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From obesity to diabetes

The raising of the levels of a protein explains weight gain that generally precedes excess of glucose in the blood

EDUARDO CESARThe profile of the majority of people who receive the diagnosis of mellitus diabetes type II, the form responsible for 90% of the cases of the illness, is very similar. When they are informed that they are showing excess glucose in the blood, the patients generally exhibit some other common traits: they are rarely less than forty years of age, they are accustomed to carrying a few extra kilos in their silhouette and their tissue is more resistant to the action of insulin, the hormone responsible for the control of sugar level in the circulatory system.

A study carried out by a team headed by the endocrinologist Ubiratan Machado, from the Biomedical Sciences Institute of the University of São Paulo (ICB/USP), may well have revealed an important clue about the biological mechanisms that initially favor the start of obesity in people who are still healthy, and later on, of diabetes, when these individuals turn themselves resistant to the action of insulin. In Brazil, diabetes type II hits 7.6% of the urban population aged between 30 and 69 years, the equivalent of 4.5 million people.

Studies on mice submitted to treatment with monosodium glutamate – which brings about an accelerated weight gain and raises the clinical status to something analogous to diabetes – show that, throughout the life of the animals, the wide variation in the levels of a transport protein of glucose, named Glut 4, in certain tissues, above all adipose tissue (rich in fat), seems to be the determining factor for the occurrence of these two events. Like a pendulum, the levels of this protein oscillate from high to low, without any known cause.

Sensitivity to insulin
According to this hypothesis, obesity, a risk factor for the occurrence of diabetes type II, begins to take shape in the organism because of an exacerbated, and unexplained, increase in the quantity of the glucose transporter protein between the end of youth and the beginning of middle age. During this phase of life, with more Glut 4 available in the fatty tissues, an increase in the sensitivity of the action of insulin occurs, thus creating a propensity to gain weight. Later, from middle age onwards, when possibly this obese individual becomes diabetic, the situation inverts itself: the levels of Glut 4 in the fatty cells (and in other types of tissue) oscillate to a low level and diminish the sensitivity of the action of insulin. Consequently, more glucose remains in the bloodstream.

The lowering of the levels of Glut 4 in diabetic patients with type II was already a well known phenomenon. So much so that the main drugs used to treat these patients aim to increase the quantity of Glut 4 and thus reestablish the sensitivity of the sufferer to insulin. The new fact with this study, published in the edition of September 6th in the magazine Life Sciences, was the detection of the precocious rise in the levels of this protein in the adipose tissues of mice that went through a swift process of weight gain.

If this line of research is to be correct, combating the hike of Glut 4 levels could be the key to avoiding the accumulation of fat and of diabetes type II. “If one day we manage to reduce the production of Glut 4 in the fatty tissues of people who are putting on weight, perhaps we can prevent the installation of obesity and even the development of diabetes type II”, Machado explains. In another line of research, researchers at the State University of Campinas (Unicamp), led by Mario Saad, are investigating the eventual implications of insulin in their brain receptors on the genesis of the accumulation of fat in diabetics. “Problems of recognition in the hypothalamus could also lead to obesity in these patients”, Saad says.

Differently from people who suffer from diabetes of type I, known as insulin-dependent, as their pancreas does not produce the necessary quantities of this hormone, patients with diabetes type II generally manufacture large quantities of insulin. The problem is that, because of some metabolic disorder, starting from a pre-determined point in life, the main tissues that are normally sensitive to insulin – the adipose cells, of the muscular skeleton and of the heart – begin to not react to the presence of this hormone with the same efficiency as previously.

In medical jargon, the specialists therefore say that these tissues develop resistance to the action of insulin, possible because of a lowering in these cells of the presence of the insulin transporting proteins, of which the most important appears to be Glut 4. Up to a certain limit, the pancreas compensates for this loss of efficiency in the action of the hormone, secreting even greater quantities of insulin. When this strategy no longer produces the desired effect, diabetes sets in the patient and his level of sugar in the bloodstream takes off.

Propensity to put on weight
In the experiment that spawned the study by Machado’s team, the researchers from the ICB followed, over a seven-month period, the weight gain and the levels of Glut 4 in two groups of mice: one that received monosodium glutamate – with a propensity to put on weight and to develop diabetes – and another that was submitted to this treatment. The measurements were carried out at three moments in the animal’s life, – two, four and seven months of age. “In human beings, these periods are equivalent to more or less twenty, forty and fifty years of age”, Machado compared.

In relation to the mice of the control group, the animals that receives the monosodium glutamate exhibited increasing quantities of the protein in two of the three moments studied. At two months, at the beginning of the process of weight gain, they showed levels of Glut 4 per unit of superficial area of the fatty cells (adipocytes) 36% higher than those verified in the control. When they had reached four months and were already visibly fat, the animals submitted to the treatment for weight gain had rates of Glut 4 in their fatty cells of 220% above that found in the reference animals.

The climb in the levels of Glut 4 was only interrupted when the mice who had received the glutamate reached seven months. In this phase, 25% fatter than their contemporaries of the control group, these animals presented reduced levels of protein in all of their tissue analyzed, including the fatty cells, which, during the process of fattening, exhibited levels above the norm for Glut 4.

Stocked up glucose
An interesting detail of the experiment: during the first two periods studied, those of two and four months, only an increase in the level of Glut 4 in the adipose cells was verified – and in no other type of tissue – of the mice submitted to the treatment of fattening. “In heart cells and in muscle skeleton cells, also sensitive to insulin, the levels of this protein did not increase in either of the two groups of mice”, Machado says. The data shows that the increase in the levels of Glut 4 seems to be very selective. With more Glut 4 at its disposition in the adipose tissues than in other parts of the body, the insulin carried out, in a more efficient manner, its work exactly in the region of the fatty cells. The result: more glucose is stored in the adipose tissues, where it is stored in the form of triglycerides as a source of energy, than in the rest of the body.

If the variations in the levels of Glut 4 in the various tissues sensitive to the action of insulin is truly one of the crucial factors for bringing on obesity and of diabetes type II, to control the working of the gene responsible for the production of this will would be an important prophylactic and therapeutic measurement of these two conditions. Unfortunately, this intention is still a distant dream. “We don’t know which of the factors regulate the expression of the gene of this protein”, comments Machado. There is, nevertheless, at least one simple measure that apparently helps the diabetics to increase their levels of Glut 4 and to optimize the action of insulin: to eat less. In a study published in 1997 in the International Journal of Obesity, Dr. Machado’s team showed that the administration of a diet with 20% less calories for obese and diabetic mice, who showed reduced indices of Glut 4, were capable of raising the quantity of this protein to normal levels in all of the tissues sensitive to insulin.

Effects of coffee and alcohol
To understand what favors and what hinders the appearance of diabetes type II is not always an easy task. Many studies point towards contradicting results. A recent example: a study by researchers fromthe National Institute of Public Health and the Environment in Holland, published last month in the respected English magazine The Lancet, suggested that the consumption of seven cups of coffee reduces by half the risk of someone developing the illness. The data is curious for one reason: caffeine, a stimulant present in coffee, has always been looked upon as a drug that made the absorption of glucose in the blood difficult and had increased the resistance to insulin.

Another recent study, conducted through the ICB, also arrived at interesting and intriguing data in terms of the possible treatments for diabetes. In a co-study with the German researcher Ralf Binsack, who was doing post doctorate work at USP,

Dr. Machado confirmed that the moderate consumption of alcohol – in truth, water with a concentration of 3% of ethanol – in mice increased their sensitivity to the action of insulin. In theory, this procedure could improve the effects of this hormone on the regulation of the quantity of glucose in the blood. “We know that, in high concentrations, alcohol is harmful to diabetics”, comments Mr. Machado, who is going to publish the results of their studies in a national scientific magazine at the beginning of next year. “But, as moderate consumption can perhaps be beneficial, we’re studying the mechanisms involved in this possible beneficial effect of ethanol.”

When the problem is in the brain

A study carried out by researchers from the State University of Campinas (Unicamp) and the Federal University of São Paulo (Unifesp) reinforces a hypothesis that has been gaining ground since the 80s: one of the causes of obesity in diabetics of type II could be related to problems in the initial stages of the action of the hormone insulin, which occurs in a region of the brain called the hypothalamus, endowed with nerve centers linked to a series of functions and sensations, among them being the control of one’s appetite.

A team of scientists, headed by Mario Saad, from the Medical Sciences School of Unicamp, has produced evidence in which one of the receptors involved in this process, the enzyme PI 3-quinase, is 50% less sensitive to the action of insulin in obese mice than in thin rodents. Since the main effect of this hormone in the hypothalamus is to reduce the ingestion of food, the malfunctioning of this receptor could be an important factor in the perpetuation of obesity in diabetics.

In one of the experiments, the researchers gave insulin to mice and realized that, in relation to their normal standard of consumption, there was a reduction of between 50% to 90% in the quantity of food ingested by the lean animals. The obese mice, nevertheless, presented a more moderate lowering in their appetite, between 30% and 45%. “For some time now we have known that insulin inhibits hunger”, comments Saad, the thematic project’s coordinator on the effects of this hormone on the central nervous system.

“Now our priority is for us to understand the means of signaling used by the hormone to perform in the hypothalamus. In this manner, we could one day develop drugs that would diminish the resistance to insulin in the brain.” Another protein involved in this process, named the enzyme MAP, was also tested, but its role did not show itself to be relevant to the question of obesity. The results of the study, which was the theme of the doctorate of José Carvalheira, from Unicamp, should come out shortly in the Journal of Clinical Investigation.

The projects
1. Regulation of the Transporter of Glicose Glut 4 in Mellitus Diabetes Type II: Role of the Resistance to Insulin; Modality Thematic project; Coordinator Ubiratan Fabres Machado – ICB/USP; Investment R$ 332,194.42
2. Molecular Mechanisms of Resistance to Insulin in the Hypothalamus and Peripheral Tissues: Influence of Leptin, Grelin and Resistin (nº 01/03176-5); Modality Thematic project; Coordinator Mario José Abdalla Saad – Unicamp; Investment R$ 1,061,489.86