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.
If patients have to fill in the difference between the control achieved with the beta cell encapsulated implant and the physiologic levels they are striving for, the shortfall may mean that there will not be much improvement in the complications. This is clear from the fact that even slight increases in blood sugar produce measurable worsening of complications: Z. Punthakee, et al, “Diabetes and Cardiovascular Disease,” Review of Cardiovascular Medicine, vol. 8, no. 3, p. 145 (2007). Patient efforts to control hyperglycemia with injected insulin will always fall short of what is needed to prevent complications, so encapsulated beta cells that cannot achieve perfect control will not do what is required.
The relation between blood sugars and diabetes pathology has been known since the DCCT study, namely, they are strongly correlated. Punthakee’s review is focused on type 2 diabetics, a topic of great interest currently. The Islet Sheet will be used first in type 1 diabetics, and for us with that disease, we are susceptible to microvascular disease as well as the macrovascular disease, the risk shared with type 2 diabetics. Clinical results with islet autografts and islet allografts using the Edmonton protocol demonstrate beyond any doubt that microvascular disease is greatly reduced. Risk of hypoglycemia is greatly reduced. Evidence from the LCT trials is starting to support this improvement for encapsulated islets.
Your concern about sub-optimal control is sound; when fasting euglycemia is not achieved, and control requires insulin injections, there are potential problems. Given the small molecule permeability and rapid diffusion kinetics , we believe that the Islet Sheet will be able to deliver euglycemia without insulin injections.
Although traditionally medicine has conceived of type 1 diabetes as a disease essentially characterized by a lack of insulin, in fact the situation is more complex, since diabetes is also a lack of insulin being delivered at the proper place in the body. In a normal person, insulin made in the pancreas initially appears in the pancreatic portal circulation and goes into the hepatic portal circulation. Insulin thus normally travels not from the pancreas into the general circulation and then back to the heart, but first goes to the liver where it is partially metabolized. A consequence of this anatomical separation of the body’s natural insulin delivery from the general circulation is that the local supply of insulin and the locally normal levels of blood sugar are different in various parts of the body at any given time.
But in the diabetic, insulin is injected outside the pancreatic portal circulation, usually subcutaneously, so it first travels to the general circulation and only later ends up in the liver. This means that even in a diabetic with a ‘perfect’ blood sugar level, there may remain a very significant degree of abnormality, since the insulin levels and the glucose levels in the various parts of the body are not physiological. All that is being tested as a substitute value for determining the patient’s ‘normality’ is arterial or venous blood from the general circulation, when what is in fact needed to measure the true physiological status of the patient is a full anatomical schematic showing how far the present glucose and insulin measures in each part of the body correspond to or diverge from the locally normal insulin and blood sugar distributions required by the local conditions, such as high or low energy use. The globally normal blood sugar level, which is now used, cannot give us the true picture in all its natural complexity.
This divergence between the normal anatomical variety of insulin and blood sugar and that in diabetic treated with insulin has never been measured, but may well explain why diabetics often feel less healthy than normal counterparts even when they have a normal blood sugar reading, or why many diabetics with excellent blood sugar control nonetheless experience complications. If the maldistribution rather than just the lack of insulin is an important factor in type 1 diabetes, then the implantation of an immunologically protected packet of porcine islet cells in the abdomen may omit an important aspect of what is needed to normalize diabetic physiology. But since the pancreas is a notoriously difficult area of the body to access for surgical interventions, if the porcine islet cell packet were to be implanted there in order more closely to replicate normal insulin distribution, the cost of the procedure would be many times higher than simply inserting it into the abdomen. Thus the number of patients treated would be so small — just because of the expense and limitation of available surgical facilities — that the gain in using pig rather than human cells to overcome the scarcity of the human cell supply might be seriously compromised.