Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders

A mitochondrial, obese technology that is used in the treatment or prevention of various diseases or disorders, and can solve problems such as limited efficacy

Inactive Publication Date: 2008-09-03
SIRTRIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many appetite suppressants are available (diethylpropion tenuate, mazindol, orlistat, phenmetrazine, phente

Method used

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  • Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders
  • Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders
  • Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1671] Example 1: Metabolic activity of sirtuin activators in diet-induced obesity (DIO) mouse model

[1672] To determine whether SIRT-1 activators prevent obesity and the associated development of insulin resistance, male C57BL6J mice chronically placed on a high-fat diet for 16 weeks were given resveratrol (by food admixture). Extensive phenotypic and molecular analyzes of mice were performed to identify regulatory pathways affected by Sirt-1 activation. See, for example Figure 17-21 The results shown.

[1673] The results showed that the mice had good tolerance to resveratrol as a food additive and did not cause anorexia. In this long-term study, 50 male C57BL6J mice (aged 5 weeks) were analyzed for 18 weeks. 10 animals as a group, divided into the following 5 groups:

[1674] 1: normal diet

[1675] 2: Normal diet + resveratrol (200mg / kg / day)

[1676] 3: High-fat diet

[1677] 4: High-fat diet + resveratrol (200mg / kg / day)

[1678] 5: High-fat diet + resveratrol (...

Embodiment 2

[1715] Example 2: Metabolic activity of sirtuin activators in the Zucker diabetic rat model

[1716] Oral administration of resveratrol (200 mg / kg), metformin (200 mg / kg), and a combination of the two to Zucker fat diabetic rats (ZOF / Gmicrl-fa / fa) twice a day (total dose 400 mg / kg / day) (200 mg / kg each) or vehicle (2% Tween 80, 10 ml / kg) for up to 42 days. Eight rats (six weeks old, 190+10 g) were used in each group. Animals were fasted for 24 hours before oral glucose tolerance test (glucose dose 2 g / kg, PO) on day 43. Blood samples were collected from the retro-orbital sinus 35 minutes before the glucose load (fasting blood glucose) and 90 minutes after the oral glucose load. Serum glucose levels were determined by a Hitachi Model 750 automatic analyzer. For the results of this experiment, see Figure 23 . Also after 43 days daily body weight and food intake showed no statistical difference among the 4 groups. Additionally, there were no differences between the four gro...

Embodiment 3

[1717] Example 3: Biochemical and histological analysis of the diet-induced obesity (DIO) mouse model

[1718] Diet-induced obesity was induced in mice as described in Example 1 above. Biochemical and histological analyzes were performed on mice fed a control diet (C), a high fat diet (HF) or a high fat diet plus 400 mg / kg / day resveratrol (HF+R400) (see Example 1).

[1719] Figure 24 shows the results of body weight change experiments, food intake experiments and body fat content experiments conducted as described in Example 1 above. Pups were fed a control diet (C), a control diet plus 400 mg / kg / day resveratrol (C+R400), a high-fat diet (HF), or a high-fat diet plus 400 mg / kg / day resveratrol (HF+R400). Rats were 9 weeks old. The upper left shows a graph of the body weight change of mice in the four diet groups over a 9-week period. The upper right shows a graph of mouse food intake expressed in kcal / 24 hr for the four diet groups. A comparison of the body fat content of m...

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Abstract

Provided herein are methods and compositions for treating or preventing metabolic disorders, such as obesity and diabetes. Methods may comprise modulating the activity or level of a sirtuin, such as SIRTl or Sir2. Exemplary methods comprise contacting a cell with a sirtuin activating compound, such as a flavone, stilbene, flavanone, isoflavone, catechin, chalcone, tannin or anthocyanidin, or an inhibitory compound, such as nicotinamide.

Description

Background technique [0001] Obesity is a chronic condition characterized by a body mass index (BMI) over 25. Both innate and environmental factors, such as exercise and diet, can cause the disorder. For example, the hormone leptin has been shown to be involved in the regulation of fat accumulation and eating behaviour. Several animal models of obesity are derived from mutations in the leptin and / or leptin receptor genes. In addition to affecting the individual's lifestyle, obesity can cause a variety of complications and diseases, including insulin resistance, type II diabetes, gallbladder disease, hypertension, cardiovascular disease, hyperlipidemia, sleep apnea, coronary artery disease, knee osteoarthritis arthritis, gout, infertility, breast cancer, endometrial cancer, colon cancer, and low back pain. [0002] Diabetes mellitus is a disease manifested by acute symptoms caused by marked hyperglycemia or ketoacidosis, or by chronic, routine metabolic abnormalities caused b...

Claims

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Application Information

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IPC IPC(8): A61K31/05A61P3/04
Inventor M·米尔本J·米尔恩J·奥威尔斯C·阿吉曼M·拉戈奇M·迪波
Owner SIRTRIS PHARMA INC
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