Transcript Document

Note
No cow’s milk or cow’s milk products
(including but not limited to cheese and
yoghurt) under the age of one year
-casein (a protein in cow’s milk) is the
putative issue with type 1 diabetes
Lecture 4a 28 January 2013
Diabetes
Type 1
Type 2
Pathology-4a
Nutritional Intervention-4b
Functional Food/Nutraceutical Approaches-4c
Pathology
Role of insulin
-produced in the beta cells of the pancreas
-initially synthesised as a single chain 86
amino acid polypeptide (pre-proinsulin)
-post-translational modification removes the
amino terminal signal peptide
what is a signal peptide?
Role of insulin
-this give rise to proinsulin
-insulin is created via the cleavage of an internal
peptide (31mer) and the A (21mer) and B(30
mer) chains of insulin are then linked together
by a disulphide linkage (enzyme responsible?)
Causes of Type 1-genetic
-concordance is 30-70 % in identical twins
-polymorphisms in HLA complex appear to
account for 40-50 % of Type 1
-HLA complex contains genes for the class II
MHC molecules which present antigen to
helper T cells and are thus involved in
initiating the immune response
-ability of class II MHC molecules to present
antigen is dependent on the amino acid
composition of their antigen binding sites
Genetic
-amino acid substitutions may influence
the specificity of the immune response
by altering the binding affinity of
different antigens for the class II
molecules
-10 % of genetic risk due to
polymorphisms in the promoter region
of the insulin gene
Causes of Type 1
-autoimmune- beta cells produced proteins that
mediate draw lymphocytes into pancreas where
they infiltrate islets (insulitis) and selectively attack
beta cells- inflammation leads to atrophy of b-cells
-immunological markers-islet cell autoantibodiesthese antibodies are directed at a series of b-cell
proteins
-environmental-viruses-coxsackie and rubella
-bovine milk
-nitrosamines
Causes of Type 2
Key risk factors for type 2 diabetes:
•Being 40 years of age or older
•Genetics stronger factor than in type 1
•Having a close relative (parent or sibling) who has type 2 diabetesgenetics
•Being a member of a high-risk population, such as those of
Aboriginal, Hispanic, Asian, South Asian or African descent-genetics
•Having a history of impaired glucose tolerance or impaired fasting
glucose
•Having heart disease
•Having a history of gestational diabetes-increased risk of type 2
diabetes in mum and offspring
•Having high blood pressure
•Having high cholesterol
•Being overweight, especially around the abdomen-though
overweight/obesity NOT THE WHOLE STORY
Type 2-no longer adult NIDDM - affects children
and insulin can be used
-genetic factors
-concordance of 70-90 % in identical twinsquestion this
-40 % if both parents have it-question this as
well
-polymorphisms or mutations in insulin
receptor and enzymes involved in glucose
homeostasis (candidates?)
-pathophysiology
-increased hepatic glucose synthesis because
as insulin sensitivity drops the ability of
insulin to promote glycogen synthesis and
suppress gluconeogenesis drops
-impaired insulin sensitivity
Pathophysiology continued
-impaired insulin production-reason is
unknown-though glucose toxicity while
undefined cripples beta cell-suggestions
-increased free fatty acids impair
b-cell function
Metabolic syndrome
-obesity
-kick-off via increased free
fatty acids
-measures
-BMI
-percentage fat-skinfolds
underwater weighing
-height-weight tables
-free fatty acids regulate
insulin sensitivity
Metabolic syndrome
-free fatty acids regulate insulin sensitivity
-free fatty acids decrease glucose
utilisation and increase hepatic
glucose production
-lipids-including decreased anti-oxidation
capacity
-increased free fatty acids
-decreased HDLc, increased CETP,
decreased LPL
-increased cholesterol, LDLc
-increased triglycerides
Metabolic syndrome
-blood pressure
-elevated
-platelet aggregation- Tripepidemiology slide
PLATELET HYPERREACTIVITY AND MYOCARDIAL
INFARCTION*
SPA STATUS
AND NUMBER
OF PATIENTS
TOTAL
MORTALITY
149
CARDIAC
EVENTS
18
33
SPA NEG.
94
6 (6.4 %)
14 (14.9 %)
SPA INT.
29
3 (10.3 %)
7
SPA POS.
26
9 (34.6 %)
12 (46.2 %)
(24.1 %)
12 MOS. DATA OF Trip et al. NEJM 322:1549 (1990)
SPA = SPONTANEOUS PLATELET AGGREGATION
Metabolic syndrome
-insulin sensitivity-receptor binding efficiency
-right shift in insulin dose response curve
and downward shift in maximal impact
-as insulin sensitivity goes down the lipids
are further perturbed
-ultimately may get pancreatic failure with
requirement for insulin injections