Jordon Tristan Walker Pfizer

Project History: In 1999-2000 our Center was involved in two

different studies, one evaluating the use of insulin to help diabetics with severe

hypoglycemia (without any other specific complications) and another a study looking at the

effects of changing the amount of insulin used. We did not record the course of myocardial

insulin resistance that came about, but it would have been within the 6th-9th years of

diabetes before I began working as an researcher on these studies. For this study I

was hired by the NIGMS IRR’s Laboratory of Endocrinology, where I wrote the protocol for

the subjects in both cases and conducted the laboratory analysis. The result of the

protocol was that the subjects we had interviewed were close to death from lactic acidosis or

insulin related coma, indicating irreversible damage to their heart tissue. Our initial

analysis showed that our subjects died from lactic acidosis due to sodium retention, as

observed after administration of large amounts of NaCl (which they likely ingested along

with their foods), caused by either retained insulin because of reduced beta-cell function

or beta cell destruction. Whatever the case, once the cDNA sequences identified the

lesions in the tissues being examined, results were drawn showing that lesions were due to

an inherited defect in a gene that causes the growth of fat cells in the skin (and the

exceedingly rare hereditary case of lipoatrophasia which leads to permanent facial

swelling and could eventually cause blindness). This discovery profoundly altered what was

presumed to be the leading cause of cardiovascular mortality in Japan, heart disease (mostly

due to atherosclerosis), especially hypertension and heart failure. These new findings led

to a more rational approach to treating diabetes, where people who had borderline glycemic

controls were considered for investigation. Thanks to modern facilities and the development of

analytical techniques, we were able to identify that even with stable and appropriate levels

in type 1 patients above 50 mg/dl, up to 220 mg/dl, LDL-cholesterol levels were also very high.

This finding led to initiation of treatment under closer supervision of specialists throughout

Japan.