APPP Quiz – Kidney and Pancreas Flashcards
What is insulin produced by?
beta cells in the islets of Langerhans of the pancreas
Glucose is by far the most important controller of insulin secretion. How does it trigger insulin secretion?
- increases ATP/ADP ratio
- closes K+ channel
- elicits depolarization of membrane
- facilitates Ca2+ entry
- causes exocytosis of secretory granules containing insulin
(can increase insulin secretion in absence of any other stimulatory agent)
What can trigger insulin secretion?
- glucose
- amino acids
- fatty acids
- sulfonylurea drugs
How do sulfonylureas increase insulin secretion?
block K+ channels by direct action on site located at or near the channel (sulfonylurea urea receptor)
What can inhibit insulin secretion?
catecholamines
What can enhance insulin secretion?
GLP-1
What happens when insulin binds to its receptor? (4)
- glucose uptake
- glycogen synthesis (in liver)
- protein synthesis (after amino acid uptake)
- lipid storage (formation in adipocytes)
How does insulin regulate glucose?
- insulin lowers plasma glucose levels by stimulating glucose uptake (with GLUT4 in muscle and adipose tissue)
- suppresses hepatic production of glucose
How does insulin regulate lipids? (2)
insulin can lower plasma triglyceride and fatty acid levels by multiple mechanisms
- increase glucose transport (which is then esterified to triglyceride)
- inhibit lipolysis
How does insulin regulate protein?
insulin increases uptake of amino acids into many tissues (muscle, liver, adipose), and stimulates protein synthesis and inhibits protein degradation
What are the net effects of insulin? (4)
- decrease blood glucose
- decrease blood triglycerides and cholesterol
- decrease blood free fatty acids
- decrease blood amino acids
What are the 3 key functions of insulin?
- help blood sugar enter body cells
- moderate breakdown of body’s reserves of carbohydrates, proteins, and fats
- inhibit glucose production in liver
What does T2D usually result in?
loss of first-phase insulin released and beta cell loss related to prolonged exposure to beta cells at high glucose, fatty acids, pro-inflammatory cytokines (TNF-a), and islet amyloid deposits
What happens to beta cells as insulin resistance develops?
- beta cells attempt to compensate by producing more insulin
- after onset of beta cell dysfunction, pancreas is no longer able to compensate via hypersecretion
- control of blood glucose gets worse, leading to impaired glucose tolerance, and increasing fasting and post-prandial glucose levels, and eventually T2D
What is glucose toxicity?
hyperglycemia itself will worse insulin resistance and beta cell function
What are the 4 laboratory tests for diabetes?
- post-prandial (casual) blood glucose
- fasting plasma glucose
- OGTT
- glycosylated hemoglobin (HbA1c)
Fasting Plasma Glucose (FPG)
mainly reflects hepatic gluconeogenesis and basal metabolic needs
- impaired fasting glucose: 6.1-6.9 mmol/L
- diabetes: ≥ 7.0 mmol/L
Postprandial (Casual) Blood Glucose
reflects dietary intake and should be monitored as it significantly contributes to overall daily glycemic profile
Glycated Hemoglobin Levels (HbA1c)
blood test based on RBC (lifespan of 120 days) that measures amount of glucose that binds to Hb
- may indicate compliance/adherence to treatment regimen
- T2D: ≥ 6.5%
Oral Glucose Tolerance Test (OGTT)
test to measure body’s ability to breakdown carbohydrates – overnight fast, then 75 g of glucose and blood drawn at 2 hours
- diabetes: ≥ 11.1 mmol/L
What does the diagnosis of diabetes require? (4)
(one of the following)
- symptoms of diabetes + random/casual blood glucose ≥ 11.1 mmol/L
- FPG ≥ 7.0 mmol/L
- OGTT (2-hr, 75 g) ≥ 11.1 mmol/L
- HbA1c ≥ 6.5%
T1D vs T2D
Ketosis
- T1D: prone (unless diet, insulin coordinated)
- T2D: resistant
T1D vs T2D
Diet
- T1D: mandatory
- T2D: controls 30-50% of cases
What are the early manifestations of T1D?
- fatigue
- weight loss
- polyuria, nocturia
- thirst (polydipsia)
- increased appetite (polyphagia)
- pruritis (itching)
- impotence (erectile dysfunction)
- infections (ie. UTI, oral, vulvovaginal candidiasis)
- ketoacidosis (metabolic acidosis)
What are the early manifestations of T2D?
- fatigue
- impotence
- T1D symptoms
What are the late manifestations of both T1D and T2D?
- ocular disease (retinopathy)
- renal disease (proteinuria)
- atherosclerosis
- neuropathies (gangerene)
- cardiac disease
- hypertension
What does insulin normally do?
takes glucose from blood and puts it into skeletal muscle and adipose tissue, in addition to preventing glucose output from liver
What are the functions of the kidney?
- remove waste products from body (urine)
- regulate blood pressure (RAA system)
- control reabsorption of water (ADH/vasopressin)
- maintain intravascular volume
- control volume and composition (ions) of body fluids
- blood filtration and reabsorption
What are the 3 layers of the glomerular capillary membrane?
- endothelium – perforated by thousands of fenestrae
- basement membrane – meshwork of collagen and proteoglycans (main filtration barrier)
- epithelial cells (podocytes)
What are the 3 mechanisms that control JGC release of renin?
- direct pressure sensing mechanisms within afferent arteriole – decreased blood pressure increases renin release
- sympathetic innervation of JGC promotes renin release via beta-1 adrenoceptor signaling – stimulation of beta-1 receptors increases renin release
- specialized cells within distal tubule called macula densa are especially sensitive to electrolyte concentration (especially NaCl) – decreased luminal NaCl delivery increases JGC renin release
Renin-Angiotensin-Aldosterone System Control of Blood Pressure
- renin is released nby JGC
- renin cleaves angiotensinogen (formed by liver) into angiotensin I
- ACE cleaves angiotensin I into angiotensin II
- ATII stimulates aldosterone secretion from adrenal cortex, which promotes renal tubular reabsorption of NaCl, increases blood volume, increases cardiac output, and increases blood pressure
- ATII also stimulates arteriolar vasoconstriction, which increases total peripheral resistance, and increases blood pressure
What are some other way ATII increases blood pressure? (2)
stimulates thirst and antidiuretic hormone (ADH/vasopressin)
- ADH can increases peripheral vascular resistance, and therefore blood pressure by acting on V1 receptor
- ADH can promote absorption of water by stimulating V2 receptor in cells of collecting duct, and AQ2 water channels are translocated to plasma membrane and water is absorbed into blood, which increases blood pressure
Proximal Tubule
Reabsorption of Na+
- NHE3 (on apical/lumen side)
- CAIV (on apical/lumen side) catalyzes cleavage of H2CO3 into water and CO2, which diffuses into cytoplasm of proximal epithelial cells
- intracellular CO2 is rapidly rehydrated to H2CO3 by cytoplasmic CAII
- H2CO3 dissociates into H+ and HCO3-
- HCO3- is co-transported with Na+ (NBC1) across basolateral membrane of epithelial cell, while H+ is counter-transported out apical side of cell via NHE3 in exchange for Na+
(Na+/K+ ATPase active on basolateral side)
Proximal Tubule
Reabsorption of Ca2+
parallels that of Na+ and water
- passive diffusion, paracellular pathway
- solvent drag (refers to solutes in ultrafiltrate that are transported back from renal tubule by flow of water rather than specifically by ion pumps or other membrane transport protein)
Proximal Tubule
Reabsorption of Glucose
SGLTs couple glucose with Na+ (1:1) and facilitate insulin independent reabsorption of filtered glucose
- SGLT2: 90% of glucose back into bloodstream in segments S1 and S2
- SGLT1: 10% of glucose back into bloodstream in segment S3
Loop of Henle
Descending Thin Limb
- permeable to water
- few mitochondria
Loop of Henle
- Na+/K+ ATPase pump maintains low intracellular sodium concentration, which provides favourable gradient for movement of sodium from tubular fluid into cell
Loop of Henle
Thick Ascending Limb
- impermeable to H2O
- high metabolic activity
- movement of Na+ primarily mediated by NKCC2 co-transporter (on apical/lumen side)
- Na+/K+ ATPase on basolateral side
- paracellular reabsorption of Mg2+ and Ca2+
Distal Tubule
What are macula densa?
highly specialized distal tubular cells at the JGC (first portion of tubule) – junction where distal convoluted tubule comes in contact with afferent arteriole
- respond to changes in Na+
- activation of macula densa typically results in renin release into bloodstream
Distal Tubule
- NCC co-transporte for Na+ reabsorption **Rx!
- mediates reabsorption of luminal Ca2+ via ion-specific Ca2+ channels (TRPV5) in apical membrane under control of parathyroid hormone, which can then cross basolateral membrane via Na+/Ca2+ exchangers and Ca2+-ATPases (exchange internal Ca2+ for external H+)
How does the kidney help maintain healthy bones?
- when extracellular Ca2+ is decreased, there is reduced activation of Ca2+-sensing receptor (CaSR) in parathyroid gland, which results in rapid increase in parathyroid hormone (PTH) secretion
- PTH acts on PTH11R receptor in kidneys to increase tubular Ca2+ reabsorption by activating TRPV5
- PTH acts on CYP27B1 in proximal tubule which promotes conversion of inactive vitamin D to active vitamin D (calcitrol – acts on intestine to increase absorption of dietary calcium via vitamin D receptor)
- PTH acts on PTH1R in bone, increasing osteoclast (that breaks down bone tissue) activity, resulting in a transfer of Ca2+ from bone tissue to blood
Collecting Ducts
Functions
- reabsorbs Na+ and water
- secretes K+
(under control of aldosterone secreted from adrenal cortex – can increase blood pressure)
Collecting Ducts
- channel for Na+
- channel for K+
- no co-transport with Na+, therefore Cl- and HCO3- are left behind, making the lumen negative – driving force that draws K+ out of cell through apical membrane K+ channel (K+ secretion)
- lumen negative potential can also move Cl- back into blood via paracellular pathway
- reabsorption of Na+ and coupled secretion of K+ is regulated by aldosterone
- passive reabsorption of water
Collecting Duct
Permeability
- permeability hormonally controlled by ADH/vasopressin
- ADH increases permeability to water, thereby concentrating the urine
- ADH stimulates GPCR in basolateral membrane (V2 receptor) – cAMP produced promotes insertion of AQP2 into apical membrane
How does the kidney help the body produce red blood cells?
- under hypoxic conditions, EPC pool increases (which requires HIF-2 signaling), and stimulates production of EPO
- EPO stimulates proliferation and differentiation of erythroid progenitors into reticulocytes (immature RBCs) and prevents apoptosis
- more reticulocytes enter circulating blood, differentiate into erythrocytes (nucleus is ejected), increasing the pool of RBCs
Describe the role of EPO in iron metabolism.
- for iron to be taken up from intestine, divalent metal transporter 1 (DMT1) is the major iron uptake system of intestinal cells
- inside these cells, ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion
- this iron can also use ferroportin to be transferred to transferrins that are iron-binding blood plasma proteins that control the level of free iron in biological fluids
- hepcidin acts on intestinal cells to decrease the amount of iron absorbed into the body
- it does so by binding to iron transporter ferroportin
- this causes ferroportin to be internalized and degraded
- as a result, more iron remains within the intestinal cell so that the iron that enters this cell gets bound to ferritin
- in the condition where EPO is decreased, a reduction in erythropoiesis means that the
erythroblast decreases erythroferrone production - hepcidin (secreted from the liver) is
maintained at higher levels by decreased erythroferrone production - an increase in hepcidin negatively affects iron absorption and mobilization (and explains the anemia associated with renal disease)
