Liraglutide prevents fast weight gain and β-cell dysfunction in male catch-up growth rats

Abstract

We reported recently that after a nutritional growth retardation, rats showed significant weight gain, central fat accumulation, dyslipidemia, and b-cell dysfunction during a catch-up growth (CUG) phase. Here, we investigated whether glucagon-like peptide-1 (GLP-1) ameliorated the rapid weight gain, central fat deposition, and b-cell dysfunction during the CUG in rats. Sixty-four male Sprague Dawley rats were stratified into four groups including normal control group, CUG group, catch-up growth with liraglutide treatment group, and catch-up growth with liraglutide and exendin 9-39 treatment group. Energy intake, body weight, and body length were monitored. Fat mass percentage was analyzed by dual energy X-ray absorptiometry scan. Plasma triglyceride and non-esterified fatty acid were measured. The b-cell mass was analyzed by morphometric analysis and signaling molecules were examined by Western blot and real-time PCR. Insulin secretion capability was evaluated by hyperglycemic clamp test. Liraglutide prevented weight gain and improved lipid and glucose metabolism in rats under CUG conditions, which were associated with reduced fasting insulin levels and improved glucose-stimulated insulin secretion. Improved b-cell function is found to be associated with increased b-cell replication as determined by b-cell density and insulin-Ki67 dual staining. Furthermore, liraglutide increased islet pancreatic duodenal homeobox-1 (Pdx-1) and B-cell lymphoma-2 transcript and protein expression, and reduced Procaspase-3 transcript and Caspase-3 p11 subunit protein expression, suggesting that expression of Pdx-1 and reduction of apoptosis may be the mechanisms involved. The therapeutic effects were attenuated in rats co-administered with exendin 9-39, suggesting a GLP-1 receptor-dependent mechanism. These studies revealed that incretin therapy effectively prevented fast weight gain and b-cell dysfunction in rats under conditions of nutrition restriction followed by nutrition excess, which is in part due to enhanced functional b-cell mass and insulin secretory capacity.

Liraglutide suppresses non-esterified free fatty acids and soluble vascular cell adhesion molecule-1 compared with metformin in patients with recent-onset type 2 diabetes

“…On the other hand, a long-term increase in NEFA levels has been associated with ROS accumulation, which causes mitochondrial stress and leads to β-cell apoptosis [ 27 , 28 ]. In a catch-up growth rat model by re-feeding with high-fat diet, liraglutide prevented the increase of plasma NEFA, increased insulin secretion, increased islet pancreatic duodenal homeobox-1 (Pdx-1) and B cell lymphoma-2 (Bcl-2) expression, and reduced procaspase-3 transcription and Caspase-3 p11 subunit protein expression, which suggested that liraglutide treatment could antagonize β-cell apoptosis caused by elevated NEFA [ 11 ].…”

Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial

“…The possible role of managing beta cell function in type 2 diabetes, as a means to delay disease progression, has been a subject of discussion among researchers [ 30 ]. GLP-1RAs have attenuated beta cell dysfunction to varying degrees both in animal models [ 31 ] and in humans with type 2 diabetes [ 32 ].…”

Favorable Effects of GLP-1 Receptor Agonist against Pancreatic β-Cell Glucose Toxicity and the Development of Arteriosclerosis: “The Earlier, the Better” in Therapy with Incretin-Based Medicine

“…Incretin-based medicine such as the GLP-1RA and DPP-IV inhibitor ameliorate glycemic control and mitigate the progression of β-cell dysfunction in human subjects and animal models. It has been reported that GLP-1RA preserves pancreatic β-cells in various types of T2DM rodents [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. For example, it was shown that when T2DM db/db mice at 10 weeks old were treated with GLP-1RA (liraglutide) for 2 weeks, metabolic variables and insulin sensitivity were improved.…”