fluctuating?

A

Type 2 is increasing while Type 1 is constant

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19
Q

Hoe to treat MODY patients? What to note?

A

Drugs that cause the pancreas to release insulin

Note: giving insulin would work too but less easy treatment - this is often given because patients are misdiagnosed

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20
Q

How to diagnose MODY?

A

Genetic testing

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21
Q

What other endocrine disorders cause high blood glucose?

A
  1. Cushing’s disease (high cortisol)
  2. Acromegaly (high GH)
  3. Pheochromocytoma (high catecholamines)
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22
Q

Describe Type 1 diabetes in detail. When do clinical symptoms arise?

A

Type IV hypersensitivity disease in which the immune system kills pancreatic β-cells

Clinical symptoms do not arise until sufficient destruction has occurred to the point where loss of normal glucose tolerance is achieved, typically years after the initial trigger (usually puberty)

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23
Q

What is the trigger of Type 1 diabetes?

A

Unknown

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24
Q

Why do females get more autoimmune diseases than men?

A

Because autoimmune diseases are triggered when hormones are in flux (puberty, pregnancy, menopause)

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25
Q

Can you become a Type 1 diabetic at any age? What to note?

A

YUP

Note: adults almost always get misdiagnosed because it is rare

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26
Q

Describe Type 2 diabetes progression.

A

Progressive loss of insulin sensitivity => as cells, typically muscle and fat, become less responsive to the action of insulin, insulin production by the pancreas is increased => this maintains normal serum glucose, but with resulting hyperinsulinemia => as insulin sensitivity falls, hyperinsulinemia is not sufficient to maintain normal glycemia => hyperglycemia results => chronic hyperglycemia => β-cell destruction and loss of insulin production => consequently elevated hyperglycemia

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27
Q

How long does the entire Type 2 diabetes progression typically require?

A

> 10 years

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28
Q

Describe a drug in development for Type 2 diabetes. Will this help? What to note?

A

Increase amount of glucose muscle cells can take up

NOPE because it will just delay the same problem occurring again

Note: it could however help endurance athletes

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29
Q

Why can some people not become 1,000 lbs?

A

Because they will become diabetic before they are able to produce more fat cells to take up more glucose

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30
Q

Treatment for Type 2 diabetics?

A
  1. Diet to decrease glucose supply => increased insulin sensitivity
  2. Exercise to increase energy utilization => increased insulin sensitivity
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31
Q

Clinical presentation of Type 1 diabetes?

A
  1. Onset < 20 years old (usually)
  2. Normal weight
  3. Decreased blood insulin
  4. Anti-islet cell antibodies
  5. Ketoacidosis is common
32
Q

Clinical presentation of Type 2 diabetes?

A
  1. Onset > 30 years old (usually)
  2. Obese
  3. Increased blood insulin
  4. No anti-islet cell antibodies
  5. Ketoacidosis is rare (only if far progressed)
33
Q

Genetic concordance in identical twins in Type 1 vs Type 2 diabetes?

A

Type 1 < 50%

Type 2 > 90%

34
Q

Describe islets cells in Type 1 vs Type 2 diabetes.

A

Type 1: early insulitis, marked atrophy and fibrosis, and β-cell depletion

Type 2: no insulitis, focal atrophy and amyloid deposits, mild β-cell depletion

35
Q

Probable cause of gestational diabetes?

A

Chorionic somatomammotropin

36
Q

Is gestational diabetes resolved after birth? What to note?

A

YUP, usually

Note: the patient has an increased risk of subsequent gestational diabetes and type 2 diabetes

37
Q

What is diabetes insipidus? Is it related to DM?

A

Defect in water reabsorption in the kidney and is not related to diabetes mellitus

38
Q

What is a good test to measure the amount of insulin produced in a given period?

A

Measure C-peptide concentration in the urine

39
Q

% of US pop that is Type 1 diabetic?

A

0.7%

40
Q

What is insulitis?

A

Disease of the pancreas caused by the infiltration of lymphocytes

41
Q

What do Type 1 and Type 2 diabetes have in common?

A

Hyperglycemia

42
Q

Effect of hyperglycemia on kidneys?

A

Excess glucose excretion => polyuria and glucosuria

43
Q

Equation for filtered load on kidneys?

A

Filtered load = GFR x blood glucose

44
Q

When does glucose start appearing in urine?

A

At normal plasma glucose, the rate of glucose delivery is easily handled by transport capacity in the proximal tubule so that no glucose is excreted

BUT, past this point, which is the tubular maximum for glucose, Tmg, (300 mg of glucose/min) the reabsorption is maximal and cannot be increased, so that we start excreting glucose

45
Q

Conversion of mM of glucose into mg/dL and mg%?

A

1 mM = 18 mg/dL = 18 mg%

46
Q

3 acute complications of DM?

A
  1. Hypoglycemia
  2. Diabetic ketoacidosis in Type 1 diabetes
  3. Hyperosmolar hyperglycemic nonketotic syndrome (HHNKS or HONKS) in Type 2 diabetes
47
Q

5 types of chronic complications of DM?

A
  1. Hyperglycemia and nonenzymatic glycosylation
    Advanced Glycosylation End-products (AGEs)
  2. Microvascular diseases:
    - Diabetic retinopathy
    - Diabetic nephropathy
    - Diabetic cardiomyopathy
    - Microangiopathy
  3. Macrovascular diseases:
    - Coronary artery disease
    - Stroke
    - Peripheral arterial disease
    - Atherosclerosis
    - HT
  4. Increased activity of polyol/sorbitol pathway:
    - Diabetic neuropathy
    - Focal neuropathy
    - Autonomic neuropathy
    - Cataracts
  5. Other:
    - Glaucoma
    - Infection (result of very poor circulation and neuropathy)
    - Gastroparesis
48
Q

How to decrease risk of DM complications?

A

Blood glucose control

49
Q

How is metabolic ketoacidosis avoided in normal patients?

A

Lipolysis => ketone body production => stimulate insulin release => decreases glucagon => decreases lipolysis

50
Q

How does diabetic ketoacidosis occur in diabetic patients?

A

Lack of insulin => high glucagon => high lipolysis => high ketone body production

51
Q

Why is HONKS dangerous?

A

High blood osmolarity => pulls water out of brain cells => death

52
Q

What is gastroparesis?

A

Condition in which your stomach cannot empty itself of food in a normal fashion

53
Q

What gives rise to gangrene in diabetics?

A
  1. Peripheral neuropathy

2. Peripheral vascular disease

54
Q

How does glucose react with proteins? Does this happen enzymatically?

A

Glucose + protein <=> shift base <=> Amadori product => protein cross-link between Amadori products = advanced glycosylation end products (irreversible)

NO ENZYMES REQUIRED

55
Q

What do advanced glycosylation end products cause?

A

Wrinkles and kidney disease and most of the diabetes complications

56
Q

What is HbA1c? What to note?

A

Glycosylated Hb: Amadori product from the reaction of Hb and glucose => measure of average blood glucose over the last week

Note: not over 120 days (life of RBC) because Amadori products are reversible

57
Q

Normal HbA1c?

A

4-5% of Hb

58
Q

Target HbA1c for diabetics?

A

7% of Hb

59
Q

Is an HbA1c measure a definitive test of diabetes?

A

NOPE

60
Q

What increases with HbA1c in Type 1 diabetics? Is this also true in Type 2 diabetics?

A

Risks of microvascular diabetic complications:

  • Diabetic retinopathy
  • Diabetic nephropathy
  • Diabetic neuropathy
  • Diabetic microalbuminuria

Not true for Type 2 diabetics

61
Q

What is the leading cause of IRREVERSIBLE blindness?

A

Diabetes (mainly from retinal damage)

62
Q

Is the prevalence of diabetic retinopathy higher in Type 1 or 2 patients?

A

Higher in type 1 (40%) than in type 2 (20%)

63
Q

What is the earliest phase of diabetic retinopathy called? Describe it.

A

Background diabetic retinopathy: the arteries in the retina become weakened and leak due to advanced glycosylation end products, forming small, dot-like hemorrhages

64
Q

What is the later phase of diabetic retinopathy called? Describe it.

A

Proliferative diabetic retinopathy: circulation problems cause areas of the retina to become ischemic => new, fragile, vessels develop (neovascularization) as the circulatory system attempts to maintain adequate oxygen levels within the retina => these delicate vessels hemorrhage easily

65
Q

Describe diabetic nephropathy.

A
  1. Leakiness of glomerular capillaries due to advanced glycosylation end products => microalbuminuria-proteinuria
  2. Nodular glomerulosclerosis due to inflammation against AGE => decreased GFR
  3. Tubulointerstitial fibrosis
  4. Arteriolar sclerosis
  5. Renal failure, hypertension, cardiovascular disease
66
Q

What is the leading cause of kidney failure?

A

Diabetes

67
Q

How do advanced glycosylation end products (AGE) change with age?

A

INCREASE

68
Q

How do we normally eliminate advanced glycosylation end products?

A

RAGE on macrophages that find them and destroy them

69
Q

Are people with both type 1 and type 2 diabetes at risk for diabetic nephropathy?

A

YUP

70
Q

In what patients is the greatest rate of progression of diabetic nephropathy seen?

A

In patients with poor control of their blood pressure

71
Q

Treatment for diabetic nephropathy? What to note?

A
  1. The main treatment, once proteinuria is diagnosed, is keeping blood pressure under control (to levels less than 130/80) with angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) => slows the progression
  2. Uncontrolled diabetes often requires dialysis

Note: even after dialysis or transplantation, people with diabetes tend to do worse than those without diabetes

72
Q

% of diabetics that develop diabetic nephropathy?

A

30%

73
Q

What does diabetic neuropathy cause? Treatment?

A

Either pain and/or loss of feeling in the toes, feet, legs, hands, and arms

Treatment: drugs that numb the pain, which does not really fix the issue

74
Q

What is a “diabetic foot”? Complication?

A

Blisters and sores may appear on numb areas of the foot “diabetic foot” because pressure or injury goes unnoticed due to diabetic neuropathy and not enough blood flow to the extremities

If foot injuries are not treated promptly, the infection may spread to the bone, and the foot may then have to be amputated

75
Q

What does diabetic autonomic neuropathy cause?

A
  1. Changes in digestion
  2. Changes in bowel and bladder function
  3. Changes in sexual response
  4. Changes in perspiration
  5. It can also affect the nerves that serve the heart and control blood pressure
76
Q

What does focal diabetic neuropathy cause?

A

Sudden weakness of one nerve, or a group of nerves, causing muscle weakness or pain

Any nerve in the body may be affected

SMP - APP Part 1 (8 decks)

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