Treating and/or preventing insulin-resistance related weight gain
Inventors
Farese, Robert Vito • Sajan, Mini Paliyath
Assignees
Office of General Counsel of VA • University of South Florida St Petersburg
Publication Number
US-10688063-B2
Publication Date
2020-06-23
Expiration Date
2034-07-30
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Abstract
Provided herein are methods of preventing or reducing weight gain in a subject in need thereof by administering 2-acetylcyclopentane-1,3-dione (ACPD).
Core Innovation
Provided herein are methods of preventing or reducing weight gain in a subject in need thereof by administering 2-acetylcyclopentane-1,3-dione (ACPD). The invention encompasses compounds, compositions, pharmaceutical formulations, and methods of using aPKC inhibitors for treating and/or preventing aPKC abnormalities. The aPKC inhibitor has a formula according to Formula I, with various substituents R1 and R2, and can be administered in various dosage forms including oral, vaginal, intravenous, transdermal, subcutaneous, intraperitoneal, or intramuscular routes.
The background describes obesity as a global epidemic and a leading preventable cause of death associated with numerous comorbidities including type 2 diabetes and metabolic syndrome. Despite extensive research and pharmaceutical and surgical treatments, effective treatments for obesity and related disorders remain an unmet need.
Insulin-resistant states such as obesity, metabolic syndrome, and type 2 diabetes mellitus are characterized by impaired glucose metabolism leading to increased insulin secretion. Protein kinase C (PKC) enzymes, particularly atypical PKC (aPKC), play key roles in regulating gluconeogenesis and lipogenesis and are implicated in the development of hepatic and systemic insulin resistance, especially in dietary-induced obesity. aPKC inhibitors act to counter abnormalities in aPKC activity that dysregulate hepatic and systemic insulin sensitivity by altering pathways involved in gluconeogenesis and lipogenesis, thus reducing dietary-induced obesity and related metabolic disturbances.
Claims Coverage
The independent claim covers methods of reducing weight gain using a specific compound in subjects with insulin resistance. The inventive features focus on the compound administered, dosage range, administration routes, and effects on weight gain.
Use of 2-acetylcyclopentane-1,3-dione (ACPD) to reduce weight gain in subjects with insulin resistance
Administering an effective amount of ACPD to subjects who have insulin resistance to reduce weight gain.
Specified effective amount and dosage ranges
The effective amount of ACPD ranges from about 0.001 mg to about 1,000 mg, with embodiments specifying from about 1 mg/kg to about 20 mg/kg body weight, including about 10 mg/kg body weight.
Administration in multiple dosage forms
The method includes administering the effective amount of ACPD in dosage forms formulated for oral, vaginal, intravenous, transdermal, subcutaneous, intraperitoneal, or intramuscular routes.
Quantified reduction in weight gain distinct from decreased food intake
The effective amount of ACPD reduces weight gain by about 1% to about 50%, including specific ranges of about 25% to about 50%, or about 50%, with the reduction not resulting from decreased food intake by the subject.
The claims cover the method of reducing weight gain in insulin-resistant subjects by administering the compound ACPD within specified dosage ranges and administration routes, achieving significant weight reduction that is not attributable to decreased food intake.
Stated Advantages
aPKC inhibitors reduce dietary-induced obesity and improve glucose tolerance and metabolic parameters in insulin-resistant states.
Compounds selectively inhibit atypical PKC without affecting other PKC isozymes or related kinases, thereby minimizing off-target effects.
Treatment reduces hepatic aPKC activity while sparing or enhancing Akt2 activity, improving insulin signaling and metabolic regulation.
Use of aPKC inhibitors leads to normalization of expression of lipogenic and gluconeogenic enzymes, reducing pathological lipid accumulation and improving systemic insulin sensitivity.
Treatment with ACPD or similar compounds can decrease weight gain without reducing food intake in subjects.
Documented Applications
Treatment or prevention of obesity, metabolic syndrome, type 2 diabetes mellitus, glucose intolerance, hyperinsulinemia, hepatosteatosis, non-alcoholic cirrhosis, hypertriglyceridemia, hypercholesterolemia, polycystic ovary disease, and Alzheimer's disease.
Reduction of weight gain in subjects with insulin resistance by administering 2-acetylcyclopentane-1,3-dione (ACPD).
Treatment of atypical protein kinase C (aPKC) abnormalities in hepatic cells by contacting with aPKC inhibitors.
Use in pharmaceutical formulations and kits for administering aPKC inhibitors to subjects with aPKC abnormalities.
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