Banting Lecture 2009: An Unfinished Journey: Molecular Pathogenesis to Prevention of Type 1A Diabetes

George S. Eisenbarth


Diabetes. 2010;59(4):759-774. 

In This Article

Abstract and Introduction


The Banting Medal for Scientific Achievement Award is the American Diabetes Association's highest scientific award and honors an individual who has made significant, long-term contributions to the understanding of diabetes, its treatment, and/or prevention. The award is named after Nobel Prize winner Sir Frederick Banting, who codiscovered insulin treatment for diabetes.


The majority of individuals, but not all, developing what is routinely diagnosed as type 1 diabetes have the immune-mediated form of the disease (type 1A) that results from T cell–mediated specific β-cell destruction. Studies of the NOD mouse model suggest that the root cause of type 1 diabetes involves germline-encoded sequences forming trimolecular complexes consisting of the insulin peptide B:9-23 presented by the class II major histocompatibility complex (MHC) molecule I-Ag7 and recognized by T cell receptors having a specific germline-encoded α-chain sequence (TRAV-5D-4*04 Vα). Utilizing genetic, autoantibody, and metabolic parameters it is now possible to predict type 1A diabetes in humans, and immune therapy can delay, but not permanently prevent, destruction of β-cells. With an increasing incidence and an estimated 1 million individuals in the U.S. developing type 1A diabetes, safe prevention has become a major international goal. Achieving this goal may come from incremental modification of immune therapies currently being tested and/or may involve a deeper understanding of the autoimmune trimolecular complexes underlying the disorder's pathogenesis.

Type 1A diabetes is associated with both devastating chronic complications and acute life-threatening ketoacidosis and hypoglycemia.[1–3] There are multiple pathways being pursued to "cure" this disease or at least dramatically ameliorate the burden it imposes on patients and their families. Continuous glucose monitoring is already improving the lives of many patients by providing "real time" information with alarms for hypo- and hyperglycemia.[4,5] Multiple groups are now studying devices that will control insulin pumps, in particular turning off insulin delivery to prevent hypoglycemia.[6] In developed countries, such devices will hopefully rapidly become the standard of care for patients with insulin-dependent diabetes.

Though many patients do not consider such mechanical devices, especially the current "first" generation of devices, as a true cure, these therapies will set the bar in evaluating immunologic therapies considered for prevention of diabetes and β-cell replacement. Thus, the bar will be high and hopefully ever higher over the next decade. At present, pancreatic (long term)[7] as well as islet transplantation (short term)[8,9] can cure type 1 diabetes but, for most patients, with unacceptable risks associated with immune suppression. It is likely that autoimmunity, in addition to alloimmunity, limits the therapeutic potential of either of these forms of transplantation.[10]

The field addressing the immunology of type 1 diabetes has grown rapidly, with thousands of relevant publications. This review can only recognize a portion of that literature and will emphasize a relatively simple hypothesis that hopefully allows presentation with a clear focus: Autoimmune type 1 diabetes results from specific β-cell destruction due to chronic T cell targeting of insulin, and the major molecular determinants of such targeting are hardwired in the genome.

Though there are clear phenotypic differences, it is remarkable at a molecular level how similar the NOD mouse and human type 1 diabetes may be. I will first review the pathogenesis of disease in the NOD mouse (where it is easier to attempt to disprove the above specific hypothesis) and then in type 1 diabetes of humans, ending with an outline of the status of clinical trials. I believe the root cause of type 1 diabetes of the NOD mouse is three genome encoded sequences, which are shown in Fig. 1. The relevant sequences are thought to be:

  • The insulin peptide B:9-23 sequence;[11]

  • The susceptible MHC I-Ag7 sequence;[12]

  • A specific T cell receptor (TCR) Vα sequence.[13]

Figure 1.

Hypothesized "primary" pathogenic trimolecular complex of the NOD class II presenting molecule: I-Ag7/insulin peptide amino acids B chain 9-23/TCR with TRAV5D-4*04.


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