Short-term IF boosts glucose homeostasis, but prolonged fasting in adolescence may impair β cell maturation—potentially linking chronic IF to type 1 diabetes risk.
Study: Chronic intermittent fasting impairs β cell maturation and function in adolescent mice. Image Credit: Pormezz/Shutterstock.com
In a recent study published in Cell Reports, researchers demonstrated that long-term (LT) intermittent fasting (IF) impairs β cell function and maturation in adolescent mice.
Background
An overconsumption of palatable and energy-rich foods characterizes modern dietary habits. IF is a dietary strategy of alternating between periods of eating and fasting and has gained considerable popularity in recent years.
Studies suggest that a fasting window of at least 10 hours, followed by an eating period for the rest of the day, is essential for metabolic benefits.
Most IF strategies have beneficial effects on metabolic parameters in mice and humans, including blood pressure, body weight, cholesterol, insulin sensitivity, and life span.
In the context of type 2 diabetes (T2D), IF leads to higher insulin synthesis and secretion gene expression, improved β cell function, and higher insulin levels. However, the impact of IF on T1D is unclear.
The study and findings
In the present study, researchers examined the effects of IF in mice at different life stages. First, they evaluated the impact of five-week (short-term, ST) and 10-week (LT) IF on food intake and body weight in young (two-month-old), middle-aged (eight-month-old), and old (18-month-old) mice. They also included age-matched controls fed ad libitum.
Middle-aged and old mice exhibited no body weight changes with ST IF, while the young group had lower body weights due to reduced food intake relative to controls.
Conversely, LT IF led to lower body weights in all groups, regardless of age. Insulin (ITTs) and glucose tolerance tests (GTTs) showed that ST IF augmented insulin sensitivity and glucose homeostasis independent of age.
By contrast, GTT improved with LT IF in old mice, while ITT did not differ from controls. Further, ITTs and GTTs were improved in middle-aged mice after LT IF, while they were not different between the intervention and control groups of young mice.
Further, glucose-stimulated insulin secretion (GSIS) tests were performed to examine β cell function in isolated primary islets. Islets from control and LT IF groups secreted similar levels of insulin at low glucose concentrations.
By contrast, islets from old mice on LT IF secreted more insulin than those from controls at high glucose concentrations. Besides, there were no significant changes in islets from middle-aged mice. Conversely, young mice on LT IF had lower GSIS than controls.
Old mice on LT IF had no changes in islet quantity, but the other age groups had lower quantities. Further, insulin content in isolated islets was elevated in old mice, unchanged in middle-aged mice, and reduced in young mice on LT-IF.
These findings suggested that LT IF impaired islet function in young mice and improved ex vivo islet function in old mice. Further, single-cell RNA sequencing (scRNA-seq) was performed on isolated islets from all age groups following LT IF. Cell clusters were assigned to major endocrine cell types based on established markers: glucagon, pancreatic polypeptide, insulin, and somatostatin.
In addition, bioinformatic analyses of β cells were performed to ascertain IF- and age-dependent transcriptomic responses.
This revealed that the β cell maturation gene set was the most significantly different between LT IF and control groups. Middle-aged and old mice had higher β cell maturation scores than controls, while the young mice had lower scores.
The team analyzed the over-representation of pathways in differentially regulated genes in β cells and identified a cluster of related pathways, including those of insulin function and T2D. Next, they leveraged the overlap of genes annotated to β cell maturation with those contributing to pathway over-representation to identify potential candidate genes.
They found that most candidate genes, including insulin 1 (Ins1), solute carrier family two member 2 (Slc2a2), and MAF BZIP transcription factor A (Mafa), were only lower in young mice exposed to LT IF.
Finally, the team analyzed bulk RNA-seq datasets of human islets from donors with T1D or T2D. It noted that the genes downregulated in young mice on LT IF had a similar downregulation pattern in samples from T1D patients.
Conclusions
In sum, the study illustrated that ST IF resulted in metabolic benefits in mice across age groups, but LT IF negatively affected β cell function in young mice.
scRNA-seq revealed a transcriptional profile associated with impaired β cell maturation in young mice, which was linked to the transcriptional signature of β cell function and maturation-related genes in T1D patients.
Overall, these findings suggest considering IF duration in younger persons, as it may aggravate diabetes outcomes.
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