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 % in identical twins -polymorphisms in HLA complex appear to account for % 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  -cells -immunological markers-islet cell autoantibodies- these antibodies are directed at a series of  -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 diabetes- genetics 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 % 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 STATUSMORTALITY CARDIAC AND NUMBER EVENTS OF PATIENTS TOTAL SPA NEG (6.4 %) 14 (14.9 %) SPA INT (10.3 %) 7 (24.1 %) SPA POS (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