Gene-environment interaction in type 1 diabetes mellitus.

Type 1 diabetes (T1D) mellitus can best be characterized as a disorder of gluco-regulation due to the insufficient production of a single critical hormone: insulin. Since the middle of the last century the most efficient pharmacologic solution has been to administer the hormone to the patient daily. Increasingly sophisticated dosing schedules together with the availability of recombinant variants of the hormone have succeeded in granting normal lifespan to type 1 diabetics. Nevertheless, no matter the degree of sophistication, current even aggressive regimens have not proven capable of faithfully recapitulating the normal performance of the endogenous insulin producing beta cells in response to glucose. This limit leads to the inevitable principal causes of morbidity and mortality associated with T1D, namely the complications of kidney and heart together with ocular and neural diseases. While insulin replacement continues to be the primary treatment, the need to establish physiologic gluco-regulation in order to avoid complications has led to multiple avenues of alternative interventions, most of which are at the experimental stage. What all of these interventions have in common, however, is the hurdle imposed by the immune system at the level of ongoing autoimmunity and, in some cases, at the level of transplant rejection by the host. Autoimmunity in T1D is characterized by an inflammatory response against the insulin-producing beta cells of the pancreas, a chronic inflammation around and in the pancreatic islets of Langerhans termed “peri-insulitis” and “insulitis”, respectively. As studied in the two classic rodent models of the disease (diabetes-prone BioBreeding, DP-BB, rat and non obese diabetic, NOD, prone mouse), early on in the acute phase of the immune attack the islets exhibit an abundant cell infiltration by mononuclear cells, macrophages and dendritic cells (DC). With time, T-cells become the major constituent of the insulitis and are responsible for the greatest beta cell damage and destruction. The clinical onset manifests once the number of surviving beta cells cannot secrete sufficient insulin to satisfy the body’s needs. A strong genetic predisposition is a conditio sine qua non of T1D and a large body of studies support that key genetic susceptibility loci affect the genesis, function and survival of immune cell subsets. To understand the critical role played by the genetic predisposition in T1D, it is necessary to consider the processes that shape Diabetes mellitus hoy