Abstract
The pharmacological effects of type 2 diabetes (T2DM) medications on lipoprotein metabolism
are difficult to assess in preclinical models because those created failure to replicate
the human condition in which insulin deficiency is superimposed on obesity-related
insulin resistance. To create a better model, we fed mice with high fat (HF) diet
and treated the animals with low dose streptozotocin (STZ) to mimic T2DM. We used
this model to evaluate the effects of canagliflozin (CANA), a drug that reduces plasma
glucose by inhibiting the sodium-glucose transporter 2 (SGLT2), which mediates ~90%
of renal glucose reabsorption] on lipid and lipoprotein metabolism. After 6 weeks
of CANA (30 mg/kg/day) treatment, the increase in total plasma cholesterol in HF-STZ
diabetic mice was reversed, but plasma triglycerides were not affected. Lipoprotein
fractionation and cholesterol distribution analysis showed that CANA kept HDL-Cholesterol,
LDL-Cholesterol, and IDL-Cholesterol levels steady while these lipoprotein species
were increased in placebo- and insulin-treated control groups. CANA treatment of HF-STZ
mice reduced post-heparin plasma lipoprotein lipase (LPL) activity at 2 (−40%) and
5 (−30%) weeks compared to placebo. Tissue-specific LPL activity following CANA treatment
showed similar reduction. In summary, CANA prevented the total cholesterol increase
in HF-STZ mice without effects on plasma lipids or lipoproteins, but did decrease
LPL, implying a potential role of LPL-dependent lipoprotein metabolism in CANA action.
These effects did not recapitulate the effect of SGLT2 inhibitors on lipids and lipoproteins
in human, suggesting that a better murine T2DM model (such as the ApoB100 humanized
CETP-overexpressing mouse) is needed next.
Key words
SGLT2 inhibitors - lipoproteins - type 2 diabetes - lipoprotein lipase
