ITRM20100403A1 - DIETETIC SUBSTANCE FOR THE TREATMENT OF OBESITY AND OTHER PATHOLOGICAL CONDITIONS SUCH AS THE INSULIN RESISTANCE AND DIABETES MELLITUS TYPE 2 - Google Patents

Description

â € œDIETIC SUBSIDY FOR THE TREATMENT OF OBESITYâ € ™ AND OTHER PATHOLOGICAL CONDITIONS SUCH AS INSULIN RESISTANCE AND TYPE 2 DIABETES MELLITUS

The present invention relates to a dietary aid for the treatment of obesity consisting of a water-soluble compound comprising a monosaturated fatty acid such as olive oil, four essential amino acids (methionine, L.phenylalanine, tryptophan and valine), one sugar (D-dextrose), as well as antioxidants such as limonene and lycopene and a natural substance with an anti-inflammatory action such as Boswelic acid.

This compound, acting on the digestion mechanism by temporarily and reversibly reducing the patient's full capacity to digest the foods ingested, has shown surprising efficacy in the treatment of obesity, resulting in weight loss, counteracting insulin resistance and also acting on the mechanisms pathogenetics concerning the recently recognized inflammatory matrix of obesity.

It is known that the Western population is overfed, so much so that the ability to store chemical energy from nutrients has become a negative factor leading to obesity. Obesity can be defined as an excess of body fat which very often causes damage to health. In fact, new evidence shows that obesity is a circumstance that predisposes and aggravates the course of other pathological conditions such as insulin resistance (IR) and type 2 diabetes mellitus.

More specifically, IR is characterized by the inability of insulin to lower blood glucose by suppressing hepatic glucose production and stimulating the use of glucose by muscles and adipose tissues.

The reduction in insulin sensitivity may be due to an inherited defect or may be acquired as a result of diabetes. Since excess fat in the body causes a reduction in sensitivity, as well as an increase in the demand for insulin, obese patients show both hyperinsulinemia and IR particularly during oral glucose tolerance tests. Once hyperinsulinemia / IR is acquired, a cascade of metabolic changes begins leading to type 2 diabetes mellitus as well as a series of abnormalities including dyslipidemia, atherosclerosis, arterial hypertension, hypercoagulability and cardiovascular disorders which are collectively known. as a metabolic syndrome.

This result is in agreement with recent studies showing that patients with IR (hyperinsulinemia) can recover their insulin response after weight loss.

The first approach in the treatment of obesity involves a diet based on the reduction of calories, an appropriate nutritional status, and an effective diet. However, since any diet is long-term as well as short-term is doomed to failure, a pharmaceutical treatment is often used as a support to improve patient compliance.

In a previous patent in the name of the same Applicant, a dietary preparation was disclosed for the treatment of obesity and dyslipoprotidemia which, taken fasting, before the actual meal, acting on the digestion mechanism, physiologically stimulated biliary and pancreatic secretion in a measure such that upon actual ingestion of food, the body was devoid of those common reserves of enzymes and bile salts necessary to trigger the digestive processes. This preparation included fats, proteins and sugars in the minimum quantities necessary to stimulate the digestive capacity of the patient when fasting. In the course of the subsequent clinical activity, it has now been surprisingly found that by integrating the fats, proteins and sugars of the p r e ce d e n t e composition c o n d eg l i a gen t the antioxidants such as limonene and lycopene and an anti-inflammatory / antioxidant as a c i d o Boswelico, the effects on insulin resistance occur on the patient even before significant weight loss: this led the applicant to hypothesize that the combination of oleic acid and other unsaturated fatty acids with said antioxidants and Boswelic acid, synergistically contributes to counteract the inhibitory effect of insulin production by the cytokine TNF-alpha, perhaps due to the fact that thanks to the reduced digestive capacity caused by the ingested compound, it seems that the anti-inflammatory agents are able to perform their action in the gastrointestinal system for a longer time.

Therefore, the object of the present invention is a chemical composition soluble in water comprising, for each dose to be taken on an empty stomach before each meal, (otherwise called mini-meal) a monounsaturated fatty acid (oleic acid from 1.5 to 3 g), four essential amino acids (methionine, L-phenylalanine, tryptophan and valine from 1 to 14 mg for each), a sugar (D-dextrose from 4 to 8 g), two antioxidants (limonene from 2 to 4 mg. and lycopene from 3.5 to 7 mg) as well as Boswelic acid (from 150 to 300 mg.). This composition is supplemented with rhubarb extract or bitter grapefruit to taste. to give it a bitter taste.

In particular, a preferred composition, always referred to a dose, is that comprising a monounsaturated fatty acid (oleic acid, 2g), four essential amino acids (methionine, L-phenylalanine, tryptophan and valine, 10 mg for each), a sugar (D-dextrose, 6 g), two antioxidants (limonene, mg. 3 and lycopene, mg. 5) as well as Boswelic acid (mg. 200). This formulation was dissolved in 150 mL of water containing a sufficient amount of citric acid to obtain a solution at pH 2.5.

Experimental data

The experimentation was conducted by comparing the effect of this composition which we will indicate with A with a pharmaceutically soluble preparation B comprising metformin (1g). This preparation was dissolved in 150 mL of water containing a sufficient quantity of citric acid to obtain a solution at pH 2.5.

In addition, a placebo formulation was made with 150 mL of water containing a sufficient amount of citric acid to obtain a pH of 2.5.

The product according to the present invention has been used to appropriately stimulate the secretion, and therefore the consumption of biliary and pancreatic juices, before the food of the normal meal reaches the duodenum. A metformin preparation and a placebo preparation were used as a positive and negative control for weight reduction, respectively. All chemical preparations were acidified to pH 2.5 to stimulate stomach functions and thus accelerate gastric emptying.

A series of 32 outpatients (11 males / 21 females, mean age 39.6 / - 12.3 years), called â € œgroup Aâ €, who presented mild to moderate obesity, was admitted to the study. All patients in this group were treated with the product of the invention (solution A) in association with a controlled diet regimen (1300 Kcal / day) and subjected to evaluation as a study population.

Another series of 32 outpatients (11 males / 21 females, mean age 38.1 / - 13.8 years), called â € œgroup Bâ € and presenting a mild-moderate obesity.

All patients in this group were treated with metformin (solution B) in combination with a controlled diet regimen (1300 Kcal / day) and considered as positive controls.

Another series of 32 outpatients (11 males / 21 females, mean age 37.8 / - 15.7 years) called â € œgroup Câ € and with mild to moderate obesity were included in the study. All patients in this group were treated with placebo (solution C) in association with a controlled diet regimen (1300 Kcal / day) and evaluated as negative controls.

Patient inclusion criteria were as follows:

body mass index (BMI) greater than or equal to 28 kg / m2. Patient exclusion criteria were age below 18 and over 65, lack of informed consent, presence of glucose intolerance, type 1 and 2 diabetes mellitus and thyroid disorders.

Each chemical preparation was administered orally, approximately 2 minutes before each of the three meals consumed daily. All procedures followed in this study were in accordance with the ethical standards of the institutional committee responsible for human experiments. Furthermore, informed consent was obtained from each patient who was studied.

Monitoring of patients under treatment Each patient who took part in the study was regularly followed up for 6 months. In detail, at the start of the study and after 1.3 and 6 months of treatment, the patient's compliance was verified through a careful examination of the food ingested daily followed, if necessary, by a specific medical interview. In order to evaluate the effectiveness of each treatment in determining weight loss, the body weight and height were measured and then the BMI, body mass index, was calculated.

In addition, to verify the effect of each treatment on the metabolic state, fasting and postprandial insulin and glycaemia, triglycerides and total cholesterol were measured using routine diagnostic methods. Finally, to evaluate the onset of side effects deriving from each treatment followed, the clinical status was also checked with particular attention to episodes of asthenia and gastro-intestinal discomfort, number of evacuations and the weight of daily stools, the values hemoglobin, sideremia, ferritin and transferrin.

The mean clinical and metabolic data of the patients at the start of the study are shown in Table 1.

The average clinical and metabolic data after six months of treatment with the dietary aid object of the invention are shown in Table 2.

Tab.1 - Average clinical and metabolic data of patients at the start of the study

Group A Group B Group C Number of patients 32 32 32

Males / females 11/21 11/21 11/21 Age (years) 39.60 ± 12.30 38.10 ± 13.80 37.80 ± 15.70 Body weight (kg) 99.60 ± 14.30 94.80 ± 11.30 97.90 ± 15.30 BMI (kg / m <2>) 34.04 ± 1.81 32.37 ± 2.67 34.26 ± 3.58 <Fasting insulin (IU / mL)> 28.88 ± 6.04 32.20 ± 2.17 29.53 ± 3.09 Post prandial insulin

<(IU / mL)> 126.65 ± 16.42 109.25 ± 13.50 117.34 ± 6.99 <Fasting blood glucose (mg / dL)> 89.44 ± 4.50 82.38 ± 5.22 77.97 ± 3.77 Post-meal blood glucose 120.88 ± 2.94 106.78 ± 5.30 117.94 ± 3.63 (mg / dL)

Triacylglycerols (mg / dL) 231.00 ± 34.70 231.70 ± 8.40 200.00 ± 54.30 Total cholesterol (mg / dL) 321.80 ± 52.90 294.20 ± 7.80 312.40 ± 22.90 Dietary regimen (Kcal / day) 1,300 1,300 1,300 Specific treatment Dietary aid Metformin Placebo

Statistical analysis

In table 1, all data are expressed as

mean value / - the standard deviation, while,

in the figures, all parameter values are

expressed as the median threshold value, quartile (first

and third quartile) and range (maximum value e

minimum).

Tab. 2 - Variations in parameters from the start of the study to 6 months of treatment (t0-t6)

Dietary aid Metformin Placebo Body weight (kg) - 16.71 ± 2.54 * ° - 12.43 ± 5.82 ° - 7.15 ± 2.40 BMI (kg / m <2>) - 5.70 ± 1.00 * ° - 4.33 ± 0.94 ° - 2.46 ± 0.76 <Fasting insulin (IU / mL)> - 16.28 ± 5.77Ë † ° - 19.81 ± 4.05 ° - 5.94 ± 4.40 Postprandial insulin

(IU / mL) - 104.60 ± 17.82 * ° - 83.93 ± 15.13 ° - 43.25 ± 7.75 <Fasting blood glucose (mg / dL)> - 4.88 ± 5.86Ëœ - 4.06 ± 6.05 - € “2.00 ± 5.36 Postprandial blood glucose 1.27 ± 5.24 - 0.66 ± 6.99 - 0.34 ± 6.38 (mg / dL)

The data are shown graphically in the figures

attached in which:

fig. 1 is a box-and-whisker diagram (median, first and third quartile, maximum and minimum) showing changes in body mass index (BMI) at different times (0.1, 3 and 6 months) since € ™ start of each treatment (dietary aid, metformin and placebo). The p-value refers to Student t and Wilcoxon tests to match the data provided on the calculated BMI values in each patient group at different times.

Fig. 2 is another box-and-whisker diagram showing changes in fasting insulin at different times from the start of treatment;

fig 3 is another box and whisker diagram c h e m o s t r a i c a m b i a m e n t i d e l l â € ™ i nsulinemia postprandial at different times from the start of treatment;

fig. 4 shows the changes in fasting blood glucose from the start of each treatment at different times;

Fig. 5 shows the changes in postprandial blood glucose at different times from the start of treatment.

Results

All patients undergoing daily treatment showed a good response.

After 6 months of treatment, the average weight loss was 16.7% in group A, 13.4% in group B and 7.3% in group C. Therefore, in patients treated with the mini-meal according to the invention, the weight loss was significantly higher than that achieved with metformin or placebo while in patients treated with metformin this parameter was significantly higher than in those who took placebo (table 2). A significant decrease in body mass index was also observed in each group, (fig. 1), although in patients treated with the mini-meal object of the invention, the reduction was higher than in those who had taken metformin, in which the decrease in BMI is greater than that of patients treated with placebo (table 2).

At the end of treatment, a significant reduction in fasting insulin was observed in each group, although in patients treated with the mini-meal this parameter decreased only after the first month of treatment (fig. 2). The greatest variation in fasting insulin was observed in patients treated with melformin and thereafter, in decreasing order, in patients taking mini-meals and those taking placebo (table 2). A significant reduction in postprandial insulinemia was observed in patients treated with the mini-meal and thereafter, in descending order, in patients who took metformin and in those treated with placebo. (table 2).

After 6 months of treatment, a significant reduction in fasting glucose was seen in each group, in patients who took the mini-meal or metformin, blood glucose levels had decreased during the first month and had remained constant from the first. in the sixth month of treatment while, in patients treated with placebo, this parameter decreased only after the first month of treatment (figure 4). In patients treated with minipasto or metformin, the reduction in fasting glucose was higher than in patients treated with placebo (Table 2). Despite the fluctuations in postprandial blood glucose levels highlighted over time, no significant reduction in this parameter was observed after each of the treatments (Figure 5 and Table 2). That is, no reduction in either triglycerides or total cholesterol was observed after any treatment.

At the end of treatment, none of the patients who took part in the study showed gastrointestinal disturbances except for an increase in the number of daily bowel movements (6.5%), although the daily stool weight had always remained below the normal level. (<200 g / 24h). Furthermore, no one showed asthenia while the iron values, that is the mean hemoglobin values, did not vary significantly (13.4 / - 0.5 vs 12.8 / -0.3 g / dL).

Discussion

Most authors agree that obesity is an excess of fat in the body which very often causes damage to health, even if the exact meaning of excess fat in the body is rather difficult to define. The limit above which the accumulation of fat assumes a pathological significance is conventionally set at about 20% of the ideal weight. Furthermore, the most correct therapeutic approach to tackle obesity involves a reduced caloric regimen, often in association with adequate physical preparation. This practice is based on a simple principle: if the supply of calories is lower than the daily requirements, the fat reserves are used for the energy balance and therefore must be reduced. A corollary to this strategy is physical exercise which in itself is designed to increase the consumption of energy stored in the form of fat. However, considering that obesity is a chronic condition, the effectiveness of any dietary regimen is limited by the patient's low willingness to follow its precepts.

From a l t r a p a r t e, u n a v o l t a c h and hyperinsulinemia / IR is acquired as an addiction to obesity, a cascade of metabolic changes originates that leads to type 2 diabetes mellitus, as well as to a series of abnormalities which together they are known as metabolic syndrome. For this reason IR is considered to be the primary defect in the history of type 2 diabetes mellitus and consequently the relative risk of developing type 2 diabetes mellitus increases with the increase of the body mass index, especially in cases of high distribution of abdominal fat.

I l l e g a m e c a u s a l e f r a l â € ™ o b e s i t Ã, IR hyperinsulinemia and type 2 diabetes mellitus is confirmed by the evidence that 85% of patients with diabetes mellitus fall into the â € œtype 2â € category and of these the 70% are overweight with a body mass index> - 30 kg / sq m.

The main purpose of the present invention is to provide an alternative method to reduce the absorption of fats and carbohydrates in a physiological way, and at the same time to intervene on the inflammatory processes in progress, reducing insulin resistance.

In this regard, our data show that the treatment with the composition object of the invention leads to a reduction in both fasting and postprandial insulinemia as well as in fasting glycaemia with a value comparable to that obtained after t r a t t a m e n t o c o n m e t f o r m i n a, a antihyperglycemic normally used in patients with type 2 diabetes mellitus.

This result, in line with current studies showing that patients with IR can recover their insulin response after weight loss, highlights a favorable effect of the new treatment on the path that leads from obesity to IR and possibly diabetes mellitus. type 2.

However, the treatment object of the invention is preferred to that with metformin for the following reasons:

metformin has no direct effect on beta-cell secretion;

reduces hyperglycemia but has no effect on euglycemia;

reduces the hepatic production of glucose;

reduces the absorption of glucose;

induces anorexia;

increases the uptake of glucose by skeletal muscle and adipose tissue,

thus leading to:

an increase in insulin binding,

an increase in the post-receptor actions of insulin,

an increase in Glut-4 glucose transporters.

The use of metformin also involves many side effects including:

gastrointestinal symptoms,

reduction in plasma levels of vitamin B12,

lactic acidosis when used in patients with nephropathy, tissue hypoxia from cardiovascular or pulmonary diseases.

On the contrary, the dietary aid object of the present invention:

reduces intestinal absorption of complex sugars and other food components;

modulates the stimulus of glucose towards insulin secretion;

induces a sense of fullness by reducing the intestinal concentration of gastroenteropancreatic enzymes in the presence of a meal,

with an increase in fecal volume as the only side effect.

Claims (6)

CLAIMS 1) Dietary subsidy for the treatment of obesity and the treatment of other pathological conditions such as insulin resistance and type 2 diabetes mellitus, characterized by the fact of including for each dose to be taken on an empty stomach before each meal, a fatty acid monosaturated such as olive oil, four essential amino acids (methionine, L.phenylalanine, tryptophan and valine), a sugar (D-dextrose), as well as antioxidants such as limonene and lycopene and an anti-inflammatory such as boswelic acid . 2) Dietary aid for the treatment of obesity and the treatment of other pathological conditions such as insulin resistance and type 2 diabetes mellitus, as in claim 1 characterized by the fact that it is added with rhubarb or bitter grapefruit extract to provide a bitter taste. 3) Dietary aid for the treatment of obesity and the treatment of other pathological conditions such as insulin resistance and type 2 diabetes mellitus, as per claim 1 characterized by the fact that each dose to be taken on an empty stomach before each meal has the following composition: - oleic acid, from 1.5 to 3 g. - methionine, L-phenylalanine, tryptophan and valine, between 0.7 to 14 mg; - D-dextrose, 4 to 8 g. - Limonene from 2 to 4 mg - lycopene from 3.5 to 7 mg - boswelic acid from 150 to 350 mg - citric acid to taste at ph 2,5-3 - rhubarb or bitter grapefruit extract to taste to give a bitter taste. 4) Dietary aid as per claim 3 characterized in that said composition is a mixture in powder or granular form comprising for each dose: - oleic acid, 4 g. - methionine, L-phenylalanine, tryptophan and valine, each in a measure of 10 mg; - D-dextrose, 6 g. - Limonene 3 mg - lycopene 5 mg - boswelic acid 200 mg. - citric acid to taste at ph 2,5-3 - rhubarb or bitter grapefruit extract to taste bitter taste. 5) Dietary aid as per each of the preceding claims characterized by the fact that said mixture is soluble in water. 6) Method of administering the dietary aid of the preceding claims characterized by the fact that it provides for the assumption on an empty stomach of a dose of the said dietary aid dissolved in a glass of water, within 3 minutes before the start of the meal.