Endocrine Abstracts

Background: Glucagon-like-peptide-1 (GLP-1) has been shown to improve body weight and glycaemic control in patients with common obesity and type 2 diabetes. Whether it confers the same metabolic benefits in monogenic syndromic obesity is unknown. This observational study aimed to examine the real-world efficacy of GLP-1 analogues in Alström syndrome (ALMS), a form of monogenic obesity.

Method: We screened all 72 UK adult patients with ALMS and offered treatment to 34 patients meeting one of the following criteria: body mass index >25, sub-optimal glycaemic control on oral hypoglycaemic medications, non-alcoholic fatty liver disease or insulin resistance. Metabolic parameters were measured at baseline and six months post-treatment.

Results: 30 patients completed 6 months of treatment with GLP-1 analogue either in the form of semaglutide or exenatide. Treatment with GLP-1 analogue reduced body weight by 5.4±3.81 kg and HbA1c by 12.0±4.85 mmol/mol (mean±SEM) equating to c.6% weight loss (P<0. 01) and c.18% reduction in HbA1c (P<0. 01). Significant improvements were also observed in serum total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and alanine aminotransferase. The improvement of metabolic parameters was more pronounced than data from polygenic obesity irrespective of weight loss. A modest increase was noted in post-treatment c-peptide levels with a treatment duration of 6 months. Preliminary experiments demonstrate that ALMS1 silenced EndoC-βH1 cells (to model ALMS) exhibit exaggerated glucose-responsive insulin release vs control cells, perhaps explaining the modest increase in plasma c-peptide with GLP-1 analogue treatment.

Conclusion: GLP-1 analogue can be considered a treatment option in patients with ALMS and perhaps other monogenic forms of syndromic obesity. Loss of ALMS1 function impacts human pancreatic beta cell function.