The prevalence of type 1 diabetes (T1D) is rising steadily. A potential contributor to the rise is vitamin D. In this systematic review, we examined the literature around vitamin D and T1D. We identified 22 papers examining the role of vitamin D in cultured β-cell lines, islets, or perfused pancreas, and 28 papers examining vitamin D in humans or human islets. The literature reports strong associations between T1D and low circulating vitamin D. There is also high-level (systematic reviews, meta-analyses) evidence that adequate vitamin D status in early life reduces T1D risk. Several animal studies, particularly in NOD mice, show harm from D-deficiency and benefit in most studies from vitamin D treatment/supplementation. Short-term streptozotocin studies show a β-cell survival effect with supplementation. Human studies report associations between VDR polymorphisms and T1D risk and β-cell function, as assessed by C-peptide. In view of those outcomes, the variable results in human trials are generally disappointing. Most studies using 1,25D, the active form of vitamin D were ineffective. Similarly, studies using other forms of vitamin D were predominantly ineffective. However, it is interesting to note that all but one of the studies testing 25D reported benefit. Together, this suggests that maintenance of optimal circulating 25D levels may reduce the risk of T1D and that it may have potential for benefits in delaying the development of absolute or near-absolute C-peptide deficiency. Given the near-complete loss of β-cells by the time of clinical diagnosis, vitamin D is much less likely to be useful after disease-onset. However, given the very low toxicity of 25D, and the known benefits of preservation of C-peptide positivity for long-term complications risk, we recommend considering daily cholecalciferol supplementation in people with T1D and people at high risk of T1D, especially if they have vitamin D insufficiency.

Vitamin D deficiency, prevalent worldwide, is linked to muscle weakness, sarcopenia, and falls. Muscle regeneration is a vital process that allows for skeletal muscle tissue maintenance and repair after injury. PubMed and Web of Science were used to search for studies published prior to May 2023. We assessed eligible studies that discussed the relationship between vitamin D, muscle regeneration in this review. Overall, the literature reports strong associations between vitamin D and skeletal myocyte size, and muscle regeneration. In vitro studies in skeletal muscle cells derived from mice and humans showed vitamin D played a role in regulating myoblast growth, size, and gene expression. Animal studies, primarily in mice, demonstrate vitamin D’s positive effects on skeletal muscle function, such as improved grip strength and endurance. These studies encompass vitamin D diet research, genetically modified models, and disease-related mouse models. Relatively few studies looked at muscle function after injury, but these also support a role for vitamin D in muscle recovery. The human studies have also reported that vitamin D deficiency decreases muscle grip strength and gait speed, especially in the elderly population. Finally, human studies reported the benefits of vitamin D supplementation and achieving optimal serum vitamin D levels in muscle recovery after eccentric exercise and surgery. However, there were no benefits in rotator cuff injury studies, suggesting that repair mechanisms for muscle/ligament tears may be less reliant on vitamin D. In summary, vitamin D plays a crucial role in skeletal muscle function, structural integrity, and regeneration, potentially offering therapeutic benefits to patients with musculoskeletal diseases and in post-operative recovery.

Fatty acid receptors have been recognized as important players in glycaemic control. This study is the first to describe a role for the medium‐chain fatty acid (MCFA) receptor G‐protein‐coupled receptor (Gpr) 84 in skeletal muscle mitochondrial function and insulin secretion. We are able to show that Gpr84 is highly expressed in skeletal muscle and adipose tissue. Mice with global deletion of Gpr84 [ Gpr84 knockout (KO)] exhibit a mild impairment in glucose tolerance when fed a MCFA‐enriched diet. Studies in mice and pancreatic islets suggest that glucose intolerance is accompanied by a defect in insulin secretion. MCFA‐fed KO mice also exhibit a significant impairment in the intrinsic respiratory capacity of their skeletal muscle mitochondria, but at the same time also exhibit a substantial increase in mitochondrial content. Changes in canonical pathways of mitochondrial biogenesis and turnover are unable to explain these mitochondrial differences. Our results show that Gpr84 plays a crucial role in regulating mitochondrial function and quality control.—Montgomery, M. K., Osborne, B., Brandon, A. E., O'Reilly, L., Fiveash, C. E., Brown, S. H. J., Wilkins, B. P., Samsudeen, A., Yu, J., Devanapalli, B., Hertzog, A., Tolun, A. A., Kavanagh, T., Cooper, A. A., Mitchell, T. W., Biden, T. J., Smith, N. J., Cooney, G. J., Turner, N. Regulation of mitochondrial metabolism in murine skeletal muscle by the medium‐chain fatty acid receptor Gpr84. FASEB J. 33, 12264‐12276 (2019). www.fasebj.org

Male fertility and sperm quality are negatively impacted by obesity. Furthermore, recent evidence has shown that male offspring from obese rat mothers also have reduced sperm quality and fertility. Here, we extend work in this area by comparing the effects of both maternal obesity and offspring post-weaning diet-induced obesity, as well as their combination, on sperm quality in mice. We additionally tested whether administration of the NAD⁺-booster nicotinamide mononucleotide (NMN) can ameliorate the negative effects of obesity and maternal obesity on sperm quality. We previously showed that intraperitoneal (i.p.) injection of NMN can reduce the metabolic deficits induced by maternal obesity or post-weaning dietary obesity in mice. In this study, female mice were fed a high-fat diet (HFD) for 6 weeks until they were 18% heavier than a control diet group. Thereafter, HFD and control female mice were mated with control diet males, and male offspring were weaned into groups receiving control or HFD. At 30 weeks of age, mice received 500 mg/kg body weight NMN or vehicle PBS i.p. for 21 days. As expected, adiposity was increased by both maternal and post-weaning HFD but reduced by NMN supplementation. Post-weaning HFD reduced sperm count and motility, while maternal HFD increased offspring sperm DNA fragmentation and levels of aberrant sperm chromatin. There was no evidence that the combination of post-weaning and maternal HFD exacerbated the impacts in sperm quality suggesting that they impact spermatogenesis through different mechanisms. Surprisingly NMN reduced sperm count, vitality and increased sperm oxidative DNA damage, which was associated with increased NAD⁺ in testes. A subsequent experiment using oral NMN at 400 mg/kg body weight was not associated with reduced sperm viability, oxidative stress, mitochondrial dysfunction or increased NAD⁺ in testes, suggesting that the negative impacts on sperm could be dependent on dose or mode of administration. Abstract Male fertility and sperm quality are negatively impacted by obesity. Furthermore, recent evidence has shown that male offspring from obese rat mothers also have reduced sperm quality and fertility. Here, we extend work in this area by comparing the effects of both maternal obesity and offspring post-weaning diet-induced obesity, as well as their combination, on sperm quality in mice. We additionally tested whether administration of the NAD⁺-booster nicotinamide mononucleotide (NMN) can ameliorate the negative effects of obesity and maternal obesity on sperm quality. We previously showed that intraperitoneal (i.p.) injection of NMN can reduce the metabolic deficits induced by maternal obesity or post-weaning dietary obesity in mice. In this study, female mice were fed a high-fat diet (HFD) for 6 weeks until they were 18% heavier than a control diet group. Thereafter, HFD and control female mice were mated with control diet males, and male offspring were weaned into groups receiving control or HFD. At 30 weeks of age, mice received 500 mg/kg body weight NMN or vehicle PBS i.p. for 21 days. As expected, adiposity was increased by both maternal and post-weaning HFD but reduced by NMN supplementation. Post-weaning HFD reduced sperm count and motility, while maternal HFD increased offspring sperm DNA fragmentation and levels of aberrant sperm chromatin. There was no evidence that the combination of post-weaning and maternal HFD exacerbated the impacts in sperm quality suggesting that they impact spermatogenesis through different mechanisms. Surprisingly NMN reduced sperm count, vitality and increased sperm oxidative DNA damage, which was associated with increased NAD⁺ in testes. A subsequent experiment using oral NMN at 400 mg/kg body weight was not associated with reduced sperm viability, oxidative stress, mitochondrial dysfunction or increased NAD⁺ in testes, suggesting that the negative impacts on sperm could be dependent on dose or mode of administration.

NMN dampened exercise-induced benefits on glucose handling in diet-induced obesity. NMN administration alongside treadmill exercise enhanced the ratio of antioxidants to prooxidants. We suggest that NMN administration may not be beneficial when NAD⁺ levels are replete.

Type 1 diabetes (T1D) is caused by the immune-mediated loss of pancreatic β-cells. Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor which is crucial for cellular responses to low oxygen. Here, we investigate the role of β-cell HIF-1α in β-cell death and diabetes after exposure to multiple low-dose streptozotocin (MLDS). MDLS triggers auto-immunity in susceptible animal models, such as non-obese diabetic (NOD) mice. These experiments used a novel mouse model with β-cell-specific deletion of HIF-1α on a NOD background (BIN mice). Mice were given 20 mg/kg MLDS for 5 consecutive days. Following MLDS, 100% of BIN mice developed frank diabetes versus 33% of floxed-control (FC) littermates and 17% of NOD controls (p < 0.001). BIN mice had obvious loss of β-cell mass (p < 0.0001) and increased necrotic areas within islets (p < 0.001). To confirm that diabetes was T1D, adoptive transfers of splenocytes from diabetic BIN and FC mice were performed on NOD-SCID (Severe Combined ImmunoDeficiency) recipients. All mice receiving BIN-splenocytes developed frank diabetes, confirming that MLDS induced true T1D. Interestingly, diabetes developed significantly faster in BIN-adoptive transfer mice compared to mice which developed diabetes after receiving an FC-adoptive transfer. These studies demonstrate the importance of β-cell HIF-1α in the preservation of β-cell mass and avoidance of auto-immunity.