Lecture 11 - Endocrine Pathophysiology I: Diabetes Flashcards
1
Q
2 most common complications of diabetes?
A
- Blindness
2. Kidney disease
2
Q
Describe the insulin signaling cascade. 7 steps
A
- Binding of insulin to its receptor
- Autophosphorylation of the insulin receptor, which then itself acts as a tyrosine kinase that phosphorylates insulin receptor substrate 1 (IRS-1)
- Numerous target enzymes, such as protein kinase B and MAP kinase are activated and these enzymes have a multitude of effects on cell function
- GLUT4 is recruited to the plasma membrane, where it facilitates glucose entry into the cell
- Transport of amino acids, potassium, magnesium, and phosphate into the cell is also facilitated
- Synthesis of various enzymes is induced or suppressed
- Cell growth is regulated by signal molecules that modulate gene expression: mRNA and IREs (insulin responsive elements)
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
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
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
6
Q
What cells of the pancreas secrete glucagon?
A
α cells of the islets of Langerhans
7
Q
What is insulin secretion by the pancreas stimulated by?
A
Glucose
8
Q
What is glucagon secretion inhibited by?
A
Insulin
9
Q
What happens in a patient when insulin is lacking?
A
Glucagon is always high, independent of the glucose level
10
Q
How to make a clinical diagnosis of diabetes mellitus? What to note?
A
- Fasting plasma glucose level > 126mg/dL (7mmol/L) - NOT DEFINITIVE
OR
- Plasma glucose levels in excess > 200mg/dL (11mmol/L) after 2 hours during an OGTT - DEFINITIVE
11
Q
What is a normal fasting blood glucose level?
A
< 100mg/dL (5.6mmol/L)
12
Q
What is an OGTT?
A
Oral Glucose Tolerance Test
13
Q
Why are hungry after a very sweet meal?
A
Because after glucose levels spike they decrease below normal due to high insulin
14
Q
What is pre-diabetes? 2 types? Describe each. What to note?
A
- 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
- 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
15
Q
Prevalence of pre-diabetes?
A
~40 percent of U.S. adults ages 40 to 74 have pre-diabetes
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
17
Q
4 types of diabetes mellitus? Describe each and % of patients.
A
- Type 1 diabetes mellitus (IDDM) [~10%] => autoimmune destruction of β-cells
- Type 2 diabetes mellitus (NIDDM) [~90%] => insulin resistance
OTHER DIABETES [<1%]
- Maturity-onset diabetes of youth (MODY) => genetic defect in insulin production or release
[~2% of young (i.e. < 15 yo) diabetics] - Gestational diabetes mellitus (GDM) => any diabetes identified during pregnancy
18
Q
How is the % of Type 1 and Type 2 diabetic patients fluctuating?
A
Type 2 is increasing while Type 1 is constant
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
20
Q
How to diagnose MODY?
A
Genetic testing
21
Q
What other endocrine disorders cause high blood glucose?
A
- Cushing’s disease (high cortisol)
- Acromegaly (high GH)
- Pheochromocytoma (high catecholamines)
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)
23
Q
What is the trigger of Type 1 diabetes?
A
Unknown
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)
25
Can you become a Type 1 diabetic at any age? What to note?
YUP
Note: adults almost always get misdiagnosed because it is rare
26
Describe Type 2 diabetes progression.
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
27
How long does the entire Type 2 diabetes progression typically require?
> 10 years
28
Describe a drug in development for Type 2 diabetes. Will this help? What to note?
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
29
Why can some people not become 1,000 lbs?
Because they will become diabetic before they are able to produce more fat cells to take up more glucose
30
Treatment for Type 2 diabetics?
1. Diet to decrease glucose supply => increased insulin sensitivity
2. Exercise to increase energy utilization => increased insulin sensitivity
31
Clinical presentation of Type 1 diabetes?
1. Onset < 20 years old (usually)
2. Normal weight
3. Decreased blood insulin
4. Anti-islet cell antibodies
5. Ketoacidosis is common
32
Clinical presentation of Type 2 diabetes?
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
Genetic concordance in identical twins in Type 1 vs Type 2 diabetes?
Type 1 < 50%
| Type 2 > 90%
34
Describe islets cells in Type 1 vs Type 2 diabetes.
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
Probable cause of gestational diabetes?
Chorionic somatomammotropin
36
Is gestational diabetes resolved after birth? What to note?
YUP, usually
Note: the patient has an increased risk of subsequent gestational diabetes and type 2 diabetes
37
What is diabetes insipidus? Is it related to DM?
Defect in water reabsorption in the kidney and is not related to diabetes mellitus
38
What is a good test to measure the amount of insulin produced in a given period?
Measure C-peptide concentration in the urine
39
% of US pop that is Type 1 diabetic?
0.7%
40
What is insulitis?
Disease of the pancreas caused by the infiltration of lymphocytes
41
What do Type 1 and Type 2 diabetes have in common?
Hyperglycemia
42
Effect of hyperglycemia on kidneys?
Excess glucose excretion => polyuria and glucosuria
43
Equation for filtered load on kidneys?
Filtered load = GFR x blood glucose
44
When does glucose start appearing in urine?
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
Conversion of mM of glucose into mg/dL and mg%?
1 mM = 18 mg/dL = 18 mg%
46
3 acute complications of DM?
1. Hypoglycemia
2. Diabetic ketoacidosis in Type 1 diabetes
3. Hyperosmolar hyperglycemic nonketotic syndrome (HHNKS or HONKS) in Type 2 diabetes
47
5 types of chronic complications of DM?
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
How to decrease risk of DM complications?
Blood glucose control
49
How is metabolic ketoacidosis avoided in normal patients?
Lipolysis => ketone body production => stimulate insulin release => decreases glucagon => decreases lipolysis
50
How does diabetic ketoacidosis occur in diabetic patients?
Lack of insulin => high glucagon => high lipolysis => high ketone body production
51
Why is HONKS dangerous?
High blood osmolarity => pulls water out of brain cells => death
52
What is gastroparesis?
Condition in which your stomach cannot empty itself of food in a normal fashion
53
What gives rise to gangrene in diabetics?
1. Peripheral neuropathy
| 2. Peripheral vascular disease
54
How does glucose react with proteins? Does this happen enzymatically?
Glucose + protein <=> shift base <=> Amadori product => protein cross-link between Amadori products = advanced glycosylation end products (irreversible)
NO ENZYMES REQUIRED
55
What do advanced glycosylation end products cause?
Wrinkles and kidney disease and most of the diabetes complications
56
What is HbA1c? What to note?
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
Normal HbA1c?
4-5% of Hb
58
Target HbA1c for diabetics?
7% of Hb
59
Is an HbA1c measure a definitive test of diabetes?
NOPE
60
What increases with HbA1c in Type 1 diabetics? Is this also true in Type 2 diabetics?
Risks of microvascular diabetic complications:
- Diabetic retinopathy
- Diabetic nephropathy
- Diabetic neuropathy
- Diabetic microalbuminuria
Not true for Type 2 diabetics
61
What is the leading cause of IRREVERSIBLE blindness?
Diabetes (mainly from retinal damage)
62
Is the prevalence of diabetic retinopathy higher in Type 1 or 2 patients?
Higher in type 1 (40%) than in type 2 (20%)
63
What is the earliest phase of diabetic retinopathy called? Describe it.
Background diabetic retinopathy: the arteries in the retina become weakened and leak due to advanced glycosylation end products, forming small, dot-like hemorrhages
64
What is the later phase of diabetic retinopathy called? Describe it.
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
Describe diabetic nephropathy.
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
What is the leading cause of kidney failure?
Diabetes
67
How do advanced glycosylation end products (AGE) change with age?
INCREASE
68
How do we normally eliminate advanced glycosylation end products?
RAGE on macrophages that find them and destroy them
69
Are people with both type 1 and type 2 diabetes at risk for diabetic nephropathy?
YUP
70
In what patients is the greatest rate of progression of diabetic nephropathy seen?
In patients with poor control of their blood pressure
71
Treatment for diabetic nephropathy? What to note?
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
% of diabetics that develop diabetic nephropathy?
30%
73
What does diabetic neuropathy cause? Treatment?
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
What is a "diabetic foot"? Complication?
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
What does diabetic autonomic neuropathy cause?
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
What does focal diabetic neuropathy cause?
Sudden weakness of one nerve, or a group of nerves, causing muscle weakness or pain
Any nerve in the body may be affected
