• Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off
Reading...
Front

Card Range To Study

through

image

Play button

image

Play button

image

Progress

1/39

Click to flip

Use LEFT and RIGHT arrow keys to navigate between flashcards;

Use UP and DOWN arrow keys to flip the card;

H to show hint;

A reads text to speech;

39 Cards in this Set

  • Front
  • Back
Type 1 Diabetes
- DEFICIENT in insulin aka don't produce insulin
- juvenile-onset
- low/undetecable plasme glucose
- LOSS of B-cells in pancreas (makes insulin)
- AUTOIMMUNE diesease - antibodies made to detroy B-cells
- Ketoacidosis -- blood pH decrease due to many KB in blood
- 5% in USA
- Stable worldwide
Type 2 Diabetes
IMPAIRED RESPONSE to insulin aka dont respond to insulin
- Adult-onset
- Associated with obesity
- Plasma insulin levels: variable
- smaller islet cells (pancreas)
- no ketoacidosis
- ~95% in USA
- Rapidly increasing globally
What happens to GLUCOSE metabolism in Type 1?
DECREASE glucose metabolism
- Decrease uptake of glucose into tissues
- Decrease phosphorylation of glucose in liver
What happens to GLUCOSE OUTPUT in Type 1?
INCREASE glucose output
- mobilization of glycogen
- increase hepatic gluconeo = RESULTS IN HIGH PLASMA GLUCOSE LEVELS
What happens to lipids in Type 1 (since body thinks you have no glucose)?
DECREASE:
- storage of lipids in adipocytes (fat cells)
- synthesis of TAGS in hepatocytes (liver cells)

INCREASE:
- mobilization of TAGs from adipocytes
- plasma levels of FFA
- oxidation of FFA (in mito) --> to make the KB
- A-CoA (in absence of CAC)
- KB production
What happens to proteins in Type 1?
INCREASE:
- catabolism of proteins
- plasma AA
SYMPTOMS of glucose in Type 1?
- Glucosuria - loss of glucose in urine

- Polyurea - loss of water & electrolytes - excessive urination
- Polydipsia - excessive thirst
- Polyphagia - increase appetite and food intake
KetoAcidosis - in Type I
KB accumulate
- Because they are acid (pK ~3.5) accumulation results in pH drop (bicarbonate system can't keep up) --> COMA --> DEATH
Complications with insulin therapy of type I?
Diabetics are hyPERglycemic, yet Type 1 diabetics are at risk for hyPOglycemia.
Why are Type I diabetics at risk with hyPOglycemia?
1. Insulin treatments LOWERS blood sugar due to increase uptake & utilization of glucose into the cells

2. Insulin SUPPRESSED glucagon release which would have been able to counter the low blood sugar by signaling glucose release from liver.
What is prediabetes?
being mildly hyPERglycemic

serves as a marker of patients at risk for type 2
What are symptoms of pre-diabetes?
1. Impairs glucose tolerance (IGT) -- increase glucose levels ~2hrs after meal (postprandial)
2. Impaired Fasting Glucose (IFG) - increase hepatic glucose production --> when glucose levels are high 6-8hrs after the meal
3. Increased HbA1c (glycosylated hemoglobin) -- indication of increase glucose levels over time; hemoglobin becomes glcosilatied in the blood if long enough with glucose; good marker of increase glucose level over time.
4. Increased risk for cardiovascular complications
---- ie: heart, disease and stroke)
---- DEcrease HDL,
---- INcrease LDL (bad ones),
---- INcrease blood TAG
What are the mechanisms underlying INSULIN RESISTANCE (Type 2)?
1. Lipid Burden Hypothesis - dysfxn of adipose
2. Role of Inflammation - dysfxn of adipose
3. Role of mitochondria - insulin resis. in liver AND muscle
What are the mechanisms underlying impaired insulin secretion/ B-cell failure?
Mainly --> B-cell dysfxn

A. Role of mito and pyruvate-cycling
B. Role of ER stress
C. Role of Amyloid fibrils
1. Lipid Burden Hypothesis (insulin resistance in obesity)
1. Normal capacity of fat tissue to store TAG DEcreases & fat cells become less sensitive to insulin = adipocyte dysfunction
2. Expression of lipid synthesis & storage genes (PPAR-gamma) INcrease in liver & muscle
3. Ectopic storage of lipids withIN liver & muscle (since fat cells are 'saturated' and cant store any more lipids)
2. Role of Adipose dysfunction in insulin resistance (insulin resistance)
1. Lean State
2. Overweight state
3. Proinflammatory state
4. Inflammatory state
Role of inflammation in Skeletal Muscle: Lean State
Balance btw lipid storage in adipocytes & lipid release for fuel
Role of inflammation in Skeletal Muscle: Overweight State
1. Adipocytes increase in size due to increase in TAG storage---> leads to --->

2. Increase in expression of TAG storage enzymes
3. Still able to maintain balance
Role of inflammation in Skeletal Muscle: Pro-inflammatory State
Further overloading with TAG cause release of MCP1 (chemoattractant)
Role of inflammation in Skeletal Muscle: Inflammatory State
1. MCP-1 attracts macrophages which release TNFa and other cytokines (these DEcrease insulin signaling)
2. Imparied TAG storage
3. INcrease lipolysis ( it is the breakdown of fats to release FA)
4. INcrease circulating TAG and FFA
5. Accumulation of lipids in muscle
What is the role of MCP-1?
It is a type of cytokine that upon inflammation of muscle attracts macrophages within adipose tissue to start releasing cytokines
3. Role of mitochondria in LIVER cell (insulin resistance)
- FA accum in Liver --> leads to insulin resistance:

1. Overnutrition --> INcrease Malonyl-CoA -->
2. Increase FA production -->
3. Increase TAG synthesis & Increase in FA metabolites: Diacylglycerol (DAG) & ceramide
4. DAG --> increase stress induced Kinases --> inhibit insulin signaling
4. Ceramides --> directly inhibit insuling signaling


1. Overnutrition --> INcrease Malonyl-CoA -->
2. INHIBITS CPT1 --> FA can'ts be oxidized in mitochondria
Why is CPT1 important?
causes FA to be taken into the mitochondria, ... which is good because...?
3. Role of mitochondria in LIVER cell (insulin resistance) -- conclusions
1. increased production of malonyl-coA --> promotes FA synthesis and inhibits FA oxidation via inhibition of CPT1
2. FAs diverted away from oxidation towards biosynthetic pathways that produce TAGs & lipid metabolites (DAG & ceramide)
3. DAG activate stress-induced kinases (PKC), which phosphorylate the insulin receptor interfering with signaling
4. Ceramide inhibit insulin signaling thru inhibition of AKT (component of insulin signaling pathway)
3. Role of mitochondria in MUSCLE cell (insulin resistance) -- conclusions
Conditions of overnutrition:
1. FA influx into the cell promotes B-oxidaion without increase in CAC flux (CAC is decreased in diabetic, reason still unknown).
2. This overload of B-oxidation (process of FA --> acetyl-CoA)(PPARd activated), leads to accumulation of byproducts derived from incomplete fat oxidation in mitochondria.
3. Byproducts made: Acylcarnitines & Reactive oxygen species. These activcate stress induced kinases --> inhibit insulin signaling
Mitochondrial overload and pyruvate cycling (B-cell failure in insulin secretion)
-Increased B-oxidation produces acetyl-coA which activated PC
-upregulation of pyruvate cycling leading to insulin hypersecretion
ER stress (B-cell failure in insulin secretion)
Chronic INcrease in workload due to increased demand in insulin secretion = ER stress --> INCREASE protein misfolding --> cell stress apoptosis
Amyloid fibrils (B-cell failure in insulin secretion)
Amylin is secreted with insulin and plays a role in glycemic regulation by slowing gastric emptying
What is normal B-cells of the pancreas release insulin?
1. Glycolysis within B-cells generates pyruvate in CYTOSOL
2. Pyruvate enters MITO and feeds into CAC thru pyruvate dehydrogenase (PDH)
3. INcrease of ATP/ADP ratios inhibit ATP-sensitive K+ channels, causing depolarization; activation of Ca2+ channels & stimulation of insulin release (TRIGGER SIGNAL)

Additional amplificationof insulin release through PYRUVATE CYCLING for amplication signals.
Role of pyruvate cycling
Role: additional ampli of insulin release from the B-cell

1. Metabolism of pyruvate --> OAA via pyruvate carboxylase (PC) generating excess CAC intermediates
2. Excess intermediates can exit the mito, enter cytosolic pathways that generate NADH, a-ketoglutarate, and GTP
3. These excess intermediates then amplify signals for insulin release (AMPLIFICATION SIGNALS)
How does increased FA oxidation results in increased pyruvate cycling? How does this result in insulin hypersecretion?
1. Overnutrition = increased lipids that enter the B-cell cytosol as FA.
2. These FA enter mito via CPT1 and so B-oxidation is increased so acetyl-coA builds up.
3. This build up activates PCarbox. which generates even more intermediates that activate the amplification signals EVEN MORE.... so insulin is even MORE hypersecreted

....this hypersecretion is what causes B-cell insulin responsiveness to decrease over time =-> insulin release
What is the NORMAL role for amylin released from B-cells? What is the role of amylin in B-cell dysfunction?
Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.
How does weight loss function to treat T2D?
Target: Adipose Tissue; DEcreases TAG content

Effect of treatment:
- DEcrease lipid burden
- INcrease capacity for lipid storage
- Restores insulin sensitivity
How do sulfonylureas function to treat T2D?
******
How does exercise function to treat T2D?
Target: AMPK, activated by INCREASE [AMP]/[ATP]

Effects:
1. Decrease: FA & cholesterol synthesis
2. Decrease: gluconeogenesis
3. Increase: FA oxidation
4. Increase: Glucose uptake
How do sulfonylureas function to treat T2D?
By increasing insulin release by inhibiting ATP-sensitive K+ channels in B-cells leading to depolarization and insulin release

... basically doing that cytosolic normal depolarization of the K+ channels to finish doing the trigger signal ... (slide 39).
How does Metformin function to treat T2D? Through what protein does it work?
Metformin = type of biguanides - suppresses glucose production in liver

1. Reduce hepatic glucose output thru inhibition of gluneo
2. Increase glucose uptake in skeletal muscle & adipocytes
3. Decrease in lipid synthesis

Mediated by activation of AMPK (a protein)

***The molecular mechanism of metformin is incompletely understood: inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP) and consequent activation of protein kinase A (PKA), and an effect on gut microbiota have been proposed as potential mechanisms
How does Thiazolidinediones function to treat T2D? Through what protein does it work?
**Works anti to the Inflammatory State of adipose dysfunction***

- Activates PPAR-g in ADIPOSE--> Affects transcription of genes involved in glucose & lipid metabolism & energy balance -->

1. Decrease lipolysis
2. Decrease FFA
3. Decrease TNFa
4. Decrease leptin
5. Increase adiponectin

- all these Improve insulin sensitivity in skeletal muscle & liver

Note: lower TG and FFA causes more subcutaneous adipose tissue and less visceral (which is better because decrease FA in portal circulation)
How do α-glucosidase inhibitors function to treat T2D?
1. Interferes with action of a-glucosidases in small intestine
---- Glucosidases - hydrolyze polysaccharides to glucose


2. Results in reduction in digestion and absorption of glucose into circulation


NOTE: Alpha-glucosidase inhibitors are oral anti-diabetic drugs used for diabetes mellitus type 2 that work by preventing the digestion of carbohydrates (such as starch and table sugar). Carbohydrates are normally converted into simple sugars (monosaccharides), which can be absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce the impact of carbohydrates on blood sugar.