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48 Cards in this Set

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  • Back
What does hyperglycemia memory mean?
It meas that sustained hyperglycemia causes substantial amounts of biochemical abnormalities and this damage is not easily reversed.
What are some cell defences against AGE's? (2)
1. NADPH-dependant oxoaldehyde reductase - metabolizes the reactive dicarbonyls.
2. AGE receptors that trigger the internalization and degradation of the AGE
** AGE linked with B-amyloid plaques (AD) and with carbonyl stress (bone lesions, a-sclerosis and amyloidosis).
Why is the retina particularly vulnerable to damage by AGE?
B/c retina has very good circulation and the differentiated cells of the eye little or no regenerative capacity.
What happens when retinal pericytes are grown on AGE - modified basement membranes? (2 things that have a common result)
(AGE also impairs one intracellular process and modifies another?)
- impaired responses to vconstrive peptide Endothelin 1 (d/t a reduction in ET receptors)
- marked cytoskeleton alterations
= ↑ pressure = ↑ risk of leaks
- also impairs intracellular lipid metabolism and
- modifies the antiooxidant enzymes catalase and Superoxide Dismutase (SOD)
AGE will cause upregulation of Vascular Endothelial Growth Factor (VEGF). What effect does this have on the retina?
↑ VEGF will ↑ vasopermeability and in doing so compromise the blood-retina barrier. When this happens there is increased risk of hemorrhage and detatchement
What are the current 2 anti-AGE strategies?
1. Fight AGE-induce X-linking:
Aminoguanidine - inhibits x-linking and has shown some success
ALT - 711 will destroy AGE x-linking and faciliate the clearance of AGE products (↑ arterial compliance)
2. Carbonyl scavengers: AmadorINS will scavenge reactive dicarbonyls and inhibit conversions of amadorI --> AGE
- Vit B 6 derivative, Pyridoxamine
With prolonged exposure to high BS, glycation (NOT glycosylation) of HgA results in the formation of HgA1c.
1. What is the specific reaction?
2. What 3 things are associated with the presence of HgA1c?
3. What is a normal HgA1c? Every ↑ 1% in HgA1c causes a __% ↑ in microvascular complications.
1. Lysine (on the Hg) + glucose --> Aldimine (schiff base) --> Ketoamine (Amadori)
2. ↑ CRP, TNFa, and IL-6, all inflamatory markers!
3. Normal = 4.0-5.9%, target: 6.6-6.9%, take action if 7.0 and greater!
Every ↑1% in HgA1c = 30%↑ in microvascular complications.
How does elevated blood sugar lead to the formation of AGE (Advanced Glycation Endproducts)?
3 steps
1. Glucose rings open up exposing a reactive aldehyde at one end
2. The aldehyde interacts with free -NH3 groups on proteins, PLP's and DNA to form Schiff bases ---> rearrange into amadori products (with ↑stability)
3. Amadori oxidized & dehydrated to reactive dicarbonyls that X-link free amino groups on PLP's and proteins = AGE formation
Sustained high levels of blood sugar leads to increased rates of glycolysis. Why is this bad?
↑ fuel for krebs = ↑ oxidative P-lation = ↑ superoxide + reactive O2 species that can oxidize the ++ polyunsaturated fats in the retina. The oxidized fats will modify proteins (also think LDL-ox).
=> oxidative stress
What is the pathological receptor-mediated process associated with AGE's?
AGE + endothelial/mesangial/Mphage cells ---> activation of NFk-B = ↑ regulation of pro-inflammatory factors.
** if you block RAGE then you can ↓ inflamatory cytokines!
If you have IDDM, why do you need to keep taking insulin when you're sick?
B/c insulin will inhibit hormone sensitive lipase and thus prevent the use of FFA as fuels. This prevents ketogenesis. The caveat being that you need to keep eating to avoid hypoglycemia. Go to hospital if unable to eat.
Is it recommended for diabetics to eat omega 3 fats? Why or why not?
No b/c while these fats may lower TG and VLDL, the also increase hepatic glucose output which is less than ideal.
Should diabetics avoid fructose? Why or why not?
Yes - at the moment anyways. Fructose will raise LDL which is bad but it appears that it may also lower HgA1C which is good but not enough to off-set the LDL!
Diabetes diagnoses is made when p.glucose exceeds certain thresholds. What are these and what are they based on?
fasting PG of >= 7.0 mmol/L
Casual PG of >= 11.1 mmol/L + symptoms
2hrs post-oral glucose challenge >= 11.1mmol/L
These are based on the risk of developing retinopathy.
What are the 2 main consequences to ↓ glucose transport into cells (ie ↓ insulin)?
If insulin low:
1. Inhibition of HSL is lost, (counter-regulators are also high and thy +--> HSL), = lipolysis gets stimulated
2. Blood sugar ↑ as does hepatic release of sugar
What are the general chemical reactions that generates ketone bodies?
TG --> FFA ---> Acetyl CoA ---> Acetoacetyl CoA ---> Acetoacetate*
= (reduction =)B-hydroxybutyrate* + (decarboxylation=)Acetone
What are the symptoms of DKA? (5)

What are the 2 main signs of DKA (associated with diuresis and CNS)?
Symptoms of DKA:
1. Fatigue, lethargy, weakness
2. Kussmal's breathing (deep!)
3. Fruity acetone on the breath
4. Nausea, vomitting & abdo pain
5. ↑ WBC
Signs:
1. HoTN & electrolye imbalances d/t osmotic diuresis
2. Coma and cerebral edema
What are the 4 steps in treating DKA and what is the principal behind them?
1. Large volume of IV fluilds -- restores ↓ ECV and flushes out sugars. Also restores kidney & brain perfusion to ↑ketone utilization
2. K+ replacement b/c ++ will have been lost in diuresis and will have shifted out of the cells (pools ↓)
3. IV insulin - keep giving until acid-base disturbance is corrected (may require giving glucose as well!)
4. Treat the precipitating medical condition.
What are 2 general (initial) results of insulin resistance?
1. ↑ hepatic GNG
2. ↓ glucose deposition in the muscle and fat.
Review the 6 risk factors for DM 2
1. Age
2. Obesity
3. sedentary lifestyle
4. Ethnicity & family Hx
5. Metabolic syndrome (HTN, dyslipidemia)
6. PCOS
How do B-cells detect and respond to blood sugar?
The influx of glucose into Beta cells results in ↑ ATP production. High levels of ATP will inhibit K+ efflux channels and the cell depolarizes, triggering a massive Ca+2 influx. The jump in intracellular Ca+2 then triggers the exocytosis of insulin-containing granules.
What is Dr. Perkin's version of the mechanism of ↑glycemia-induced damage?
High rates of glycolysis will generate ↑[superoxides] and this will interupt normal glucose metabolism causing a build-up of earlier, toxic glucose metabolites.
What is one way of treating / preventing diabetic retinopathy?
Use laser photocoagulation to create scars that will keep retinal layers together in the event of a hemorrhage.
Describe the progression of the diabetic neuropathy
1. The high blood sugars will kill the small peripheral sensory nerves and this can be quite painful
2. Will eventually get stocking --> glove loss in sensation
3. Can get ulcers, infections and amputations d/t loss of feeling
What should you recommend to pt's as strategies for "vascular portection"
1. Good BS and lipid control
2. ↓ / control Bp
3. LIfestyle and diet (smoking cessation)
4. ASA or other anti-platelet therapy
5. ACE - inhibitors
We covered 3 big diabetes clinical trials: DCCT, EDIC and UKPDS. What did the DCCT look at and what did it find?
What were the drawbacks to tight control?
The Diabetes Control & Complication Trial (DCCT):
- randomized pt's to either conventional or tight BS control.
- found 2% lower HgA1c in tight group, and a ↓ in prevalance & progression of complications.
- Downside: ↑ incidence of Hoglycemia and some (~10%) wt gain
We covered 3 big diabetes clinical trials: DCCT, EDIC and UKPDS. What did EDIC look at and what did it find?
(2 main things)
EDIC:
- followed ppl from DCCT and found no cognifive consequqnces associated with hypoglycemic events
- found that low HgA1c has sustained protective effects, but that the tight control was difficult for ppl to follow
We covered 3 big diabetes clinical trials: DCCT, EDIC and UKPDS. What did the UKPDS look at and what did it find?
Found that tight BS control results in a 12% ↓ in any diabetes-related endpoint (MI, microvascular events, retinopathy, nephropathies, etc).
What are the 3 basic steps in the management of DM 2?
1. Improve insulin insensitivity by diet, exercise and metformin (only use drug if HgA1c ↑)
2. Give insulin secrete-agogues (sulfonylureas) to ↑ insulin
3. Give exogenous insulin as a last resort (end-stage DM2)
What is the difference between metformin and glyburide? Why is this important?
Metformin will potentiate the activity of insulin that is already in the body (will not add any!)
Glyburide will push pancreas to make more insulin regardless of a person's metabolic state.
As a result metformin can cause ↓glycemia but glyburide can't!
For each class of oral hypoglycemics, list the main mechanism and an example of the dug:
1. Insulin sensitizers (2 actions & 2drugs)
2. Insulin secretagogues (1 action & 2 drugs)
3. Others (2 actions & 2 drugs)
1. Insulin Sensitizers
↓ Glucose production in liver (Biguanidines/metformin, Thiazolidinediones*)
↑ peripheral glucose uptake (Thiazolidinediones)
2. Secretagogues
- ↑ insulin secretion ( Sulfonylureas - glyburide, Meglitinides - repaglinide)
3. Others
↓ Glucose absorption ( a-glucosidase inhibitors - Acarbose)
↓ glucose production & ↑ insulin secretion (incretin mimetics and DPP-4 inhibitors (exenatide)
What are the 2 main categories for hypoglycemia symptoms? What are some examples of each type of symptom?
1. Adrenergic:
- anxiety, hunger, trembling, confusion, sweating, agitation, Tcardia
2. Neuroglycopenic:
- ↑confusion --> somnolence --> seizure ---> coma
** with repeated episodes of hypoglycemia the adrenergic response becomes less and less sensitive
What is one of the draw-backs to giving BID doses of NPH?
What is one of the ways of getting around this?
Will get a peak around lunchtime and if this meal gets missed = hypoglycemia!
To get around this can split dose into TID
What type of insulin is better for basal levels (after NPH)?
What is even better still?
Long-acting analogues glargine or detemir allow you to avoid the lunchtime peak.
Having an insulin pump that gives hour by hour doses of insulin - eliminates peaks and allows you to mimic the early morning rise in insulin (that off-sets the early morning rise in cortisol)
What are the 3 steps to treating acute hypoglycemia?
What do you do if the person is unconscious?
1. Administer 10-20g of glucose (route depends on LOC)
2. Re-check BS in 10min - if still low repeat above
3. Follow with complex carb snack (sandwich or crackers + cheese)
** if unconscious give glucagon IM
What is the somogyi effect?
If you give too much lunchtime insulin you cause prolonged hypoglycemia which causes stress resulting in a high blood sugar level rebound (brought about by the counter-regulators).
"reactive high BS in am d/t an unrecognized low at night"
What happens to an athelete with DM1 during exercise?
The exercise causes an ↑ in adrenalin and this will raise the BS. Therefore must give extra insulin when exercise is planned.
Why was inhaled insulin abandoned?
b/c insulin is also a growth factor and there was some concern that it could cause cancerous tumors. It was also very difficult to get the right dosing via inhalation.
What is the mechanism of action for:
- biguanides
Metformin:
Acts on an AMP-dependant protein kinase that senses the ratio of AMP:ATP in the cell. When the ratio is high (ATP is low) and the kinase (metformin) stimulates the uptake of glucose into the cell.
What is the mechanism of action for sulfonylureas?
Glyburide, Meglitinide:
- blocks the K+ efflux channel in the Beta cells (normall blocked by high ATP from ++ glucose). This causes depolarization --> Ca influx ---> Insulin exocytosis
What is the mechanism of action for:
Thiazolidinediones
Actose
-↑ a TF PPAR-y to promote the development of new, smaller, insulin-sensitive adipocytes.
** associated with wt gain, edema and CHF (black box warning!)
What is the mechanism of action for:
a-glucosidase inhibitors
Prandase Precose
Competitively inhibit the brush-border enzyme a-glucosidase, thereby preventing the up-take of glucose.
SE: will cause flatulence
What is the modification to insulin for each of the following analogues:
- Lispro
- Aspart
- NPH
- Detemir
- Glargin
Shor-acting:
- Lispro: Lis-Pro switch places
- Aspart: an asp is substituted

Intermediate acting:
- NPH: insulin + protamine (<--- interacts with insulin to form insolube complexes once injected)

Long -acting
- Detemir: F-acid attached that ↑likelihood of aggregation & binding to alb
- Glargin: insoluble @ physiologic pH = precipitates at injection site = ↑ aggregation and v.slow release!
What is the mechanism behind the autoimmune destruction of B-islet cells?
1. Debris from B-cells gets ingested and presented by APC's
2. A T-cell comes along and their TC-receptor recognizes the presented little bit of B-cell
3. T-cell gets activated/programmed to go forth and kill!
There are 4 main genetic contributors to type 1 DM. How do Human Leukocye Antigen genes contribute?
(what are they and what do they do?)
HLA genes: cell surface proteins on APC's. They bind antigen's and interact with T-cell receptors. DIfferent forms of this gene will cause different interaction and different levels of risk. Susceptibility forms are found in 90% of kids w/DM - T1, and protective forms are found in <1% of them.
There are 4 main genetic contributors to DM-1. Insulin genes are the second most important. What is the mechanism behind their role?
There is a region of Variable Number Tandem Repeats before the insulin gene. If this region is short then = less production of insulin. If there is not enough insulin being produced then levels in the thymus will be too low to cause deletion of T-cells with Ab's to insulin. Thus the anti-autoimmune mechanism is thwarted!
Given that there is an T-cell mediated autoimmune component to DM1, what is one way of preventing this disease?
In what 3 ways did it do this?
Can give pt's CD3 antibodies - study found this resulted in the maintenance or improvement of pancreatic insulin producing abilities.
How?
1. Blocked the T-cell receptors
2. inhibited T-cells (that are destroying beta's)
3. Activate protective T-regulatory cells
What are 3 other autoimmune diseases that tend to be associated with type 1 diabetes?
1. Celiac disease (7X)
2. Thyroid disease (3X)
3. Gastritis (3X)