JP7833758B2 - Treatment or improvement agent for type 1 diabetes - Google Patents

Description

This invention relates to an agent for improving or treating type 1 diabetes, and more particularly to an agent for mitigating postprandial blood glucose fluctuations in patients with type 1 diabetes.

Fatty acids are an important energy source for living organisms, supplied through diet, biosynthesis, and lipolysis in adipose tissue. Fatty acids are classified into short-chain fatty acids (6 or fewer carbon atoms), medium-chain fatty acids (6-10 carbon atoms), and long-chain fatty acids (12-20 carbon atoms). Fatty acids function not only as an energy source but also as signaling molecules involved in various intracellular processes.

For example, some medium-chain and long-chain fatty acids act as agonists for G protein-coupled receptors such as GPR40 and GPR120.
GPR40 is highly expressed in cells of the small intestine. When an agonist activates GPR40, incretins such as GLP-1 and GIP are secreted, and these incretins act on pancreatic β-cells to promote insulin secretion. In addition, GPR40 is also expressed in pancreatic β-cells, and agonists directly promote insulin secretion by activating GPR40.

GPR120 is highly expressed in cells of the small intestine. When an agonist activates GPR120, cholecystokinin (CCK) and incretins are secreted. CCK has several effects, including promoting pancreatic juice secretion by acting on pancreatic gland cells, slowing the rate at which the stomach sends its contents to the duodenum, and promoting bile excretion.
Furthermore, GPR120 is also expressed in macrophages. When an agonist activates GPR120, it inhibits TGF-β-activated kinase (TAK-1), which plays a central role in cytokine signaling. TAK-1 is activated by numerous cytokines and, by activating nuclear factor κB (NF-κB) and c-Jun N terminal kinase (JNK), induces inflammation, anti-apoptosis, lymphocyte differentiation and activation, infection defense, osteoclast differentiation, carcinogenesis, cancer metastasis, and angiogenesis. Regarding blood glucose levels, inhibiting TAK-1 suppresses the inflammatory signaling pathway and reduces insulin resistance.

Therefore, medium-chain and long-chain fatty acids, which act as agonists of GPR40 and GPR120, are expected to be effective therapeutic agents for type 2 diabetes, characterized by impaired insulin secretion and insulin resistance.

For example, Patent Document 1 reports that certain long-chain fatty acids, which are saturated or unsaturated fatty acids with 18 or 20 carbon atoms and have one hydroxyl group or carbonyl group, activate peroxisome proliferative receptor (PPAR) γ. Since PPAR γ promotes glucose uptake in muscles and improves insulin sensitivity, Patent Document 1 states that these specific long-chain fatty acids are useful as a treatment for diabetes.

Here, type 2 diabetes is characterized by impaired insulin secretion or insulin resistance, so there are many medications available and it is relatively easy to control the symptoms. In contrast, type 1 diabetes is characterized by extremely low or depleted insulin secretion due to the destruction of pancreatic β-cells, so insulin therapy is the basis, and it is very difficult to control the symptoms.
Patients with type 1 diabetes inject insulin before meals to control the rise in blood glucose levels after eating, but it is difficult to determine the optimal timing for administration to properly regulate blood glucose levels. Administering insulin immediately before a meal results in ineffective insulin, leading to hyperglycemia after the meal, followed by a sharp drop in blood glucose levels, causing fatigue and drowsiness. Similarly, administering insulin 30 minutes before a meal also results in hyperglycemia afterward. On the other hand, administering insulin 15 minutes before a meal effectively suppresses the rise in blood glucose levels after eating (DIABETES CARE 33, No.10, 2010, 2152-2155).
Therefore, because patients need to administer insulin 15 minutes before meals, they have to worry about when they injected their insulin each time they eat, which is a burden for them. If they could inject insulin immediately before or at the same time as meals, the burden on patients would be greatly reduced.

Patent No. 6671576

The present invention aims to provide an agent for improving or treating type 1 diabetes, which can suppress the rise in postprandial blood glucose levels when insulin is administered immediately before or at the same time as a meal.

The inventors of this invention conducted extensive research to solve the above problems and found that administering alpha-linolenic acid to patients with type 1 diabetes immediately before or at the same time as a meal can mitigate the rise in postprandial blood glucose levels, even when insulin is administered immediately before or at the same time as a meal.
The present invention was completed based on the above findings and provides the following [1] to [6].
[1] An agent for improving or treating type 1 diabetes, containing alpha-linolenic acid , which is administered to patients with type 1 diabetes immediately before or at the same time as a meal.
[2] The agent for improving or treating type 1 diabetes described in [1], which is used in combination with insulin, and the insulin is administered to a patient with type 1 diabetes immediately before or at the same time as a meal.
[3] The agent for improving or treating type 1 diabetes according to [1] or [2], wherein the improvement or treatment of type 1 diabetes is the mitigation of postprandial blood glucose fluctuations in patients with type 1 diabetes.
[4] An agent for improving or treating type 1 diabetes as described in [3], which alleviates the rise and/or rapid drop in postprandial blood glucose levels.
[5] An agent for improving or treating type 1 diabetes according to any of [1] to [4], which improves or treats type 1 diabetes without promoting insulin secretion or improving insulin sensitivity.
[6] An agent for improving or treating type 1 diabetes according to any one of [1] to [5], which improves or treats type 1 diabetes by activating GPR120.

As mentioned earlier, insulin therapy is the basic treatment for type 1 diabetes. If insulin could be injected immediately before or at the same time as meals, patients would no longer need to worry about the timing of insulin injections and meals each time, making daily life much easier. However, injecting insulin immediately before a meal typically causes a rapid spike in blood glucose levels 30 minutes later, followed by a rapid drop, leading to fatigue and drowsiness. Furthermore, it's not simply a matter of injecting insulin well before a meal; injecting 30 minutes before a meal is insufficient to control the postprandial rise in blood glucose levels, and 15 minutes before a meal is considered ideal (DIABETES CARE 33, No.10, 2010, 2152-2155). Therefore, type 1 diabetic patients must constantly be mindful of maintaining a 15-minute gap between insulin administration and meals, which places a significant burden on them.

In this regard, according to the present invention, by administering alpha-linolenic acid immediately before or at the same time as a meal, even if insulin is administered immediately before or at the same time as a meal, the rise in postprandial blood glucose levels can be suppressed, preventing blood glucose levels from rising too high. Furthermore, symptoms such as fatigue and drowsiness caused by a rapid drop in excessively high blood glucose levels can also be suppressed. As a result, patients no longer need to worry about the timing of insulin administration after every meal, and their quality of life (QOL) is greatly improved.

Furthermore, since type 1 diabetes accounts for only 5-10% of all diabetic patients, there are few drugs available to improve or treat the symptoms of type 1 diabetes. This invention is highly significant because it increases the number of drugs that can improve or treat the symptoms of type 1 diabetes.

Furthermore, since alpha-linolenic acid is a food-derived ingredient, the agent of the present invention is useful because its safety has been established.

This graph shows the time course of blood glucose levels in type 1 diabetic model rats after administering alpha-linolenic acid and insulin immediately before glucose administration. In Figure 1, the ALA group is the group that received alpha-linolenic acid.

The present invention will be described in detail below.
The present invention provides an agent for improving or treating type 1 diabetes, which contains alpha-linolenic acid and is administered to patients with type 1 diabetes immediately before or at the same time as a meal.

The formulation of the present invention can be used to create a food composition, a pharmaceutical composition, or a quasi-drug composition, which may be formed from alpha-linolenic acid and, if necessary, additives or other physiologically or pharmacologically active ingredients.
The concentration of alpha-linolenic acid in the composition can be 0.001% or more by weight, 0.1% or more by weight, 1% or more by weight, 5% or more by weight, 10% or more by weight, 20% or more by weight, 30% or more by weight, 40% or more by weight, 50% or more by weight, 60% or more by weight, 70% or more by weight, 80% or more by weight, or 90% or more by weight, relative to the total amount of the composition. Within this range, a sufficient amount of alpha-linolenic acid to sufficiently mitigate blood glucose fluctuations can be contained in a composition that can be consumed without difficulty. Furthermore, the concentration of alpha-linolenic acid in the composition can be 95% or less by weight, 90% or less by weight, 80% or less by weight, 70% or less by weight, 60% or less by weight, 50% or less by weight, 40% or less by weight, 30% or less by weight, 20% or less by weight, 10% or less by weight, 5% or less by weight, or 1% or less by weight, relative to the total amount of the composition. Within this range, the composition will be easy to formulate, or easy to eat or drink as a food.

(Pharmaceutical composition / Quasi-drug composition)
The pharmaceutical composition and quasi-drug composition can be prepared as an orally administered formulation.
Examples of solid oral formulations include tablets, powders, granules, fine granules, pills, and capsules (soft capsules, hard capsules). Since alpha-linolenic acid is a liquid oil, soft capsules are preferred. One or more additives such as excipients, binders, disintegrants, lubricants, fluidizers, colorants, flavoring agents, sweeteners, fragrances, preservatives, or antiseptics may be added to the formulation.
Examples of liquid oral formulations include liquid preparations, elixirs, suspensions, emulsions, lemonades, and syrups. Liquid formulations may contain one or more additives such as pH adjusters, buffers, thickeners, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, colorants, and fragrances.

(Food composition in pharmaceutical form)
The agent of the present invention can be a food composition in the form of an orally administered preparation, such as a supplement. Examples of dosage forms and additives for the orally administered preparation include those listed as pharmaceutical compositions and quasi-drug compositions.

The concentration of alpha-linolenic acid in solid oral administration preparations as pharmaceutical compositions, quasi-drug compositions, or food compositions can be 5% or more by weight, 10% or more by weight, 20% or more by weight, 30% or more by weight, 40% or more by weight, 50% or more by weight, 60% or more by weight, 70% or more by weight, 80% or more by weight, or 90% or more by weight, relative to the total amount of the composition. Within this range, a sufficient amount of alpha-linolenic acid to adequately mitigate blood glucose fluctuations can be contained in a composition that can be consumed without difficulty. Furthermore, the concentration of alpha-linolenic acid in the composition can be 95% or less by weight, 90% or less by weight, 80% or less by weight, 70% or less by weight, 60% or less by weight, 50% or less by weight, 40% or less by weight, 30% or less by weight, or 20% or less by weight, relative to the total amount of the composition. Within this range, the composition will be easy to formulate or easy to consume as food.

The concentration of alpha-linolenic acid in liquid oral administration preparations as pharmaceutical compositions, quasi-drug compositions, or food compositions can be 0.001% or more by weight, 0.1% or more by weight, 1% or more by weight, 5% or more by weight, 10% or more by weight, 20% or more by weight, 30% or more by weight, 40% or more by weight, or 50% or more by weight, relative to the total amount of the composition. Within this range, a sufficient amount of alpha-linolenic acid to adequately mitigate blood glucose fluctuations can be contained in a composition that can be consumed without difficulty. Furthermore, the concentration of alpha-linolenic acid in the composition can be 70% or less by weight, 60% or less by weight, 50% or less by weight, 40% or less by weight, 30% or less by weight, 20% or less by weight, 10% or less by weight, 5% or less by weight, or 1% or less by weight, relative to the total amount of the composition. Within this range, the composition will be easy to formulate or easy to consume as a food.

(Composition of general food products)
The agent of the present invention may be a composition in which alpha-linolenic acid is incorporated into a general food product. For example, if alpha-linolenic acid is incorporated into solid foods such as jelly, agar confectionery, gum, candy, and baked goods (cookies, biscuits, etc.), or into liquid foods such as beverages, tea drinks, coffee drinks, dairy drinks, fruit and vegetable juices, and soft drinks, patients can easily consume them to suppress fluctuations in blood glucose levels.

The concentration of alpha-linolenic acid in a solid general food composition can be 0.001% or more by weight, 0.1% or more by weight, 1% or more by weight, 5% or more by weight, 10% or more by weight, 20% or more by weight, 30% or more by weight, 40% or more by weight, or 50% or more by weight, relative to the total amount of the composition. Within this range, a sufficient amount of alpha-linolenic acid to mitigate blood glucose fluctuations can be contained in a composition that can be consumed without difficulty. Furthermore, the concentration of alpha-linolenic acid in the composition can be 70% or less by weight, 60% or less by weight, 50% or less by weight, 40% or less by weight, 30% or less by weight, 20% or less by weight, 10% or less by weight, 5% or less by weight, or 1% or less by weight, relative to the total amount of the composition. Within this range, the composition will be easy to eat.

The concentration of alpha-linolenic acid in a liquid general food composition can be 0.001% or more by weight, 0.1% or more by weight, 1% or more by weight, 5% or more by weight, 10% or more by weight, 20% or more by weight, 30% or more by weight, 40% or more by weight, or 50% or more by weight, relative to the total amount of the composition. Within this range, a sufficient amount of alpha-linolenic acid to mitigate blood glucose fluctuations can be contained in a composition that can be consumed without difficulty. Furthermore, the concentration of alpha-linolenic acid in the composition can be 70% or less by weight, 60% or less by weight, 50% or less by weight, 40% or less by weight, 30% or less by weight, 20% or less by weight, 10% or less by weight, 5% or less by weight, or 1% or less by weight, relative to the total amount of the composition. Within this range, the composition will be easy to drink.

The food composition may be used as a nutritional supplement, health supplement, nutritional adjustment food, food for specified health uses, food with nutritional function claims, or food with functional claims.

(Bioactive ingredients / Pharmacologically active ingredients)
Physiologically active or pharmacologically active ingredients that can be combined with alpha-linolenic acid include extracts of edible mushrooms (such as *Boletus edulis*, *Boletus luteus*, *Boletus reticulatus*, *Aspergillus orientalis*, *Lyophyllum decastes*, *Lactarius deliciosus*, *Cortinarius violaceus*, *Cortinarius fuciformis*, *Cortinarius sarmentosus*, *Cortinarius leucobryum*, *Cortinarius verrucous*, *Cortinarius pulcherrimus*, *Cortinarius indusiatus*, etc.), lactic acid bacteria fermented liquid and its extracts, grain koji or its extracts, yeast or its extracts, tea flower extract, Job's tears extract, and corn silk extract. Examples of ingredients include Cistanche tubulosa extract, kidney bean extract, mulberry leaf extract, papaya extract, green tea-derived flavonols or their glycosides (such as catechins), indigestible dextrin, polydextrose, inulin, oligosaccharides, vegetable charcoal, barley β-glucan, citrus fiber, psyllium seed gas, guar gum enzyme hydrolysate, lecithin, soybean extract, butyric acid bacteria fermented liquid, plum extract, perilla extract, desulfated kotalanol, salacinol, cocoa polyphenols, and cocoa butter.
These enhance the effect of alpha-linolenic acid in suppressing blood glucose elevation.

In the case of food compositions, pharmaceutical compositions, and quasi-drug compositions, instead of preparing the agent of the present invention by incorporating alpha-linolenic acid , the agent of the present invention can also be prepared by incorporating an oil containing alpha-linolenic acid and a component that can dissociate fatty acids from triglycerides. For example, the agent of the present invention containing alpha-linolenic acid can be obtained by mixing perilla oil, flaxseed oil, shiso oil, etc., which are rich in alpha-linolenic acid as constituent fatty acids, with an acid, alkali, or lipase.

Method of administration: The agent of the present invention is administered immediately before or at the same time as a meal.
The period immediately before a meal refers to the time from five minutes before the meal begins until the meal actually begins. In particular, the period from four minutes before, especially three minutes before, especially two minutes before, and especially one minute before, until the meal actually begins is preferable, as this further reduces the burden on the patient.
Furthermore, "at the same time as the meal" refers to the initial period of the meal, but since the absorption of sugar from the small intestine begins after the meal starts, it is preferable to take the food within 5 minutes of starting the meal, preferably within 4 minutes, preferably within 3 minutes, preferably within 2 minutes, preferably within 1 minute, and especially preferably immediately at the start of the meal.

The agent of the present invention can be administered in a daily dose of α-linolenic acid of 300 mg or more, more preferably 1 g or more, and more preferably 2 g or more. Within this range, fluctuations in postprandial blood glucose levels can be sufficiently mitigated. Furthermore, since α-linolenic acid is a food component, there is no particular upper limit on the dosage of the agent of the present invention, but it is sufficient to administer the daily dose of α-linolenic acid in a range of 15 g or less, more preferably 12.5 g or less, more preferably 10 g or less, and more preferably 7.5 g or less.

The agent of the present invention can be administered to patients in a dose of 100 mg or more, more preferably 300 mg or more, and more preferably 600 mg or more, of alpha-linolenic acid per meal. Within this range, fluctuations in postprandial blood glucose levels can be sufficiently mitigated. Furthermore, since alpha-linolenic acid is a food component, there is no particular upper limit on the dosage of the agent of the present invention, but it is sufficient to administer the amount of alpha-linolenic acid per meal to patients in a dose of 5 g or less, more preferably 4 g or less, more preferably 3 g or less, and more preferably 2 g or less.

The agent of the present invention can be used in combination with insulin.
Insulin-containing preparations include rapid-acting insulin preparations, long-acting insulin preparations, and rapid-acting and long-acting insulin preparations. Rapid-acting insulin preparations are designed to supplement insulin secreted after meals, long-acting insulin preparations supplement basal insulin secreted throughout the day, and rapid-acting and long-acting insulin preparations supplement both postprandial and basal insulin secretion. The agent of the present invention may be used in combination with insulin in the form of a rapid-acting insulin preparation or a rapid-acting and long-acting insulin preparation.
Furthermore, insulin analogs, which have the same effect as insulin, can also be used, and in this invention, insulin analogs are included as part of insulin.

Insulin can be administered immediately before or at the same time as a meal.
The period immediately before a meal refers to the time from five minutes before the meal begins until the meal actually begins. In particular, the period from four minutes before, especially three minutes before, especially two minutes before, and especially one minute before, until the meal actually begins is preferable, as this further reduces the burden on the patient.
Furthermore, "at the same time as the meal" refers to the initial period of the meal, but since the absorption of sugar from the small intestine begins after the meal starts, it is preferable to take the food within 5 minutes of starting the meal, preferably within 4 minutes, preferably within 3 minutes, preferably within 2 minutes, preferably within 1 minute, and especially preferably immediately at the start of the meal.

In particular, administering the agent of the present invention simultaneously with insulin further reduces the burden on the patient.

The agent of the present invention, which mitigates fluctuations in blood glucose levels , can mitigate or suppress the rise and/or rapid drop in postprandial blood glucose levels, particularly both, in patients with type 1 diabetes, and can therefore be used as an agent for improving or treating type 1 diabetes.
Mitigating the rise in blood glucose levels means mitigating the rate of increase in blood glucose levels, that is, suppressing blood glucose overshoot. By suppressing overshoot, the time during which blood glucose levels remain within the therapeutic range (80-180 mg/dL) is extended, thereby enhancing the therapeutic effect of type 1 diabetes. When the agent of the present invention mitigates the rise in blood glucose levels, it can reduce the peak value of postprandial blood glucose levels; therefore, the agent of the present invention can also be used as a postprandial blood glucose lowering agent or a preventive agent for postprandial hyperglycemia. Generally, postprandial hyperglycemia refers to a condition in which blood glucose levels remain above 140 mg/mL two hours after a meal, and the postprandial hyperglycemia in the present invention, i.e., postprandial hyperglycemia when insulin is administered immediately before or at the same time as a meal to patients with type 1 diabetes, is also defined in this context.
Furthermore, mitigating a rapid drop in blood glucose levels means reducing the rate at which blood glucose levels decrease. When the agent of the present invention mitigates a rapid drop in blood glucose levels, it can suppress excessive hypoglycemia, and therefore the agent of the present invention can also be used as a preventive agent for hypoglycemia. In the present invention, hypoglycemia refers to a state in which blood glucose levels are 100 mg/mL or less.

The agent of the present invention can mitigate postprandial blood glucose fluctuations through GPR120 activation. Therefore, the agent of the present invention can mitigate postprandial blood glucose fluctuations without promoting insulin secretion or improving insulin sensitivity.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.
Evaluation of the effect of suppressing blood glucose elevation in animal models of type 1 diabetes.
(1) Creation of a type 1 diabetes model rat
Male SD rats (5 weeks old) were acclimatized for one week, and then administered streptozocin (STZ) aqueous solution intraperitoneally twice, with an STZ dose of 1 mL/kg. The STZ aqueous solution used for the first dose was 60 mg/mL and the second dose was 100 mg/mL. One day was left between the first and second doses. One week after the first STZ aqueous solution dose, a 20 w/v% glucose aqueous solution was administered, and rats that did not show an increase in blood insulin concentration after administration were used in the study. This dose of STZ successfully created a type 1 diabetes model rat.
Fasting was initiated at 6 PM the day before the experiment. Insulin aspart (trade name, Novorapid) was administered, and blood glucose levels were measured every two hours. Insulin aspart was administered to maintain blood glucose levels between 70 and 150 mg/dL. Blood glucose levels were measured 12 hours after the final insulin aspart administration, and rats with blood glucose levels between 50 and 350 mg/dL were randomized to ensure that there was no significant difference in blood glucose levels among the groups.

(2) Evaluation of the effect of suppressing blood glucose elevation Four rats of type 1 diabetes model were administered human recombinant insulin (Novolin R) at a dose of 0.1 U/kg, immediately followed by administration of the test drug solution at a dose of 5 mL/kg, and then immediately after that, administration of a 20 w/v% glucose aqueous solution at a dose of 10 mL/kg.
The test drug solution was olive oil for the control group and alpha-linolenic acid (2.5 g/5 mL)/olive oil for the ALA group.
Blood glucose levels were measured via the tail vein using a Freestyle Precision blood glucose monitoring electrode immediately before, 15 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes after glucose solution administration.

The results are shown in Figure 1. Because blood glucose levels varied immediately before administration, the difference in blood glucose levels is shown with the immediate blood glucose level set to 0. In Table 1, * indicates that the difference between groups was P < 0.05 in the Student's t-test.
Administering alpha-linolenic acid mitigated the rise in blood glucose levels after glucose administration. Furthermore, in the control group, while blood glucose levels rose sharply after glucose administration and then rapidly decreased, administering alpha-linolenic acid moderated the rate of decrease in blood glucose levels.
It has been found that administering long-chain fatty acids, which function as GPR120 ligands, immediately before or at the same time as a meal can mitigate the rapid rise and fall in blood glucose levels, even when insulin is administered immediately before or at the same time as a meal.

The agent of the present invention is extremely useful in significantly improving the quality of life (QOL) of patients with type 1 diabetes because it enables insulin administration immediately before or during meals.

Claims (5)

A treatment for type 1 diabetes containing alpha-linolenic acid, administered to patients with type 1 diabetes immediately before or at the same time as a meal, and used in combination with insulin, wherein the insulin is administered to the same patient immediately before or at the same time as a meal. The therapeutic agent for type 1 diabetes according to claim 1, wherein the improvement or treatment of type 1 diabetes is the mitigation of postprandial blood glucose fluctuations in patients with type 1 diabetes. A therapeutic agent for type 1 diabetes according to claim 2, which alleviates the rise and/or rapid drop in postprandial blood glucose levels. A therapeutic agent for type 1 diabetes according to any one of claims 1 to 3, which improves or treats type 1 diabetes without promoting insulin secretion or improving insulin sensitivity. A therapeutic agent for type 1 diabetes according to any one of claims 1 to 4, which improves or treats type 1 diabetes by activating GPR120.