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End2.1 - Diabetes mellitus -1
Physiology of the islets of
Langerhans and pathophysiology of
diabetes mellitus
© Saffron Whitehead
• Anatomy and histology of the pancreas
•
•
•
Control of insulin and glucagon secretion
Actions of insulin and glucagon
Diabetes type 1 and 2 defined and their
aetiologies
•
Overview of treatment of diabetes in relation
to insulin deficiency and resistance
Arrangement of cells in a
single islet
Single islet surrounded by
exocrine acini
Synthesis of
insulin
Synthesis of glucagon and post translational processing in the pancreas and gut
*
*
*
Incretins - increase insulin response to glucose
Major factors controlling insulin secretion
Major factors controlling glucagon secretion
Control of insulin and glucagon secretion
Arterial blood
Arteriole
Canaliculi
GLUT 2
o
o
o
o
Insulin
o
o
o
o
Glucagon
o
Insulin secreting
granules
o
Som, PP
o
o
Venule
Venous blood
Ionic control of insulin release from pancreatic  cell
Glucose
Glucokinase
Glucose-6-phosphate
Exocytosis
Mitochondria
ATP-sensitive K+
(K+ATP) channel SUR1
Insulin
ATP
-
K+
ATP
ADP
Ca2+
Kir
-70mV
Voltage-dependent
Ca2+ channel
Depolarization
+
Insulin
Uptake of glucose into
adipose tissue, skeletal
muscle and cardiac
muscle
Uptake of ffa’s/amino
acids in adipose/ muscle
tissue
Stimulation of glycogen
synthesis, inhibition of
glycogenolysis
Inhibition of
gluconeogenesis,
lipolysis and
proteolysis
Metabolic paths of
glucose
Glycogen
glycogenolysis
GLUTs
+
Circulation
+
+
Glucose -6
phosphate
Glucose
-
glycolysis
PROTEIN
+
gluconeogenesis
lipolysis
Pyruvate
FAT
lipogenesis
+
TCA
cycle
+
-
Stimulatory and inhibitory
effects of insulin on the
fate of glucose
Formation of ketone bodies
In diabetes oxaloacetate
is consumed by the
gluconeogenic pathway
Excess acetyl CoA is
shunted into formation
of ketone bodies
Family of glucose transporters
Insulin
Insulin signaling
in muscle
P
P
P
P
SHC
P
IRS
P
1,2,3
P
P
Endosome
GLUT-4
vesicles
PDK1
SOS
RAS
PKB
RAF, MEK, MAPK
Increased glycogen
synthase
FOS, ELK-->
gene transcription
TRANSLOCATION OF GLUT4 TO
PLASMA MEMBRANE
SNAREs - family of
membrane-associated
proteins mediating
membrane fusion events
P
P
P
P
IRS
P
PI- 3P,
P
PI- 3,4-P2
etc.
PDK1
SNAP-23
* t-SNAREs
PKB
Syntaxin-4
GLUT- 4
VAMP-2
* (v-SNARE)
vesicles
PI-P,
PI- 4-P2
etc.
* Found in insulin sensitive
adipocytes and skeletal muscle
Aetiology of type 1 and type 2 diabetes mellitus
-cell destruction with
absolute insulin deficiency
Combination of insulin
resistance* and deficiency
• Genetic associations
• Environmental factors viruses, dietary agents
• Immune markers autoimmunity
• Genetic associations
• Environmental factors obesity, poor fetal
development
* Loss of receptors, reduced
affinity for insulin and/or defect in
post-receptor signaling
Endocrine causes of secondary
diabetes Cushing’s
acromegaly
phaeochromocytoma
Explain why
EXPERIMENTAL MODEL OF PANCREATIC  CELL DESTRUCTION
IN AUTOIMMUNE DISEASE
NO
Macrophage
TNF-
 cell
IL-1
MHC class II
Antigen
Receptor
IFN-
FAS
CD4+
FAS Ligand
CD4+
Perforin
CD8+
T cells
Clinical characteristics of MODY and type 2
diabetes
Characteristic
MODY
Type 2
Inheritance
Monogenic, autosomal
dominant
Polygenic
Age at onset
Usually <25 years
Usually 40-60yrs
Pedigree
Usually multi-generational
Rarely
multigenerational
Body habitus
Non-obese
Usually obese
Metabolic syndrome
Mild hyperglycaemia
diabetes
Diabetes, insulin
resistance
Glucose
Proteins*
(enzyme and
transcription factors)
implicated in the
aetiology of MODY
* Genes expressing
these proteins are
all present in the
pancreatic beta cell
Nucleus
Glucose
Glucokinase (2)
HNF-4 (1)
Glucose-6HNF-1 (3)
phosphate
IPF-1 (4)
HNF-1 (5)
NeuroD1 (6) Glycolysis
Mitochondria
ATP
Ca2+
K+ATP
Insulin
Ca2+
Depolarization
MODY 2 - Glucokinase deficiency
Impaired fasting glucose (?)
Usual treatment (?)
MODY 1, 3 and 5 (HNF-4 HNF-1 HNF-1) - abnormal
transcriptional regulation of gene expression leading to defects in
metabolic signaling of insulin secretion, beta cell mass or both
Usual treatment (?)
MODY 4 & 6 (IPF-1, NeuroD1) - abnormal transcriptional regulation
of beta cell development
Usual treatment (?)
HNF - hepatocyte nuclear factor
IPF - insulin promoter factor
NeuroD - neurodifferentiation factor
Genetic lessons learned from the study of MODY
Treatments for diabetes
•
Insulin replacement
Human insulins; islet cell transplantation (experimental)
•
Insulin secretagogues
Sulphonyl ureas (e.g. tolbutamide) - K-ATPase channel of islet
cell
Incretins (e.g. GLP-1) (research only)
Sulphonyl ureas bind to the SUR1 protein associated with the K+
channel and like ATP induces closure.
Glucose
Glucokinase
Sulphonyl ureas
Glucose-6-phosphate
Exocytosis
Mitochondria
Insulin
ATP
ATP-sensitive K+
(K+ATP) channel
SUR1
-
K+
ATP
ADP
Ca2+
Kir
-70mV
Voltage-dependent
Ca2+ channel
Depolarization
+
Treatments for diabetes
•
Insulin replacement
Human insulins; islet cell transplantation (experimental)
•
Insulin secretagogues
Sulphonyl ureas (e.g. tolbutamide) - bind to and induce
closure of the K-ATPase channel of islet cell
Incretins (e.g. GLP-1) (research only)
•
Insulin sensitizers
Biguanide e.g. metformin; decreased hepatic glucose
production and increased glucose utilization (action?)
Thiazolidinediones e.g. rosiglitazone or pioglitazone
(PPAR- agonist) - what are PPAR’s?
Peroxisome proliferator-activated receptors PPARs ()
•
Originally identified as orphan nuclear
receptors
•
Family of nuclear transcription factors like
steroid receptors
•
Targets of several classes of drugs including
the thiazolidinediones
•
PPAR regulates adipocyte differentiation
and apoptosis, extracellular lipid metabolism
(e.g. increased clearance of triglycerides),
macrophage differentiation and insulin
sensitivity
Co-activator complex
CREB
SRC1 etc.
Transcription
control
PPAR
Activation of transcription
by thiazolidinedione
compounds interacting
with PPAR , dimerization
with the RXR and, after
binding with the PPRE,
initiation of transcription
RXR
HAT
TZD
Basal transcriptional
machinery
DBD
RNA polymerase
DBD
PPRE
PPAR response
element
TATA
Histone deacetylation
opening up active
conformation and
chromatin remodelling
Transcription
Possible mechanisms by which thiazolidinediones may
enhance insulin actions
Via PPAR in adipocytes*
•
•
•
•
Direct stimulation of increased glucose disposal in adipocytes
Indirect stimulation of increased glucose disposal in muscle
Reduced TNF, leptin
Reduced free fatty acids*
Via extra-adipocytic PPAR
•
Direct or indirect stimulation of increased glucose disposal in
muscle
* PPAR
is not expressed in skeletal muscle
* Insulin resistance increases production of triglycerides from liver->
atherogenesis. Thus treatment of insulin resistance with TZD’s may
improve both glycaemic control and macrovascular complications
Treatments for diabetes
•
Insulin replacement
Human insulins; islet cell transplantation
•
Insulin secretagogues
Sulphonyl ureas (e.g. tolbutamide) - K-ATPase channel of
islet cell
Incretins (e.g. GLP-1) (research only)
•
Insulin sensitizers
Biguanide e.g. metformin - (action?)
Thiazolidinediones e.g. rosiglitazone or pioglitazone
(PPAR- agonist)
•
Carbohydrate absorption - -glucosidase inhibitor e.g.
ascarbose
•
Treatment of obesity - appetite suppressants e.g.
sibutramine; pancreatic lipase inhibitors e.g. orlistat