Time-restricted feeding improves insulin secretion and prevents hyperglycemia in diabetes-prone mice despite obesity

Background: Lifestyle changes remain the most sustainable measures to prevent metabolic diseases, such as type 2 diabetes (T2D), or to mitigate its associated complications. Time-restricted feeding (TRF) has already been shown to promote health in humans and mice. However, the mechanisms mediating the beneficial effects in metabolically challenged mice, specifically on insulin secretion, have not yet been thoroughly investigated.

Methods: Male diabetes-prone New Obese Zealand (NZO) mice were subjected to a TRF regime with 6 hours access to food/day for 4 or 8 weeks starting at 16 weeks of age, after an obese phenotype had developed, and compared to ad libitum fed controls (AL). Metabolic tests for glucose and mixed-meal tolerance and comprehensive plasma analysis were performed. In perifusion experiments with freshly isolated islets of Langerhans, the capacity for insulin secretion in response to stimuli such as glucose plus/minus palmitic acid (PA) or exendin-4 (Ex-4) was tested.

Results: Food intake in TRF-mice was not different from controls as a result of hyperphagia during food access. Consequently, body weight was not different in TRF-mice compared to controls. However, TRF-mice were protected from hyperglycemia whereas 30% of AL-mice developed a T2D-like phenotype. In addition, hepatic fat was reduced in TRF-mice compared to hyperglycemic controls. Glucose tolerance of TRF-mice was preserved relative to normo- and hyperglycemic AL-mice. Insulin secretion of primary islet cells was diminished in hyperglycemic AL-mice, whereas normoglycemic AL- and TRF-mice displayed similar insulin secretion capacities under low (2.8 mM) or high (16.7 mM) glucose stimulation, as well as high glucose in combination with PA or Ex-4 indicating preserved islet function in these mice.

Conclusions: Despite the hyperphagia of TFR mice, these animals were protected from a T2D-like phenotype compared to control mice, accompanied by normoglycemia, improved glucose tolerance and insulin secretion. Ongoing analysis of plasma samples, including incretin levels and beta-cell related parameters such as proinsulin and c-peptide, will help to decipher the beneficial effects of TRF on insulin secretion.

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Publication History

Article published online:
18 April 2024