Biochemistry of T1D Flashcards
What is the issue with T1D?
The cells in the pancreas produce little or no insulin, bc they get destroyed due to autoimmune disease
-> daily insulin required
What are the symtoms of T1D?
Symptoms develop quickly, often in young people
-Frequent urination, excessive thirst, extreme hunger
-extreme fatigue, blurred vision, sudden weight loss, irritably (angry)
T1D vs T2D:
T1D: may benefit from diet change but they will always need medication
-no or less insulin produced
T2D: not fully understood
-Insulin is there but is not working properly
-insulin receptors not shaped normally
-not all the glucose transporter are open
Which cells in the Islet cells are predominant?
ß- cells: release Insulin
How is the insulin secretion in the pancreas stimulated?
how is it different from liver cells?
-Pancreas: by glucose uptake -> INSULIN secretion
-Liver cells: have insulin receptors and bind insulin -> GLUCOSE uptake
How does Insulin secretion work -> Pathway:
GLUCOSE enters the cell -> undergoes GLYCOLYSIS to produce ATP through the Krebs cycle and oxidative phosphorylation
-ATP is used to shuts down the K+ channel -> which causes depolarization of the cell membrane opening up the Ca channel -> Ca influx causes Insulin secretion
How can drugs in patients with heart disease be affected by Calcium channel blockers?
Ca channel blockers are present on the surface of myocytes -> taking too much can affect pancreatic cells and block insulin secretion -> High blood sugar
What does the structure of Insulin look like?
-Preproinsulin with 3 subunits
-Proinsulin -> Signal sequence cleaved and disulfide bonds formed
-INSULIN: C-peptide removed
Subunits left: A and B
Why is insulin not produced properly in T1D patients?
-It is believed that viral infections can cause lymphocytes to develop in the pancreas and attack and destroy ß-cells
-Assumption of genetic component: HLA-gene (responsible for recognizing foreign substances) allowing lymphocytes to develop (not a good proof for T1D)
What is the immune system targeting in the beta cells?
-Glutamic Acid Decarboxylase (GAD) recognized in 80% of T1D cases
-> Enzyme responsible for metabolizing glutamate to GABA (neurotransmitter)
What is the immune system targeting in the beta cells?
-Glutamic Acid Decarboxylase (GAD) recognized in 80% of T1D cases
-> Enzyme responsible for metabolizing glutamate into GABA, a Neurotransmitter (not known why GAD is attacked)
What is the consequence of the attack on GAD in pancreatic cells?
-immune system recognizes GAD as ‘foreign’, then
several anti‐GAD antibodies will be formed
-Antibodies attack beta cells and lyse them + they don’t regenerate -> Life long disease
What are the metabolic responses AFTER a meal that doesn’t work in diabetes patients?
-Gluconeogenesis: turned ON bc no insulin response that there is enough Glucose
-Glycogen synthesis: OFF bc there is no Glucose to make Glycogen
-Glucose uptake: OFF
-Fatty acid breakdown: ON to make glucose
-Ketogenesis: ON to make glucose
-Amino acid breakdown: ON to make Glucose
Which metabolic response is only present in T1D patients?
Ketogenesis: Last way to produce glucose
What is the overall response of the liver to low glucose in diabetes?
Type 1 patients make excess glucose via gluconeogenesis; break down fats to ketone bodies for glucose production;
-> appear to be “starving”.
Metabolic starvation pathways in the liver:
-Protein degradation -> amino acids used for citric cycle + excess amino acids excreted in the urine
-Citric acid cycle intermediates to shunt into glyconeogenesis
-Fatty acids imported and converted to Acetyl-CoA (needed for citric cycle)
-> Lack of citric cycle intermediate causes accumulation of Acetyl-CoA
How does the brain get fuel to work in the starvation stage?
It uses Ketone bodies from the liver, formed by accumulated Acetyl-CoA as fuel + takes glucose that is left in the liver
How do Ketone bodies accumulate in the liver when fasting (don’t eat for days or fasting from carbohydrates?
Excess of Ketone bodies bc of accumulated Acetyl-CoA
-> Fatty acids (imported from adipocytes) -> Acetyl-CoA
-> Lack of citric acid intermediates -> no citric cycle entry of Acetyl-CoA
What condition is associated with excess of Ketone bodies in diabetis patients?
Diabetic Ketoacidosis
Ketones accumulated: Acetoacetate, acetone (fruity breath)
How is diabetic ketoacidosis characterized?
-Hyperglycemia over 300 mg/dl
-low bicarbonate
-acidosis (pH < 7.3) due to ketones
-detectable ketones in breath and urine
Why does the pH gets acidic in the blood in diabetic ketoacidosis?
By increase of H+ due to ketones
