ulabeLes aLhophyslology

Clalre 8ryanL
clb4g09[soLon.ac.uk
WhaL we're golng Lo cover
8aslc glucose, lnsulln & pancreas physlology
1ype 1 vs 1ype 2
ukA
PCnk
Pypoglycaemla
Long Lerm compllcauons
WhaL ls dlabeLes melllLus?
A group of dlsorders characLerlsed by hyperglycaemla
lnsulln declency
lnsulln reslsLance
. or boLh
An overvlew of glucose meLabollsm
Clucose Clucose-6-phosphaLe Clycogen
ACoA/yruvaLe LacLaLe
kreb's
cycle
2 A1
36 A1
CC
2
+ P
2
C

Ml1CCPCnu8lA
C?1CLASM
Clycolysls
Anaeroblc (Corl)
epude hormones wlLh opposlng eecLs
AcLs Lo decrease
blood glucose
!"!#$%&'
AcLs Lo lncrease
blood glucose
'!)!#$%&'
! cells
" cells
lnsulln vs Clucagon
8elease Lrlggered by:
1. MeLabollLes e.g. ^ glucose, ^ lA, ^AAs
2. Pormones - ^ guL hormones, adrenallne
3. nerves - nS
4. urugs - sulphonylureas
Acuons:
$* +,-./012
3 4561 /7 +,-./01 -86591 :*6/ .1,,0
j glucose release from llver

Cn faLs: ^ llpogenesls (adlpose ussue), j llpolysls and oxldauon
Cn proLelns: j proLeolysls, ^ proLeln synLhesls

lnsulln: mechanlsm of acuon
ln
su
lln

8
e
ce
p
Lo
r
CLu1 4
l8S-1
l3k
uk1
k8
uses llJk os o secooJ messeoqet
lk8 sumolotes ttooslocouoo of
Clu14 to tbe cell membtooe
1ype 1 vs 1ype 2
);81 < );81 =
230,000 people
10 of dlabeLes
2.3 mllllon people
90 of dlabeLes
AbsoluLe lnsulln declency lnsulln reslsLance
PLA u84 - llnked Lo 8A and SLL
30 concordance ln MZ Lwlns
1-cell medlaLed desLrucuon of beLa cells
?auLolmmune
?vlrally Lrlggered - slmllar proLelns on vlral coaL Lo
Lhose on beLa cells, body auacks vlrus, body auacks
beLa cells
lnsulln blnds Lo recepLor buL no lncrease ln glucose
LransporLers
Clucose can'L geL lnLo Lhe cell ! hlgh blood glucose
Sumulauon of beLa cells Lo produce more lnsulln !
hyperlnsullnaemla
lmpolteJ qlocose toletooce ot tbls stoqe wltb post-
ptooJlol blqb qlocose

. 1beo ofet mooy yeots, Jecompeosouoo of beto cells
lnsulln levels drop Lo normal
8lood glucose very hlgh ! dlagnosls of uM
LvenLually beLa cells become exhausLed and Lhere ls
lnsulln declency as ln 11uM
ukA
Lack of lnsulln
Why?
SLress/lnfecuon
uecreased lnsulln lnLake
glucose
glucose
glucose
glucose
glucose
glucose
glucose
glucose
glucose
LoLs of glucose ln Lhe
bloodsLream whlch
can'L geL lnLo cells so
1,1>561? @,//?
+,-./01A
BC;814+,;.51D:5E
Cell
Cells shl Lo oLher subsLraLes
Lo produce energy: 84/61:*0
and ,:8:?0

8yproducLs of Lhls are fauy
aclds ! keLone bodles
lnsulln ls also a regulaLor of Lhe na
+
/k
+
pump and exchange
becomes abnormal
lnLracellular k
+
becomes low
normal k
+
levels ln plasma as ughL conLrol by kldneys
. buL Lhe enure body has become hypokalaemlc
When you x Lhe slLuauon and glve lnsulln, k
+
rapldly oods
lnLo Lhe cells ! pauenL's plasma suddenly becomes low ln k
+

1herefore k
+
ls added Lo bags of uld ln LreaLmenL of ukA

glucose
glucose
glucose
glucose
glucose
glucose
lasma glucose ls
above Lhe 41*5,
6C410C/,?
$0D/F. ?:-410:0
5*? +,;./0-4:5
G1C;?45F/*
'/D5
G156C
!.:?/0:0 and H16/0:0
H-00D5-,
@4156C:*+
IJC5-0F/*
2-3 morLallLy
60-90 morLallLy wlLh cerebral oedema
KoLenually GH!?
olyurla
olydlpsla
olyphagla + welghL loss
uklng (n&v)
uluresls and dehydrauon
ulzzlness
ua - menLal sLaLe changes
keLouc breaLh
kussmaul breaLhlng
Abdo paln & cramps
ArryLhmla + arresL
<Jmmol/l ot -- lo otloe
<11.1mmol/l
veooos pn <7.J
keLonaemla
Pyperglycaemla Acldaemla
Alms of LreaLmenL
L,-:?0 6/ ./441.6 ?1C;?45F/*
0.9 sallne
40mmol k
+
added Lo each bag Lo avold hypokalaemla
SLrlcL uld balance: nC Lube and caLheLer wlLh uld balance charL
Check elecLrolyLes and glucose every hour
&*0-,:*
0.1 unlLs/kg lnLravenous lnsulln lnfuslon (lvll)
8educe glucose by 3mmol/L per hour, fasLer ! lncreased rlsk cerebral oedema due Lo
rapld changes ln serum osmolallLy
&*64/?-.1 <MN +,-./01 OC1* #P0Q<R
need Lo keep Lhe lnsulln golng Lo swlLch o keLogenesls, buL lf you don'L add glucose
Lhe pauenL wlll become hypoglycaemlc
)4156 6C1 -*?14,;:*+ .5-01
PCnk SLaLe
Can develop due Lo Lhe same reasons as ukA
More common ln frall elderly

IJ641D1 C;814+,;.51D:5 STRMU O:6C 014-D C;814/0D/,54:6; STVRMU
PyperosmolarlLy leads Lo osmouc shl of waLer lnLo Lhe lnLravascular comparLmenL = severe
lnLracellular dehydrauon
Csmouc dluresls wlLh slgnlcanL dehydrauon and alLered menLal sLaLe
CverL keLosls does noL occur as low levels of lnsulln prevenL llpolysls, buL levels are lnsumclenL Lo
reduce blood glucose
W:+*0 5*? 0;D86/D02 marked dehydrauon, weakness, confuslon, neurologlcal slgns or selzures.
Coma ls rare, aecung only 10. lf Lhey are dehydraLed, whaL slgns mlghL Lhey have?
'/D8,:.5F/*02 Lhromboembollc evenLs, lnfarcuon, ulC, cerebral oedema, muluorgan fallure
Cverall morLallLy up Lo 30 - sllghLly more Lhan ukA as elderly populauon
lasma osmolallLy and anlon gap
lasma osmolallLy ls lncreased ln ukA and PCnk
lasma osmolallLy = 2(na + k) + urea + Clucose
ln ukA, usually >290 mCsm/kg
ln PCnk, usually >320 mCsm/kg
Anlon gap = (na - Cl) + PCC
3

ln ukA, usually >13 mmol/L
Pypoglycaemla
Whlpple's Lrlad:
Pypoglycaemla
SympLoms aurlbuLable Lo a low blood sugar level
8esoluuon of sympLoms wlLh correcuon of hypoglycaemla
usually a pauenL on lnsulln or sulphonylureas
SympLoms:
SnS medlaLed 2.3-3: lncreased P8, sweaung, pallor, ne Lremor
CenLral 'neuroglycopenla' <2.3: blurred vlslon, slurred speech,
dlsorlenLauon, coma, cardloresplraLory arresL
Long Lerm compllcauons
V D5:* 856CO5;0 /7 856C/,/+;
1. non-enzymauc glycosylauon l.e. dlrecL LoxlclLy of hyperglycaemla on cells
ulrecLly relaLed Lo poorly conLrolled blood glucose levels (lncreased levels = lncreased rlsk)
Clycosylauon of collagen and proLelns become 'advanced glycosylauon end producLs' (ACL)
1rap lnLersuual proLelns ln blood vessels (eg. LuL) ! aLherogenesls
1rap albumln ln renal vessels ! Lhlckened glycosylaLed basemenL membrane
ACL recepLors cause release of cyLoklnes ! lncreased endoLhellal permeablllLy and procoagulauon
2. Acuvauon of roLeln klnase C
ulacylglycerol (uAC) ls a second messenger, hyperglycaemla lncreases synLhesls
uAC and calclum lons acuvaLe kC ln cells
kC acuvauon has many downsLream eecLs:
roanglogenlc molecules e.g. vascular endoLhellal growLh facLor (vLCl)
robrouc molecules e.g. Lransformlng growLh facLor beLa (1Cl)
3. olyol aLhway
ln cells LhaL do noL requlre lnsulln for glucose upLake, hyperglycaemla causes lncreased lnLracellular glucose
Aldose reducLase Lransforms lL lnLo sorblLol (a polyol), whlch ls Lransformed lnLo frucLose
lncreased lnLracellular osmolarlLy and waLer lnux ! cell oedema
lncreased rlsk of oxldauve sLress (anuoxldanL reserves are reduced wlLh sorblLol meLabollsm)