Das Pankreas bei Diabetes mellitusMorphologie und mehr

Matthias LöhrProfessor of Gastroenterology

Gastrocentrum

Karolinska University Hospital

©M. Löhr 2012

ThemenThemen

• Pankreasphysiologie

• Die Philosophie der Evolution

• Pankreasmorphologie bei Diabetes mellitus

• Pankreasfunktion bei Diabetes mellitus

©M. Löhr 2012Löhr & Klöppel in Hahn/Riemann, Gastroenterologie, Thieme 1994

Die morphologische GrundlageDie morphologische Grundlage• Intime „geographische“

Beziehung zwischen exokrinem und endokrinem Pankreas

• Blutfluß arteriell => Insel => exokrines Pankreas

©M. Löhr 2012

Blutfluß in & aus den InselnBlutfluß in & aus den Inseln

Nyman et al., J Clin Invest 2008, 118: 3790-3797

• Der arterielle Blutflußgeht ins Zentrum der Inseln und geht zur Peripherie der Insel

• Der „venöse“ Ausflußgeht ins exokrine Pankreas

– Hohe Konzentrationen der Inselhormone

©M. Löhr 2012

Endo-Exo-AxisEndo-Exo-Axis

Korc et al., Science 1981, 213: 351-352

Insulin is trophisch für das exokrine Pankreas

= Insulin ist ein „growth factor“ L

ipase

100 µm

©M. Löhr 2012

On the origin of species… and the exocrine pancreas

On the origin of species… and the exocrine pancreas

Roach et al., J Mol Evol 1997; 45:640–652

©M. Löhr 2012

The Worm thingThe Worm thing

• Cells with zymogens (digestive enzymes) interspersed in the lining o the primitive digestive tube

www.bio.sunyorange.edu

©M. Löhr 2012

FischpankreasFischpankreas

• Both dispersed endocrine and exocrine cells

Youson &Al-Mahrouki, General &Comparative Endocrinology 116, 303–335 (1999)

©M. Löhr 2012

Pankreas in SäugetierenPankreas in Säugetieren

Fig. 2 Pancreas models in vertebrate embryos. (a) 5.5-mm pig embryo. (b) 20-mm pig embryo. (c) 11-mm rabbit

embryo. (d) 10.7-mm cat embryo. (e) 7.5-mm human embryo. (f) 13.6-mm human embryo. (After F. W. Thyng,

Models of the pancreas in embryos of the pig, rabbit, cat and man, Amer. J. Anat., 7:488–503, 1907)

©M. Löhr 2012

Der WalDer Wal

Quay, Journal of Mammalogy Vol. 38, No. 2 (May, 1957), pp. 185-192

©M. Löhr 2012

Endo-Exo Achse & EntwicklungEndo-Exo Achse & Entwicklung• Um sich vom Frosch und Neunauge

zu Menschen und Mäusen (& Wal) zu entwickeln, müssen

– Genügend Verdauuungsenzyme zum Aufschluß der Nahrung (speziell Fetten) zur Verfügung stehen

• Muss das exokrine Pankreas genug großsein

– Wofür ein Wachstumsfaktor (Insulin) gebraucht wird

• KONSEQUENZ:

Das ENDOKRINE Pankreas sitzt im EXOKRINEN Pankreas

Roach et al., J Mol Evol 1997; 45:640–652

©M. Löhr 2012

Superiority of vertebratesWhy they increase in growth and capabilities

Superiority of vertebratesWhy they increase in growth and capabilities

Species Pancreas/BW

Islets

Human 0.001 ✔

Whale 0.0008 ✔

Fish 0.00001

Xenopus 0.0001

Horse 0.001 ✔

Mouse 0.01 ✔

Dog 0.002 ✔

©M. Löhr 2012

Endo-Exo-AxisEndo-Exo-Axis

Korc et al., Science 1981, 213: 351-352

Insulin is trophisch für das exokrine Pankreas

= Insulin ist ein

„growth factor“Lip

ase

100 µm

©M. Löhr 2012

No insulin – no growth?!No insulin – no growth?!

©M. Löhr 2012

Insulo-acinar portal system: Exocrine pancreas exposed to high concentrations of islet hormones

100 µm

Insulin

Trophic effects

Halo phenomenon

Enzyme releasein response to

stimulants ↑

Glucagon, SST, PP

Atrophic effects

Inhibition of exocrine

function

Healthy subjectsHealthy subjects

� Atrophy � Loss of halos

� Exocrine insufficiencyExocrine insufficiency

- +

DiabeticsDiabetics

Islet-acinar axis in diabetesIslet-acinar axis in diabetes

Keller & Layer Gut 2005;54:Suppl 6: vi9-29

©M. Löhr 2012

Insulinpositivität bei Diabetes mellitusInsulinpositivität bei Diabetes mellitus

• Reduktion auf

– 0-5% in Typ I (IDDM)

– 10-50% in Typ II (NIDDM)

Löhr & Klöppel, Diabetologia 1987, 30: 757-762Klöppel, Löhr et al., Surv & Synth Path Res 1985 4: 110-125

©M. Löhr 2012

Exokrine Atrophie bei DiabetesExokrine Atrophie bei Diabetes

Löhr & Klöppel, Diabetologia 1987, 30: 757-762

• Acinar tissue is significantly reduced in both type 1 and type 2 diabetes

©M. Löhr 2012

Exokrine Atrophie bei DiabetesExokrine Atrophie bei Diabetes

Löhr & Klöppel, Diabetologia 1987, 30: 757-762

Lö

hr

& K

löp

pe

l, E

xp

& C

lin

En

do

cri

no

log

y &

Dia

be

tes

198

8, 7:

17

-20

©M. Löhr 2012

Pancreas atrophy in DiabetesPancreas atrophy in Diabetes

longstanding insulin-dependent Diabetes Mellitus

Löhr & Klöppel, Diabetologia 1987, 30: 757-762

©M. Löhr 2012

Pancreas volume in DiabetesPancreas volume in Diabetes

Löhr & Klöppel, Diabetologia 1987, 30: 757-762

©M. Löhr 2012

Size of pancreas in diabetes mellitusSize of pancreas in diabetes mellitusA

rea o

f p

an

cre

as (

cm

2)

Dandona P et al. BMJ, 291, 1985

US

©M. Löhr 2012

Size of pancreas in diabetes mellitusSize of pancreas in diabetes mellitus

0

50

100

150

T1D T2D Controls

Pancreatic volume, ml

p=<0.001

p=<0.001

CT

Goda K et al. Acta Diabetol 38:145-149, 2001

©M. Löhr 2012

Duct changes in DiabetesDuct changes in Diabetes

• Who‘s on FIRST?

– Hen & egg problem

Andrén-Sandberg & Hardt, JOP 2005, 6: 382-405

Rauischholzhausen Symposium on the endocrine & exocrine Pancreas

©M. Löhr 2012

Diabetes

type

Pancreatic

duct

Normal n

(%)

CP°I n (%) CP°II n (%) CP°III n

(%)

IDDM 4 (10.8) 11 (29.7) 14 (37.8) 8 (21.6)

NIDDM 31 (27.4) 23 (20.4) 35 (31) 24 (21.2)

Sum 35 (23.3) 34 (22.7) 49 (32.7) 32 (21.3)

Hardt et al., Pancreatology 2002

PankreasgangmorphologiePankreasgangmorphologie

©M. Löhr 2012

The patient with diabetes mellitusThe patient with diabetes mellitus

• Do patients with diabetes mellitushave

– Exocrine insufficiency

– Clinical symptoms

©M. Löhr 2012

• Grobe Korrelation von EPI mit Diabetes mellitus

• Moderate endokrine Insuffizienz vor moderater EPI

Lankisch et al., Digestion 1993, 54: 148

Exokrin ƒ EndokrinExokrin ƒ Endokrin

©M. Löhr 2012

• SPT demonstrates a predominantly acinar loss in secretory capacity

• Bicarbonate is less affected

01020304050

60708090

100

fasting Endogenous

Stimulation

Exogenous

Stimulation%

no

rma

l

Bikarbonat

Amylase

Lipase

CT

* * * *****

Gröger et al., Diabetes 1999

Pancreatic function in DiabetesPancreatic function in Diabetes

©M. Löhr 2012

PEI in Diabetes mellitusPEI in Diabetes mellitus

Andrén-Sandberg & Hardt, JOP 2005, 6: 382-405

Rauischholzhausen Symposium on the endocrine & exocrine Pancreas

©M. Löhr 2012Löhr & Klöppel, Diabetologia 1987, 30: 757

Diabetes in the PancreasDiabetes in the Pancreas

• Mikroangiopathy

– Reduced blood flow

– Reduction of trophic factors (Insulin)

100 µm

©M. Löhr 2012

Diarrhea in Diabetes MellitusDiarrhea in Diabetes Mellitus

• Patients with long-standing Diabetes mellitus may NOT show all the symptoms of PEI because of

– Diabetic gastropathy

– Autonomic neuropathy

el Newihi et al., Dig Dis Sci. 1988; 33(6): 705-710

©M. Löhr 2012

The patient with diabetes mellitusThe patient with diabetes mellitus

• Natural course and consequences of exocrine insufficiency

©M. Löhr 2012

PEI in DMPEI in DM

• Some patients may progress, others don’t

Creutzfeld et al., Digestion 2005;72:71–75

©M. Löhr 2012

PEI in Diabetes mellitusPEI in Diabetes mellitus

Andrén-Sandberg & Hardt, JOP 2008, 9: 541-575

Rauischholzhausen Symposium on the endocrine & exocrine Pancreas

©M. Löhr 2012

Disorders affecting multiple endocrine systems

Disorders affecting multiple endocrine systems

Syndrome Endocrine Pancreas Exocrine PancreasShwachman syndrome ? Atrophy/ 1° EPI

Ataxia-teleangiectasia Diabetes Mellitus 2° EPI

Pseudohypoparathyroidism Diabetes Mellitus 2° EPI

Myotonic dystrophy Diabetes Mellitus 2° EPI

Fanconi syndrome Diabetes Mellitus 2° EPI

Werner syndrome Diabetes Mellitus 2° EPI

Schmidt syndrome Diabetes Mellitus (Type 1b) 2° EPI

Wolfram syndrome Diabetes Mellitus (IDDM) 2° EPI

Laurence-Moon-Biedl syndr Diabetes Mellitus 2° EPI

Alström syndrome Diabetes Mellitus 2° EPI

Klinefelter syndrome Diabetes Mellitus 2° EPI

©M. Löhr 2012

New genetic defectsNew genetic defects

• First genetic defect described to affect both the endocrine and the exocrine pancreas

Ræder et al., Nat Genet 2006, 38: 54-62

©M. Löhr 2012

BücherBücher

Thank you very much for your attention

©M. Löhr 2012

Epidemiology of chronic pancreatitisEpidemiology of chronic pancreatitis

• Incidence (new diagnoses)

– 5/100.000 inhabitants

• Prevalence (number of patients with disease)

– 25/100.000 inhabitants

• For comparison

– Diabetes: 4000/100.000 inhabitants

– Pancreatic cancer: 10/100.000 inhabitants

©M. Löhr 2012

Diabetes & PEIDiabetes & PEI

• Diagnosis of the underlying cause of– Diabetes

• Type 1

• Type 2

• Type 3

– PEI• Chronic pancreatitis

• Autoimmune pancreatitis

• Pancreatic cancer

• Rare diseases (Shwachman)

– DM & PEI• syndromes

©M. Löhr 2012

Nerves & VesselsNerves & Vessels

Rodriguez-Diaz et al., Cell Metabolism 2011, 14: 45–54

©M. Löhr 2012

Diagnostic value of fecal elastase-1Diagnostic value of fecal elastase-1

• Test of choice– Best of the available

• Relatively speaking!

– Highly practicable• Small amount of stool• Easy assay (ELISA)

– quick

– Reasonable cost/effort factor

25-83 % 33-100% 75-100%

Siegmund & Löhr: Meta-analysis of pancreatic function tests. Z Gastroenterol 2004, 42: 1117-1128

©M. Löhr 2012

• Diabetics:227 (98-386)

• Controls:544 (377-702)

• Diabetes duration12,5 ± 10,5 y

• If elastase < 100 then correlation with HbA1c, Diabetes duration and age at manifestation

Icks et al., Z Gastro 2001

PEI in DiabetesPEI in Diabetes

©M. Löhr 2012

PEI in DMPEI in DM

Hardt et al., Pancreatology 2003, 3: 395-402

• More than 1,000 patients with type 1 and type 2 diabetes mellitus

• Fecal elastase-1 measurements

©M. Löhr 2012

Pancreas volume & function in DiabetesPancreas volume & function in Diabetes

Löhr & Klöppel, Diabetologia 1987, 30: 757-762Hardt et al., Pancreatology 2003, 3: 395-402

©M. Löhr 2012

There is an elephant in the roomThere is an elephant in the room

• Animal also suffered from diarrhea

©M. Löhr 2012

PEI in Diabetes MellitusPEI in Diabetes Mellitus

• Mild to moderate PEI may have a clinical impact– Clinical context

• Patients with Diabetes mellitus have an increased risk to develop PEI– Pancreatic function tests should

be employed

Evidence 2b

©M. Löhr 2012

Fecal fat in Diabetes mellitusFecal fat in Diabetes mellitus

Hardt et al., Dig Dis Sci 2003, 48: 1688-1692

©M. Löhr 2012

Pathologic pancreatic duct morphology in ERCP:

40% of patients with IDDM (n=43)

58% of ICA-positive NIDDM (n=12)

9% of ICA-negative NIDDM (n=22)

PankreasgangmorphologiePankreasgangmorphologie

[Nakanishi et al, 1994]