Mouse Metabolism and Diabetes Research

With wearying frequency come press releases announcing that a new approach has cured diabetes in animals and that the human cure is only a few years away.  Frequently such reports turn out to be wrong.  So why don’t animal results predict what all diabetics hope for?

The answer: it depends on the animal.  Specifically, it depends on the size of the animal.

Thanks to the work of Richard Bergman of USC glucose metabolism, as controlled by insulin, is a solved problem.  (Dr. Bergman is an advisor to the Solving Diabetes project.)  He is not an M.D.; rather, was trained in engineering and approached diabetes physiology as an engineering problem.  He broke the animal body into a set of ‘boxes’ such as the liver, the pancreas and the peripheral blood, and studied how insulin and glucose moved between them and how those movements were affect by the amounts of components insulin and glucose.

The paper linked above is his speech on the occasion of winning the Banting Award in 2006, the highest recognition of scientific achievement in diabetes. In his Banting address Bergman started with his earliest work and reviewed the topics it led to, most recently work on the genetic basis of type 2 diabetes.  I will focus on one facet: what the Bergman model tells us about using islets to treat type 1 diabetes.

Bergman showed that the way a healthy mammal disposes of a glucose load is remarkably simple, and can be modeled using only three parameters: insulin level, insulin sensitivity, and glucose sensitivity.  To see how that works look at figure 2 from Bergman’s Banting lecture.

Bergman Figure

Glucose disposal occurs throughout the body as all tissues take what they need for their own energy production.  To keep blood sugar steady as much sugar as is used must be added to the blood.  While fasting the liver makes new glucose, and following a meal carbohydrate absorbed from the meal provides needed glucose.  But any sizable meal leads to more sugar coming into the blood than can be immediately used.  That’s where insulin comes in.

The islets sense the higher level of blood glucose and secrete insulin.  Insulin stimulates certain tissues – liver, muscle and fat – to take up more glucose than their immediate needs.  Most is stored as glycogen, a kind of glucose polymer, which can be rapidly mobilized during fasting after the insulin levels drop.

So far, this fits our usual picture of how insulin works: we inject rapid insulin and our blood sugar drops.  The insulin directly causes certain tissues to take up glucose.  Bergman calls this insulin-mediated glucose uptake.  But, it turns out that when you directly measure how much glucose uptake is mediated by insulin, insulin only explains about half of total body glucose uptake after a meal. What is causing the other half of the glucose to disappears after a meal?  According to Bergman’s measurements, it is the glucose itself that is causing glucose update.  He calls this glucose effectiveness.

So to summarize, in order to keep blood sugar constant, the body responds two ways as glucose is absorbed from food.  First, the glucose causes more glucose to be taken up.  Second, glucose causes insulin secretion, and the insulin causes glucose uptake.  In a human being, after a mixed meal, about 60% of blood sugar uptake is insulin mediated; in the smaller dog, about 40% of  of blood sugar uptake is insulin mediated.  A dog, like a human, is a large mammal.

Small mammals make insulin, but the insulin is not needed as much for handling glucose after meals.  In fact, almost all glucose uptake in mice following a meal is glucose mediated.  In other words the rise in mouse insulin after a meal has almost no effect on glucose uptake.

This is wildly counterintuitive and is not appreciated by islet researchers.  When islets are implanted into mice, scientists often inject glucose then measure it over time, the ‘glucose tolerance test (GTT)’.  But since the glucose itself is causing glucose uptake, all mice GTTs are the same because they aren’t responding to their own insulin.

So why do mice make insulin if they don’t need it to handle sugar?  The role of insulin in mice is to potentiate glucose-mediated glucose uptake.  So a mouse without insulin loses its sensitivity to glucose – and with insulin regains it and stops being diabetic.  But the timing of the insulin is unimportant.  In short, implanting a capsule filled with insulin in a form that comes out slowly works as well as implanting an islet in a mouse (as has been shown experimentally).

In other words, the information in a mouse GTT tells you no more than the fasting glucose of the mouse!

So next time you read diabetes has been cured in animals by X, and you see at the animal is a mouse, then you know that there is a big gap between that mouse and a human that must have perfectly timed insulin levels. We at Cerco Medical use rodents in our research, mainly rats (much bigger than mice so an islets sheets is implanted easily).  But we pretty much limit metabolic measurements to fasting glucose.

When the time comes to study how well the Islet Sheet restores metabolism, we will use large animals.  And we won’t claim the Islet Sheet works until we have shown it in pigs or other large mammals.

This entry was posted on Wednesday, June 3rd, 2009 at 10:25 am and is filed under Scott's Opinion. You can follow any responses to this entry through the RSS 2.0 feed. You can skip to the end and leave a response. Pinging is currently not allowed.