Barth syndrome is a mitochondrial disorder caused by Tafazzin (TAZ) mutations, which impair cardiolipin remodelling and contribute to systemic metabolic alterations. While islet dysfunction has been implicated in Barth syndrome, its underlying mechanisms remain unknown. We aimed to determine how Tafazzin (Taz) deficiency affects mouse pancreatic islet metabolism and hormone secretion, and whether systemic signals, such as circulating factors, modulate these effects in vivo. In vivo and in vitro models were used to separate direct islet effects from systemic influences of Taz deficiency.
We used a mouse model of global Taz knockdown (Taz-KD) and combined in vivo and in vitro approaches to assess pancreatic islet metabolism, morphology and hormone secretion. Islet function was evaluated under basal and glucotoxic conditions. Transcriptomic profiling was performed to identify gene expression changes in isolated islets from Taz-KD mice and following in vitro Taz-KD. Additionally, we examined the role of the circulating factor fibroblast growth factor 21 (FGF-21) in modulating islet function.
Despite impaired cardiolipin remodelling, pancreatic islets from Taz-KD mice maintained insulin secretion, supported by compensatory mechanisms such as increased glucose uptake, expanded mitochondrial volume and increased metabolic parameters. In addition, alpha cell mass and glucagon secretion were significantly increased in Taz-KD islets. These islet-specific adaptations occurred alongside improved whole-body glucose tolerance, elevated circulating FGF-21 levels and enhanced glucose uptake in brown adipose tissue. In contrast, in vitro Taz-KD led to impaired islet function and reduced insulin secretion. Transcriptomic analysis revealed distinct gene expression patterns between in vivo and in vitro Taz-KD models. While in vivo upregulation of genes related to N-acetylglucosamine biosynthesis and O-GlcNAcylation were related to compensatory mechanisms, in vitro Taz-KD affected, among others, the MAPK pathway, contributing to islet dysfunction. Notably, islet incubation with FGF-21 was able to restore insulin secretion after in vitro Taz-KD.
Our findings demonstrate that while Taz and cardiolipin remodelling are essential for beta cell physiology, systemic and islet-specific compensatory mechanisms preserve insulin secretion in vivo in Taz-KD mice, alongside increased glucagon secretion. These adaptations probably contribute to the altered metabolic phenotype observed in Barth syndrome and highlight a potential role for hormones and circulating factors such as FGF-21 in maintaining islet function and glucose homeostasis.
© 2025. The Author(s).

The glucose-dependent insulinotropic polypeptide receptor (GIPR) is the target of several approved and investigational drugs for type 2 diabetes and obesity. Missense coding variation in GIPR could confer phenotypic effects through altered constitutive or functional responses to GIP or alter the efficacy of pharmacological agents targeting this receptor. We aimed to provide a deep understanding of the cellular and physiological impacts of individual GIPR coding variants and the mechanisms underpinning these effects. By studying a panel of the 30 highest prevalence GIPR coding variants in HEK293 cells, INS-1 β-cells and pancreatic islets, we found that many show impaired cAMP responses to physiological GIP stimulation. Population-based association analysis highlighted that these loss-of-function GIPR variants decrease BMI but increase glycaemia. In many cases, reduced function was at least partly driven by reduced variant expression at the cell surface due to impaired stability and redirection towards proteasomal degradation pathway. Molecular dynamics simulations suggest distinct variant-induced perturbations in inter- and intra-helical interactions within the transmembrane region which interfere with receptor stability and signalling. This study highlights the mechanisms and consequences of GIPR coding variation, which may have implications for the therapeutic targeting of this receptor in metabolic disease.

Blockade of the glucagon receptor (GCGR) has been shown to improve glycemic control. However, this therapeutic approach also brings side effects, such as α-cell hyperplasia and hyperglucagonemia, and the mechanisms underlying these side effects remain elusive. Here, we conduct single-cell transcriptomic sequencing of islets from male GCGR knockout (GCGR-KO) mice. Our analysis confirms the elevated expression of Gcg in GCGR-KO mice, along with enhanced glucagon secretion at single-cell level. Notably, Vgf (nerve growth factor inducible) is specifically upregulated in α cells of GCGR-KO mice. Inhibition of VGF impairs the formation of glucagon immature secretory granules and compromises glucagon maturation, lead to reduced α-cell hypersecretion of glucagon. We further demonstrate that activation of both mTOR-STAT3 and ERK-CREB pathways, induced by elevated circulation amino acids, is responsible for upregulation of Vgf and Gcg expression following glucagon receptor blockade. Thus, our findings elucidate parts of the molecular mechanism underlying hyperglucagonemia in GCGR blockade.
© 2025. The Author(s).

Barth syndrome is a multisystem genetic disorder caused by mutation in TAFAZZIN , a gene that encodes a phospholipid:lysophospholipid transacylase important for cardiolipin remodeling. Barth Syndrome patients suffer from a number of symptoms including early heart failure, fatigue, and systemic metabolic alterations, including hypoglycemia. The endocrine pancreas is central to glucose homeostasis, however, the impact of defective cardiolipin remodeling on pancreatic islet function and the consequences for systemic metabolism is unclear. Surprisingly, in a mouse model with global TAFAZZIN knockdown, we observed improved glucose tolerance compared to wildtype littermates. We show that pancreatic islet metabolism and secretory function are robustly maintained through various compensatory mechanisms including increased glucose uptake and increased mitochondrial volume. Transcriptomics analyses revealed increased expression of genes encoding proteins involved in N-acetylglucosamine synthesis and protein O -linked N-acetylglucosaminylation. These pathways might provide a molecular mechanism for coupling metabolic changes to mitochondrial volume regulation.

The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 individuals with congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and located near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth and 24 years, and the severity of the phenotype was also variable. Mutant enzymes were expressed and purified for enzyme kinetics in vitro. Mutant enzymes had low glucose half-saturation concentration values and an increased enzyme activity index compared with wild-type GK. We performed functional evaluation of islets from the pancreata of three children with GCK-HI who required pancreatectomy. Basal insulin secretion in perifused GCK-HI islets was normal, and the response to glyburide was preserved. However, the threshold for glucose-stimulated insulin secretion in perifused glucokinase hyperinsulinism (GCK-HI) islets was decreased, and glucagon secretion was greatly suppressed. Our evaluation of novel GCK disease-associated mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response.
Our evaluation of six novel and two previously published activating GCK mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. These studies provide insights into the pathophysiology of GCK-hyperinsulinism and the dual role of glucokinase in β-cells and α-cells to regulate glucose homeostasis.
© 2023 by the American Diabetes Association.