Diabetes - the search for earlier detection and for replacement of lost insulin-producing cells

Izelle Theunissen, MRC NEWS

The early bird catches the worm - or so the saying goes. That's also true for spotting type 2 diabetes. Dr Sonia Wolfe-Coote, Director of the MRC's Diabetes Research Group, tells of the Group's research towards finding new technologies for early detection methods and for ß-cell replenishment.  Epidemiological evidence suggests that the typical Western lifestyle has a price tag - as more and more people adopt the 'fatty food no exercise' way of life, so the incidence of type 2 diabetes is soaring. 

According to Dr Wolfe-Coote this is especially applicable in the case of black South Africans experiencing the change from rural to urban life. The effect of this change in lifestyle could possibly be exacerbated by what happened in the womb before birth - known as in utero programming. 

"The diet of a rural mother 'programmes' her unborn baby's pancreas for the rural diet. When that baby grows and eventually moves to an urban area, his pancreas may be compromised, because urbanisation often means a change to a high-fat diet, which his pancreas is not at all used to," Dr Wolfe-Coote explains.

Maturity onset diabetes, or type 2 diabetes as it is now called, is usually diagnosed either by raised fasting blood sugar or impaired glucose tolerance testing. But it might already be too late. "Generally, by the time type 2 diabetes is diagnosed, irreparable damage has already been done and the secondary effects of the disease have developed. We believe, and have evidence, that there are extensive and irreversible changes that occur before you display an abnormal blood sugar level," says Dr Wolfe-Coote. So it makes sense to develop a method whereby type 2 diabetes could be diagnosed earlier. This could prevent progression to full-blown type 2 diabetes, with all of its complications, or even permit reversal of early pathological changes related to the disease.

Because their physiology is so similar to that of humans, the Diabetes Research Group uses the vervet monkey (Cercopithecus aethiops) to study various diets and the pathological changes they induce. "The aim of these studies is to emulate the dietary induced changes associated with the rural to urban transition and to monitor early metabolic pathophysiological changes and their progression with time," Dr Wolfe-Coote says.

A group of monkeys is being fed restricted amounts of a high-fat diet. This emulates the situation of newly urbanised Africans eating restricted amounts of a Western-type diet due to limited income. In a parallel study the Group is also looking at the effects of the same diet in unrestricted amounts, to emulate that of people with a higher income. Results of the study Dr Wolfe-Coote says that the study pinpointed two very interesting effects. "We were surprised by the rapid initial effects that the high-fat diet had on the blood chemistry of the monkeys. After only 17 days on the diet, there were already notable changes. Insulin and pro-insulin levels and glucose clearance rates were reduced, while the glucagon, free fatty acids, total cholesterol, LDL cholesterol and leptin levels were raised," says Dr Wolfe-Coote.

According to her, levels of some of the parameters 'evened out' after a while, but after 12 to 18 months on this diet they became unstable. "Two of the monkeys are severely compromised and are well on their way to developing type 2 diabetes," she says, "while most of the others are displaying erratic or abnormal blood chemistry with extended time on the diet." The team's other plans include putting other groups of monkeys on a high-fat diet for shorter periods of time to measure whether they return to 'normal' and how long this will take and also to trace how the changes seen at 17 days are developed.

The other interesting phenomenon the Group noted was that no two monkeys exhibited exactly the same response to the high-fat diet, but displayed changes in different combinations of parameters. Also some fluctuated only mildly, and some took longer to display pathology, while two monkeys exhibited marked changes right from the start. Different parameters Dr Wolfe-Coote says there are other methods currently recommended to detect type 2 diabetes. "One of these is the HbA1c value. This represents the average of the glucose levels in the blood for the previous six weeks. It paints a much more accurate picture than the fasting blood glucose test which only represents the glucose levels for that moment. What is interesting is that despite all of the adverse changes we observed in the parameters we measured in our studies, fasting glucose levels remained within the normal range, although HbA1c values increased gradually in all monkeys after 19-21 months. This would suggest that while glucose levels after a good night's sleep are still normal, the capability to reduce glucose after feeding may be compromised." So fasting glucose testing would not be an early detector of impending diabetes.

It has been suggested that an increased proinsulin/insulin ratio could be an earlier detector of type 2 diabetes. Insulin is produced in the pancreas in the form of a much bigger molecule which is processed to form proinsulin. This breaks down further to produce insulin. One of the effects of type 2 diabetes is that your body still produces proinsulin, but it isn't all broken down to form insulin. "A higher proinsulin/insulin ratio would therefore be an earlier indication of diabetes," Dr Wolfe-Coote says, "and our results to date would support this."

The Group is also investigating other possible ways to detect type 2 diabetes as early as possible. "We think that glucagon levels might be part of a possible earlier formula for detection. This is the chemical released when blood sugar levels drop and which ensures blood sugar levels remain normal by stimulating release of stored sugar from the liver," she says. "We have shown that glucagon levels increase in monkeys on a high fat diet." ß replenishment Found in the pancreas, ß -cells are responsible for the production and secretion of insulin. Pancreas autopsies of people with type 2 diabetes have shown an average reduction in ß-cell mass of 50 - 60%, and we have shown similar results in monkeys on a high fat diet for 18 months. If ß-cells are reduced in number, then the capacity to produce insulin drops. These insulin-producing cells are found in clusters, called islets. 

Scientists at the Diabetes Research Group are now able to regenerate these islets in the pancreases of ordinary healthy monkeys. This is done by various means of perturbation - removing a piece of the pancreas, tying a suture or piece of cellophane around the pancreas, or even just by squeezing the pancreas!

They are now investigating how this happens at the molecular level. If this is known, it may be possible, ultimately, to develop a 'pill' to induce regeneration of lost ß-cells in both type 1 (juvenile) and type 2 diabetes. "We've found that a gene which produces a protein known to be associated with proliferation is 'switched on' after such a perturbation. It is known that cells 'talk' with each other via chains of biochemical reactions known as signal transduction pathways and we've managed to identify the initial signal transduction pathway in the process of regeneration," Dr Wolfe-Coote says. The search for the subsequent pathways is held up by lack of staff and funding. "We hope that by means of collaboration with international colleagues, we shall be able to apply for external funding to continue with this work," she says.

Courtesy of the MRC NEWS For more information about this research, please contact Dr Wolfe-Coote at tel. (021) 938-0276 or e-mail: sonia.wolfe-coote@mrc.ac.za.


November 2001