Disease Information

General Information of the Disease (ID: DIS00239)

• Name: Insulin-resistance syndrome
• ICD: ICD-11: 5A44

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Fenofibrate

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein phosphatase 3 catalytic subunit alpha (PPP3CA) [1]

• Sensitive Disease: Insulin-resistance syndrome [ICD-11: 5A44.0]
• Molecule Alteration: Function; Activation
• Sensitive Drug: Fenofibrate
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Intracellular calcium flux signaling pathway; Activation; hsa05207
• Cell Pathway Regulation: TFEB/TFE3 nuclear translocation; Activation; hsa04137
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: CaMKKbeta-AMPK signaling pathway; Activation; hsa04152
• In Vivo Model: HFD-fed mouse model; Mus musculus
• Mechanism Description: Administration of fenofibrate effectively ameliorated glucose intolerance and insulin resistance in HFD-fed mice. In this study, fenofibrate treatment appeared to increase intracellular calcium flux and TFEB/TFE3 nuclear translocation and autophagy through two different mechanisms. One is the aforementioned calcium-mediated upregulation of the CaMKKbeta-AMPK pathway and the other is the activation of the calcium-dependent dephosphatase calcineurin subunit PPP3CA.

Gliquidone

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: RAC serine/threonine-protein kinase (AKT) [2]

• Sensitive Disease: Insulin-resistance syndrome [ICD-11: 5A44.0]
• Molecule Alteration: Function; Activation
• Sensitive Drug: Gliquidone
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: Sur1 knockout rats model; Rattus norvegicus
• Experiment for Drug Resistance: IPGTT assay; IPITT assay; Hyperinsulinemic-euglycemic clamp test assay
• Mechanism Description: Gliquidone alleviates hepatic insulin resistance by increasing glycogen synthesis and decreasing gluconeogenesis in vivo. The mechanism of gliquidone might be related to the activation of AKT, rather than AMPK.

Nicorandil

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tribbles homolog 3 (TRIB3) [3]

• Sensitive Disease: Insulin-resistance syndrome [ICD-11: 5A44.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Nicorandil
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: PERK signaling pathway; Inhibition; hsa04137
• In Vitro Model: L6 cells; Skeletal muscle; Rattus norvegicus (Rat); CVCL_0385
• In Vivo Model: Adult Sprague-Dawley rats model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Glucose tolerance test, insulin tolerance test
• Mechanism Description: Nicorandil attenuates high glucose-induced insulin resistance by suppressing oxidative stress-mediated ER stress PERK signaling pathway.

Sitagliptin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dipeptidyl peptidase 4 (DPP4) [4]

• Sensitive Disease: Insulin-resistance syndrome [ICD-11: 5A44.0]
• Molecule Alteration: Function; Inhibition
• Sensitive Drug: Sitagliptin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is currently indicated as an adjunctive treatment to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (DM). Sitagliptin is used to help mitigate insulin resistance after burn injury.

References

• Ref 1: Fenofibrate, a PPARAlpha agonist, reduces hepatic fat accumulation through the upregulation of TFEB-mediated lipophagy .Metabolism. 2021 Jul;120:154798. doi: 10.1016/j.metabol.2021.154798. Epub 2021 May 11. 10.1016/j.metabol.2021.154798
• Ref 2: Gliquidone ameliorates hepatic insulin resistance in streptozotocin-induced diabetic Sur1(-/-) rats .Eur J Pharmacol. 2021 Sep 5;906:174221. doi: 10.1016/j.ejphar.2021.174221. Epub 2021 Jun 1. 10.1016/j.ejphar.2021.174221
• Ref 3: Nicorandil attenuates high glucose-induced insulin resistance by suppressing oxidative stress-mediated ER stress PERK signaling pathway .BMJ Open Diabetes Res Care. 2021 Apr;9(1):e001884. doi: 10.1136/bmjdrc-2020-001884. 10.1136/bmjdrc-2020-001884
• Ref 4: Evaluation of the use of sitagliptin for insulin resistance in burn patients .Int J Burns Trauma. 2020 Oct 15;10(5):237-245. eCollection 2020.