Download McLovin`s Wisdom #1 – The Kidney, Diabetes Type 1 DM Type 2

McLovin’s Wisdom #1 – The Kidney, Diabetes
Definition
Epidemiology
(prevalence in
Australia)
Onset
Aetiology
Pathology
Type 1 DM
Insulin deficient
<1% in population (10%)
Type 2 DM
Insulin resistant
8%
<40 (Kumar: <20)
Takes weeks-months from
the initial autoimmune
Genetic predisposition
Trigger
>30
Years (insidious)
Destruction of ß-cells
(autoimmune destruction) 
insulin deficiency
Symptoms/signs Polyuria, polydipsia, weight
loss, wasting, glycosuria,
ketoacidosis/coma, fatigue,
vomiting (ketones –
hangover)… if uncontrolled
then get the hyperglycaemic
signs
Treatment
Insulin replacement
Lifestyle: Obesity/Lack of
exercise
Genetic predisposition
Age
(Mnemonic = LAG)
Insulin resistance 
ß-cell exhaustion
Neuropathy  tingling, loss
of sensation, foot ulcers
Macrovascular/microvascular
disease (esp. blindness)
Diet/exercise (lifestyle),
metformin (oral
medications), insulin
injection (sometimes),
bariatric surgery
Kidney arterial progression: Renal a.  segmental  interlobar  arcuate 
interlobular
Two kidneys are different heights, s
From the front to the back: vein, then ureter, then a.
Post = a.
Mid = u.
Ant = v.
The macula densa has its effect on the afferent arteriole.
 Label:
o PCT
o Thick dLH
o Thin dLH
o Thin aLH
o Thick aLH
o DCT
Collecting duct
Papilla
Urinary pole
Vascular pole
Afferent a.
Efferent a.
Bowman’s capsule
 Parietal layer
 Visceral layer (podocytes)
PCT has brush border, whereas DCT has a clean, large lumen. Collecting
duct has more cells (distal collecting duct becomes more columnar ?)
Thick tubules are thicker because of their cuboidal histology, versus the
squamous histology of thin tubules
Podocytes act as a sieve
o The glomerular capillaries are fenestrated and covered in a
glycocalyx layer
o Outside the capillaries are a basement membrane
Macula densa detect NaCl changes in the afferent a.
o Act on the juxtaglomerular cells, which renin
o Renin effects the conversion of angiotensinogen to angiotensin I,
which is then converted by ACE to angiotensin
o Salt concentration decreases, want to increase the GFR (because if
the RPF and hence GFR drop, then the plasma going through the
tubule has greater chance to have the salt reabsorbed, so low salt
means our GFR is too low). We increase GFR through:
 Autoregulation (altering vasoconstriction of
afferent/efferent a’s)
 Renin release (note AT2 has several
 Macula densa releases NO – also contributes to the
autoregulation that occurs (e.g. afferent/efferent
vasoconstriction control)
RPF decreases  GFR decreases
Functions of different parts:
o PCT
 2/3 water reabsorbes
 2/3 salt reabsorbed (basolaterial Na-K ATPase and an
apical Na-amino acid cotransport OR Na-glucose
cotransporter OR Na-H+ proton pump). Then Cl- follows
due to electrostatic movement. Water follows by osmosis
 50% of urea is reabsorbed – increases extracellular
osmolality in the medulla
 100% of glucose is reabsorbed (via SGLT-2 with GLUT2
then SGLT-1 with GLUT1)
o Thin dLH
 Impermeable to salts, urea
 15% water reabsorption
o Thin aLH
 Impermeable to water
 Passive reabsorption of NaCl
o
o
o
o
o
o
o






 Small amount of urea then goes into the tubule
o Thick aLH
 Impermeable to water
 Active transport of NaCl
 Na-2Cl-K symporter
o DCT
 Impermeable to water
 Active transport of NaCl
o Collecting duct
 ADH  AQP2 (changing whether
 NH3/NH4+ deal (check acid-base lecture)
 Sodium ion channels (Na-2Cl-K transporters with the Na-KATPase)
 Still concentrating urine and adjusting water reabsorption
Equations lecture
 Diagram: Substance A, B, C, D
 Completely secreted, Completely reabsorbed, Partially reabsorbed,
Partially secreted
 No secretion/reabsorption = Inulin or creatinine
 Completely secreted = PAH – paraaminohippuric acid
 Completely reabsorbed = glucose in non diabetic/non pregnant
 Partially reabsorbed = NaCl, vitamin C
 Partially secreted = urea
 Clearance = UV/P
 RPF = Clearance of PAH
 GFR = volume filtered per minute
 GFR = Clearance of Inulin
 Filtered load = GFR*(plasma concentration of substance)
 C>GFR  secretion
 SNGFR = Kf[(P_GC – P_T)-(π_GC-π_T)]
o Π_T~0
 GFR = ∑SNGFR
McLovin’s Wisdom #2 – Biochemistry
Tissue
Carbs
Ketones
Muscle
Y
Y
Liver
Y
N
Neurons
Y
Y
Adipose
Y
Y
RBC
Y
N

Fat
Y
Y
N
Y
N
Lactate
Y(cardiac)
Y
N
N
N
Definitions of anabolism and catabolism, and how ATP stores energy
Fats
Polysaccharides
Break down to fatty acids Break down to glucose
and glycerol (lipase and
and monosaccharides
colipase)
Proteins
Amino acids
All of these are converted to acetyl-CoA via a series of reactions that we’ll look at
later.
The acetyl-CoA then feeds into the TCA cycle
Amino acids are split into their carbon skeletons (TCA cycle) and their
ammonium groups, which are fed into the urea cycle
Starch  amylase etc  glucose
Mg2+ is always a cofactor for an ATP-consuming reaction.
PFK2 – inhibited by glucagon. Stimulated by insulin. PFK2 – stimulates PFK1 and
inhibits F-bisphosphatase
PFK1 – inhibited by ATP. Stimulated by ADP and AMP.
G-6-P is where glycogen metabolism fits in.
He put up the stoichiometry of glycolysis
Pyruvate can do a few things
 Acetaldehyde  ethanol (yeast)
 Lactate (people)
Fructose (DHAP in liver or F-6-P in fat tissue) and galactose enter the pathway
earlier on. Essential fructosuria – benign, don’t get energy from fructose.
Hereditary fructose intolerance – occurs in a later step in the pathway (after an
irreversible step – the substance trapped has a phosphate attached – build up of
F-6-P).
Galactosemia – past an irreversible step, you have a buildup of G-1-P (cataracts,
splenomegaly, mental retardation).
Pyruvate  acetyl coa with pyruvate dehydrogenase (one NADH produced)
Fatty acid  fatty acyl-CoA (cytoplasm)  fatty acyl-CoA (mitochondria)
[canitine transport system, inhibited by malonyl CoA]  fatty acyl-CoA (n-1) +
acetyl-CoA [beta oxidation]
Glycerol enters the pathway at DHAP (via G-3-P; uses ATP and produces either
NADH or FADH2)
Proteins in the body are not just “stored” – they are always doing something
Transamination
Alpha keto acid  amino acid
Transaminase
Important because when we break down amino acids to use the carbon
backbone in TCA cycle, we produce an ammonium. The ammonium is
transported to the liver in a non-toxic form (glutamate), where the urea cycle is
carried out. Urea cycle converts the
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NH3 + CO2 + aspartate + 3 ATP + 2 H2O → urea + fumarate + 2 ADP + 2 Pi + AMP + PPi
2 NH3 + CO2 + 3 ATP + H2O → urea + 2 ADP + 4 Pi + AMP
TCA cycle
Everything is down to acetyl-CoA now.
Point = produce NADH and FADH2 (electron carriers) to
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Pyruvate, Isocitrate, Alpha-ketoglutarate dehydrogenases (are activated by ADH
and inhibited by ATP)… except PDH is also inhibited by citrate.
Acetyl-CoA + 3NAD+ + FAD+ + GDP + Pi + 2H2O  CoA + 3NADH + 3H+ + FADH2
+ GTP + 2CO2
Overall: glucose  10 NADH + 2FADH2 + 4ATP/GTP
Some of the NADH were produced in the first part of glycolysis (cytoplasm), so
need to be moved to the mitochondria (malate/aspartate and glycerol-3-P
shuttles), to feed into the electron transport chain. Malate/aspartate = heart and
liver. GAP shuttle
10 H+ inside from NADH and 6+ inside from FADH2. Each ATP needs a total of
H+ to be produced.
Electron transport chain
Complex 1: pumps 4H+
Complex 3: pumps 2H+
Complex 4: pumps 4H+
TLDR: NADH pumps 10; FADH2 pumps 6.
NADHNAD+ + H+ at the beginning.
FADH2  FAD+ at complex 2
At complex 4, 1/2O2 + 2H+  H2O (the H+s are reacted with oxygen to reduce it
to water. Hence oxygen is needed).
ATP synthase.
4H+ going through ATP synthase produce 1 ATP (3H+ go through there, and 1H+
used to transport the ATP back out into the intermembrane space – the outer
mitochondrial membrane is just permeable to ATP)
Hence because one NADH produces 10 ATP, there are 2.5 ATP produced per
NADH (similarly, FADH2 produces 1.5 ATP).
Chemiosmosis = uncoupled nature of the proton pump to the ATP synthase.