Korean J Physiol Pharmacol.  2018 Sep;22(5):493-501. 10.4196/kjpp.2018.22.5.493.

The combination of canagliflozin and omega-3 fatty acid ameliorates insulin resistance and cardiac biomarkers via modulation of inflammatory cytokines in type 2 diabetic rats

• Safhi MM
• Anwer T
• Khan G
• Siddiqui R
• Moni Sivakumar S
• Alam MF

• KMID: 2418999
• DOI: http://doi.org/10.4196/kjpp.2018.22.5.493

Abstract

The present study was carried out with the hypothesis that combination of canagliflozin and omega-3 fatty acid may have potential effect on insulin level, insulin resistance, cardiac biomarkers, inflammatory cytokines and histological studies in type 2 diabetes mellitus (DM). Type 2 DM was induced by injecting nicotinamide (120 mg/kg, i.p.) 15 min before STZ (60 mg/kg) injection. Canagliflozin (5 and 10 mg/kg) and omega-3 fatty acid (300 mg/kg) were given for 28 days after confirmation of diabetes. Biochemical estimations revealed elevated levels of glucose, insulin, HOMA-R and inflammatory cytokines in diabetic group. Daily dosing of alone canagliflozin and omega-3 fatty acid slightly reduced elevated levels of glucose, insulin, HOMA-R and inflammatory cytokines (IL-1β, IL-2, and TNFα), whereas canagliflozin and omega-3 fatty acid combination has reduced these biochemical parameters significantly when compared with diabetic group. Similarly in diabetic group the levels of cardiac biomarkers such as lipid profile, LDH, CKMB and troponin were significantly increased. Elevated levels of cardiac biomarkers were significantly reduced after daily dosing of alone canagliflozin and omega-3 fatty acid. Canagliflozin and omega-3 fatty acid combination has offered better improvement in cardiac biomarkers compared to alone canagliflozin and omega-3 fatty acid. Histopathological analysis also supported the above hypothesis that combination therapy (canagliflozin and omega-3 fatty acid) offered better protection against degenerative changes in β-cells of pancreas as compared to alone treatment with these drugs. Thus the present study revealed that canagliflozin and omega-3 fatty acid can be used as potential combination therapy in type 2 DM along with cardiac complication.

Keyword

Hyperinsulinemia; Inflammatory cytokines; Nicotinamide; Streptozotocin; Type 2 diabetes mellitus

MeSH Terms

Animals
Biomarkers*
Canagliflozin*
Cytokines*
Diabetes Mellitus, Type 2
Glucose
Hyperinsulinism
Insulin Resistance*
Insulin*
Interleukin-2
Niacinamide
Pancreas
Rats*
Streptozocin
Troponin
Biomarkers
Canagliflozin
Cytokines
Glucose
Insulin
Interleukin-2
Niacinamide
Streptozocin
Troponin

Figure

• 

  Fig. 1 Effect of canagliflozin and omega-3 fatty acid on glucose levels in STZ+nicotinamide treated diabetic rats. ##p<0.001 versus group I (normal), **p<0.001 versus group II (diabetic).

• 

  Fig. 2 Effect of canagliflozin and omega-3 fatty acid on insulin levels in STZ+nicotinamide treated diabetic rats. ##p<0.001 versus group I (normal), nsp>0.05, **p<0.001 versus group II (diabetic).

• 

  Fig. 3 Effect of canagliflozin and omega-3 fatty acid on HOMA-R levels in STZ+nicotinamide treated diabetic rats. ##p<0.001 compared with group I (normal), **p<0.001 compared with group II (diabetic).

• 

  Fig. 4 Effect of canagliflozin and omega-3 fatty acid on LDH levels in STZ+nicotinamide treated diabetic rats. ##p<0.001 versus group I (normal), *p<0.01, **p<0.001 versus group II (diabetic).

• 

  Fig. 5 Effect of canagliflozin and omega-3 fatty acid on CKMB levels in STZ+nicotinamide treated diabetic rats. ##p<0.001 compared with group I (normal), **p<0.001 compared with group II (diabetic).

• 

  Fig. 6 Effect of canagliflozin and omega-3 fatty acid on troponin I levels in STZ+nicotinamide treated diabetic rats. Group-I – not detected (ND), nsp>0.05, **p<0.001 compared with group II (diabetic).

• 

  Fig. 7 Effect of canagliflozin and omega-3 fatty acid on histology of pancreatic β-cells. Hematoxylin and eosin-stained sections of rat pancreas: (A) represents group I (normal) rat showing normal lobules of pancreatic acini and β-cells. (B) represents group II (diabetic) rat showing lobules of pancreatic acini with areas of fibrosis and depletion of β-cells. (C) represents pancreatic section of omega-3 fatty acid treated rat showing fibrosis of pancreatic acini with degenerated β-cells. (D, E) indicate pancreatic section of only canagliflozin treated rat showing mild fibrosis of pancreatic acini with slight increase in the size of β-cells. (F, G) indicate pancreatic section of combination of canagliflozin and omega-3 fatty acid showing normal lobules of pancreatic acini and β-cells.

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