case 8: type 1 diabetes mellitus

Question 1

Diagnosis Standard for DM

Answer 1

– Guideline from American Diabetes Association (ADA)
* Diabetes
– Fasting plasma glucose ≥ 126 mg/dl (7.0 mmol/l) or
– or 2-hr plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during an oral glucose tolerance test
– or a random plasma glucose ≥ 200 mg/dl (11.1 mmol/l)
– or Hb A1C ≥ 6.5%
* Pre-diabetes – 100-125 mg/dl; normal – less than 100 mg/dl (from ADA)

Question 2

Tonicity

Answer 2

*Tonicity refers to the total [solutes]
* Differences in tonicity lead to osmotic
movements of water
– Isotonic
– Hypotonic
– Hypertonic
* “Water follows salt” (or solute) across
cell membranes as long as the solutes
are osmotically active & the membrane
is permeable to water
* Water moves from hypotonic (high
[water])(less solutes than water molecule) to hypertonic (low [water]) compartment, with semipermeable membrane in between

Question 3

ECF and ICF

Answer 3

• Life on Earth originated in the sea
• Our cells are bathed in tissue (interstitial) fluid
  – Tissue (interstitial) fluid is similar to sea water, very salty!
• ECF – high [Na+] & [Cl-]
• ICF – high [K+], low [Na+] & [Cl-]
  – The importance of Na+-K+ ATPase

Question 4

ECF and Sea Water

Answer 4

• What would happen when a saltwater fish is placed in freshwater? Why?
  – Sea water – hypertonic
  – Fish’s cells – hypertonic
  – Freshwater – hypotonic
  ~ water through osmotic pressure will go into cell of fish, they will have to adapt or they will die
• What would happen if our cells are bathed in freshwater?
  ~ our cells would have to be bathed in ICF of isotonic to ECF, but different electrolytes concentration

Question 5

The Concept of Homeostasis

Answer 5

• Composition of this bathing fluid is critical to many cellular functions
• Homeostasis – the composition of ECF must be maintained constant
• Which body system maintains the constancy of ECF composition?
  – Cardiovascular system?
  – Digestive system?
  – Nervous system?
  – Respiratory system?
  – Urinary system?

Question 6

The Need of Kidneys for Homeostasis

Answer 6

• Regulation of food intake by CNS – mainly the quantity of food
  – Over-ingestion -> signals to hypothalamus -> satiety
  – Under-ingestion -> signals to hypothalamus -> hunger
  – Comparatively indiscriminative on nutrients
• Digestive system – very efficient absorption of nutrients (~100%)
  – Salty food -> more Na+ & Cl- in ECF, regardless the need by the body (to maintain homeostasis person needs to drink a lot of water) (cause hypertension in young age)
  – Food rich in K+ -> more K+ in ECF, regardless the need by the body (too much K+ can induce action potential by muscle)
• Cardiovascular system seeks to control blood pressure with little regard to components of blood
• The kidneys controls composition of extracellular fluid (ECF: Interstitial fluid + plasma) and is thus the body’s main system of homeostasis

Question 7

Kidneys and Homeostasis

Answer 7

• Through filtering and reabsorption of blood plasma into urine, the kidneys:
  – Regulate ECF volume (plasma and interstitial fluid)
  – Regulate ECF components through filtering of blood plasma into urine to adjust ECF concentrations of:
• Electrolytes (Na+, K+, Cl-)
• Minerals (PO4-3, Mg++, Ca++)
• Acid-base balance (HCO3-, H+)
• Toxic products of metabolism (uremic toxins)
• Homeostasis – the maintenance of the internal constancy, based not on what an animal ingests but rather on what its urinary
  system keeps

Question 8

Structure of Kidneys – Nephrons

Answer 8

• Nephrons – the basic functional unit to form urine
• 1. Renal tubular components
     – Nephron tubule – glomerular capsule → proximal tubule (PT) → loop of Henle (LOH) (desc. & asce. limbs) → distal tubule (DT) → collecting duct (CD) → calyx
     – Loop of Henle & medullary collecting ducts are located in medulla
• 2. Renal vascular components

Question 9

Basic Nephron Processes

Answer 9

• Renal handling of any substance – Ask 4 questions:
  – Is it filtered, reabsorbed, secreted, or degraded?
• Basic nephron processes
  – Glomerular filtration
  – Tubular reabsorption & secretion in the proximal tubules (PT)
  – Tubular reabsorption & secretion in the loop of Henle (LOH)
  – Tubular reabsorption & secretion in the distal tubules (DT) & collecting ducts (CD)

Question 10

GFR – Values

Answer 10

• Glomerular filtration rate (GFR; ml/min)
  – Volume of filtrate produced by both kidneys each minute ~115 in women; 125 in men
  * < 90 ml/min – lower kidney function
• GFR – 125 ml/min → ~7.5 L/hr → ~ 180 L/day of glomerular filtrate
  – Blood volume? (5.5-6 L)
  Plasma volume?
• Without reabsorption of salt and water – dehydration & electrolyte imbalance (totally dehydrated in 24 min)
• The vol. of urine is ~ 1-2 L/day (1%) → > 99% of filtrate is reabsorbed
• Obligatory water loss – minimal urine volume required to excrete metabolic waste (400 - 600 ml)

Question 11

Renal Tubular Epithelial Cells

Answer 11

• Renal tubular epithelial cells:
  – Apical membrane (brush border) – face lumen (filtrate)
  – Basolateral membrane – face interstitial fluid, then plasma (ATPase located at basement membrane area)
  – Mitochondria – near basement membrane
• Transport pathways & mechanism:
  – Pathways – transcellular & paracellular
  – Mechanisms – gradient limited (depends on passive permeability) & tubular maximum, TM (high affinity, related to amount & flow rate)

Question 12

Reabsorption in PT – Sodium

Answer 12

• Na+ – secondary active cotransport
  – Apical membrane – by facilitated
  diffusion using Na+-glucose cotransporters (SGLT)
  – Basolateral membrane – by active
  transport of Na+-K+ pumps (ATPase)
  – Maintain low intracellular [Na+] to
  allow facilitated diffusion at apical
  membrane
  – Na+ enter plasma by simple diffusion
• Na+-substrate cotransporter (symport)
  – cotransport Na+ with amino acids,
  some vitamins & phosphate
  – Glucose & amino acids are
  transported against concentration
  gradient until tubular fluid
  concentration is nearly zero

Na has difficulty going out, eventually glucose in glomerular filtrate will be the same as Na glucose concentration in glomerular capillary because no difficulty to exchange

Question 13

Reabsorption in PT – Cl- & Water

Answer 13

• Secondary active transport of Na+ from
  filtrate into interstitial fluid & recycle of
  K+ (K+ channels are leaky) from PT cell
  into interstitial fluid creates a potential
  difference across PT cell membrane
  – → movement of cations (“+”)
  establishes luminal “-” potential
• Luminal “-” potential → attracts luminal
  anions (Cl-) move to interstitial fluid
  then to blood (transcellular &
  paracellular)
• → establishes osmotic gradient
• → luminal water moves to interstitial
  fluid then to blood (transcellular by
  aquaporins & paracellular)
• PT filtrate remains isotonic due to
  water movement

Question 14

Glucose Reabsorption in PT

Answer 14

• Blood glucose & amino acids (AA) are easily filtered by glomeruli
• Reabsorption of glucose & amino acids – by secondary active transport (for reabsorption of glucose and amino acids)
  – Sodium-glucose linked transporter
  (SGLT) in apical membrane
  – GLUT in basolateral membrane – facilitated diffusion
• Normally, >99% of glucose reabsorbed
  before end of proximal tubule
• Reabsorption of AA in PCT (>99%) is
  similar with different carriers
• SGLT inhibitors used for treatment of
  type 2 diabetes mellitus (metabolic syndrome (so glucose cannot be transported with Na, glucose will be present in lumen which will reduce glucose from cell and into interstitial fluid then to blood circulation, so blood glucose will be reduced overall)

elimination/transport of Na out of cell into interstitial fluid and into blood requires energy. SGLT does not require energy but to maintain Na concentration low in cell requires ATPase

Question 15

Salt & Water Reabsorption in PT

Answer 15

• Reabsorption in proximal tubule (PT) – ~ 65% tubular fluid (salt & water) is reabsorbed in PT → interstitial fluid → blood
  – Water (~115 L/day) follows the osmotic pressure of salt → no change in osmolality of tubular fluid (filtrate) → total [solute] remains at 300 mOsm (isotonic)
  – Salts & water reabsorption is a necessity. Without reabsorption of salt & water the body will have dehydration & electrolyte imbalance

more than 99% of salt and water will be reabsorbed into lumen of renal tubule back into body

Question 16

Basic Nephron Processes

Answer 16

• Renal handling of any substance – Ask 4 questions:
  – Is it filtered, reabsorbed, secreted, or degraded?
• Basic nephron processes
  – Glomerular filtration
  – Tubular reabsorption & secretion in the proximal tubules (PT)
  – Tubular reabsorption & secretion in the loop of Henle (LOH)
  – Tubular reabsorption & secretion in the distal tubules (DT) &
  collecting ducts (CD)

Question 17

Terrestrial Mammals

Answer 17

• In terrestrial mammals, freshwater intake is sporadic; salt intake is not coupled to water intake → requires separate control of salt &
  water somewhere in the renal tubules
• In PT, 65% of the filtrate is absorbed but separates no water from salt
• LOH – where separation of water from salt starts (~20% but not under hormonal regulation)
• need to be separated eventually because along the renal tubule there is separation of salt reabsorption and water reabsorption and starts at LOH)
• Renal medulla – part of PT, LOH & medullary collecting ducts
• Osmotic pressure of the medullary interstitial fluid (1,200-1,400 mOsm) at the bottom of LOH is 4 x that of plasma (300 mOsm)
• juxtamedullary nephron is majority of nephron, and cortical nephron are important in control of separating water and Na reabsorption)
• The separate control of salt & water – starts from the loop of Henle (LOH) (a must, not hormonally-regulated in LOH), followed by distal tubule (DT) & collecting duct (CD) (hormonally-regulated)
• Solution – conserve H2O and salt, allow urine-concentrating ability of LOH
• Kangaroo rat
• A rodent that can survive in desert with virtually no drinking water
• Has much longer LOH than in most other terrestrial mammals
• Enable maximum concentration of urine and so minimizes water loss

Question 18

Loop of Henle – Selectivity

Answer 18

• Thin descending limb cells
  – Permeable to water (aquaporin 1 in apical & basolateral membrane) (H2O reabsorption)
• Thin ascending limb cells
  – Impermeable to water; permeable to passive diffusion of NaCl & urea
• Thick ascending limb cells
  – Many mitochondria, metabolic active
  – Many Na+-K+ ATPase
  – Impermeable to water & urea
  – Active transport of NaCl

Question 19

Thick Ascending Limb of LOH

Answer 19

• Basolateral membrane
  – Na+-K+ ATPase (highest # in entire renal tubule) – Na+ actively transported out of cells into interstitial space by Na+-K+ ATPase (3 Na out and 2 K in), creating electrochemical gradient for Na+ (low inside cells)
  – Cl- (electron neutrality) – Cl− follows Na+ passively due to electrical attraction via Cl- channels & K+-Cl- cotransporters
• Apical membrane
  – Na+-K+- 2 Cl- cotransporters (NKCC2) – Na+ moves down its electrochemical gradient from lumen into tubular cells via NKCC2,
  drives the secondary active transport of Cl− and K+,
  – K+ channel – most of the reabsorbed K+ leaks back into tubular fluid thru K+ channel in the apical membrane
• Net effect – tubular fluid Na+, Cl− to interstitium, no net effect on K+ (bc it can easily go out)
• Na and Cl reabsorbed from lumen into cell then to interstitial fluid

Na, K, 2 Cl taken from lumen into ep cells require no ATP initially. K is leaky and goes back to lumen but Na will be taken and bound by Na/K pump to pump 3 Na out in exchange for 2 K back into cell. this requires ATP. Na needs to be low in the cytosol bc of Na/K pump in basolateral area

Question 20

Lasix

Answer 20

• Loop diuretics – diuretic (any chemical that causes diuresis -> production of large amount of urine) and natriuretic (diuresis bc of retention of Na in renal tubule in filtrate)
• Action
  – Blocks NKCC2 → fail to establish hyperosmotic medullary interstitial fluid → cannot concentrate urine → diuresis & natriuresis
• Net effect
  – Loss of medullary interstitial hyper-osmolarity
  – Loss of water, Na+ and Cl− in urine

Question 21

Tubular Transport Maximum (TM)

Answer 21

• Actively reabsorbed substances in renal tubules exhibit a TM
  – TM can establish large gradients
  – Cotransport with Na+ (secondary active transport)
  – High specificity for individual compounds
  – Saturability – limited # of transport carrier proteins
  – Once exceeds TM → excretes in urine
  – TM values usually above the normal filtered loads (glucose 180 mg/dL)
  – Usually involves transport of organic molecules

if glucose concentration is too high, the filtrate in glomerular will be same as in blood plasma, 200 or more mg/dl. subject can only reabsorb so much glucose so there will be left over glucose in lumen cannot be reabsorbed

Question 22

Glucose Handling by PT

Answer 22

• Glucose TM = 375 mg/min (SGLT2, function in PT)
• Threshold 180-200 mg/dL (TM values usually above normal filtered
  loads), if over → glucosuria
• increase SGLT2 expression in PT in type 2 DM → increase threshold → increase glucose
  reabsorption → increase plasma glucose → exacerbates hyperglycemia
• Drug Industry develops SGLT2 inhibitors for treatment of type 2 diabetes mellitus (metabolic syndrome)

threshold is 1%

Question 23

Daily Loss of Sugar in This Patient

Answer 23

• For this patient, plasma glucose = 900 mg/dl = 9 mg/ml
  – (For now) assuming GFR for this patient is normal at 120 ml/min
  – → 9 mg/ml x 120 ml/min = 1,080 mg/min (from glomerular capillaries to renal tubules)
  – Max reabsorption of glucose by PCT is 375 mg/min (rate)
  – → 1080-375 = 705 mg/min (glucose left over that can’t be reabsorbed each minute)
  – → 42,300 mg/hr, or 42.3 g/hr
  – → 1,015 g/day , or ~1 kg/day

Question 24

Questions

Answer 24

1. Is losing 1.0 kg of glucose per day a lot? yes
2. If a DM patient stops eating sugar, how much will that help?
   - By not eating sugar can only help a little.
3. Where is that much of sugar from?
   - gluconeogenesis

Question 25

What is the major substrate for gluconeogenesis in this patient?

Answer 25

Mostly from muscle proteins as the substrate
(gluconeogenesis- conversion of non-carbohydrate substrates to glucose: substrates include lactate, glycerol, glucogenic amino acid)

Question 26

Mechanism of Polyuria

Answer 26

• Glycosuria – excretion of glucose in urine
• Glucose mol. wt. = 180
  – → 705 mg/min of glucose excreted in urine from this patient
  – → = 705 (mg/min) / 180 g = ~3.92 mOsm/min
  – → or 5,645 mOsm/day
• Normal urinary concentrating max ability is 1,200 mOsm/L of urine
• Just to dilute 5,645 mOsm of glucose, one would need [5,645 (mOsm) / 1,200 (mOsm/L)] = 4.7 L of water.
• Note: other solutes in filtrate need additional water (Na,Cl,K) i.e. actual urine volume is much greater than 4.7 L
• This is the origin of polyuria

normal person excretes 1.5-2 L urine

Question 27

Solute Diuresis

Answer 27

• Solute diuresis (osmotic diuresis) – increased urine volume caused by the presence of certain solutes in the
  lumen of renal tubules
• Solute diuresis results in polyuria
• 900 mg/dl of glucose is NOT an absurd number for uncontrolled type 1 DM
• The urinary bladder signal the urge of urination occurs every 200-400 ml, with max capacity at 500 ml
  – Capacity of bladder before initiating micturition reflex

Question 28

Polyuria – a Social Disorder

Answer 28

• Glucose draws 4.7 L of water into tubular lumen = 4,700 ml
• 4,700 ml / 400 ml for each urination
  = 12 urinations just because of filtered glucose
• Plus the effect of other solutes, it is
  not uncommon for an uncontrolled
  diabetes patient to urinate 12
  liters/day (will be discussed later in
  this case)

Question 29

Change in [NaCl] in the Presence of Glucose

Answer 29

• PT normally reabsorb 65% of filtered NaCl, urea & water
• At PT, water can move freely following osmotic P → the filtrate at PT ALWAYS remains isotonic (300 mOsm)
• This patient – the presence of non-reabsorbable solutes in PT lumen (glucose)
  – 360 – 300 = 60 mM glucose retains its osmotic equivalent of water
• With glucose drawing more water in the lumen, luminal electrolytes are diluted
• Summary – At PT, solutes must remain isotonic in filtrate → in the presence of glucose → decrease filtrate [NaCl]

Question 30

The Countercurrent System

Answer 30

• Countercurrent heat exchange system in the legs of aquatic birds and penguins
  – Through heat exchange gradient the arterial blood warms up venous blood returning to the body
• A similar principle exists in kidneys – the countercurrent multiplier system

blood circulation flows in opposite direction

Question 31

The Countercurrent Systems in Kidneys

Answer 31

• Comprised of 2 countercurrent systems – 1. countercurrent multiplier system (LOH) to establishes vertical osmotic gradient; (deepest part of medulla highest osmotic and salt concentration 1,4000, cortex is equivalent to blood so 300 mOsm) and 2. countercurrent exchange system (vasa recta) to take away water from medullary interstitial fluid

Question 32

The Countercurrent Multiplier System

Answer 32

• Countercurrent + multiplier
• Countercurrent
  – Countercurrent flow in opposite
  directions & close proximity of loop’s limbs
  – → allows interaction of ascending & descending limbs
• Multiplier (positive feedback)
  – The more salt the ascending
  limb extrude → the more
  concentrated the interstitial fluid
  → the more water to diffuse out
  of descending limb → a gradual
  increasing concentration of
  medullary interstitial fluid from
  cortex to outer medulla to inner
  medulla

Na+ is actively removed from ascending
LOH → water in descending LOH leaves
by osmosis

ascending limb not permeable to water, but it is for salt reabsorption through active transport. salt can be reabsorbed through epithelial cells from ascending limb into medullary interstitial fluid. water can be reabsorbed from descending limb but not salt. the more NaCl is being actively transported from filtrate through epithelial cells into medullary interstitial fluid , the easier the water will be attracted out of filtrate through ep cells into medulla because of osmotic pressure. the more water taken out, the higher the concentration of salt in descending limb

ascending limb there’s a lot of salt available for transport out of cells, so osmolarity of filtrate from bottom of ascending to surface and distal tubule becomes more diluted. this builds up a gradient of osmolarity, deeper medulla the higher the osmolarity which drags water out

the more salt taken out of ascending limb, the more water is taken out of descending limb, making high salt concentration at bottom of LOH, making active transport of salt in ascending limb easier

Question 33

Vasa Recta

Answer 33

• The straight (recta) portion of the
  peritubular capillary
• Accounts for ~ 5-10% of renal plasma flow
  – Very slow flow → low enough not to
  disturb the medullary hyperosmotic
  concentration
  – Arranged that descending &
  ascending limbs are parallel to and
  immediately adjacent → allows the
  exchange of the permeable materials
  in the descending limb vasa recta to
  be short-circuited over to the
  ascending limb vasa recta → forms a
  passive countercurrent exchange
  system

Question 34

The Countercurrent Exchange System

Answer 34

• Special arrangements of vasa recta
  – Walls are permeable to H2O, NaCl & urea
  – Colloid osmotic P (π) inside vasa recta (π c)
  »> medullary interstitial fluid (π i)
• The countercurrent exchange system
  – Hypertonic salts & urea in medullary
  interstitial fluid diffuse into blood of
  descending capillary loop then passively
  diffuse out of ascending capillary loop (no
  net movement of salts)
  – H2O moves into ascending capillary limbs
  more than H2O moves out of descending
  limbs due to (π c&raquo_space;> π i)
  – Net effect – removal of reabsorbed water
  while leaving much of urea/Na/Cl behind in
  the medullary interstitium → hyperosmotic
  medullary interstitial fluid is maintained

colloid osmotic pressure more in blood than interstitial fluid, this is why more water is taken back to blood circulation which maintains medullary interstitial fluid in high concentration

Question 35

Urea’s Contribution to the Hyperosmolality

Answer 35

• Urea contributes about 40-50% of the medullary interstitial osmolality at the tip of LOH
  – 600 mmolar urea = ~600 mOsm; 300 mmolar NaCl = ~600 mOsm
  – Total osmolarity is ~1200 mOsm

Question 36

The Hyperosmotic Renal Medullary Fluid

Answer 36

• Major contributors
  – Active transport of Na+, co-transport of K+ & Cl- and other ions out of the thick portion of ascending limb LOH into medullary interstitium
  – Facilitated diffusion of urea from the inner medullary collecting ducts into medullary interstitium
  – Active transport of ions from the collecting ducts into the medullary interstitium
• So what good is the multiplication and hyperosmotic renal medullary fluid?
  – Separate control of salt and water reabsorption (filtrate osmolarity)
  – The ability to produce concentrated or dilute urine, depends on the body’s need

Question 37

Summary of Countercurrent System

Answer 37

• Essential requirements
  – Needs ATP to transport salt → establishes Na+ gradient
  – Selective permeability to water, salt and urea
  – Minimal cortico-medullary mixing
• Return of material via the vasa recta
  – Countercurrent exchange system
  – Low flow rate (maintain cortico-medullary gradient)
• Role of urea
  – Recycled from MCD to loop
  – Replaces other osmotic equivalents (NaCl) so more Na+ can be moved without exceeding gradient limitation

Question 38

Filtrate at PT – Changes in [NaCl]

Answer 38

• This patient – decrease [NaCl] in PT filtrate with the presence of glucose (glucose drags more water to be retained in lumen of PT, so less water will be reabsorbed rom PT into blood) (increased water dilutes NaCl)
• The lower filtrate [NaCl] establishes a gradient for back diffusion of NaCl from peritubular capillaries into tubular lumen → decrease reabsorption of NaCl & urea in PT → decrease plasma [NaCl] (now osmotic pressure is in favor of salt going back from blood to interstitial fluid to ep cells to lumen)
• → decrease reabsorption of filtrate NaCl into blood → increase total amount of
  filtrate NaCl in PT then in the descending LOH (concentration is reduced but total amount is increased because they can’t be reabsorbed because of presence of glucose)

Question 39

Effect of DM on Renal Filtrate

Answer 39

• For this patient’s, filtrate in LOH:
  – 1. increase Filtrate volume → increase filtrate flow rate → thick ascending limb
  LOH has less time to reabsorb salt
  – 2. decrease Filtrate [NaCl] in LOH → more difficult for thick ascending limb to reabsorb NaCl → decrease NaCl is pumped out of thick
  ascending loop → decrease NaCl to medullary interstitial fluid
• As a result, the osmolality of medullary interstitial fluid in this patient is lower than normal
• decrease Osmolality of medullary interstitial fluid → decrease the maximal
  ability of kidney to concentrate urine → more difficult for ascending LOH to reabsorb salt → vicious cycle → major increase urine volume (polyuria) & salt (NaCl) loss in urine → hyponatremia, hypochloremia and increased plasma osmolality

Question 40

Basic Nephron Processes

Answer 40

• Renal handling of any substance – Ask 4 questions:
  – Is it filtered, reabsorbed, secreted, or degraded?
• Basic nephron processes
  – Glomerular filtration
  – Tubular reabsorption & secretion in the proximal tubules (PT) (reabsorbed normally around 65% total volume of filtrate and no separation of salt and water)
  – Tubular reabsorption & secretion in the loop of Henle (LOH) (reabsorption of salt by ascending limb, reabsorption of water by descending limb, it is NOT under hormonal regulation)
  – Tubular reabsorption & secretion in the distal tubules (DT) & collecting ducts (CD)
  (regulated by hormones)

Question 41

Renin Secretion in Diabetes

Answer 41

• decrease Plasma [Na+] → sensed by juxtaglomerular apparatus → increase renin
  secretion from the granular cells →… → increase aldosterone → increase Na+
  reabsorption in DT & cortical CD (main)
• For this patient, increased renin secretion is caused by lower plasma [Na+]. It partially compensates the lower plasma [Na+]

Question 42

Reabsorption in DT & Cortical CD

Answer 42

• Aldosterone (secreted by stimulation of angiotensin II) acts on late DT (minor) and cortical CD (major) to reabsorb Na+ and secrete K+, thus promoting Na+ retention and K+ loss from blood
• The aldosterone-induced K+ secretion is the main means by which K+ can be eliminated in the urine
• Aldosterone secretion
  – Stimulated directly by a rise in blood K+ and indirectly by a fall in blood Na+

Question 43

Homeostasis of K+

Answer 43

• Secretion of K+– mainly at DT & cortical CD, influenced by aldosterone
• Aldosterone → increase K+ & H+ secretion in exchange for Na+ reabsorption (K+ & H+ compete for the same exchangers)
• Can you explain the issues about acidemia, hyperkalemia and hypobicarbonatemia?
• acidemia is because of presence of ketone bodies (2/3 ketone bodies are very acidic: beta hydroxybutyrate and acetoacetate) so there’s an increase in H+ concentration in blood which occupies a lot of exchange opportunity originally co-used by K+ and H+, this maintains K+ in the blood which causes hyperkalemia
• when there’s acidemia, the increased H+ in the blood, the bicarbonate ions in blood will try to buffer the H+ by combining H+ and forming carbolic acid, from carbolic acid it will become dissolved CO2 plus H20, so this is a way to buffer the H+ concentration by bicarbonate ions, so now these bicarbonate ions are being used to neutralize H+, causing hypobicarbonatemia

Question 44

Antidiuretic Hormone (ADH)

Answer 44

• ADH (arginine vasopressin → increase blood pressure bc increase reabsorption of water, increasing blood volume increases blood pressure) is synthesized in hypothalamus, stored in posterior pituitary
• Stimuli (mainly changes in plasma osmolality) → ADH secretion
• Retain water in the body by
  – Inserting of water channels (aquaporin-
  2) into apical membrane of medullary
  collecting duct tubular cells → help
  concentrate urine and decrease plasma
  osmolality
  – Vasoconstriction → increase peripheral
  vascular resistance → increase BP, important
  in hypovolemic shock

Question 45

Aquaporins

Answer 45

• Aquaporin-2 – produced in the principal cells of medullary CD, stored in secretory vesicles, responds to ADH
• Medullary CD also contains other
  aquaporins, not ADH-regulated

refer to picture

Question 46

ADH and Aquaporin-2

Answer 46

• ADH → increase insertion of aquaporin-2 into the apical membrane of principal cells of medullary CD
  – ADH also stimulates transcription of the aquaporin-2 gene
• increase aquaporin-2 insertion → increase water reabsorption from tubular lumen → cells → medullary interstitium → vasa recta

Question 47

ADH & Urine Concentrating/Diluting Mechanism

Answer 47

• increase Plasma osmolality → increase ADH secretion → increase ADH-ADH R’ → increase cAMP…→ increase insertion of aquaporin-2 → increase water reabsorption → increase water exits through aquaporin-3 or aquaporin-4 to interstitium then blood → increase blood volume, decrease plasma osmolality, decrease urine volume

refer to picture

Question 48

Why is the renin secretion increased?

Answer 48

This patient still has a functional RAAS (renin & aldosterone) in response to lower plasma [Na+] & a functional ADH system in response to increased plasma osmolality. The increased secretions of renin, aldosterone & ADH, however, are not enough to fully compensate for the effect of solute diuresis

Question 49

Revision of Calculation on Polyuria

Answer 49

• Normal urinary concentrating max ability is 1,200 mOsm/liter
• Just to dilute 5,645 mOsm of glucose, one would need [5,645 (mOsm) / 1,200 (mOsm/L)] = 4.7 L of water.
• 4,700 ml / 400 ml for each urination = 12 urinations just because of filtered glucose
• More dilute factors from NaCl and urea
• Each micturition reflex is initiated at 200-400 (max = 500ml) in the urinary bladder → a minimum of ~30 times to restroom/day

Question 50

Solute Diuresis – Summary

Answer 50

• Solute diuresis (osmotic diuresis) – increased urine volume caused by the presence of certain solutes in the lumen of renal tubules
• When solute present in renal tubular lumen cannot be reabsorbed:
  – → increase Filtrate osmotic P in tubular lumen
  – → increase Retention of water within the lumen & decrease reabsorption of water
  – → increase urine output (i.e. diuresis)
  – → Polyuria
  – → Dehydration due to polyuria
  – → Polydipsia (increasing fluid intake) to quench excessive thirst

Question 51

Explanation on Hyperphagia

Answer 51

• Hyperphagia (polyphagia) – excessive hunger or increased appetite
• In DM, lack of insulin (type 1) or insulin resistance (type 2)
• → Glucose cannot move into the insulin-sensitive cells (skeletal & cardiac cells, adipose cells)
• → Cells are starved of glucose
• → Send out hunger signals brain (hypothalamus)
• → Hyperphagia in diabetic patients