Jay S Skyler

University of Miami, Florida 33136, USA

Type 1 diabetes is characterized by immune-mediated pancreatic islet B-cell destruction, absolute insulin deficiency, and thus dependence on insulin therapy for the preservation of life1. The type 1 diabetes disease process involves (1) a genetic predisposition, conferred principally by 'diabetogenic' genes in the major histocompatibility complex (MHC) on the short arm of chromosome 6; (2) non-genetic (environmental) factors that appear to act as triggers in genetically susceptible people; and (3) activation of immune mechanisms targeted against pancreatic islet B-cells. The initial immune response engenders secondary and tertiary responses which collectively result in impairment of B-cell function, progressive destruction of B-cells, and consequent development of type 1 diabetes. The process is insidious and may evolve over many years, with the overt expression of clinical symptoms becoming apparent only when most B-cells have been destroyed. Yet, even at disease onset, 10-20% of B-cells remain. Improvement in their function accounts for the 'honeymoon' period often seen during the first years after onset of type 1 diabetes.

Over the last two decades, much investigation has been directed at interdicting the type 1 diabetes disease process, both during the stage of evolution of the disease and at the time of disease onset2-14. The goal of intervention prior to disease onset is to arrest immune destruction and thus delay or prevent clinical disease. The goal of intervention at disease onset is to halt the destruction of B-cells, perhaps allowing residual B-cells to recover function, thus lessening the severity of clinical manifestations.

Studies aimed at delay or prevention of clinical type 1 diabetes are critically dependent on the ability to identify individuals at risk of the disease. Although family members of patients with type 1 diabetes have a 10- to 20-fold increased risk compared to the general population, amongst newly diagnosed patients with type 1 diabetes only 10-15% have a relative known to have the disease15. Thus, efforts have been directed at identifying potential risk markers both in relatives and, to a lesser extent, in the general population. Because case finding is easier among relatives (due to their 10- to 20-fold increased risk), most intervention studies aimed at disease prevention have focused on relatives. All evidence suggests that the type 1 disease process is the same in sporadic non-familial cases16,17 as it is in relatives18,19.

Although studies in animal models have used degree of insulitis as a histo-pathological indicator of the type 1 diabetes disease process, histological studies in human beings are very limited20. Thus, B-cell function (insulin secretion), measured by assessing C-peptide response (either basal or more likely, in response to a provocative challenge) has been used to evaluate interventions in new-onset type 1 diabetes21, while the evolution from prediabetes to overt hyperglycemia has been used in trials prior to disease onset.

This chapter will review evidence concerning interventions designed to interdict the type 1 diabetes disease process. To facilitate the discussion, the evolution of the disease can be divided into a number of stages, depicted in Figure 4.1, through which individuals progress. Interruption of the sequence at any stage is likely to be important13. The stages are: (1) genetic susceptibility, modulated by genetic protection, identified by finding of susceptibility genes without dominant protective genes; (2) initiation of autoimmunity, presumably by an environmental trigger, with a cellular immune response leading to immune-mediated islet infiltration (insulitis), with the stage identified by the presence of circulating autoantibodies; (3) impairment of B-cell function resulting in loss of first-phase insulin response (FPIR) during an intravenous

Figure 4.1.

glucose tolerance test (IVGTT); (4) impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), but without overt diabetes; (5) clinical onset of type 1 diabetes; (6) 'total' diabetes with loss of all B-cell function and mass (evidenced by lack of any C-peptide response to provocative challenge).

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment