Pharmacological reduction of NEFA restores the efficacy of incretin-based therapies through GLP-1 receptor signalling in the beta cell in mouse models of diabetes
Type 2 diabetes mellitus is associated with reduced incretin effects. Although previous studies have shown that hyperglycaemia contributes to impaired incretin responses in beta cells, it is largely unknown how hyperlipidaemia, another feature of type 2 diabetes, contributes to impaired glucagon-like peptide 1 (GLP-1) response. Here, we investigated the effects of NEFA on incretin receptor signalling and examined the glucose-lowering efficacy of incretin-based drugs in combination with the lipid-lowering agent bezafibrate.
We used db/db mice to examine the in vivo efficacy of the treatment. Beta cell lines and mouse islets were used to examine GLP-1 and glucose-dependent insulinotropic peptide receptor signalling.
Palmitate treatment decreased Glp1r expression in rodent insulinoma cell lines and isolated islets. This was associated with impairment of the following: GLP-1-stimulated cAMP production, phosphorylation of cAMP-responsive elements binding protein (CREB) and insulin secretion. In insulinoma cell lines, the expression of exogenous Glp1r restored cAMP production and the phosphorylation of CREB. Treatment with bezafibrate in combination with des-fluoro-sitagliptin or exendin-4 led to more robust glycaemic control, associated with improved islet morphology and beta cell mass in db/db mice.
Elevated NEFA contributes to impaired responsiveness to GLP-1, partially through downregulation of GLP-1 receptor signalling. Improvements in lipid control in mouse models of obesity and diabetes increase the efficacy of incretin-based therapy.
- Pharmacological reduction of NEFA restores the efficacy of incretin-based therapies through GLP-1 receptor signalling in the beta cell in mouse models of diabetes
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Volume 56, Issue 2 , pp 423-433
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- Dipeptidyl peptidase-4
- Glucagon-like peptide 1
- Glucose-dependent insulinotropic polypeptide
- Non-esterified fatty acid
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- Author Affiliations
- 1. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Rm 114038, 9/F, Clinical Science Building, Prince of Wales Hospital Shatin, Hong Kong, SAR, People’s Republic of China
- 2. Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, People’s Republic of China
- 3. Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, SAR, People’s Republic of China
- 4. Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
- 5. Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People’s Republic of China