Marvin Siperstein (1925-1997) became notorious in the diabetes world for starting the basement membrane controversy which rumbled on for ten years from 1968. The spark was a paper in which Siperstein and colleagues reported that 90% of diabetic patients over age 19 and 50% of ‘prediabetics’ (offspring of two diabetic parents) had thickened muscle (quadriceps) capillary basement membranes (MCBM). Thickening did not correlate with duration or severity of diabetes - a sharp contrast to clinical studies which always showed that a longer duration of diabetes was associated with more microvascular complications. It was also suggested that basement membrane thickening did not occur in non-genetic forms of diabetes; in 8 patients with chronic pancreatitis, only one had thickening. Siperstein and colleagues concluded that, ‘These results indicate that thickening of the muscle capillary basement membranes is a characteristic of genetic diabetes mellitus, and further, that the hyperglycemia of diabetes is probably not the factor responsible for the microangiopathy characteristic of diabetes mellitus.’
Siperstein’s main opponent was the pathologist Joseph R Williamson of St Louis. Contradictory results led to arguments about methodology. Siperstein claimed that fixation with glutaraldehyde (used by Williamson) rather than osmium (which Siperstein used) lessened the sensitivity of the measurement. Another disagreement was where in its circumference the MCBM should be measured and how many readings were necessary. Much ink was spilt discussing the merits of various techniques of fixation and measurement but the more serious problem of poor reproducibility was glossed over. Some workers found a 25% variation of basement membrane thickness in adjacent capillaries from the same biopsy while others found that it could vary as much as two fold in adjacent biopsies taken at the same time from a single patient.To resolve the question of whether the discrepant findings in prediabetics were real or apparent, the National Institutes of Health sponsored a cooperative study involving the laboratories of Williamson and Siperstein. This showed that the results in Siperstein’s laboratory were not reproducible and the controversy fizzled out.
His other great scientific interest was cholesterol metabolism on which he began research in the 1950s and made many contributions. Arguably the most important was to show that cholesterol biosynthesis is normally regulated by a negative feedback system whereby cholesterol feeding suppresses cholesterol synthesis by inhibiting the rate-limiting enzyme HMGCoA reductase. He showed that loss of feedback leads to overproduction of cholesterol. This became the foundation for the Nobel Prize-winning work of his proteges, Michael Brown and Joseph Goldstein and led to the development of statins. Marvin was a most engaging person who was more cultured and widely read than many doctors.
^ Williamson JR, Kilo C. A commonsense approach resolves the basement membrane controversy and the NIH Pima Indian study. Diabetologia 1979;17:129-131.