Rossi Flashcards
Go through the circle of events that occur in diabetes mellitus with respect to: ketone bodies, pH changes, buffering, and compensatory mechanisms
decreased insulin sensitivity to glucose (or no insulin) causes hyperglycemia leading to hyperinsulemia; acts like glucagon thus stimulating lipolysis which leads to increased plasma ketones; increased KB causes a decrease in pH
the decrease in pH is buffered by:
- ICF: proteins (Hb) and organic phosphates
- ECF: bicarb, proteins, inorganic phosphates
Compensation: since the body is in METABOLIC acidosis (because their is an accumulation of non-volatile acids), compensate by hyperventilating to increase alveolar respiration and decrease pCO2 thus decreasing [H+] bringing the pH back towards normal (**doesn’t exceed normal)
also there is an increase in urinary acid excretion (as NH4+ increase)
what is the effect of diabetes related hyperglycemia on the reabsorption of water/Na?
hyperglycemia leads to excess glucose that is SECRETED (because it surpasses Tm and tubules can’t resorb anymore) this leads to an osmotic diuresis in which water and Na+ aren’t resorbed as much because they normally resorption is iso-osmotic and Na+ is staying to balance the high osmolality of the urine;
** so although the Na+ concentration may be lower in TF, the absolute amount of Na+ left behind in the TF is GREATER; thus hyperglycemia increases BOTH Na+ and H2O excretion (more brought downstream)
leads to polyuria; leads to a decrease in ECF volume because a lot of water is leaving to balance out glucose
How are ketoacids (weak acids) buffered in the cell?
conjugate base of the ketoacid has transporters that can pump it into the cell along with H+ (THUS ELECTRONEUTRALITY IS MAINTAINED); there is no need for K+ to shift out of cell (like what happens with a strong acid buffering)
**Thus the acidosis in uncontrolled diabetes mellitus is NOT the cause of high plasma (or ECF) K+ seen in diabetic patients**
What is the cause of high plasma K+ seen in untreated diabetic patients?
NOT DUE TO ACIDOSIS (BECAUSE KETOACIDS ARE WEAK ACIDS)
due to high plasma osmolality that occurs when insulin is not present;
when insulin IS present, glucose in the ECF can enter the cells and be metabolized to CO2 and H2O. Thus the contribution of ECF glucose to the osmolality is minimal ~ 5mosm/kgH20 and STAYS CONSTANT. (blood glucose does not vary that much in normal individuals)
In the absence of insulin (as in diabetes) glucose cannot enter the cell (ignore brain for now), and the ECF osmolality rises; this causes a shift of gluid from the ICF to the ECF until the osmolalities are equalized AT A HIGHER OVERALL OSMOLALITY!
As fluid leaves the cell, the cell shrinks and K+ in the ICF increases (due to this decrease in fluid; not due to an increase in K+) leading to K+ leaving the cell (high to low) and entering the ECF causing ECF [K+] to increase and the AMOUNT of K+ in ICF to decrease (even though the CONCENTRATION is elevated from what it was originally) … thus a K+ (ICF) deficit that will lead to an H+ deficit and high K+ in plasma
What happens as a result of the high plasma K+ in diabetes mellitus?
trigers secretion of aldosterone (to decrease K+ and increase Na+) ** while the adernals respond to Na/K ratio, the ratio is most sensitive to K+ concentrations;
Aldosterone acts on the principal cell of the distal nephron to increase K+ secretion (and Na+ reabsorption) in order to mitigate the high K+ concentration;;
So now we have HYPER aldosteronism triggered by hyperglycemia
What are the factors that affect Distal Na+ reabsorption and K+ secretion?
Increase Na+ resorption and increase K+secretion:
- Aldosterone (due to high plasma [K+] from the glucose that is impermeable and K+ trying to balance it)
- Increased Na+ load to the distal tubule (Na+ not reabsorbed proximally due to osmotic diuresis)
Decrease Na+ resorption and Increase K+ secretion
- Non-resorbable anions (from ketoacids that exceed the Tm and are left in the lumen)
- High tubular fluid flow rate (due to osmotic diuresis and high fluid flow from upstream)
So plasma [K+] is high and:
- in the presence of aldosterone (due to low ECF volume and blood pressure) K+ will be secreted
- the high Na load (from osmotic diuresis upstream) will also increase K+ losses
- the presense of non-reabsorbed ketoacids makes the tubular potential more negative and more K+ secreted
- high tubular fluid flow rate will increase K+ losses in urine
NET RESULT: THE BODY BECOMES K+ DEPLETED, even though the PLASMA K+ is HIGH;
ICF K which cannot be measure directly is in deficit (big time)
What happens to the Na+ in diabetes mellitus?
hyperglycemia causes and increase in osmotic diuresis and less Na+ is resorbed; thus more Na+ gets to the distal tubule, and the increased Na+ load causes increase Na+ resorbption and increased K+ secretion; But the transporters Tm is exceeded and not all of the Na+ that now available (due to diuresis) can be resorbed;
Also the increase in ketoacids brings an overall negative charge in the urine (non-resorbable anions) as they exceed their Tm. Causes more Na+ to be secreted to balance the charge;
Even though aldosterone is triggered by the increase in plasma K+, and causes and increase in H2O and Na+ reabsorption, the Tm is exceeded. as more and more Na+ is not being reabsorbed, there is a net decrease in plasma volume, increasing even more aldosterone and causing more K+ secretion
NET RESULT: Na+ is excreted into the urine despite the ECF volume depletion
Thus, hyperglycemia due to diabetes mellitus (insulin insensitivity/absence) results in:
ketoacidosis ketoaciduria glycosuria osmotic diuresis (loss of Na+ and H2O) hyperkalemia (high blood [K+]) with total body K+ deficit Hyperaldosteronism (secondary to high plasma [K+] ) which induces distal K+ secretion limited distal Na+ resorbption despite aldosterone due to nonreabsorbed anions Increased distal K+ secretion (due to the effect of high aldosterone (from high plasma [K+] and ECF volume depletion), unresorbable anions, and increased Na+ load and flow Total body Na+ and K+ deficit WORSENS!!
Why does aldosterone increase in diabetes mellitus?
- high plasam K+ concentration
- Low ECF volume (due to loss of Na and water leading to lower blood pressure and renin secretion, thereby stimulating the renin-angiotensin-aldosterone cascade)
Although the increased Na load to the principal cell AND aldosterone would increase Na reabsorption, the increased nonreabsorbed anions (ketoacids) will limit the ability of the distal nephron to make up for the na+ tat was not reabsorbed in the prox tubule due to osmotic diuresis
How does osmotic diuresis contribute to the corticomedullary gradient?
osmotic diuresis (due to high glucose in diabetes) causes an increase in flow of fluid though the loop of Henle since less Na+ and water are reabsorbed upstream in the Prox tubule; The delivery of solute at this speed exceeds the rate at which the thick ascending limb of Henle can reabsorb solute, resulting in less solute reabsorbed and then the gradient in the interrstitium will not be as steep.
How does the corticomedullary gradient effect water resorption and diabetes meillitus?
the CM gradient is less steep (due to the high flow rate of filtrate through the PT due to decreased resorption because of osmotic diuresis)
This causes a smaller gradient in the CD/DT for water resorption and thus less water is reabsorbed (more excreted); Result is that PLASMA osmolality increases (less water in to dilute it) and thus ADH expression is increased; but DESPITE THE PRESENCE OF ADH, the person with uncontrolled diabetes will not be able to resorb water optimally; thus POLY uria occurs.
due to polyuria, polydipsia (increased thirst) also occurs. if you don’t drink water to compensate for the loss of water, then increased [Na+] in plasma will cause further K+ secretion because the [K+] will also increase!
Also polyuria results in increased water and Na+ deficits that result in decreased ECF volume and decreased venous return and decreased blood pressure
What happens as a result of decreased ECV in diabetes?
hypotension and tachycardia (to compensate)
The decrease in ECV causes:
- DIRECT RENIN secretion (due to less Cl- seen at distal tubule/macula densa)
- INDIRECT RENIN secretion via a decrease in stretch = baroreflex to increase renal sympathetic nerve activity and increase plasma catecholamine concentration resulting in increased renin secretion
- INHIBITION OF RENIN due to increased Na+ load at JG cells, but blood pressure is a more powerful stimuli, so this is overwritten
Increased renin = increased angiotensin II = increased aldosterone (which is already stimulated by high plasma [K+])
* even eating a high Na+ sodium diet cannot compensate for the large fluid/Na+ loss in uncontrolled DM
What SHOULD happen when renal nerve activity and plasma catecholamines are high??
Decrease in ECV = decreased blood volume = decrease venous return to heart = decreased cardiac output = decreased blood pressure = baroreceptor reflex = increased renal sympathetic nerve activity and increased plasma catecholamines = 1. increased proximal Na+/H20 reabsorptions 2.afferent arteriole VASOCONSTRICTION = decreased GFR = decreased filtered Na/H2O = DECREASED urinary excretion of Na+ and decreased URINE FLOW
** this doesn’t happen in diabetic patients (person exhibits polyurea, even if DM is controlled due to osmotic diuresis)
What are some of the actions of Angiotensin II?
- increased vasoconstriction to increase BP
- increased aldosterone synth and secretion to decrease Na+ excretion and increase K+ excretion
- Increased thirst and increased ADH secretion
- increased efferent constriction (to maintain GFR), increased proximal Na+ reabsorption, decreased renin secretion (negative feedback)
most of these actions are not possible in diabetes because:
- decreased blood volume = decreased venous return = decreased cardiac output = decreased BP (even though vasoconstriction occurs)
- Na+ increased due to osmotic diuresis and nonreabsorbable anions so it can’t be reabsorbed well (it is excreted a lot)
- sometimes drinking water is not possible (ie: coma, vomitting etc)
*** that’s why if a pt has severe volume loss and is on an ACE inhibitors (that prevent angiotensin II) it is super dangerous (even though a lot of times ACE inhibitors are good for preventing diabetic kidney disease or diabetic heart failure)
What are the GENERAL effects of diabetes?
hyperglycemia (hyperosmolality) = metabolic acidosis = profound K+ depletion with high K+ concentration = Na and water depletion = cause high plasma osmolality = ECF volume depletion and hypotension = baroreflex activation of RAAS, ADH, sympathetic nervous system (catecholamines) and increased HR
PROBLEM = HIGH GLUCOSE TREATMENT = INSULIN (and replace lost Na+ K+ and H2O)
What happens in heart failure with respect to the kidney? (generally)
heart failure = kidney increases Na+ and H2O reabsorption because it receives ‘signals’ that the ECF volume is decreased; resulting in EXCESS NA+ and H2O in the body and the patient presents with edema, shortness of breath, low plasma [Na+] and osmolality
How much of total body water is in each compartment? what solutes are in ECF/ICF?
TBW = 0.6 * LEAN BODY WT ECV = 1/3 TBW ISV = 3/4 ECV PV = 1/4 ECV
ICV = 2/3 TBW
Solutes:
Na, Cl, bicarb = ECF
K, organophos, protein = ICF
Osmolality = 300 osm
How does Fick’s principle relate to Na/Water balance?
Na in = Na out
water in = water out
IN NORMAL PATIENTS
How is water balanced in the body?
osmolality (tonicity) is regulated within +/- 1%; because the solutions are electroneutral, in ECF,
Na = Cl + HCO3- + proteins etc.
THUS PLASMA OSMOLALITY = 2* PLASMA [Na+]
if water is lost then:
there is an increase in osmolality which stimulates increased ADH and thirst = increased drinking and decreased water excretion = decreased osmolality back to normal
THUS REGULATING OSMOLALITY = REGULATES [Na+]
**abnormal plasma osmolality or plasma [Na+] is due to disturbed H2O balance
** Na CONCENTRATION does not tell you the Na content in the body, rather it is directly proportional to plasma osmolality and therefore the PLASMA Na+ CONCENTRATION tell us the AMOUNT OF WATER in the body
How is Na balanced in the body?
the AMOUNT of Na determines the size of ECV (because Na is confined to ECV)
ECV * plasma osmolality = TOTAL amount of solute in ECF and the major solute = Na so the Posm = Pna;
if the amount of Na is constant then the size of ECV = constant