非アゴニストPPARγリガンドの抗糖尿病作用は,Cdk5媒介のリン酸化を阻害する
Jang Hyun Choi1, Alexander S Banks, Theodore M Kamenecka
1Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|September 6, 2011
まとめ
PPARγのリン酸化を標的とする新しい化合物は,新しい抗糖尿病薬を提供する. SR1664は,従来のチアゾリジンダイオンとは異なり,体重増加などの一般的な副作用なしに,糖尿病を効果的に治療します.
科学分野:
- バイオケミストリー バイオケミストリー
- 薬理学 薬理学とは
- エンドクリノロジー エンドクリノロジー
背景:
- ペロキシソーム増殖器活性化受容体ガンマ (PPARγ) は,チアゾリジンジオン (TZD) 抗糖尿病薬の標的である.
- TZDはアゴニストであるが,肥満に関連したCdk5媒介PPARγリン酸化を阻害する.
- 既存のPPARγ薬は,水分保持や体重増加などの副作用を引き起こす.
研究 の 目的:
- PPARγのリン酸化を標的とする新しい合成化合物を開発する.
- 古典的アゴニズムを欠くユニークな結合モードを持つ化合物を調査する.
- 新しい化合物の抗糖尿病作用と副作用プロフィールを評価する.
主な方法:
- 独特のPPARγ結合を持つ新しい化合物を合成した.
- 培養アディポサイトとインスリン抵抗性のマウスモデルにおける化合物の活性評価.
- Cdk5媒介PPARγのリン酸化と骨形成に対する評価された効果 in vitro.
主要な成果:
- 新しい化合物は,古典的アゴニズムなしで,Cdk5媒介PPARγリン酸化を阻害しました.
- 化合物SR1664は,生体内で強力な抗糖尿病作用を示した.
- SR1664は,水分保持,体重増加を引き起こしたり,培養における骨形成に影響を与えなかった.
結論:
- Cdk5媒介のPPARγリン酸化をターゲットにすることで,糖尿病に対する新しい治療戦略が提供されます.
- SR1664は,副作用のプロファイルが改善された潜在的な新型抗糖尿病薬のクラスを表しています.
- 選択的PPARγ調節は,現在のTZD治療の限界を克服することができます.
関連する概念動画
Dipeptidyl Peptidase 4 Inhibitors
Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a significant...
GPCRs Regulate Adenylyl Cylase Activity
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
Two...
Glucagon-like Receptor Agonists
Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by the...
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by the...
cAMP-dependent Protein Kinase Pathways
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
Oral Hypoglycemic Agents: Biguanides and Glitazones
Biguanides, particularly metformin (Glucophage), are insulin sensitizers that enhance glucose uptake, thereby reducing insulin resistance. Unlike sulfonylureas, metformin doesn't prompt insulin secretion, which helps to curb hypoglycemia risk. Metformin is beneficial in treating conditions like polycystic ovary syndrome due to its insulin-resistance reduction capability. The drug's primary action involves curtailing hepatic gluconeogenesis, a significant contributor to high blood glucose levels...
Oral Hypoglycemic Agents: Glinides
Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively manages...

