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Nutrition 3701

DIABETES-Pathology - 29 September 2010

I.               Types of Diabetes

II.              Focus on Type II diabetes-why?

III.             A review of insulin function

IV.             Development of insulin resistance

V.               Insulin resistance

Obesity                

Weight loss

VI.       FOCUS ON LIPID ISSUES BECAUSE HEART DISEASE FREQUENTLY IS THE CAUSE OF DEATH IN THESE TYPE II PATIENTS AND IS AMENABLE TO NUTRITIONAL INTERVENTION

VII.       INSULIN RESISTANCE-THE LIPID KICKOFF

VIII.      INSULIN RESISTANCE- THE  SEQUELAE OF THE LIPID KICK OFF

I. TYPES OF DIABETES

Diabetes- Type I-autoimmune response that destroys B-cells in the pancreas-little or no insulin secretion

Diabetes- Type II-

a)        insulin present but ineffective= insulin resistance = insulin sensitivity (insensitivity a better word)-can have lower insulin secretion  with insulin resistance (rare strong genetic influence)

b)        but in at least half the cases insulin secretion is normal or above normal but have hyperglycemia   (therefore relative insulin deficit or resistance or insulin sensitivity (insensitivity) (milder genetic influence)

Ultimately get decline in insulin synthesis but B-cell mass drops only 20-40 % so this is unlike Type I diabetes

II. FOCUS ON TYPE II DIABETES-why?

-more amenable to nutritional intervention-

Type I diabetes  is more substantially genetic

and post-onset type II diabetes is impossible to substantially reverse nutritionally

Type II  is less genetic and

-post-onset type II diabetes is possible to substantially reverse nutritionally

III. A review of insulin function

        insulin increases resulted in the intracellular positioning of glucose transporter- glucose transporter moves glucose into the cell for metabolism (from intracellular location to cellular membrane  location)

IV. Development of insulin resistance

                Decreased peripheral glucose uptake due to decreased sensitivity to insulin action

V.  INSULIN RESISTANCE- caused by obesity and genetics

Obesity- particularly central obesity   

            -dietary factors induce obesity

-obesity reduces fluidity of insulin receptor and can impact post insulin signalling

                including appropriate translocation of glut  transporter proteins

                                -get decrease in b-cell mass

         - Weight loss (fat loss)- get increased insulin sensitivity

Genetic-combined genetic defects in the insulin receptor and post-insulin signalling

VI. Focus on lipid issues

because atherosclerotic heart disease is frequently the cause of death in these type II patients and is amenable to nutritional prevention

VII. Insulin resistance-THE LIPID KICKOFF

                -the lipid kickoff- disturbances in lipid metabolism result ultimately in insulin resistance- how is that the case?

                Obesity leads to increased concentration of  free fatty acids (FFA) in the plasma

                        -free fatty acids are fatty acids not attached to any other molecule- eg triglyceride

-increased concentration of free fatty acids in the plasma is due to increased flow of FFA from adipose cells into circulation

Increased FFA in plasma leads to increased oxidation of FFA in cells (eg liver and muscle) that leads to a feedback mechanism that inhibits passage of glucose from glucose protein transporters into the cell-this gives insulin resistance

Note that when insulin contacts its receptor on a cell it sends a signal for transporter molecules from deep in the cell  to move to the cell surface- once at the cell surface these protein transporters capture the glucose and bring it inside the cell

VIII. INSULIN RESISTANCE-THE SEQUELAE OF THE LIPID KICKOFF

Once insulin resistance sets in then get:

                Nerve glycosylation (attachment of  glucose to proteins) -slows neural impulses

                Decreased HDL-cholesterol due to increased triglycerides  and increased activity of a protein that removes cholesterol from HDL and moves that cholesterol to the LDL

                 Decreased HDL-c due to glycosylation  of VLDL which lowers activity of lipoprotein lipase (LPL) which in turn is significantly responsible for     the production of HDL- such responsibility arises from the assignment of lipids originally in VLDL and chylomicrons to HDL in part due to the action of LPL.

                Increased LDL-cholesterol due to increased activity of a protein that removes cholesterol from HDL and moves that cholesterol to the LDL-increase in activity of this protein is due to glycosylation of that  protein

-also have increased levels of small dense LDL due to decreased levels of LPL activity which allows increased persistence of VLDL which readily accepts lipid from LDL resulting in small dense LDL

-small dense LDL taken up much more aggressively into arterial wall than are larger less dense LDL

-also have increased glycated LDL which are  taken up much more aggressively into arterial wall than less glycated LDL

                Increased oxidation of LDL-in part due to increased oxidation of increased FFA in plasma-oxidation of  FFA sets up further oxidation of lipids in LDL

-increased  LDL oxidation also due to lower antioxidant capacity of plasma-due to lower concentration  of antioxidant chemicals  in plasma

-oxidised LDL taken up much more aggressively into arterial wall than are non-oxidised or less oxidised LDL

                             Increased platelet reactivity

                                                -due to increased plasma FFA, VLDL, LDL and decreased HDL

                        Decreased HDL-c, increased LDLc (including increased oxidation of LDL), increased platelet aggregation and increased protein

                                          glycosylation all lead to narrowing of the vasculature