Shortly after the launch of Solving Diabetes we received a number of penetrating questions from “J P Marat”. With his permission the resulting dialogue with Scott King has been edited for inclusion in Straight Talk. “J P Marat” is the pen name of a diabetes researcher in Canada. The dialogue has been formatted to enable further dialogue from readers.
You are probably aware of the increasing interest in benfotiamine as an oral medication to prevent the metabolism of excess glucose in diabetics to the advanced glycation end products which are the ultimate cause of diabetic complications. This drug has a half-century record of use as an extremely safe over-the-counter remedy for alcoholic neuritis. Although data began emerging in the mid-1990s showing its capacity to block the formation of diabetic complications from excess blood sugar, it was only with M. Brownlee’s publication of its effectiveness in Nature: Medicine in February, 2003, that interest in benfotiamine really took off. Now numerous clinical studies in humans clearly demonstrate that it can block complication formation whatever the blood sugar level. (Du X, et al, “Oral Benfotiamine Plus Alpha Lipoic Acid Normalises Complication-Causing Pathways in Type 1 Diabetes,” Diabetologia, vol. 51, no. 10, p. 1930 (2008)) Potentially, benfotiamine may render the abnormal blood sugar levels of diabetics harmless and their elaborate blood sugar control rituals unnecessary, all at a cost of about $3 a day with a drug so safe that its German manufacturer states in its benfotiamine package insert that “in case of overdose, no medical intervention is required.” Since there is no risk of overdose of this drug, in principle a perfect screening of the complication-forming capacity of excess blood sugar levels could be achieved by saturating the body with benfotiamine. This would, in effect, chemically imitate the effect of perfect blood sugar normalization, while yet not requiring intensive blood sugar management or risking the dangers of hypoglycemia.
If you compare this completely safe, inexpensive, and effective product, which is available today, with the implantation of porcine islet cells many years from now to provide a treatment which will certainly be very expensive, which may be unsafe, which will probably be impermanent, which cannot be made available on a large scale for many more years, and which may not permit the vast majority of patients to normalize blood glucose levels since the control provided by the porcine cells will still have to be topped up by exogenous insulin injections based on patient guesswork, then I wonder if there will still be a role for encapsulated porcine xenografts in the diabetic therapeutic milieu ten years from now?
If you believe that large doses of benfotiamine would chemically imitate the effect of perfect blood sugar, then your conclusions follow: dosing with a benign and inexpensive pill would be cheaper and more effective than any form of islet transplantation. But I don’t believe that one can chemically simulate the effect of perfect blood sugar in the presence of high blood sugar.
I think there is confusion between the end point and a surrogate end point. Blood sugar itself is not why we fight diabetes. The vascular problems of diabetes are why we try to cure it. Blood sugar is a surrogate end point, and a good one; it is near-universally believed that continuous euglycemia will result in elimination of diabetic vascular disease. Now Brownlee’s theory is that chemical reactions of proteins with sugar form ‘glycated proteins’ which are the cause of the vascular problems. (HbA1c is one such protein). It is the bridge from sugar to vasculature. In his Banting lecture he called it “A Unifying Mechanism.” I don’t think that is right; it is an oversimplification of a chemically and biologically complicated situation. To me it is like saying that HbA1c causes diabetes complications. No, it is just correlated.
Benfotiamine is not the first therapy that Brownlee thought would prevent diabetes complications. (I remember when he first proposed his hypothesis.) The proof would come with clinical results. I am not fully up on the literature, but what I have seen talks about ‘complication-causing pathways’ and ‘therapeutic rationales.’ I want to see actual reduction in, e.g., retinopathy, in human populations. I can’t find it. Does it exist?
I have always been pretty underwhelmed by the Brownlee theory. Certainly for myself I would prefer euglycemia from the Islet Sheet to reduction of complications because with euglycemia you don’t get complications to reduce.
If high blood sugar per se were so extremely toxic, I doubt that nature would have populated the world with so many animal species lacking a pancreas (such as frogs) or having enormously high blood sugar as a constant, normal state (such as hummingbirds): see J. Hargrove, “Adipose Energy Stores” Nutrition Journal, vol. 4, p. 36 (2005). The fact that patients who have survived 50 years or more with type 1 diabetes have, on average, huge HbA1c levels (greater than 10%), but still seem almost perfectly protected from complications suggests that something more than hyperglycemia is necessary to produce the vascular and neurological changes associated with diabetes: see G. Gill, et al, “Insulin-Dependent Diabetes of over 50 Years’ Duration” Practical Diabetes International, vol. 10, no. 2, p. 60 (2005). Perhaps the highly varied fates diabetic patients have with the same average blood sugar levels indicates that the complications arise from a ‘gunpowder and match’ mechanism, in which hyperglycemia is the gun powder which lies dormant unless the patient has the ‘match’ of the required enzymes in the necessary concentration to process it into harmful AGEs. If so, then since the ‘match’ can be immediately, safely, simply, and inexpensively extinguished by benfotiamine, while the ‘gunpowder’ can only be expensively, elaborately, imperfectly, and sometime in the future neutralized by islet cell encapsulation, some of the research resources now spent on islet cell encapsulation might profitably be devoted first to clinical studies of benfotiamine.
I doubt that this will ever happen, however, since while there is an enormous amount of money to be made in selling diabetics various drugs and devices to bridge the gap between the blood sugar control they can achieve and the control they are told they should achieve, there would be little or no profit in promoting benfotiamine as an unpatentable substitute for these expensive treatments.