Disease Information

General Information of the Disease (ID: DIS00111)

• Name: Type 2 diabetes mellitus
• ICD: ICD-11: 5A11

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Canagliflozin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Solute carrier family 5 member 2 (SLC5A2) [1]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Function; Inhibition
• Sensitive Drug: Canagliflozin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Treatment with the SGLT2 (sodium-glucose cotransporter 2) inhibitor canagliflozin results in early and sustained reductions in systolic blood pressure in people with type 2 diabetes and chronic kidney disease, regardless of baseline blood pressure, number of blood pressure lowering agents, and history of apparent treatment-resistant hypertension.

Doxepin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Facilitated glucose transporter member 4 (GLUT4) [2]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxepin
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• In Vivo Model: Male C57BL/6J mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Intraperitoneal glucose tolerance test (IPGTT)
• Mechanism Description: Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice. Doxepin exacerbated insulin resistance and glucose intolerance with lower Akt phosphorylation, GLUT4 expression, and renal damage as well as higher reactive oxygen species and interleukin 1 and lower catalase, superoxide dismutase, and glutathione peroxidase levels. Doxepin administration potentially worsens renal injury, nonalcoholic fatty liver disease, and diabetes.

Insulin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: CREB/ATF bZIP transcription factor (CREBZF) [3]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Adipocyte-specific basic region-leucine zipper (B-ZIP) transcription factor knockout mice, which are called A-ZIP/F-1 fatless mice due to a lack of white fat tissue, are hyperinsulinemic and hyperglycemic, due to severe defects in IRS-1 and -2 associated PI3K activity in muscle and liver. The overexpression of preadipocyte factor-1 (Pref-1), a secreted protein that inhibits adipocyte differentiation, also induced the characteristics of lipodystrophic models, that is, reduced adipose tissue mass, dyslipidemia, and insulin resistance. In addition, the inhibition of de novo sphingolipid biosynthesis by adipocyte-specific knockout of serine palmitoyltransferase 2 (Sptlc2), which catalyzes the first step of de novo sphingolipid synthesis, exhibited impaired adipose tissue development and a lipodystrophic phenotype, which progressed to systemic insulin resistance. The ability to form unilocular lipid droplets in white adipocytes is required to maintain the ability of white adipocytes to store lipids. Knock out mice of fat-specific protein 27 (Fsp27) showed multilocular lipid droplets in adipocytes and increased lipolysis, resulting in hepatic steatosis and insulin resistance.

Key Molecule: Cell death activator CIDE-3 (CIDEC) [3]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Adipocyte-specific basic region-leucine zipper (B-ZIP) transcription factor knockout mice, which are called A-ZIP/F-1 fatless mice due to a lack of white fat tissue, are hyperinsulinemic and hyperglycemic, due to severe defects in IRS-1 and -2 associated PI3K activity in muscle and liver. The overexpression of preadipocyte factor-1 (Pref-1), a secreted protein that inhibits adipocyte differentiation, also induced the characteristics of lipodystrophic models, that is, reduced adipose tissue mass, dyslipidemia, and insulin resistance. In addition, the inhibition of de novo sphingolipid biosynthesis by adipocyte-specific knockout of serine palmitoyltransferase 2 (Sptlc2), which catalyzes the first step of de novo sphingolipid synthesis, exhibited impaired adipose tissue development and a lipodystrophic phenotype, which progressed to systemic insulin resistance. The ability to form unilocular lipid droplets in white adipocytes is required to maintain the ability of white adipocytes to store lipids. Knock out mice of fat-specific protein 27 (Fsp27) showed multilocular lipid droplets in adipocytes and increased lipolysis, resulting in hepatic steatosis and insulin resistance.

Key Molecule: Preadipocyte factor (PREF-1) [3]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Adipocyte-specific basic region-leucine zipper (B-ZIP) transcription factor knockout mice, which are called A-ZIP/F-1 fatless mice due to a lack of white fat tissue, are hyperinsulinemic and hyperglycemic, due to severe defects in IRS-1 and -2 associated PI3K activity in muscle and liver. The overexpression of preadipocyte factor-1 (Pref-1), a secreted protein that inhibits adipocyte differentiation, also induced the characteristics of lipodystrophic models, that is, reduced adipose tissue mass, dyslipidemia, and insulin resistance. In addition, the inhibition of de novo sphingolipid biosynthesis by adipocyte-specific knockout of serine palmitoyltransferase 2 (Sptlc2), which catalyzes the first step of de novo sphingolipid synthesis, exhibited impaired adipose tissue development and a lipodystrophic phenotype, which progressed to systemic insulin resistance. The ability to form unilocular lipid droplets in white adipocytes is required to maintain the ability of white adipocytes to store lipids. Knock out mice of fat-specific protein 27 (Fsp27) showed multilocular lipid droplets in adipocytes and increased lipolysis, resulting in hepatic steatosis and insulin resistance.

Key Molecule: Serine palmitoyltransferase long chain base subunit 2 (SPTLC2) [3]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Adipocyte-specific basic region-leucine zipper (B-ZIP) transcription factor knockout mice, which are called A-ZIP/F-1 fatless mice due to a lack of white fat tissue, are hyperinsulinemic and hyperglycemic, due to severe defects in IRS-1 and -2 associated PI3K activity in muscle and liver. The overexpression of preadipocyte factor-1 (Pref-1), a secreted protein that inhibits adipocyte differentiation, also induced the characteristics of lipodystrophic models, that is, reduced adipose tissue mass, dyslipidemia, and insulin resistance. In addition, the inhibition of de novo sphingolipid biosynthesis by adipocyte-specific knockout of serine palmitoyltransferase 2 (Sptlc2), which catalyzes the first step of de novo sphingolipid synthesis, exhibited impaired adipose tissue development and a lipodystrophic phenotype, which progressed to systemic insulin resistance. The ability to form unilocular lipid droplets in white adipocytes is required to maintain the ability of white adipocytes to store lipids. Knock out mice of fat-specific protein 27 (Fsp27) showed multilocular lipid droplets in adipocytes and increased lipolysis, resulting in hepatic steatosis and insulin resistance.

Key Molecule: Glutamine--fructose-6-phosphate aminotransferase 1 (GFPT1) [3]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Marshall et al. first suggested O-GlcNAcylation modulated insulin sensitivity and showed that the effects of glucose-induced insulin resistance could be blocked by inhibiting GFAT using amidotransferase inhibitors such as O-diazoacetyl-L-serine (azaserine) or 6-diazo-5-oxonorleucine (DON). Subsequently, it was established that glucosamine induces insulin resistance.

Key Molecule: Serine palmitoyltransferase small subunit B (SPTSB) [3]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Obese rats with insulin resistance have consistently been reported to exhibit elevated hepatic and muscle ceramide contents. Inhibition of ceramide synthesis using myriocin, an inhibitor of serine palmitoyltransferase, prevented insulin resistance and attenuated ceramide contents in fat-fed mice.

Key Molecule: O-GlcNAcase (OGA) [3]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Recently, skeletal muscle-specific O-GlcNAc transferase (OGT) knockout mice on a HFD were reported to have low plasma glucose levels and glucose tolerances. Moreover, the overexpression of O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, significantly improved whole-body glucose tolerance and insulin sensitivity in db/db mice, and O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino-N-phenylcarbamate (PUGNAc) (an OGA inhibitor) suppressed insulin-mediated glucose uptake in adipocytes.

Key Molecule: O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) [3]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Recently, skeletal muscle-specific O-GlcNAc transferase (OGT) knockout mice on a HFD were reported to have low plasma glucose levels and glucose tolerances. Moreover, the overexpression of O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, significantly improved whole-body glucose tolerance and insulin sensitivity in db/db mice, and O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino-N-phenylcarbamate (PUGNAc) (an OGA inhibitor) suppressed insulin-mediated glucose uptake in adipocytes.

Key Molecule: Lipoprotein lipase (LPL) [3]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Several studies have shown that lipid accumulation in liver and skeletal muscle caused by short-term HFD feeding or lipid/heparin infusions induce insulin resistance in rats. In addition, overexpression of lipoprotein lipase (LPL) in liver or muscle induced peripheral insulin resistance and the accumulation of lipid in respective tissues, and skeletal muscle-specific LPL deletion enhanced insulin signaling in HFD challenged muscle. Furthermore, deleting fat transport proteins such as CD36 or FATP-1 increased insulin-mediated glucose uptake in skeletal muscle, and liver-specific knockdown of FATP2 or FATP5 significantly reduced HFD-induced hepatosteatosis and increased glucose tolerance.

Key Molecule: Protein kinase C theta (PRKCT) [3]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The DAG hypothesis of lipid-induced insulin resistance is that interference of insulin signaling by activated protein kinase C (PKC) results from the accumulation of DAG within insulin-sensitive tissues. In a manner similar to that observed in liver, the accumulation of intramyocellular DAG impairs insulin signaling and muscle glucose uptake by activating PKCtheta (muscle-type nPKC), which elicits the phosphorylation of IRS-1 at Ser1101 and blocks the insulin-stimulated phosphorylation of IRS-1. Large-scale studies have also corroborated the DAG-PKC induced hypothesis of insulin resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ceramide synthase 6 (CERS6) [3]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Also, liver-specific knock out of ceramide synthase 6 (CerS6) decreased hepatic ceramide levels (especially C16:0 species), protected against HFD-induced obesity, and improved glucose tolerance.

Key Molecule: Glutamine--fructose-6-phosphate aminotransferase 1 (GFPT1) [3]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Marshall et al. first suggested O-GlcNAcylation modulated insulin sensitivity and showed that the effects of glucose-induced insulin resistance could be blocked by inhibiting GFAT using amidotransferase inhibitors such as O-diazoacetyl-L-serine (azaserine) or 6-diazo-5-oxonorleucine (DON). Subsequently, it was established that glucosamine induces insulin resistance.

Key Molecule: Glutamine--fructose-6-phosphate aminotransferase 1 (GFPT1) [3]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Marshall et al. first suggested O-GlcNAcylation modulated insulin sensitivity and showed that the effects of glucose-induced insulin resistance could be blocked by inhibiting GFAT using amidotransferase inhibitors such as O-diazoacetyl-L-serine (azaserine) or 6-diazo-5-oxonorleucine (DON). Subsequently, it was established that glucosamine induces insulin resistance.

Key Molecule: Serine palmitoyltransferase small subunit B (SPTSB) [3]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Obese rats with insulin resistance have consistently been reported to exhibit elevated hepatic and muscle ceramide contents. Inhibition of ceramide synthesis using myriocin, an inhibitor of serine palmitoyltransferase, prevented insulin resistance and attenuated ceramide contents in fat-fed mice.

Key Molecule: O-GlcNAcase (OGA) [3]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Recently, skeletal muscle-specific O-GlcNAc transferase (OGT) knockout mice on a HFD were reported to have low plasma glucose levels and glucose tolerances. Moreover, the overexpression of O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, significantly improved whole-body glucose tolerance and insulin sensitivity in db/db mice, and O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino-N-phenylcarbamate (PUGNAc) (an OGA inhibitor) suppressed insulin-mediated glucose uptake in adipocytes.

Key Molecule: O-GlcNAcase (OGA) [3]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Recently, skeletal muscle-specific O-GlcNAc transferase (OGT) knockout mice on a HFD were reported to have low plasma glucose levels and glucose tolerances. Moreover, the overexpression of O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, significantly improved whole-body glucose tolerance and insulin sensitivity in db/db mice, and O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino-N-phenylcarbamate (PUGNAc) (an OGA inhibitor) suppressed insulin-mediated glucose uptake in adipocytes.

Key Molecule: CD36 molecule (CD36) [3]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Several studies have shown that lipid accumulation in liver and skeletal muscle caused by short-term HFD feeding or lipid/heparin infusions induce insulin resistance in rats. In addition, overexpression of lipoprotein lipase (LPL) in liver or muscle induced peripheral insulin resistance and the accumulation of lipid in respective tissues, and skeletal muscle-specific LPL deletion enhanced insulin signaling in HFD challenged muscle. Furthermore, deleting fat transport proteins such as CD36 or FATP-1 increased insulin-mediated glucose uptake in skeletal muscle, and liver-specific knockdown of FATP2 or FATP5 significantly reduced HFD-induced hepatosteatosis and increased glucose tolerance.

Key Molecule: Long-chain fatty acid transport protein 1 (S27A1) [3]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Several studies have shown that lipid accumulation in liver and skeletal muscle caused by short-term HFD feeding or lipid/heparin infusions induce insulin resistance in rats. In addition, overexpression of lipoprotein lipase (LPL) in liver or muscle induced peripheral insulin resistance and the accumulation of lipid in respective tissues, and skeletal muscle-specific LPL deletion enhanced insulin signaling in HFD challenged muscle. Furthermore, deleting fat transport proteins such as CD36 or FATP-1 increased insulin-mediated glucose uptake in skeletal muscle, and liver-specific knockdown of FATP2 or FATP5 significantly reduced HFD-induced hepatosteatosis and increased glucose tolerance.

Key Molecule: Very long-chain acyl-CoA synthetase (S27A2) [3]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Several studies have shown that lipid accumulation in liver and skeletal muscle caused by short-term HFD feeding or lipid/heparin infusions induce insulin resistance in rats. In addition, overexpression of lipoprotein lipase (LPL) in liver or muscle induced peripheral insulin resistance and the accumulation of lipid in respective tissues, and skeletal muscle-specific LPL deletion enhanced insulin signaling in HFD challenged muscle. Furthermore, deleting fat transport proteins such as CD36 or FATP-1 increased insulin-mediated glucose uptake in skeletal muscle, and liver-specific knockdown of FATP2 or FATP5 significantly reduced HFD-induced hepatosteatosis and increased glucose tolerance.

Key Molecule: Bile acyl-CoA synthetase (S27A5) [3]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Insulin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Several studies have shown that lipid accumulation in liver and skeletal muscle caused by short-term HFD feeding or lipid/heparin infusions induce insulin resistance in rats. In addition, overexpression of lipoprotein lipase (LPL) in liver or muscle induced peripheral insulin resistance and the accumulation of lipid in respective tissues, and skeletal muscle-specific LPL deletion enhanced insulin signaling in HFD challenged muscle. Furthermore, deleting fat transport proteins such as CD36 or FATP-1 increased insulin-mediated glucose uptake in skeletal muscle, and liver-specific knockdown of FATP2 or FATP5 significantly reduced HFD-induced hepatosteatosis and increased glucose tolerance.

Insulin recombinant

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Long non-protein coding RNA (UC.333) [4]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Down-regulation; Interaction
• Resistant Drug: Insulin recombinant
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Male db/db mice;C57BL/6 mice model; Mus musculus
• Experiment for Molecule Alteration: Microarray assay; Western bloting analysis; Fluorescence in situ hybridization; Overexpression assay; Knockdown assay
• Mechanism Description: Ultraconserved element uc.333 increases insulin sensitivity by binding to miR-223.

Key Molecule: Long non-protein coding RNA (UC.333) [4]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Down-regulation; Interaction
• Resistant Drug: Insulin recombinant
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Male db/db mice;C57BL/6 mice model; Mus musculus
• Experiment for Molecule Alteration: Microarray assay; Western bloting analysis; Fluorescence in situ hybridization; Overexpression assay; Knockdown assay
• Mechanism Description: UC.333 improves IR by binding to miR-223; thus, uc.333 may be a useful target for the treatment and prevention of IR.

Key Molecule: Long non-protein coding RNA (RISA) [5]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Up-regulation; Expression
• Resistant Drug: Insulin recombinant
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: C2C12 cells; Skeletal muscle; Homo sapiens (Human); CVCL_0188
• In Vivo Model: Male C57BL/6 mice model; Mus musculus
• Experiment for Molecule Alteration: Knockdown assay; Overexpression assay
• Mechanism Description: Risa regulates insulin sensitivity by affecting autophagy and suggest that Risa is a potential target for treating insulin-resistance-related diseases.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [6]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Down-regulation; Expression
• Resistant Drug: Insulin recombinant
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: Male C57BL/6J mouse model; Mus musculus
• Experiment for Molecule Alteration: RAP-PCR; qRT-PCR
• Mechanism Description: The overall metabolic impact of the absence of Malat1 on adipose tissue accretion and glucose intolerance is either physiologically not relevant upon aging and obesity, or that it is masked by as yet unknown compensatory mechanisms.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [7]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Down-regulation; Expression
• Resistant Drug: Insulin recombinant
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Male C57BL/6J mouse model; Mus musculus
• Experiment for Drug Resistance: Glucose tolerance test assay
• Mechanism Description: H19 LncRNA Promotes Skeletal Muscle Insulin Sensitivity in Part by Targeting AMPK.

Key Molecule: Matrin 3, pseudogene 2 (Matr3-ps2) [8]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Up-regulation; Expression
• Resistant Drug: Insulin recombinant
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: C2C12 cells; Skeletal muscle; Homo sapiens (Human); CVCL_0188
• In Vivo Model: Male C57BLKS/J db/db mice model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Mechanism Description: ENSMUST00000160839 was up-regulated in the PA-treated C2C12 myotubes compared with the control cells via qPCR detection.

Metformin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Solute carrier family 2 member 4 (SLC2A4) [9]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Metformin
• Experimental Note: Discovered Using In-vivo Testing Model
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: OGTT assay
• Mechanism Description: The administration of chebulagic acid significantly reduced blood glucose by increasing insulin secretion. Further,chebulagic acid treatment increased the protein expression PPAR-Gamma and GLUT4 on insulin target tissues which indicates that chebulagic acid improved insulin sensitivity. PPAR-Gamma is a type of ligand-activated nuclear transcription factor that is associated with fat differentiation, obesity, and insulin resistance. The ability of insulin to reduce blood glucose levels results from the suppression of hepatic glucose production and increased glucose uptake in muscle and adipose tissue via GLUT4.

Key Molecule: Peroxisome proliferator-activated receptor gamma (PPARG) [9]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Metformin
• Experimental Note: Discovered Using In-vivo Testing Model
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: OGTT assay
• Mechanism Description: The administration of chebulagic acid significantly reduced blood glucose by increasing insulin secretion. Further,chebulagic acid treatment increased the protein expression PPAR-Gamma and GLUT4 on insulin target tissues which indicates that chebulagic acid improved insulin sensitivity. PPAR-Gamma is a type of ligand-activated nuclear transcription factor that is associated with fat differentiation, obesity, and insulin resistance. The ability of insulin to reduce blood glucose levels results from the suppression of hepatic glucose production and increased glucose uptake in muscle and adipose tissue via GLUT4.

Investigative Drug(s) 1 drug(s) in total

D-Glucose

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [10]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Up-regulation; Interaction
• Resistant Drug: D-Glucose
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vivo Model: Male C57BL/6 mice; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western bloting analysis; ELISA assay; RIP experiments assay; RNA pull down assay; Dual luciferase assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LncRNA MALAT1 interacts with transcription factor Foxo1 to represses SIRT1 transcription in high glucose incubated HK-2 cells, which promotes high glucose-induced HK-2 cells injury.

Key Molecule: X inactive specific transcript (XIST) [11]

• Resistant Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Down-regulation; Interaction
• Resistant Drug: D-Glucose
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ARPE-19 cells; Eye; Homo sapiens (Human); CVCL_0145
• Experiment for Molecule Alteration: Luciferase assay; qRT-PCR
• Mechanism Description: XIST, likely through competitive binding of hsa-miR-21-5p, provides protection against hyperglycemia-associated injury in human retinal pigment epithelial cells.

References

• Ref 1: Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights From the CREDENCE Trial .Circulation. 2021 May 4;143(18):1735-1749. doi: 10.1161/CIRCULATIONAHA.120.048740. Epub 2021 Feb 8. 10.1161/CIRCULATIONAHA.120.048740
• Ref 2: Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice .Pharmaceuticals (Basel). 2021 Mar 16;14(3):267. doi: 10.3390/ph14030267. 10.3390/ph14030267
• Ref 3: Insulin Resistance: From Mechanisms to Therapeutic Strategies .Diabetes Metab J. 2022 Jan;46(1):15-37. doi: 10.4093/dmj.2021.0280. Epub 2021 Dec 30. 10.4093/dmj.2021.0280
• Ref 4: Ultraconserved element uc.333 increases insulin sensitivity by binding to miR-223Aging (Albany NY). 2020 Apr 17;12(8):6667-6679. doi: 10.18632/aging.103020. Epub 2020 Apr 17.
• Ref 5: Down-regulation of Risa improves insulin sensitivity by enhancing autophagyFASEB J. 2016 Sep;30(9):3133-45. doi: 10.1096/fj.201500058R. Epub 2016 Jun 1.
• Ref 6: Loss of Malat1 does not modify age- or diet-induced adipose tissue accretion and insulin resistance in micePLoS One. 2018 May 10;13(5):e0196603. doi: 10.1371/journal.pone.0196603. eCollection 2018.
• Ref 7: H19 lncRNA Promotes Skeletal Muscle Insulin Sensitivity in Part by Targeting AMPKDiabetes. 2018 Nov;67(11):2183-2198. doi: 10.2337/db18-0370. Epub 2018 Sep 10.
• Ref 8: RNA-sequencing analysis reveals the potential contribution of lncRNAs in palmitic acid-induced insulin resistance of skeletal muscle cellsBiosci Rep. 2020 Jan 31;40(1):BSR20192523. doi: 10.1042/BSR20192523.
• Ref 9: Chebulagic acid attenuates HFD/streptozotocin induced impaired glucose metabolism and insulin resistance via up regulations of PPAR Gamma and GLUT 4 in type 2 diabetic rats. Toxicol Mech Methods. 2022 Mar;32(3):159-170. doi: 10.1080/15376516.2021.1976333. Epub 2021 Sep 22.
• Ref 10: Long non-coding RNA MALAT1 interacts with transcription factor Foxo1 to regulate SIRT1 transcription in high glucose-induced HK-2 cells injuryBiochem Biophys Res Commun. 2018 Sep 5;503(2):849-855. doi: 10.1016/j.bbrc.2018.06.086. Epub 2018 Jul 14.
• Ref 11: Long noncoding RNA XIST enhances ethanol-induced hepatic stellate cells autophagy and activation via miR-29b/HMGB1 axisIUBMB Life. 2019 Dec;71(12):1962-1972. doi: 10.1002/iub.2140. Epub 2019 Aug 16.