Term
| How does glucose regulate insulin secretion in beta cells? |
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Definition
1) Glucose uptake occurs by facilitated diffusing through Glut2 (insulin-independent).
2) Intracellular glucose metabolism increases the ATP;ADP ratio, which closes K-ATP channel.
3) K-channel closing depolarizes membrane and opens voltage-gated calcium channels that lead in increase in intracellular Calcium.
4) Insulin is secreted.
Aside. Pre-proinsulin (ER) is transported to Golgi where it is cleaved to proinsulin and proinsulin is cleaved to mature insulin and C-peptiide. Mature insulin is released by regulated secretion in granules. |
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Term
| What is the connection between KIR6.2 and the soulfonylurea receptor protein SUR1, and hyperinsulinemia of infancy and permanent neonatal diabetes mellitus? |
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Definition
They are subunits of the K-ATP channel in pancreatic beta-cells.
Binding of ATP to KIR6.2 results in channel closure.
Binding of sulfonylurea drugs to SUR1 results in channel closure and increased insulin secretion (treat type to diabetes).
Innactivating mutations in these genes can cause hyperinsulinemia (secretion in absense of blood glucose.
Activating mutations can cause PNDM (reduced insulin secretion, hyperglycemia) |
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Term
| A patient presents with activating mutations in the SUR1 and KIR6.2 genes. What condition is associated? |
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Definition
| Permanent neonatal diabetes mellitus, characterized by reduced insulin signaling, hyperglycemia and low birth weight. |
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Term
True:False
You notice your patient has increased Na content and you suspect increased extracellular fluid content (ECFV)? |
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Definition
| True- Na is the major extracellular ion and would create a great deal of extracellular fluid by osmotic forces |
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Term
| How is sodium reabsorbed (primarily in the proximal tubules of the nephron) from the urinary space into the bloodstream |
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Definition
Crosses 2 membranes of nephron
1) Facilitated Diffusion across apical membranes.
2) Active Transport across basolateral membranes via Na/K ATPase |
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Term
| What is Aldosterone's primary action on nephron cells? |
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Definition
Increases Na reabsorption in the collecting tubule by increasing apical expression of ENaC channels (more accurately; residency time in the membrane).
Aldosterone induces SgK, when co-expressed with ENaC, increases ENaC expression. SgK does not phosphorylate ENaC directly, but Nedd4 and prevents its interaction with ENaC (Nedd4 is an E3 ubuiquitin ligase associated with targeted degradation of ENaC
Recall, aldosterone is a steroid hormone. |
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Term
| A patient with pseudohyperaldosteronism has suffered with severs hypertension since infancy. What condition is this and how does it occur? |
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Definition
Liddle's Syndrome.
Mutations in ENaC subunits inhibit interactions with Nedd4, preventing ENaC proteosomal degradation and increasing Na reabsorption. |
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Term
1) Describe the regulation of the CFTR protein?
2) How can it go awry? |
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Definition
1) cAMP (PKA-dependent phosphorylation at regulatory domain) and ATP-dependent (nucleotide binding domain)
2) CFTR is a chloride channel, but it also interacts with ENaC (through its regulatory domain) in the apical surface of exocrine epithelia cells. CFTR is inhibitory in most cells, except in sweat cells.
Therefore, loss of function leads to reduced Cl- efflux and increased Na (and water) uptake into airway epithelia cells, thereby lowering the water content of mucosal cells. In sweat glands, it reduces Cl- and Na+ influx and makes SALTY SWEAT. |
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Term
| What happens to the F508del CFTR Mutant Protein? Why might you be concerned clinically? |
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Definition
1) Reduces plasma membrane expression due to inefficient trafficking through ER-G pathway (misfolded versions are degraded by ERAD pathway
2) ER accumulation can cause toxicity if it exceeds ERAD sensitivity and misfolded protein response (MPR). |
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