FR3080533A1 - USE OF IL-6 FOR THE TREATMENT OF DIABETES - Google Patents

Abstract

The present invention relates to the treatment of diabetes of hyperglycemia via oral administration of IL-6. The invention allows regulation of blood glucose as well as the reduction of side effects associated with diabetes as well as those associated with known treatments.

Description

USE OF IL-6 FOR THE TREATMENT OF DIABETES

The present invention relates to the treatment of type 2 diabetes by decreasing hyperglycemia and improving insulin sensitivity via oral administration of IL-6. The invention regulates blood sugar and reduces the side effects associated with diabetes as well as those associated with known treatments.

Interleukin-6 (IL-6) is one of the most important inflammatory cytokines involved in cell communication. IL-6 has been identified as being involved in tissue regeneration, inflammation, defense against pathogens. However, the signaling relayed by IL-6 is also involved in the genesis and progression of many pathologies such as rheumatoid arthritis, inflammatory bowel disease and septicemia. IL-6 can induce signaling either via a membrane receptor or via a soluble form (sIL-6R), generated by alternative splicing or proteolysis by metalloproteases.

The Il-6 / sIL-6R complex can then associate with the ubiquitous transmembrane protein gpl30, which activates intracellular signaling cascades, such as the JAK / STAT pathway. The IL-6R receptor, which is abundant in extracellular fluid, including plasma and cerebrospinal fluid, is rather proinflammatory.

From a metabolic point of view, IL-6 is strongly associated with chronic inflammation, including low grade inflammation, associated with obesity and type 2 diabetes. IL-6 is secreted by immune cells (T and B lymphocytes, macrophages ...) but also by other cell types (muscle tissue, adipose tissue, endothelial cells, neurons ...). IL-6 has long been recognized as an initiator of insulin resistance, particularly because perfusion of peripheral IL6 can interfere with the action of insulin in mice and because the neutralization of IL- 6 improves insulin resistance in inflammatory models.

Despite its suggested detrimental role in glucose homeostasis, a growing body of evidence identifies IL-6 as a homeostatic regulator of glucose energy and metabolism. In support of this, mice lacking IL-6 expression develop systemic insulin resistance and late obesity.

In addition, IL-6 promotes the expansion of pancreatic alpha cells during obesity as well as insulin secretion via increased production of glucagon-like peptide (GLP) -1, and is a crucial mediator for regulatory action. of glucose-dependent insulinotropic peptide (GIP) in glucose control.

Raising IL-6 during obesity has been shown to be an adaptive mechanism in the body to increase insulin production and improve glucose tolerance to combat resistance to insulin.

It has been noted that exercise induces secretion of muscle-derived IL-6, resulting in an increase in systemic IL-6 to levels 100 times higher than the baseline levels, which is associated with better availability of peripheral energy and increased sensitivity to peripheral and hypothalamic insulin.

In addition, IL-6 influences the regulation of energy homeostasis in the central nervous system. Indeed, IL-6 plays a critical role in the physiology of neuronal tissue. Second, IL-6 can activate the hypothalamic zone to increase energy expenditure and decrease body weight gain.

All of this indicates a key but ultimately somewhat confused role for IL-6 in glucose metabolism and diabetes in general.

Diabetes, whether type 1 or 2, is an increasingly prevalent disease. In France, the diabetic population is currently estimated at 3 million individuals. With 400 new cases diagnosed every day, it will be close to 5 million by 2022.

Treatments for type 2 diabetes are for example metformin, thiazolidinedione, sulphonylurea, and / or insulin. These treatments are not without side effects

Diabetic patients present with numerous intestinal disorders (diarrhea, constipation, etc.) due in particular to an alteration in the activity of the enteric nervous system, responsible for the secretory and motor functions of the gastrointestinal tract. These disorders, which can affect up to 75% of patients, primarily affect the quality of life of these patients.

The consequences of diabetes on the digestive tract and the increased incidence of the disease will lead the hepato-gastroenterologists to be more and more confronted with the digestive consequences of the diabetic disease.

There therefore remains a need for treatment, effective and devoid of side effects for treating diabetes but also its associated side effects of the gastroenteropathic type.

The inventors of the present invention have in fact discovered that the administration of IL-6 by the oral route allows a decrease in duodenal contractility in diabetic mice and thus improves the diabetic status of the animal via a decrease in the fasting hyperglycemia, restoring the communication between the intestine-brain axis and the peripheral organs involved in the regulation of carbohydrate homeostasis, to improve insulin sensitivity at the muscular level.

This is how the present invention relates to the following embodiments:

1. 11-6 for use in the treatment of oral diabetes.

2. IL-6 for its use according to embodiment 1, characterized in that the diabetes is type 2 diabetes.

3. IL-6 for its use according to embodiment 1 or 2;

characterized in that the amount of IL-6 for each daily administration is between 10 nM and 1 μΜ.

In the context of the present invention, the dosage corresponds to a daily oral administration (s) of IL-6, comprised between 10 nM and 1 μΜ and preferably comprised between 50 nM and 750 nM, and more particularly, of at least at least 100 nM, at least 150 nM, at least 200 nM, at least 250 nM, at least 300 nM, at least 400 nM, at least 500 nM, preferably between 200 nM and 1 μΜ per day, preferably around 400 nM.

The advantage of the present invention also lies in the small amount of active ingredient delivered. IL-6 administered in small quantities acts at the duodenal level by modulating the intestinal contractility and is not absorbed in the general blood circulation.

4. IL-6 for its use according to one of the preceding embodiments, characterized in that the diabetes is associated with at least one disorder of the gastroenteropathic type and that the said disorder is reduced.

5. IL-6 for its use according to embodiment 4, characterized in that the gastroenteropathic type disorder is chosen from diarrhea, transit disorders, constipation, for example.

6. IL-6 for its use according to one of the preceding embodiments, characterized in that the diabetes is treated with a second antidiabetic molecule, in particular chosen from metformin, thiazolidinedione, sulphonylurea, and / or insulin , or other known anti-diabetic molecule.

7. IL-6 for its use according to embodiment 6, characterized in that the side effects associated with the second molecule are reduced.

8. Combination product comprising the following components: a component (A) comprising IL-6 and at least one pharmaceutically acceptable excipient; a component (B) comprising an antidiabetic agent, preferably chosen from metformin, thiazolidinedione, sulphonylurea, and / or insulin, and at least one pharmaceutically acceptable excipient.

9. Product according to embodiment 8, in which the components (A) and (B) are suitable for simultaneous, separate or spread over time administration.

In a particular case, component (A) is suitable for oral administration. In another particular case, component (B) is suitable for oral administration.

10. Product according to one of embodiments 8 or 9, for its use in the treatment of diabetes in a patient.

According to one embodiment, the combination product is suitable for oral administration, in particular of IL-6.

11. Oral pharmaceutical composition comprising IL-6 and a pharmaceutically acceptable excipient.

12. Composition according to embodiment 11, characterized in that the pharmaceutically acceptable excipient comprises an enteric excipient.

A gastro-resistant drug is a drug which does not dissolve in the stomach, and which will thus allow a release of the active substance, IL-6 at the duodenal level.

Gastro-resistant formulations are designed to release the drug into the intestinal compartment. According to the European Pharmacopoeia 8.0, gastroresistant dosage forms are delayed-release dosage forms intended to resist gastric fluid and to release their active principle in the intestinal fluid, in particular at the level of the lumen of the dudodenum. The gastro-resistance minimizes the food effect of the pharmaceutical composition of the present invention and, thus, improves the bioavailability of the drug and allows in the present case to release it where it exerts its effect, that is to say at duodenal level. By way of illustration The gastro-resistant pharmaceutical composition of the present invention comprises IL-6 molecularly dispersed in a mixture containing an enteric polymer and a non-enteric polymer. The pharmaceutical composition of the present invention can also be in granular form, whereby the granules can be coated with an enteric polymer. It is preferred that the enteric coating of the granules and the enteric polymer component of the granules comprise the same enteric polymer. According to a preferred embodiment, the granules consist of IL-6, an enteric polymer and a non-enteric polymer and optionally any other pharmaceutically acceptable excipient.

According to one embodiment, the invention relates to an oral pharmaceutical composition as described above for its use in the oral treatment of diabetes, in particular of type 2 diabetes.

The invention also relates to a pharmaceutical composition according to the invention for the oral treatment of diabetes associated with at least one gastroenteropathic type disorder and that said disorder is reduced.

The enteropathic disorder can be chosen from diarrhea, transit disorders, constipation, for example.

13. A method of treating diabetes comprising oral administration of IL-6 to a diabetic patient, in particular a type 2 diabetic patient.

14. Method for limiting the intestinal absorption of glucose by reducing intestinal contractility, in particular duodenal, in a diabetic patient comprising oral administration of IL-6.

The reduction in intestinal contractility limits the absorption of glucose at the duodenal level and at the same time reduces blood sugar.

15. It is also an object of the present invention to target IL-6 for its oral use to modulate intestinal contractility, in particular duodenal.

16. IL-6 for its use according to embodiment 15, characterized in that the modulation consists in a reduction.

17. Method for regulating glycemia in a diabetic patient comprising bringing IL-6 into contact with the duodenal mucosa.

18. Method according to embodiment 17, characterized in that the contacting is carried out by oral administration.

19. Use of IL-6 for the manufacture of a medicament for the oral treatment of diabetes, in particular type 2 diabetes.

20. 11-6 for its use for the treatment, orally, of a pathology mediated by an alteration of the intestinal contractility, in particular duodenal. In particular, the alteration is a decrease.

21. IL-6 for its use according to embodiment 20, characterized in that the pathology is chosen from diabetes,

especially type 2 diabetes, its complications and his side effects such as obesity and the unrest of type gastrointestinal enteropathic. 22. IL-6 for its use for the treatment of

hyperglycemia, orally.

23. IL-6 for its separate, simultaneous or sequential use with an antidiabetic compound, in particular chosen from metformin, thiazolidinedione, sulphonylurea, and / or insulin or other known antidiabetic molecule, for the treatment of hyperglycemia .

By targeting the neurons of the enteric nervous system, the inventors have thus demonstrated that a reduction in duodenal contractility, following the oral administration of IL-6, in diabetic mice improves the diabetic status of the animal. This results in 1) a decrease in fasting hyperglycemia, and 2) by a restoration of the intestine-brain axis to improve insulin sensitivity. This second effect allows better use of glucose by cells, in particular muscle, and also contributes to the control of blood sugar.

The molecule according to the invention, IL-6, is a cytokine the effects of which on this cellular / molecular target are unknown orally.

FIGURES

Figure 1: In vivo measurement of the amplitude of mechanical duodenal contraction in response to oral administration of water (HFD60% control) or IL-6 0.03pg for one week, n = 5 per group. ** p <0.01 vs HFD60%

Figure 2: In vivo measurement of the amplitude of mechanical colonic contraction in response to oral administration of water

HFD60%) or IL-6 0.03pg for one week.

HFD60%.

(control by group. p vs

Figure 3: Effects of oral administration of water (HFD control) or IL-6 0.03 pg for one week on blood sugar in HFD mice, after 6 hours on an empty stomach, n = 10 per group. * p <0.05 vs HFD control.

Figure 4: Effects of oral administration of water (HFD control) or

IL-6 0.03pg for one week on glycemia in HFD mice, after 12 hours on an empty stomach, n = 10 per group.

* p <0.05 vs HFD control.

EXAMPLE

Ten-week-old male C57BL / 6J mice (Charles River Laboratory, l'Arbresle, France) were housed under conditions free of specific pathogens and in a controlled environment (room temperature 23 ± 2 C, 12h day cycle) with free access to food and water.

Experiments were carried out in accordance with European Community regulations on the protection of animals and were approved by the local committee for the protection and use of animals. The mice were fed a high fat diet (HFD) containing 20% protein, 35% carbohydrates and 60% fat (Research Diet, New Brunswick, New Jersey, United States). These mice became obese and insulin resistant after 2 months of this HFD diet.

Isotonic contraction measurement

The mice were euthanized under nourished conditions. After dissection, the duodenum or segments of the colon were washed in Krebs-Ringer / glucose bicarbonate buffer (pH 7.4) in an atmosphere of 95% O ₂ - 5% CO ₂ . Duodenum or colon segments were then incubated in an oxygenated Krebs-Ringer solution for 30 minutes at 37 ° C, then attached to the isotonic sensor and immersed in the same medium maintained at 37 ° C. The load applied to the lever was 2g (20mN). After fixation of the intestinal segments, basal contractions were recorded for 15 minutes.

The mice were treated daily with an oral gavage of 100 μL of each product (control (water) or IL-6 0.03 μg / mouse) during the last week of HFD treatment previously used.

To assess duodenal contractility, data were recorded in fed mice, corresponding to the phase where segmental gut waves are generated to increase the rate of absorption of nutrients.

Fasting blood sugar assessment

As described above, the mice were treated daily with an oral gavage of 100 μΐ of each product (Control (water) or IL-6 0.03pg) during the last week of HFD treatment as previously used (Fournel, A. et al. Gut 66, 258-269 (2017)).

After six or twelve hours of fasting, the plasma glucose is assessed with a glucometer (Accu Chek Active, Roche).

RESULTS

Impact of chronic oral IL-6 treatment on intestinal contractility

First, we measured the effect of IL-6 on the duodenal contraction under ex vivo conditions. Using isotonic sensor, we observed that oral administration of IL-6 inhibits mechanical contractions of the duodenum (Figure 1). In addition, we measured the contraction of the colon and found that it was slightly decreased in mice treated with IL-6 (p = 0.0651) (Figure 2).

Impact of chronic IL-6 treatment on fasting blood sugar

Oral treatment with IL-6 for one week lowers the blood glucose level in fasting diabetic mice, regardless of the duration of the fast, i.e. 6 hours (Figure 3) or 12 hours (Figure 4).

CONCLUSIONS

For the first time, the inventors have demonstrated that oral IL-6 can modulate the duodenal contraction in diabetic mice supplemented with a diet high in fat at 60%. In addition, IL-6 reduces deleterious hyperglycemia in these mice. There is a positive correlation between intestinal contraction and glucose uptake.

These results suggest that the reduction in blood sugar induced by oral IL-6 treatment is due to a decrease in intestinal contractility. This would promote intestinal absorption and restore the intestinal axis in diabetic mice.

in-brain education "

Claims (13)

1. 11-6 for use in the treatment of oral diabetes. 2. IL-6 for its use according to claim 1, characterized in that the diabetes is type 2 diabetes. 3. IL-6 for its use according to one of claims 1 or 2, for the manufacture of a composition suitable for the administration of IL-6 in an amount between 10 nM and 1 μΜ. 4. IL-6 for its use according to one of the preceding claims, characterized in that the diabetes is associated with at least one disorder of the gastroenteropathic type and that the said disorder is reduced. 5. IL-6 for its use according to claim 4, characterized in that the gastroenteropathic type disorder is chosen from diarrhea, transit disorders and constipation. 6. IL-6 for its use according to one of the preceding claims, characterized in that the diabetes is treated by a second antidiabetic molecule, in particular chosen from metformin, thiazolidinedione, sulphonylurea, and / or insulin. 7. IL-6 for its use according to claim 6, characterized in that the side effects associated with the second molecule are reduced. 8. Combination product comprising the following components: a component (A) comprising IL-6 and at least one excipient Pharmaceutically acceptable clean copy claim set; a component (B) comprising an antidiabetic, and at least one pharmaceutically acceptable excipient. 9. Product according to claim 8, in which the components (A) and (B) are adapted for simultaneous, separate or spread over time administration. 10. Oral pharmaceutical composition comprising IL-6 and a pharmaceutically acceptable excipient. 11. Composition according to claim 10, characterized in that the pharmaceutically acceptable excipient comprises an enteric excipient. 12. IL-6 for its oral use to modulate intestinal contractility, in particular duodenal. 13. IL-6 for use in the treatment of hyperglycemia, orally.