Zinc is an essential micronutrient with diverse catalytic, structural, and regulatory roles across various life forms. Its essentiality for human health was recognized in the 1960s, but advancements in understanding the functions of zinc at the tissue, cell, and subcellular levels have accelerated, particularly with the identification of zinc transporters. Zinc homeostasis is primarily facilitated by two families of transporters, the SLC30A/ZNT (zinc transporters) and SLC39A/ZIP (Zrt-Irt-Like Proteins). Among these, the ZNT family transporter ZNT8 has been well-studied for its involvement in insulin production, secretion, and the viability of pancreatic β cells. However, the roles of ZIP family transporters in β cell insulin-related functions remain less explored. There have been studies implicating regulatory roles of ZIP4, ZIP5, ZIP6, and ZIP7 in β cells and emerging evidence for the involvement of ZIP8 and ZIP14 in β cell function. Despite these insights, the limited number of studies on ZIP family transporters highlights the need to consolidate existing literature to identify gaps and establish targeted, comprehensive research approaches that can further elucidate their critical roles in cellular zinc homeostasis and insulin metabolism. In this review, we first address the role of zinc in insulin production, secretion, and action. Second, we discuss the known ZIP transporters that potentially facilitate zinc delivery to specific cell compartments, focusing on literature addressing zinc and zinc transporters specifically relevant to insulin and glucose metabolism.

Diabesity is a modern epidemic that indicates a strong association between obesity and diabetes. Key enzymes have been identified in the development and progression of both diseases, DPP-IV in glucose uptake and FAS in fatty acid synthesis. In both cases, the molecular mechanisms of how each one acts separately have been described, and which are the key inhibitory drugs and molecules for each one. However, although it is known that there is an association between both clinically and molecularly, the mechanism has not been elucidated; therefore, this review focuses on proposing a mechanism of convergence of DPP-IV and FAS in diabesity, and the possible mode of action in which bioactive peptides obtained from plant and animal sources can inhibit these two enzymes in a similar way as drugs do.

Recent data from the South Asian subregion have raised concern about the dramatic increase in the prevalence of metabolic diseases, which are influenced by genetic and lifestyle factors.

The aim of this systematic review was to summarize the contemporary evidence for the effect of gene-lifestyle interactions on metabolic outcomes in this population.

PubMed, Web of Science, and SCOPUS databases were searched up until March 2023 for observational and intervention studies investigating the interaction between genetic variants and lifestyle factors such as diet and physical activity on obesity and type 2 diabetes traits.

Of the 14 783 publications extracted, 15 were deemed eligible for inclusion in this study. Data extraction was carried out independently by 3 investigators. The quality of the included studies was assessed using the Appraisal Tool for Cross-Sectional Studies (AXIS), the Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I), and the methodological quality score for nutrigenetics studies.

Using a narrative synthesis approach, the findings were presented in textual and tabular format. Together, studies from India (n = 8), Pakistan (n = 3), Sri Lanka (n = 1), and the South Asian diaspora in Singapore and Canada (n = 3) reported 543 gene-lifestyle interactions, of which 132 (∼24%) were statistically significant. These results were related to the effects of the interaction of genetic factors with physical inactivity, poor sleep habits, smoking, and dietary intake of carbohydrates, protein, and fat on the risk of metabolic disease in this population.

The findings of this systematic review provide evidence of gene-lifestyle interactions impacting metabolic traits within the South Asian population. However, the lack of replication and correction for multiple testing and the small sample size of the included studies may limit the conclusiveness of the evidence. Note, this paper is part of the Nutrition Reviews Special Collection on Precision Nutrition.

PROSPERO registration No. CRD42023402408.

Diabetes is a rapidly growing global health concern projected to affect one in eight adults by 2045, which translates to roughly 783 million people. The profound metabolic alterations often present in dysglycaemia significantly increase the risk of cardiovascular complications. While genetic susceptibility plays a crucial role in diabetes and its vascular complications, identifying genes and molecular mechanisms that influence both diseases simultaneously has proven challenging. A key reason for this challenge is the pathophysiological heterogeneity underlying these diseases, with multiple processes contributing to different forms of diabetes and specific cardiovascular complications. This molecular heterogeneity has limited the effectiveness of large-scale genome-wide association studies (GWAS) in identifying shared underlying mechanisms. Additionally, our limited knowledge of the causal genes, cell types and disease-relevant states through which GWAS signals operate has hindered the discovery of common molecular pathways. This review highlights recent advances in genetic epidemiology, including studies of causal associations that have uncovered genetic and molecular factors influencing both dysglycaemia and cardiovascular complications. We explore how disease subtyping approaches can be critical in pinpointing the unique molecular signatures underlying both diabetes and cardiovascular complications. Finally, we address critical research gaps and future opportunities to advance our understanding of both diseases and translate these discoveries into tangible benefits for patient care and population health.

We present metacp an open-source software package which implements an abundance of statistical methods for the combination of both independent p-values, with methods such as Fisher's, Stouffer's and Edgington's, and dependent p-values, with methods such as Brown's method and the Cauchy Combination Test.

The tool is available in Python and STATA, it is very fast, and it is easy to use, requiring only minimal input. It offers a useful resource for combining both independent and dependent p-values, responding to diverse analytical needs for practitioners performing meta-analyses and bioinformaticians developing tools for a variety of applications. Depending on the input data it can be used for gene-based testing, for analysis of multiple traits in GWAS, or for combining diverse multi-omics data such as those of a TWAS, a colocalization or an RNA-seq study.

Compared to other similar packages (like poolr or metap), metacp implements the largest collection of statistical methods for this problem, offering users the flexibility to choose from a wide variety of approaches. Being available both as a standalone Python tool and as a STATA command, metacp is accessible to a broad and diverse audience, including practitioners conducting meta-analyses across various fields and bioinformaticians developing new tools where p-value combination is a crucial component.

TCF7L2 harbors the strongest genetic association with diabetes identified thus far. However, its function in liver has remained unclear. Here, we find using mice with liver-specific deletion, that Tcf7l2 plays a central role in maintaining hepatic zonation. That is, in the normal liver, many genes show gradients of expression across the liver lobule; in the absence of Tcf7l2 , these gradients collapse. One major consequence is the disorganization of glutamine metabolism, with a loss of the glutamine production program, ectopic expression of the glutamine consumption program, and a decrease in glutamine levels. In parallel, metabolomic profiling shows glutamine to be the most significantly decreased metabolite in individuals harboring the rs7903146 variant in TCF7L2 . Taken together, these data indicate that hepatic TCF7L2 has a secondary role in glycemic control, but a primary role in maintaining transcriptional architecture and glutamine homeostasis.

Insulin resistance (IR) is a metabolic disorder characterized by an impaired response to insulin. This condition is associated with excess adiposity and metabolic inflammation, contributing to an increased risk for related chronic diseases. Single-nucleotide polymorphisms (SNPs) can affect genes related to metabolic pathways which are related to IR and the individual response to nutrients and dietary patterns, affecting metabolic inflammation and insulin sensitivity. This narrative review explores the current evidence on interactions between genetic variants and dietary factors, specifically their effects in modulating IR and metabolic inflammation. A comprehensive search of the literature was conducted in PubMed, Google Scholar, and Web of Science, and a total of 95 articles were reviewed. The key findings reveal that SNPs in the TCF7L2, ADIPOQ, and TNF genes significantly influence metabolic responses and modulate the effects of the Mediterranean diet on biomarkers of inflammation and IR. Genotype-dependent variations in IR and inflammation biomarkers were observed in the response to different diets for SNPs in the TCF7L2, ADIPOQ, and TNF genes. Additionally, polygenic risk scores (PRSs) can also predict the response to the intake of nutrients and specific diets, and offer a promising tool for assessing genetic predisposition to IR. This review underscores the pivotal role of an individual's genetic background in the effects of their nutrient intake and in the responses to dietetic interventions, thereby laying the foundation for personalized and effective nutritional strategies tailored to each individual's necessity in mitigating IR and its associated risk factors for chronic diseases.

The TCF7L2 gene is a significant genetic factor contributing to the risk of metabolic and cardiovascular diseases (CVD). We previously found that subjects with the TT genotype of TCF7L2 rs7903146 variant, who consume a low-fat diet (LF) had a higher incidence of stroke than subjects with the CC genotype. Yet this association was abolished in subjects with the TT genotype who consumed a Mediterranean-type diet (MetD). However, the mechanism by which MetD diet modulates the association between TCF7L2 and CVD risk is unclear. This study aims to validate these findings under real-world conditions and clinical practice to elucidate the biological mechanisms involved in this correlation.

Thirty-five participants with BMI ranging from 27 to 34 kg/m2 were recruited based on rs7903146 genotype. Of those consented to participate, 21 had the CC and 14 had the TT genotype. Participants were randomly assigned to two dietary intervention groups, ensuring an equal distribution of CC and TT carriers. Each participant followed one of two diets (LF or MetD) for one week, followed by a 10-day washout period before switching to the other diet for one week. Blood samples were collected before and after each diet for metabolomic analysis using nuclear magnetic resonance (NMR) spectroscopy. The differential effect of the diets on triglyceride-rich lipoproteins was determined based on TCF7L2 genotype.

The MetD significantly reduced triglyceride-rich lipoprotein concentrations compared to the LF diet. After consuming the LF diet, TT carriers exhibited more small VLDL particles, potentially contributing to CVD risk compared to CC carriers. However, this difference in risk was not observed with the MetD. Furthermore, the order in which the two diets were crossed affected the triglyceride-rich lipoprotein profile, with LF-MetD regimen showing a stronger effect on triglyceride-rich lipoproteins (TRL) levels than the MetD-LF regimen.

Our findings suggest that rs7903146 TT carriers benefit more from a MetD than a LF diet in terms of their triglyceride-rich lipoprotein profile, which may reduce their risk of CVD. These results support the notion that genotype is a factor in determining the extent to which the MetD affects cardiovascular health.

Type 2 diabetes mellitus (T2D) is a significant health concern. Research using non-human primates, which develop T2D with similar symptoms and pancreatic changes as humans, is crucial but limited by long timelines and low success rates.

We targeted capture sequenced 61 normal and 81 T2D cynomolgus monkeys using a primer panel that captured 269 potential regulatory regions potentially associated with T2D in the cynomolgus monkey genome. 80 variants were identified to be associated with T2D and were used to construct a genetic prediction model. Among 8 machine learning algorithms tested, we found that the best prediction performance was achieve when the model using support vector machine with polynomial kernel as the machine learning algorithm (AUC = 0.933). Including age and sex in this model did not significantly improve the prediction performance. Using the genetic prediction model, we further screened 22 monkeys and found 13 were high risk while 9 were low risk. After feeding the 22 monkeys with high-energy food for 32 weeks, we found all the 9 low risk monkeys did not develop T2D while 4 out of 13 high risk monkeys (31 %) develop T2D.

This method greatly increased the success rate of establishing T2D monkey models while decreased the time needed compared to traditional methods. Therefore, we developed a new high-efficiency method to establish T2D monkey models by combining the genetic prediction model and high-energy diet, which will greatly contribute to the research on the clinical characteristics, pathogenesis, complications and potential new treatments.

Type 2 diabetes mellitus (T2DM) is associated with chronic hyperglycemia, leading to severe complications, including increased risk of cancer. Protein tyrosine phosphatase non-receptor type 3 (PTPN3) is implicated in both T2DM and cancer progression. The aim of the present study was to investigate the role of PTPN3 genetic polymorphisms and expression in patients with T2DM, as well as to examine changes in body weight, blood glucose levels, and hepatic PTPN3 expression in db/db obese mice in comparison with control mice at 4, 16 and 32 weeks. A total of 469 patients with T2DM and 1,699 healthy control subjects were analyzed for PTPN3 genetic polymorphisms using blood samples. Additionally, the body weight of genetically diabetic obese db/db mice and genotype control mice, and their fasting blood glucose and PTPN3 mRNA and protein expression levels were assessed in the respective liver tissues at different stages of T2DM progression (4, 16 and 32 weeks) using reverse transcription-quantitative PCR, western blot and immunohistochemistry staining analyses. The allele C frequency of rs75235286 (82.1 vs. 79.1%, P=0.044) and allele G frequency of rs17202063 (82.8% vs. 79.5%, P=0.027) in PTPN3 SNPs differed significantly between T2DM patients and healthy controls. Additionally, the body weight of db/db mice and blood glucose levels were significantly increased from the 4th to 32nd week compared with control mice. Furthermore, db/db mice exhibited significantly elevated hepatic mRNA and protein expression levels of PTPN3 compared with control mice, especially at the 32nd week. Taken together, these findings suggested that an increased level of PTPN3 expression may serve a role in the progression of diabetic complications in patients with T2DM, highlighting the importance of further investigation into PTPN3 as a potential therapeutic target to decrease cancer risk and enhance treatment outcomes in T2DM.

This research investigated how physical activity (PA) might impact the expression of several microRNAs, specifically miR-126, miR-146a, miR-34a, miR-124a, miR-155, and miR-221, in the blood of elderly individuals with type 2 diabetes (T2D). Additionally, the study examined the relationship between these microRNAs and markers of vascular endothelial dysfunction, including vascular endothelial growth factor (VEGF), apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB), to assess their potential in the prevention, early detection, and treatment of diabetes.

This correlational observational study involved 100 male participants, aged between 18 and 65 years, all of whom had been living with type 2 diabetes (T2D) for over six years. The participants were divided into three groups: inactive, moderate, and active, depending on their level of physical activity (PA). Real-time PCR and immunoassays were employed to measure the expression of selected miRNAs, as well as VEGF, apoA-I, apoB, and diabetic management indicators. PA levels were determined using ACTi graph GT1M accelerometer (model WAM 7164; Fort Walton Beach, FL) and energy expenditure was measured in the form of metabolic equivalent (MET) by indirect calorimetry method.

The expression levels of miR-146a, miR-34a, and miR-124a were significantly higher in patients with higher physical activity, while no such increase was observed for the other miRNAs in less active participants. Additionally, PA-active individuals showed a more pronounced decrease in fasting blood sugar (FBS), insulin resistance (IR), fasting insulin (FINS), HOMA-IR, HbA1c (%), and levels of VEGF, apoAI, apoB, and the apoB/apoA-I ratio. The alteration in miRNA expression was positively associated with physical activity, VEGF, apoAI, apoB, the apoB/apoA-I ratio, and diabetes-related metrics, while being inversely related to BMI.

In diabetic patients with higher physical activity levels, circulating miR-146a, miR-34a, and miR-124a showed elevated expression, accompanied by a notable decrease in vascular biomarkers, including apoAI, apoB, and the apoB/apoA-I ratio. The findings revealed a strong correlation between these vascular biomarkers and the physiological responses of miR-146a, miR-34a, and miR-124a, though larger studies are required to validate these results further.

Not applicable.

The American Heart Association (AHA), in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, nutrition, sleep, and obesity) and health factors (cholesterol, blood pressure, glucose control, and metabolic syndrome) that contribute to cardiovascular health. The AHA Heart Disease and Stroke Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, brain health, complications of pregnancy, kidney disease, congenital heart disease, rhythm disorders, sudden cardiac arrest, subclinical atherosclerosis, coronary heart disease, cardiomyopathy, heart failure, valvular disease, venous thromboembolism, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).

The AHA, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States and globally to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2025 AHA Statistical Update is the product of a full year's worth of effort in 2024 by dedicated volunteer clinicians and scientists, committed government professionals, and AHA staff members. This year's edition includes a continued focus on health equity across several key domains and enhanced global data that reflect improved methods and incorporation of ≈3000 new data sources since last year's Statistical Update.

Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.

The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

The demarcation between monogenic and polygenic type 2 diabetes (T2D) is less distinct than previously believed. Notably, recent research has highlighted a new entity, that we suggest calling oligogenic forms of T2D, serving as a genetic link between these two forms. In this opinion article, we have reviewed scientific advances that suggest categorizing genes involved in oligogenic T2D. Research focused on polygenic T2D has faced challenges in deepening our comprehension of the pathophysiology of T2D due to the inability to directly establish causal links between a signal and the molecular mechanisms underlying the disease. However, the study of oligogenic forms of T2D has illuminated distinct causal connections between genes and disease risk, thereby indicating potential new drug targets.

Diabetes is a leading cause of global mortality and disability, and its economic burden is substantial. This Review focuses on type 2 diabetes, which makes up 90-95% of all diabetes cases. Type 2 diabetes involves a progressive loss of insulin secretion often alongside insulin resistance and metabolic syndrome. Although obesity and a sedentary lifestyle are considerable contributors, research over the last 25 years has shown that type 2 diabetes develops on a predisposing genetic background, with family and twin studies indicating considerable heritability (ie, 31-72%). This Review explores type 2 diabetes from a genetic perspective, highlighting insights into its pathophysiology and the implications for precision medicine. More specifically, the traditional understanding of type 2 diabetes genetics has focused on a dichotomy between monogenic and polygenic forms. However, emerging evidence suggests a continuum that includes monogenic, oligogenic, and polygenic contributions, revealing their complementary roles in type 2 diabetes pathophysiology. Recent genetic studies provide deeper insights into disease mechanisms and pave the way for precision medicine approaches that could transform type 2 diabetes management. Additionally, the effect of environmental factors on type 2 diabetes, particularly from epigenetic modifications, adds another layer of complexity to understanding and addressing this multifaceted disease.

Background and Aims: Older adults are particularly susceptible to type 2 diabetes mellitus (T2DM) due to factors such as age-related insulin resistance, decreased physical activity, and deficiency of micronutrients, especially zinc. Studies have suggested that the risk allele of the zinc transporter 8 gene (SLC30A8) single-nucleotide poly-morphism (SNP) rs13266634 may contribute to T2DM susceptibility in addition to the complex protein interactions and alterations in the protein expressions and modifications associated with T2DM. This study was implemented to study the associations between SLC30A8 polymorphism, serum zinc levels, and the profiles of proteins differentially expressed in nondiabetic (n = 116) and prediabetic/diabetic (n = 149) subjects. Methods: SNP genotyping using TaqMan® assay and proteomic analysis by LC-MS/MS were performed in each group. Results: The results showed a higher risk of diabetes in individuals with the risk genotype CC accompanied by a low serum zinc level than in those with other genotypes. Profiles of proteins differentially expressed between the groups were identified and shown to be particularly associated with zinc-related functions, zinc transporter 8, and glucose metabolism. Proteins exclusively expressed in prediabetes/diabetes were assigned to a Reactome pathway related to zinc transporter and insulin processing. Conclusions: Our findings suggest that individuals carrying at least one copy of SLC30A8 rs13266634 accompanied by a low serum zinc level might be susceptible to T2DM, which could be due to alterations in insulin signaling and zinc metabolism. Understanding this relationship deepens our understanding of the genetic and molecular mechanisms underlying T2DM risk, offering potential targets for therapeutic intervention and prevention strategies.

Insulin degrading enzyme (IDE) is a dimeric 110 kDa M16A zinc metalloprotease that degrades amyloidogenic peptides diverse in shape and sequence, including insulin, amylin, and amyloid-β, to prevent toxic amyloid fibril formation. IDE has a hollow catalytic chamber formed by four homologous subdomains organized into two ~55 kDa N- and C- domains (IDE-N and IDE-C, respectively), in which peptides bind, unfold, and are repositioned for proteolysis. IDE is known to transition between a closed state, poised for catalysis, and an open state, able to release cleavage products and bind new substrate. Here, we present five cryoEM structures of the IDE dimer at 3.0-4.1 Å resolution, obtained in the presence of a sub-saturating concentration of insulin. Analysis of the heterogeneity within the particle populations comprising these structures combined with all-atom molecular dynamics (MD) simulations permitted a comprehensive characterization of IDE conformational dynamics. Our analysis identified the structural basis and key residues for these dynamics that were not revealed by IDE static structures. Notably arginine-668 serves as a molecular latch mediating the open-close transition and facilitates key protein motions through charge-swapping interactions at the IDE-N/C interface. Our size-exclusion chromatography-coupled small-angle X-ray scattering and enzymatic assays of an arginine-668 to alanine mutant indicate a profound alteration of conformational dynamics and catalytic activity. Taken together, this work highlights the power of integrating experimental and computational methodologies to understand protein dynamics, offers the molecular basis of unfoldase activity of IDE, and provides a new path forward towards the development of substrate-specific modulators of IDE activity.

Although diabetes is now a global epidemic, China has the highest number of affected people, presenting profound public health and socioeconomic challenges. In China, rapid ecological and lifestyle shifts have dramatically altered diabetes epidemiology and risk factors. In this Review, we summarize the epidemiological trends and the impact of traditional and emerging risk factors on Chinese diabetes prevalence. We also explore recent genetic, metagenomic and metabolomic studies of diabetes in Chinese, highlighting their role in pathogenesis and clinical management. Although heterogeneity across these multidimensional areas poses major analytic challenges in classifying patterns or features, they have also provided an opportunity to increase the accuracy and specificity of diagnosis for personalized treatment and prevention. National strategies and ongoing research are essential for improving diabetes detection, prevention and control, and for personalizing care to alleviate societal impacts and maintain quality of life.

Diabetes Type 1 and Type 2 are widely occurring diseases. In spite of a vast amount of biomedical literature about diabetic processes in general, links to certain biological processes are only becoming evident these days. One such area of biology is the sulfation of small molecules, such as steroid hormones or metabolites from the gastrointestinal tract, as well as larger biomolecules, such as proteins and proteoglycans. Thus, modulating the physicochemical propensities of the different sulfate acceptors, resulting in enhanced solubility, expedited circulatory transit, or enhanced macromolecular interaction. This review lists evidence for the involvement of sulfation pathways in the maintenance of functional pancreatic beta-cell mass and the implications for diabetes, grouped into various classes of sulfated biomolecule. Complex heparan sulfates might play a role in the development and maintenance of beta-cells. The sulfolipids sulfatide and sulfo-cholesterol might contribute to beta-cell health. In beta-cells, there are only very few proteins with confirmed sulfation on some tyrosine residues, with the IRS4 molecule being one of them. Sulfated steroid hormones, such as estradiol-sulfate and vitamin-D-sulfate, may facilitate downstream steroid signaling in beta-cells, following de-sulfation. Indoxyl sulfate is a metabolite from the intestine, that causes kidney damage, contributing to diabetic kidney disease. Finally, from a technological perspective, there is heparan sulfate, heparin, and chondroitin sulfate, that all might be involved in next-generation beta-cell transplantation. Sulfation pathways may play a role in pancreatic beta-cells through multiple mechanisms. A more coherent understanding of sulfation pathways in diabetes will facilitate discussion and guide future research.

Zinc transporter 8 (ZnT8) is highly expressed in pancreatic beta cells, localizes to insulin secretory granules (ISG), and regulates zinc content. ZnT8 gene polymorphisms have revealed a relationship between ZnT8 activity and type 2 diabetes (T2D) risk, however, the role of beta-cell ZnT8 is not well understood. A beta cell specific ZnT8 knockout (ZnT8 BKO) mouse model was investigated. ZnT8 BKO islets showed significantly reduced ZnT8 gene expression and reduced zinc content. Compared to controls, ZnT8 BKO mice displayed significantly elevated plasma insulin levels and improved glucose tolerance following acute insulin resistance induced via S961. Glucose stimulated insulin secretion from isolated ZnT8 BKO pancreatic islets revealed enhanced insulin secretion capacity. The difference in insulin secretion between ZnT8 BKO and control islets was negated upon zinc supplementation, and the inhibitory effect of zinc on insulin secretion was confirmed in human islets. These results indicate that the loss of ZnT8 activity and accompanying reduced cellular zinc are associated with increased insulin secretion capacity. The reduction in secreted insulin content upon zinc supplementation in ZnT8 BKO islets suggests that ISG-released zinc normally tempers insulin secretion.

Although the association between HHEX, IGF2BP2, and FTO polymorphisms and the risk of GDM has been investigated in several studies, the findings have been inconsistent across different populations. The study aimed to investigate the association between genetic polymorphisms and GDM risk in a Chinese population.

502 control volunteers and 500 GDM patients were enrolled. IGF2BP2 rs11705701 and rs4402960, FTO rs9939609, and HHEX rs1111875 and rs5015480 were all genotyped using the SNPscan™ genotyping assay. The independent sample t-test, logistic regression, and chi-square test were used to assess the variations in genotype and allele and their relationships with the risk of GDM. The blood glucose level, gestational week of delivery, and newborn weight were compared using a one-way ANOVA.

After adjusting for confounding factors, the results show that the rs1111875 heterozygous (OR=1.370; 95% CI: 1.040-1.805; P = 0.025) and overdominant (OR=1.373; 95% CI: 1.049-1.796; P = 0. 021) models are significantly associated with an increased risk of GDM, especially for the age ≥ 30 years group: heterozygote (OR=1.646; 95% CI: 1.118-2.423; P=0.012) and overdominant (OR=1.553; 95% CI: 1.064-2.266; P = 0.022) models. In the age ≥ 30 years, the rs5015480 overdominant model (OR=1.595; 95% CI: 1.034-2.459; P = 0.035) and the rs9939609 heterozygote model (OR=1.609; 95% CI: 1.016-2.550; P=0.043), allele (OR=1. 504; 95% CI: 1.006-2.248; P = 0.047), dominant model (OR=1.604; 95% CI: 1.026-2.505; P = 0.038), and overdominant model (OR=1.593; 95% CI: 1.007-2.520; P = 0.047) were associated with a significantly increased risk of GDM; Additionally, people with the TC genotype of rs1111875 had a substantially higher 1-hour blood glucose level than TT genotype (P < 0.05). The results of the meta-analysis showed that the A allele of rs11705701 was associated with an increased risk of diabetes mellitus (P < 0.05).

The study indicates that the TC genotype of rs1111875 is linked to a higher risk of GDM, particularly in women aged 30 years or older. Additionally, rs5015480 and rs9939609 were significantly associated with GDM in the same age group. These SNPs may therefore be more closely linked to GDM in older mothers.

Both zinc transporter 8 (ZnT8) and somatostatin (Sst) play crucial roles in the regulation of insulin and glucagon secretion. However, the interaction between them in controlling glucose metabolism was not well understood. The aim of this study was to explore the interactive effects of a double knockout of Znt8 and Sst on insulin and glucose metabolism in mice.

Co-expression of ZnT8 with hormones secreted from gastrointestinal endocrine cells of mice was determined using immunofluorescence. Male Znt8 knockout (Znt8KO), Sst knockout (SstKO), double knockout for Sst and Znt8 (DKO), and the wild-type (WT) mice were fed a regular chow diet (CD) or a high-fat diet (HFD) at 3 weeks old for 15 weeks. Weights and fasting or fed glucose levels were determined. Glucose and insulin tolerance tests were performed; metabolic-relevant hormone levels including insulin, glucagon, glucagon-like peptide 1, Pyy, and leptin were determined.

ZnT8 is co-expressed with Sst in a subpopulation of endocrine D cells in the gastrointestinal tract. The absence of ZnT8 expression resulted in an increased density of the dense cores in the secretory granules of the D cell. DKO mice had reduced weight compared to WT when maintained on the CD. Compared to Znt8KO and SstKO, DKO mice did not show significant differences in fed or fasting blood glucose level regardless of dietary conditions. However, the CD-fed DKO mice had impaired insulin secretion without alterations in islet morphology or numbers. Moreover, DKO mice displayed diet-induced insulin resistance and disrupted secretion of metabolic-related hormones.

Somatostatin as well as a normal insulin sensitivity are required for normalizing glucose metabolism in Znt8KO mice. ZnT8 may play a role in regulating fat mass and leptin secretion. These findings shed light on the multifaceted nature of Znt8 and Sst interactions, opening new avenues to understand their roles in controlling glucose metabolism and fat mass.

Genome-wide association studies (GWAS) have significantly advanced the identification of genetic susceptibility variants associated with complex diseases. As of 2023, approximately 800 variants predisposing individuals to the risk of type 2 diabetes (T2D) were identified through GWAS, and the majority of studies were predominantly conducted in European populations. Despite the shared nature of the majority of genetic susceptibility loci across diverse ethnic populations, GWAS in non-European populations, including Japanese and East Asian populations, have revealed population-specific T2D loci. Currently, polygenic risk scores (PRSs), encompassing millions of associated variants, can identify individuals with a higher T2D risk than the general population. However, GWAS focusing on microvascular complications of diabetes have identified a limited number of disease-susceptibility loci. Ongoing efforts are crucial to enhance the applicability of PRS for all ethnic groups and unravel the genetic architecture of microvascular complications of diabetes.

Posttransplant diabetes mellitus (PTDM) is a prevalent complication of liver transplantation and is associated with cardiometabolic complications. We studied the consequences of genetic effects of liver donors and recipients on PTDM outcomes, focusing on the diverse genetic pathways related to insulin that play a role in the development of PTDM. One thousand one hundred fifteen liver transplant recipients without a pretransplant diagnosis of type 2 diabetes mellitus (T2D) and their paired donors recruited from 2 transplant centers had polygenic risk scores (PRS) for T2D, insulin secretion, and insulin sensitivity calculated. Among recipients in the highest T2D-PRS quintile, donor T2D-PRS did not contribute significantly to PTDM. However, in recipients with the lowest T2D genetic risk, donor livers with the highest T2D-PRS contributed to the development of PTDM (OR [95% CI] = 3.79 [1.10-13.1], P = .035). Recipient risk was linked to factors associated with insulin secretion (OR [95% CI] = 0.85 [0.74-0.98], P = .02), while donor livers contributed to PTDM via gene pathways involved in insulin sensitivity (OR [95% CI] = 0.86 [0.75-0.99], P = .03). Recipient and donor PRS independently and collectively serve as predictors of PTDM onset. The genetically influenced biological pathways in recipients primarily pertain to insulin secretion, whereas the genetic makeup of donors exerts an influence on insulin sensitivity.

Gene therapy utilizes nucleic acid drugs to treat diseases, encompassing gene supplementation, gene replacement, gene silencing, and gene editing. It represents a distinct therapeutic approach from traditional medications and introduces novel strategies for genetic disorders. Over the past two decades, significant advancements have been made in the field of gene therapy, leading to the approval of various gene therapy drugs. Gene therapy was initially employed for treating genetic diseases and cancers, particularly monogenic conditions classified as orphan diseases due to their low prevalence rates; however, polygenic or complex diseases exhibit higher incidence rates within populations. Extensive research on the etiology of polygenic diseases has unveiled new therapeutic targets that offer fresh opportunities for their treatment. Building upon the progress achieved in gene therapy for monogenic diseases and cancers, extending its application to polygenic or complex diseases would enable targeting a broader range of patient populations. This review aims to discuss the strategies of gene therapy, methods of gene editing (mainly CRISPR-CAS9), and carriers utilized in gene therapy, and highlight the applications of gene therapy in polygenic or complex diseases focused on applications that have either entered clinical stages or are currently undergoing clinical trials.

Type 2 diabetes mellitus (T2DM) is a complex chronic disease characterized by decreased insulin secretion and the development of insulin resistance. Previous genome-wide association studies demonstrated that single-nucleotide polymorphisms (SNPs) present in genes coding for ion channels involved in insulin secretion increase the risk of developing this disease. We determined the association of 16 SNPs found in CACNA1D, KCNQ1, KCNJ11, and CACNA1E genes and the increased probability of developing T2DM. In this work, we performed a case-control study in 301 Mexican adults, including 201 cases with diabetes and 100 controls without diabetes. Our findings indicate a moderate association between T2DM and the C allele, and the C/C genotype of rs312480 within CACNA1D. The CAG haplotype surprisingly showed a protective effect, whereas the CAC and CGG haplotypes have a strong association with T2DM. The C allele and C/C genotype of rs5219 were significantly associated with diabetes. Also, an association was observed between diabetes and the A allele and the A/A genotype of rs3753737 and rs175338 in CACNA1E. The TGG and CGA haplotypes were also found to be significantly associated. The findings of this study indicate that the SNPs examined could serve as a potential diagnostic tool and contribute to the susceptibility of the Mexican population to this disease.

Islet amyloid polypeptide (IAPP) is co-secreted with insulin from pancreatic ß-cells. Its oligomerisation is regarded as disease driving force in type 2 diabetes (T2D) pathology. Up to now, IAPP oligomers have been detected in affected tissues. IAPP oligomer concentrations in blood have not been analysed so far. Using the IAPP single-oligomer-sensitive and monomer-insensitive surface-based fluorescence intensity distribution analysis (sFIDA) technology, levels of IAPP oligomers in blood plasma from healthy controls and people with T2D in different disease stages where determined. Subsequently, the level of IAPP oligomerisation was introduced as the ratio between the IAPP oligomers determined with sFIDA and the total IAPP concentration determined with ELISA. Highest oligomerisation levels were detected in plasma of people with T2D without late complication and without insulin therapy. Their levels stand out significantly from the control group. Healthy controls presented with the lowest oligomerisation levels in plasma. In people with T2D without complications, IAPP oligomerisation levels correlated with disease duration. The results clearly demonstrate that IAPP oligomerisation in insulin-naïve patients correlates with duration of T2D. Although a correlation per se does not identify, which is cause and what is consequence, this result supports the hypothesis that IAPP aggregation is the driving factor of T2D development and progression. The alternative and conventional hypothesis explains development of T2D with increasing insulin resistance causing exhaustion of pancreatic ß-cells due to over-secretion of insulin, and thus IAPP, too, resulting in subsequent IAPP aggregation and fibril deposition in the pancreas. Further experiments and comparative analyses with primary tissues are warranted.

Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes.

A lack of social relationships is increasingly recognized as a type 2 diabetes (T2D) risk. To investigate the underlying mechanism, we used male KK mice, an inbred strain with spontaneous diabetes. Given the association between living alone and T2D risk in humans, we divided the non-diabetic mice into singly housed (KK-SH) and group-housed control mice. Around the onset of diabetes in KK-SH mice, we compared H3K27ac ChIP-Seq with RNA-Seq using pancreatic islets derived from each experimental group, revealing a positive correlation between single-housing-induced changes in H3K27ac and gene expression levels. In particular, single-housing-induced H3K27ac decreases revealed a significant association with islet cell functions and GWAS loci for T2D and related diseases, with significant enrichment of binding motifs for transcription factors representative of human diabetes. Although these H3K27ac regions were preferentially localized to a polymorphic genomic background, SNVs and indels did not cause sequence disruption of enriched transcription factor motifs in most of these elements. These results suggest alternative roles of genetic variants in environment-dependent epigenomic changes and provide insights into the complex mode of disease inheritance.

We have previously identified a parasite-derived peptide, FhHDM-1, that prevented the progression of diabetes in nonobese diabetic (NOD) mice. Disease prevention was mediated by the activation of the PI3K/Akt pathway to promote β-cell survival and metabolism without inducing proliferation. To determine the molecular mechanisms driving the antidiabetogenic effects of FhHDM-1, miRNA:mRNA interactions and in silico predictions of the gene networks were characterised in β-cells, which were exposed to the proinflammatory cytokines that mediate β-cell destruction in Type 1 diabetes (T1D), in the presence and absence of FhHDM-1. The predicted gene targets of miRNAs differentially regulated by FhHDM-1 mapped to the biological pathways that regulate β-cell biology. Six miRNAs were identified as important nodes in the regulation of PI3K/Akt signaling. Additionally, IGF-2 was identified as a miRNA gene target that mediated the beneficial effects of FhHDM-1 on β-cells. The findings provide a putative mechanism by which FhHDM-1 positively impacts β-cells to permanently prevent diabetes. As β-cell death/dysfunction underlies diabetes development, FhHDM-1 opens new therapeutic avenues.

With over 450 genes, solute carriers (SLCs) constitute the largest transporter superfamily responsible for the uptake and efflux of nutrients, metabolites, and xenobiotics in human cells. SLCs are associated with a wide variety of human diseases, including cancer, diabetes, and metabolic and neurological disorders. They represent an important therapeutic target class that remains only partly exploited as therapeutics that target SLCs are scarce. Additionally, many small molecules reported in the literature to target SLCs are poorly characterized. Both features may be due to the difficulty of developing SLC transport assays that fulfill the quality criteria for high-throughput screening. Here, we report one of the main limitations hampering assay development within the RESOLUTE consortium: the lack of a resource providing high-quality information on SLC tool compounds. To address this, we provide a systematic annotation of tool compounds targeting SLCs. We first provide an overview on RESOLUTE assays. Next, we present a list of SLC-targeting compounds collected from the literature and public databases; we found that most data sources lacked specificity data. Finally, we report on experimental tests of 19 selected compounds against a panel of 13 SLCs from seven different families. Except for a few inhibitors, which were active on unrelated SLCs, the tested inhibitors demonstrated high selectivity for their reported targets. To make this knowledge easily accessible to the scientific community, we created an interactive dashboard displaying the collected data in the RESOLUTE web portal (https://re-solute.eu). We anticipate that our open-access resources on assays and compounds will support the development of future drug discovery campaigns for SLCs.

The photoreceptor cilium is vital for maintaining the structure and function of the retina. However, the molecular mechanisms underlying the photoreceptor cilium integrity and retinal homeostasis are largely unknown. Herein, it is shown that kinesin family member 11 (KIF11) localizes at the transition zone (connecting cilium) of the photoreceptor and plays a crucial role in orchestrating the cilium integrity. KIF11 depletion causes malformations of both the photoreceptor ciliary axoneme and membranous discs, resulting in photoreceptor degeneration and the accumulation of drusen-like deposits throughout the retina. Mechanistic studies show that the stability of KIF11 is regulated by an interplay between its UFMylation and ubiquitination; UFMylation of KIF11 at lysine 953 inhibits its ubiquitination by synoviolin 1 and thereby prevents its proteasomal degradation. The lysine 953-to-arginine mutant of KIF11 is more stable than wild-type KIF11 and also more effective in reversing the ciliary and retinal defects induced by KIF11 depletion. These findings identify a critical role for KIF11 UFMylation in the maintenance of photoreceptor cilium integrity and retinal homeostasis.

Zinc is an essential trace element that is involved in many biological processes and in cellular homeostasis. In pancreatic β-cells, zinc is crucial for the synthesis, processing, and secretion of insulin, which plays a key role in glucose homeostasis and which deficiency is the cause of diabetes. The accumulation of zinc in pancreatic cells is regulated by the solute carrier transporter SLC30A8 (or Zinc Transporter 8, ZnT8), which transports zinc from cytoplasm in intracellular vesicles. Allelic variants of SLC30A8 gene have been linked to diabetes. Given the physiological intracellular localization of SLC30A8 in pancreatic β-cells and the ubiquitous endogenous expression of other Zinc transporters in different cell lines that could be used as cellular model for SLC30A8 recombinant over-expression, it is challenging to develop a functional assay to measure SLC30A8 activity. To achieve this goal, we have firstly generated a HEK293 cell line stably overexpressing SLC30A8, where the over-expression favors the partial localization of SLC30A8 on the plasma membrane. Then, we used the combination of this cell model, commercial FluoZin-3 cell permeant zinc dye and live cell imaging approach to follow zinc flux across SLC30A8 over-expressed on plasma membrane, thus developing a novel functional imaging- based assay specific for SLC30A8. Our novel approach can be further explored and optimized, paving the way for future small molecule medium-throughput screening.

High workload-induced cellular stress can cause pancreatic islet β cell death and dysfunction, or β cell failure, a hallmark of type 2 diabetes mellitus. Thus, activation of molecular chaperones and other stress-response genes prevents β cell failure. To this end, we have shown that deletion of the glucose-regulated protein 94 (GRP94) in Pdx1+ pancreatic progenitor cells led to pancreas hypoplasia and reduced β cell mass during pancreas development in mice. Here, we show that GRP94 was involved in β cell adaption and compensation (or failure) in islets from leptin receptor-deficient (db/db) mice in an age-dependent manner. GRP94-deficient cells were more susceptible to cell death induced by various diabetogenic stress conditions. We also identified a new client of GRP94, insulin-like growth factor-1 receptor (IGF-1R), a critical factor for β cell survival and function that may mediate the effect of GRP94 in the pathogenesis of diabetes. This study has identified essential functions of GRP94 in β cell failure related to diabetes.

The molecular pathogenesis of diabetes is multifactorial, involving genetic predisposition and environmental factors that are not yet fully understood. However, pancreatic β-cell failure remains among the primary reasons underlying the progression of type-2 diabetes (T2D) making targeting β-cell dysfunction an attractive pathway for diabetes treatment. To identify genetic contributors to β-cell dysfunction, we investigated single-cell gene expression changes in β-cells from healthy (C57BL/6J) and diabetic (NZO/HlLtJ) mice fed with normal or high-fat, high-sugar diet (HFHS). Our study presents an innovative integration of the causal network perturbation assessment (ssNPA) framework with meta-cell transcriptome analysis to explore the genetic underpinnings of type-2 diabetes (T2D). By generating a reference causal network and in silico perturbation, we identified novel genes implicated in T2D and validated our candidates using the Knockout Mouse Phenotyping (KOMP) Project database.

Type 2 diabetes (T2D) prevalence in adults at a younger age has increased but the disease status may go unnoticed. This study aimed to determine whether the onset age and subsequent diabetic complications can be attributed to the polygenic architecture of T2D in the Taiwan Han population. A total of 9,627 cases with T2D and 85,606 controls from the Taiwan Biobank were enrolled. Three diabetic polygenic risk scores (PRSs), PRS_EAS and PRS_EUR, and a trans-ancestry PRS (PRS_META), calculated using summary statistic from East Asian and European populations. The onset age was identified by linking to the National Taiwan Insurance Research Database, and the incidence of different diabetic complications during follow-up was recorded. PRS_META (7.4%) explained a higher variation for T2D status. And the higher percentile of PRS is also correlated with higher percentage of T2D family history and prediabetes status. More, the PRS was negatively associated with onset age (β = -0.91 yr), and this was more evident among males (β = -1.11 vs. -0.76 for males and females, respectively). The hazard ratio of diabetic retinopathy (DR) and diabetic foot were significantly associated with PRS_EAS and PRS_META, respectively. However, the PRS was not associated with other diabetic complications, including diabetic nephropathy, cardiovascular disease, and hypertension. Our findings indicated that diabetic PRS which combined susceptibility variants from cross-population could be used as a tool for early screening of T2D, especially for high-risk populations, such as individuals with high genetic risk, and may be associated with the risk of complications in subjects with T2D. NEW & NOTEWORTHY Our findings indicated that diabetic polygenic risk score (PRS) which combined susceptibility variants from Asian and European population affect the onset age of type 2 diabetes (T2D) and could be used as a tool for early screening of T2D, especially for individuals with high genetic risk, and may be associated with the risk of diabetic complications among people in Taiwan.

Variants at the SLC30A8 locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be the sole driver of T2D risk at this locus, recent studies have provided evidence for lowered expression of SLC30A8 mRNA in protective allele carriers. In the present study, we examined multiple variants that influence SLC30A8 allele-specific expression. Epigenomic mapping has previously identified an islet-selective enhancer cluster at the SLC30A8 locus, hosting multiple T2D risk and cASE associations, which is spatially associated with the SLC30A8 promoter and additional neighboring genes. Here, we show that deletion of variant-bearing enhancer regions using CRISPR-Cas9 in human-derived EndoC-βH3 cells lowers the expression of SLC30A8 and several neighboring genes and improves glucose-stimulated insulin secretion. While downregulation of SLC30A8 had no effect on beta cell survival, loss of UTP23, RAD21, or MED30 markedly reduced cell viability. Although eQTL or cASE analyses in human islets did not support the association between these additional genes and diabetes risk, the transcriptional regulator JQ1 lowered the expression of multiple genes at the SLC30A8 locus and enhanced stimulated insulin secretion.

In Māori and Pacific adults, the CREBRF rs373863828 minor (A) allele is associated with increased body mass index (BMI) but reduced incidence of type-2 and gestational diabetes mellitus. In this prospective cohort study of Māori and Pacific infants, nested within a nutritional intervention trial for pregnant women with obesity and without pregestational diabetes, we investigated whether the rs373863828 A allele is associated with differences in growth and body composition from birth to 12-18 months' corrected age. Infants with and without the variant allele were compared using generalised linear models adjusted for potential confounding by gestation length, sex, ethnicity and parity, and in a secondary analysis, additionally adjusted for gestational diabetes. Carriage of the rs373863828 A allele was not associated with altered growth and body composition from birth to 6 months. At 12-18 months, infants with the rs373863828 A allele had lower whole-body fat mass [FM 1.4 (0.7) vs. 1.7 (0.7) kg, aMD -0.4, 95% CI -0.7, 0.0, P = 0.05; FM index 2.2 (1.1) vs. 2.6 (1.0) kg/m2 aMD -0.6, 95% CI -1.2,0.0, P = 0.04]. However, this association was not significant after adjustment for gestational diabetes, suggesting that it may be mediated, at least in part, by the beneficial effect of CREBRF rs373863828 A allele on maternal glycemic status.