Abstract Aims/hypothesis The aim of this work was to investigate the association between macronutrient intakes and continuous glucose monitoring (CGM) metrics in individuals with type 1 diabetes. ...Methods In 470 individuals with type 1 diabetes of the GUTDM1 cohort (65% female, median age 40 IQR 28–53 years, median diabetes duration 15 IQR 6–29 years), we used logistic regression to establish associations between macronutrient intakes and the CGM metrics time in range (TIR, time spent between 3.9–10.0 mmol/l blood glucose, optimally set at ≥70%) and time below range (TBR, <3.9 mmol/l blood glucose, optimally set at <4%). ORs were expressed per 1 SD intake of nutrient and were adjusted for other macronutrient intakes, age, sex, socioeconomic status, BMI, duration of type 1 diabetes, pump use, insulin dose and alcohol intake. Results The median (IQR) TIR was 67 (51–80)% and TBR was 2 (1–4)%; the mean ± SD energy intake was 6879±2001 kJ, fat intake 75±31 g, carbohydrate intake 162±63 g, fibre intake 20±9 g and protein intake 70±24 g. A higher fibre intake and a lower carbohydrate intake were associated with higher odds of having a TIR≥70% (OR 95% CI 1.64 1.22, 2.24 and 0.67 0.51, 0.87, respectively), whereas solely a higher carbohydrate intake was associated with TBR<4% (OR 1.34 95% CI 1.02, 1.78). Conclusions/interpretation A higher fibre intake is independently associated with a higher TIR. A higher carbohydrate intake is associated with less time spent in hypoglycaemia, a lower TIR and a higher time above range. These findings warrant confirmatory (interventional) investigations and may impact current nutritional guidelines for type 1 diabetes. Graphical Abstract
A recently published study by Bell et al. shows altered immunotolerance in people with type 1 diabetes by dietary supplementation of modified resistant starch fibre.
Abstract
The nucleotide-binding, leucine-rich-repeat-containing protein, NLRX1 is recognized as a host factor which promotes HIV-1 infection of myeloid cells by suppressing HIV-1 reverse transcribed ...DNA induced and STING-mediated innate immune response. However, the function of NLRX1 in HIV-1 infection of CD4 T cells, the major cells responsible for HIV-1 replication in vivo, is still unrevealed. Here we found NLRX1 still acted as a host factor required for HIV-1 infection of the human T cell line, primary CD4 T cells, and CD4 T cell-reconstituted humanized mice through a mechanism involved in cell intrinsic pathways but not innate immune cytokines. In the perspective of virology, we found NLRX1 facilitated both of the integration of HIV-1 cDNA and HIV-1 LTR-mediated viral gene transcription. By using SILAC-based quantitative proteomics, we characterized that HIV-1 infection-induced expression of genes involved in the electron transport chain (ETC) of mitochondria through an NLRX1 dependent mechanism. Consistent with the proteomics data, HIV-1 infection led to increased oxidative phosphorylation in Jurkat T cell line but not in the counterpart containing shRNAs against NLRX1. In addition, inhibition of oxidative phosphorylation by mitochondrial complex I inhibitors suppressed HIV-1 infection in Jurkat cells, while forcing expression of genes involved in ETC rescued the deficiency of HIV-1 replication in NLRX1-deficient cells. Importantly, treating humanized mice with FDA-approved drug, metformin which targets mitochondrial complex I, significantly reduced HIV-1 viral load. This study demonstrated the potential of targeting NLRX1 and applying metformin in suppressing HIV-1 replication in patients.
Abstract Aims/hypothesis Use of genetic risk scores (GRS) may help to distinguish between type 1 diabetes and type 2 diabetes, but less is known about whether GRS are associated with disease severity ...or progression after diagnosis. Therefore, we tested whether GRS are associated with residual beta cell function and glycaemic control in individuals with type 1 diabetes. Methods Immunochip arrays and TOPMed were used to genotype a cross-sectional cohort ( n =479, age 41.7 ± 14.9 years, duration of diabetes 16.0 years IQR 6.0–29.0, HbA 1c 55.6 ± 12.2 mmol/mol). Several GRS, which were originally developed to assess genetic risk of type 1 diabetes (GRS-1, GRS-2) and type 2 diabetes (GRS-T2D), were calculated. GRS-C1 and GRS-C2 were based on SNPs that have previously been shown to be associated with residual beta cell function. Regression models were used to investigate the association between GRS and residual beta cell function, assessed using the urinary C-peptide/creatinine ratio, and the association between GRS and continuous glucose monitor metrics. Results Higher GRS-1 and higher GRS-2 both showed a significant association with undetectable UCPCR (OR 0.78; 95% CI 0.69, 0.89 and OR 0.84: 95% CI 0.75, 0.93, respectively), which were attenuated after correction for sex and age of onset (GRS-2) and disease duration (GRS-1). Higher GRS-C2 was associated with detectable urinary C-peptide/creatinine ratio (≥0.01 nmol/mmol) after correction for sex and age of onset (OR 6.95; 95% CI 1.19, 40.75). A higher GRS-T2D was associated with less time below range (TBR) (OR for TBR<4% 1.41; 95% CI 1.01 to 1.96) and lower glucose coefficient of variance (β −1.53; 95% CI −2.76, −0.29). Conclusions/interpretation Diabetes-related GRS are associated with residual beta cell function in individuals with type 1 diabetes. These findings suggest some genetic contribution to preservation of beta cell function. Graphical Abstract
Introduction: A significant proportion of individuals with type 1 diabetes (T1D) have long-term preservation of beta-cell function. Residual beta-cell function (RBCF) is associated with fewer ...long-term complications and hypoglycemic events. Yet, little is known about the influence of RBCF on daily glycemic control. Therefore, we investigated the associations between RBCF and daily markers of glycemic control in individuals with T1D.
Methods: In this cross-sectional study 500 individuals with T1D were included (41.0 ±14years), 64% female, HbA1c 55.6 ±12mmol/mol, median T1D duration 14 years IQR: 6-29years. As a validated marker of RBCF, postprandial urinary C-peptide/creatinine ratios (UCPCR) were measured. Time in euglycemic range (TIR) (3.9-10mmol/L) and hypoglycemic range (TUR) (<3.9-10mmol/L) were monitored 14 days prior to the study visit, with a continuous glucose monitoring device. Spearman correlations were calculated in Rstudio.
Results: The median UCPCR was 0.03 (IQR: 0.00-0.88) nmol/mmol and strongly correlated with duration of T1D (r = -0.651, p < 0.001). Higher UCPCR correlated with longer TIR (r = 0.330, p < 0.001), lower mean glucose levels (r =-0.318, p=0.005) and shorter TUR (r= -0.237, p <0.001) and lower glucose variation (-0.356, p <0.001). In line, higher UCPCR associated with lower HbA1c levels (r= -0.183, p<0.001) and less 24-hour insulin use (r = -0.183, p = <0.001). The associations remained significant in linear regression models when adjusted for sex, age, plasma glucose and duration of diabetes.
Conclusion: UCPCR correlates with more time in range, shorter time under range, and lower HbA1c levels in individuals with T1D. Beneficial effects of beta-cell preservation in T1D may therefore be attributable to less intermittent glucotoxicity and hypoglycaemic episodes.
Disclosure
C.Fuhri snethage: None. M.Nieuwdorp: Advisory Panel; caelus health. N.Hanssen: Consultant; Novo Nordisk, Research Support; Novo Nordisk. T.J.Mcdonald: None. E.Rampanelli: None. P.De groen: None. A.W.M.Schimmel: None. D.Van raalte: Consultant; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc., Research Support; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc. C.B.Brouwer: None. R.A.Oram: Consultant; Janssen Research & Development, LLC, Research Support; Randox R & D. B.O.Roep: None.
Funding
DNF DON Grant 2020 (2020.10.002)
Previous studies have reported gut microbiome alterations in Hashimoto's autoimmune thyroiditis (HT) patients. Yet, it is unknown whether an aberrant microbiome is present before clinical disease ...onset in participants susceptible to HT or whether it reflects the effects of the disease itself. In this study, we report for the first time a comprehensive characterization of the taxonomic and functional profiles of the gut microbiota in euthyroid seropositive and seronegative participants. Our primary goal was to determine taxonomic and functional signatures of the intestinal microbiota associated with serum thyroid peroxidase antibodies (TPOAb). A secondary aim was to determine whether different ethnicities warrant distinct reference intervals for accurate interpretation of serum thyroid biomarkers.
In this cross-sectional study, euthyroid participants with (
= 159) and without (
= 1309) TPOAb were selected from the multiethnic (European Dutch, Moroccan, and Turkish) HEalthy Life In an Urban Setting (HELIUS) cohort. Fecal microbiota composition was profiled using 16S rRNA sequencing. Differences between the groups were analyzed based on the overall composition (alpha and beta diversity), as well as differential abundance (DA) of microbial taxa and functional pathways using multiple DA tools.
Overall composition showed a substantial overlap between the two groups (
> 0.05 for alpha-diversity;
= 0.39 for beta-diversity), indicating that TPOAb-seropositivity does not significantly differentiate gut microbiota composition and diversity. Interestingly, TPOAb status accounted for only a minor fraction (0.07%) of microbiome variance (
= 0.545). Further exploration of taxonomic differences identified 138 taxa nominally associated with TPOAb status. Among these, 13 taxa consistently demonstrated nominal significance across three additional DA methods, alongside notable associations within various functional pathways. Furthermore, we showed that ethnicity-specific reference intervals for serum thyroid biomarkers are not required, as no significant disparities in serum thyroid markers were found among the three ethnic groups residing in an iodine-replete area (
> 0.05 for thyrotropin, free thyroxine, and TPOAb).
These findings suggest that there is no robust difference in gut microbiome between individuals with or without TPOAb in terms of alpha and beta-diversity. Nonetheless, several taxa were identified with nominal significance related to TPOAb presence. Further research is required to determine whether these changes indeed imply a higher risk of overt HT.
Aims/hypothesis
The general population is ageing, involving an enhanced incidence of chronic diseases such as type 2 diabetes. With ageing, DNA methylation of
FHL2
increases, as well as expression of ...the four and a half LIM domains 2 (FHL2) protein in human pancreatic islets. We hypothesised that FHL2 is actively involved in glucose metabolism.
Methods
Publicly available microarray datasets from human pancreatic islets were analysed for FHL2 expression. In FHL2-deficient mice, we studied glucose clearance and insulin secretion. Gene expression analysis and glucose-stimulated insulin secretion (GSIS) were determined in isolated murine FHL2-deficient islets to evaluate insulin-secretory capacity. Moreover, knockdown and overexpression of FHL2 were accomplished in MIN6 cells to delineate the underlying mechanism of FHL2 function.
Results
Transcriptomics of human pancreatic islets revealed that individuals with elevated levels of HbA
1c
displayed increased FHL2 expression, which correlated negatively with insulin secretion pathways. In line with this observation, FHL2-deficient mice cleared glucose more efficiently than wild-type littermates through increased plasma insulin levels. Insulin sensitivity was comparable between these genotypes. Interestingly, pancreatic islets isolated from FHL2-deficient mice secreted more insulin in GSIS assays than wild-type mouse islets even though insulin content and islet size was similar. To support this observation, we demonstrated increased expression of the transcription factor crucial in insulin secretion, MAF BZIP transcription factor A (MafA), higher expression of GLUT2 and reduced expression of the adverse factor c-Jun in FHL2-deficient islets. The underlying mechanism of FHL2 was further delineated in MIN6 cells. FHL2-knockdown led to enhanced activation of forkhead box protein O1 (FOXO1) and its downstream genes such as
Mafa
and
Pdx1
(encoding pancreatic and duodenal homeobox 1), as well as increased glucose uptake. On the other hand, FHL2 overexpression in MIN6 cells blocked GSIS, increased the formation of reactive oxygen species and increased c-Jun activity.
Conclusions/interpretation
Our data demonstrate that FHL2 deficiency improves insulin secretion from beta cells and improves glucose tolerance in mice. Given that FHL2 expression in humans increases with age and that high expression levels of FHL2 are associated with beta cell dysfunction, we propose that enhanced FHL2 expression in elderly individuals contributes to glucose intolerance and the development of type 2 diabetes.
Data availability
The human islet microarray datasets used are publicly available and can be found on
https://www.ncbi.nlm.nih.gov/geo/
.
Graphical abstract
The prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in type 1 diabetes remain unclear. Therefore, we investigated the prevalence and severity of MASLD in ...type 1 diabetes and assessed which clinical features are most important in predicting MASLD severity.
A total of 453 individuals with type 1 diabetes (41.6 ± 15.0 years, 64% female, body mass index BMI 25.4 ± 4.2 kg/m2, and HbA1c 55.6 ± 12 mmol/mol) underwent vibration-controlled transient elastography (VCTE), with a controlled attenuation parameter (CAP) score for steatosis (≥280.0 dB/m) and a liver stiffness measurement (LMS) for fibrosis (≥8.0 kPa). A machine learning Extra-Trees classification model was performed to assess the predictive power of the clinical features associated with type 1 diabetes with respect to steatosis and fibrosis.
The prevalence of hepatic steatosis and fibrosis was 9.5% (95% CI, 6.8-12.2) and 3.5% (95% CI, 1.8-5.2). Higher LMS was associated with a longer duration of type 1 diabetes (median 30.5 IQR 18.0-39.3 years vs 15.0 IQR 6.0-27.0 years), and individuals were older, had a higher BMI (mean 27.8 ± 5.2 vs 25.3 ± 4.1 kg/m2), and a higher CAP score (mean 211.4 ± 51.7 dB/m vs 241.4 ± 75.6 dB/m). The most important predictive features of fibrosis were duration of type 1 diabetes, age, and systolic blood pressure, with a mean ± SD area under the curve of 0.73 ± 0.03.
Individuals with type 1 diabetes and high blood pressure, older age, higher BMI, and longer duration of disease could be considered at high-risk for developing MASLD.
Type 1 diabetes (T1D) is an auto-immune disease that destructs insulin-producing pancreatic beta-cells within the islets of Langerhans. The incidence of T1D has tripled over the last decades, while ...the pathophysiology of the disease is still largely unknown. Currently, there is no cure for T1D. The only treatment option consists of blood-glucose regulation with insulin injections and intensive monitoring of blood glucose levels. In recent years, perturbations in the ecosystem of the gut microbiome also referred to as dysbiosis, have gained interest as a possible contributing factor in the development of T1D. Changes in the microbiome seem to occur before the onset of T1D associated auto-antibodies. Furthermore, rodent studies demonstrate that administering antibiotics at a young age may accelerate the onset of T1D. This review provides an overview of the research performed on the epidemiology, pathophysiology, interventions, and possible treatment options in the field of the gut microbiome and T1D.
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