Note

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Lecture 4a 31 January 2011 Diabetes

Type IType II

 Pathology-4aNutritional Intervention-4bFunctional 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 I-genetic-concordance is 30-70 % in identical twins

-polymorphisms in HLA complex appear to account for 40-50 % of type I

 -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 I-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 -cells -immunological markers-islet cell autoantibodies-these antibodies are directed at a series of -cell proteins -environmental-viruses-coxsackie and rubella

-bovine milk-nitrosamines

Type II-no longer adult NIDDM - affects children and insulin can be used

-genetic factors

-concordance of 70-90 % in identical twins- question 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 -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- Trip- epidemiology slide

PLATELET HYPERREACTIVITY AND MYOCARDIAL INFARCTION*

SPA STATUS MORTALITY CARDIAC AND NUMBER EVENTSOF PATIENTS

TOTAL 149 18 33SPA NEG. 94 6 (6.4 %) 14 (14.9 %)

SPA INT. 29 3 (10.3 %) 7 (24.1 %)

SPA POS. 26 9 (34.6 %) 12 (46.2 %)

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