Mechanistic View on the Effects of SGLT2 Inhibitors on Lipid Metabolism in Diabetic Milieu - PubMed (original) (raw)

Review

Mechanistic View on the Effects of SGLT2 Inhibitors on Lipid Metabolism in Diabetic Milieu

Habib Yaribeygi et al. J Clin Med. 2022.

Abstract

Chronic hyperglycemia induces pathophysiologic pathways with negative effects on the metabolism of most substrates as well as lipids and lipoproteins, and thereby induces dyslipidemia. Thus, the diabetic milieu is commonly accompanied by different levels of atherogenic dyslipidemia, which is per se a major risk factor for subsequent complications such as atherosclerosis, coronary heart disease, acute myocardial infarction, ischemic stroke, and nephropathy. Therefore, readjusting lipid metabolism in the diabetic milieu is a major goal for preventing dyslipidemia-induced complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of relatively newly introduced antidiabetes drugs (including empagliflozin, canagliflozin, dapagliflozin, etc.) with potent hypoglycemic effects and can reduce blood glucose by inducing glycosuria. However, recent evidence suggests that they could also provide extra-glycemic benefits in lipid metabolism. It seems that they can increase fat burning and lipolysis, normalizing the lipid metabolism and preventing or improving dyslipidemia. Nevertheless, the exact mechanisms involved in this process are not well-understood. In this review, we tried to explain how these drugs could regulate lipid homeostasis and we presented the possible involved cellular pathways supported by clinical evidence.

Keywords: cholesterol; diabetes mellitus; lipids; lipogenesis; lipolysis; oxidative stress; sodium-glucose cotransporter-2 inhibitors; β-oxidation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

SGLT2 is responsible for glucose and sodium reabsorption in the renal proximal tubules. SGLT2 inhibitors inhibit this process and induce urinary glucose (and sodium) excretion.

Figure 2

Figure 2

Summary of the nutrients’ absorption, lipid synthesis, and storage in adipose tissue.

Figure 3

Figure 3

The main forms of dyslipidemia-induced diabetic complications.

Figure 4

Figure 4

Possible mechanisms involved in SGLT2i dependent lipid biogenesis. SGLT2 inhibition reduces lipogenesis and induces lipolysis upregulating ACC (acetyl-CoA carboxylase) and FAS (fatty acid synthase) and downregulating Scd-1 (Stearoyl-CoA desaturase-1), PDE38 (Phosphodiesterase 3B), SREBP-1c (sterol response element-binding protein 1c), CIDEC (Cell death inducing-DFFA like effector C), Chrebp-β (Carbohydrate response element-binding protein-beta), and the activity of complex 1 of MRC.

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