Hyperglycaemia and diabetic microangiopathy

Abstract

In their editorial, Professor Lundbaek and his colleagues bring forth a number of noteworthy issues regarding capillary basement membrane thickening and the carbohydrate abnormalities of diabetes. Many of these points have been raised previously by Williamson [1] and no doubt some of them have concerned other investigators in this field. We are therefore pleased to attempt a clarification of these issues. Professor Lundbaek's editorial raises three critical questions:

Alterations in the Basement Membrane (Heparan Sulfate) Proteoglycan in Diabetic Mice

“…2 " 5 In diabetics, marked thickening of basement membranes is seen in capillaries and the kidney glomeruli and this change is believed to underlie premature degeneration of the kidneys, - 7 Although the basement membranes are thicker, they are more porous. 8 "…”

A common sense approach resolves the basement membrane controversy and the NIH Pima Indian study

“…Siperstein et al alluded to only part of the problem when they stated that "for unknown technical reasons, all the values obtained with osmium fixation for normal, prediabetic and diabetic patients in the NIH (Pima) study were higher than those obtained earlier" [2]. They did not acknowledge that the very much higher MCBM width values obtained for osmium-fixed tissue from normal Caucasians in the Pima study are virtually identical to those from glutaraldehyde-fixed tissues.…”

“…Siperstein, Feingold and Bennett [2] have interpreted the preliminary data as: 1) documenting the presence of MCBM thickening in approximately 50% of prediabetic Pima Indians, confirming Siperstein's earlier report of significant MCBM thickening in 50% of Caucasian prediabetics and supporting his previous observations and conclusions regarding MCBM thickening in diabetics, and 2) "demonstrating that differences in methodology, far from being minor, probably account for the failure of studies using glutaraldehyde-fixed tissue to observe quadriceps MCBM thickening in prediabetic subjects." Gunderson, Osterby and Lundbaek [1] question the validity of these interpretations and are concerned by apparent data discrepancies in this and in previous reports by Siperstein et al When the Pima data are examined critically in terms of their biological and statistical implications, and in the context of data previously published by Siperstein et al [3], two points become clear: 1) the Pima data regarding fixative effects on the frequency of MCBM thickening in prediabetic and diabetic Pimas are inconclusive, and 2) data derived from osmium-fixed tissue in Siperstein's laboratory are not reproducible.…”

“…The central issue of two recent editorials by Gunderson et al [1] and by Siperstein et al [2] concerns the interpretation of muscle capillary basement membrane (MCBM) measurements obtained from the NIH-sponsored Pima Indian study (a co-operative study invoIving our laboratory as well as that of Siperstein et al, co-ordinated by Dr. P. Bennett and associates). Siperstein, Feingold and Bennett [2] have interpreted the preliminary data as: 1) documenting the presence of MCBM thickening in approximately 50% of prediabetic Pima Indians, confirming Siperstein's earlier report of significant MCBM thickening in 50% of Caucasian prediabetics and supporting his previous observations and conclusions regarding MCBM thickening in diabetics, and 2) "demonstrating that differences in methodology, far from being minor, probably account for the failure of studies using glutaraldehyde-fixed tissue to observe quadriceps MCBM thickening in prediabetic subjects."…”

The basement membrane controversy

“…Siperstein's group has recently suggested that all diabetes is autosomal recessive [3]. As previously implied [4], that is akin to saying that the earth is flat. Confirming the view of extensive heterogeneity in IID, Tattersall et al [7] when studying 37 conjugal diabetic families, found the prevalence of diabetes among the offspring to vary from zero to nearly 100%, strongly suggesting that more than one genotype was involved.…”