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Journal of Molecular Endocrinology Jun 2024Pregnancy requires metabolic adaptations in order to meet support fetal growth with nutrient availability. In this study, the influence of pregnancy on metabolically...
Pregnancy requires metabolic adaptations in order to meet support fetal growth with nutrient availability. In this study, the influence of pregnancy on metabolically active organs (adipose tissues in particular) was investigated. Our results showed that maternal weight and adipose mass presented dynamic remodeling in the periparturient mice. Meanwhile, pregnancy mice displayed obvious glucose intolerance and insulin resistance in late pregnancy as compared to non-pregnancy, which were partially reversed at parturition. Further analysis revealed that different fat depots exhibited site-specific adaptions of morphology and functionality as pregnancy advanced. Brown and inguinal white adipose tissue (BAT and IngWAT) exhibited obviously decreased thermogenic activity; by contrast, gonadal white adipose tissue (GonWAT) displayed remarkably increased lipid mobilization. Notably, we found that mammary gland differentiation was enhanced in IngWAT, followed by BAT, but not in GonWAT. These result indicated that brown and white adipose tissues might synergistically play a crucial role in maintaining the maxicum of energy supply for mother and fetus, which facilitates the mammary duct luminal epithelium development as well as the growth and development of fetus. Accompanied with adipose adaptation, however, our results revealed that the liver and pancreas also displayed significant metabolic adaptability, which together tended to trigger the risk of maternal metabolic diseases. Importantly, pregnancy-dependent obesity in our mice model resembled the disturbed metabolic phenotypes of pregnant women such as hyperglyceridemia and hypercholesterolemia. Our findings in this study could provide valuable clues for better understanding the underlying mechanisms of metabolic maladaptation, and facilitate the development of the prevention and treatment of metabolic diseases.
PubMed: 38941267
DOI: 10.1530/JME-24-0012 -
Archives of Animal Nutrition Jun 2024Dietary fibre is mainly classified according to its chemical characteristics but structure and particle size of fibre-rich feedstuff can also be decisive for digestion...
Dietary fibre is mainly classified according to its chemical characteristics but structure and particle size of fibre-rich feedstuff can also be decisive for digestion and performance. So far, only few studies investigated this in pigs. This experiment aimed to compare coarse and finely ground dried hemp plants and apple pomace regarding performance and ileal and total tract nutrient digestibility of growing pigs. Coarse or finely ground apple pomace or dried hemp plants were added to the diet of 56 nine weeks old growing pigs (DanBred x Duroc), housed in flat decks with each 2 animals. The growing pigs received the experimental diets for three weeks while performance was recorded. Eight pigs per group were sacrificed and digesta and organ tissue sampled. The stomach health was evaluated by visually scoring of the mucosa integrity. Apparent ileal (AID) and total tract digestibility (ATTD) were calculated using titanium dioxide as marker. Statistical analyses were performed using two-way ANOVA ( < 0.05). The highest feed intake (fibre particle size, = 0.018) and bodyweight gain (fibre particle size, = 0.018; fibre source x particle size interaction, = 0.040), was observed in animals fed finely ground apple pomace, while the feed conversion ratio was 8-12% lower in pigs fed finely ground fibre sources ( = 0.012). No differences in stomach mucosa integrity were detected between the groups. The relative pancreas ( = 0.045), stomach ( < 0.001), and jejunum ( = 0.010) weights were higher in animals fed diets containing apple pomace. In contrast, the relative liver, caecum and colon weights were not affected by fibre source or particle size. The AID of protein and amino acids was not affected, while ATTD was increased by fibre source (hemp vs. apple pomace) reducing faecal nitrogen excretion. The AID of calcium was increased when diets contained apple pomace ( < 0.001), while zinc AID and ATTD were enhanced when diets contained dried hemp ( = 0.016; = 0.016, respectively). Our results suggest that the structure as well as the chemical characteristics should be considered in a future fibre evaluation system in pigs.
PubMed: 38941242
DOI: 10.1080/1745039X.2024.2368284 -
Magyar Sebeszet Jun 2024Bevezetés: A posztoperatív pancreasfistula mind proximalis, mind distalis pancreatectomia után a legjelentősebb sebészi szövődménynek számít. A...
Bevezetés: A posztoperatív pancreasfistula mind proximalis, mind distalis pancreatectomia után a legjelentősebb sebészi szövődménynek számít. A szakirodalomban nincs egyértelműen ajánlott, megbízható módszer ezen probléma kiküszöbölésére, emiatt történnek újítások szerte a világon. Jelen közleményünkben a technikai innovációinkról számolunk be. Anyag és módszerek: 2013. január 1-jétől 2023. november 30-ig terjedő időszakban 205 Whipple-műtétet végeztünk nyitottan, mely során a pancreatojejunalis anastomosist az általunk módosított dohányzacskó-öltéses módszerrel készítettük el. 2019. január 1. és 2023. november 30. között pedig 30 betegnél történt nyitott distalis pancreatectomia, amikor a pancreascsonkot az általunk kifejlesztett technikával, szabad rectus fascia-peritoneum grafttal fedtük, majd azt cirkuláris öltéssel rögzítettük. Közleményünkben ezen két módszerrel elért eredményeket ismertetjük. Eredmények: a demográfiai adatok megfeleltek a betegségnél szokásosnak. A posztoperatív ápolási idő és a transzfúzió igény terén észlelt különbségek tükrözték a kétféle beavatkozás eltérő invazivitását. A releváns pancreasfistula kialakulási rátája kedvező képet mutatott, Whipple-műtét után 7,3% volt, míg distalis pancreatectomát követően nem fejlődött ki. A reoperációs és a halálozási arányok megfeleltek az elvártaknak és korreláltak a műtétek kiterjedtségével. Következtetés: pancreas resectiók utáni komplikációk csökkentésére tett törekvéseink során a módosított dohányzacskó-öltéses pancreatojejunostomia és a pancreascsonk fedésére kidolgozott módszerünk egyaránt kedvező eredményekkel járt.
Topics: Humans; Pancreatic Fistula; Postoperative Complications; Female; Male; Pancreatectomy; Middle Aged; Pancreaticojejunostomy; Aged; Pancreaticoduodenectomy; Treatment Outcome; Adult
PubMed: 38941151
DOI: 10.1556/1046.2024.20002 -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2024The purpose of the present study was to investigate the modeling time of type 2 diabetes mellitus (T2DM) mouse model induced by high fat diet (HFD) alone and the effects...
The purpose of the present study was to investigate the modeling time of type 2 diabetes mellitus (T2DM) mouse model induced by high fat diet (HFD) alone and the effects of HFD on the pathology and function of organs related to glucose and lipid metabolism. C57BL/6 mice were fed with normal diet (NC group) or HFD (HFD group). The time of successful T2DM modeling was evaluated by measuring body weight, fasting blood glucose and glucose tolerance at time points of 0, 4, 8, 12, 16 and 20 weeks. The functional and pathological changes of glucose and lipid metabolism related organs were evaluated by detecting insulin tolerance, plasma lipid levels, vascular function, as well as HE staining of pancreas and liver. The results showed that compared with the NC group, the HFD group had significantly increased body weight after 8 weeks of HFD. After 16 weeks of HFD, the HFD group exhibited impaired fasting glucose tolerance. After 20 weeks of HFD, the HFD group mice reached diabetic state, showing impaired glucose tolerance and insulin resistance, islet volume reduction and vacuolar degeneration; Large number of lipid droplets appeared in liver cells, and the level of AMPK phosphorylation in liver tissue was significantly increased in the HFD groups, compared with the NC group; There was endothelial dependent diastolic dysfunction in the thoracic aorta of the HFD group; Compared with the NC group, the HFD group mice showed a significant increase in urinary protein levels. These results suggest that T2DM mouse model can be successfully established by HFD induction alone for 20 weeks. The model is characterized by insulin resistance, fatty liver, hyperlipidemia, vascular dysfunction, renal dysfunction and pathological changes of islet and liver cells, which are similar to those of T2DM patients. Therefore it can be used as an ideal animal model for T2DM research.
Topics: Animals; Diabetes Mellitus, Type 2; Mice; Diet, High-Fat; Mice, Inbred C57BL; Male; Disease Models, Animal; Insulin Resistance; Lipid Metabolism; Diabetes Mellitus, Experimental; Liver
PubMed: 38939933
DOI: No ID Found -
Journal of Medical Economics Jun 2024AimsWe aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm)...
AimsWe aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm) treatment on people with CF, caregivers, and healthcare systems.Material and MethodsThis retrospective study used linked real-world data from Swedish national population-based registries and the Swedish CF Quality Registry to assess clinical, economic, and societal burden and CFTR impact in CF. Records from people with CF and a ten-fold control population without CF matched by sex, birth year, and location were compared during 2019. Outcomes for a subset aged >6 years initiating lumacaftor/ivacaftor (LUM/IVA) in 2018 were compared 12 months pre- and post-treatment initiation.ResultsPeople with CF (n = 743) had >10 times more inpatient and outpatient specialist visits annually vs controls (n = 7406). Those aged >18 had an additional 77·7 (95% CI: 70·3, 85·1) days of work absence, at a societal cost of €11,563 (95% CI: 10,463, 12,662), while caregivers of those aged <18 missed an additional 6.1 (5.0, 7.2) workdays. With LUM/IVA treatment, people with CF (n = 100) had significantly increased lung function (mean change in ppFEV [3·8 points; 95% CI: 1·1, 6·6]), on average 0·5 (95% CI: -0·8, -0·2) fewer pulmonary exacerbations and 45·2 (95% CI: 13·3, 77·2) fewer days of antibiotics. Days of work lost by caregivers of people with CF aged <18 decreased by 5·4 days (95% CI: 2·9, 7·9).ConclusionCF is associated with a high clinical economic and societal burden in Sweden. Improvements in clinical status observed in people with CF treated with LUM/IVA were reflected in reduced caregiver and societal burden.
PubMed: 38939921
DOI: 10.1080/13696998.2024.2373000 -
Molecular Therapy. Nucleic Acids Jun 2024Small interfering RNAs (siRNAs) are revolutionizing the treatment of liver-associated indications. Yet, robust delivery to extrahepatic tissues remains a challenge....
Small interfering RNAs (siRNAs) are revolutionizing the treatment of liver-associated indications. Yet, robust delivery to extrahepatic tissues remains a challenge. Conjugating lipids (e.g., docosanoic acid [DCA]) to siRNA supports extrahepatic delivery, but tissue accumulation remains lower than that achieved in liver by approved siRNA therapeutics. Early evidence suggests that functionalizing DCA with a head group (e.g., phosphatidylcholine [PC]) may enhance delivery to certain tissues. Here, we report the first systematic evaluation of the effect of PC head group chemistry on the extrahepatic distribution of DCA-conjugated siRNAs. We show that functionalizing DCA with a PC head group enhances siRNA accumulation in heart, muscle, lung, pancreas, duodenum, urinary bladder, and fat. Varying the size of the linker between the phosphate and choline moiety of the PC head group altered the extrahepatic accumulation of siRNA, with the optimal linker length being different for different tissues. Increasing PC head group valency also improved extrahepatic accumulation in a tissue-specific manner. This study demonstrates the structural impact of the PC moiety on the biodistribution of lipid-conjugated siRNA and introduces multiple novel PC variants for the chemical optimization of DCA-conjugated siRNA. These chemical variants can be used in the context of other lipids to increase the repertoire of conjugates for the extrahepatic distribution of siRNAs.
PubMed: 38938759
DOI: 10.1016/j.omtn.2024.102230 -
Frontiers in Endocrinology 2024Insulin resistance (IR) and beta cell dysfunction are the major drivers of type 2 diabetes (T2D). Genome-Wide Association Studies (GWAS) on IR have been predominantly...
Insulin resistance (IR) and beta cell dysfunction are the major drivers of type 2 diabetes (T2D). Genome-Wide Association Studies (GWAS) on IR have been predominantly conducted in European populations, while Middle Eastern populations remain largely underrepresented. We conducted a GWAS on the indices of IR (HOMA2-IR) and beta cell function (HOMA2-%B) in 6,217 non-diabetic individuals from the Qatar Biobank (QBB; Discovery cohort; n = 2170, Replication cohort; n = 4047) with and without body mass index (BMI) adjustment. We also developed polygenic scores (PGS) for HOMA2-IR and compared their performance with a previously derived PGS for HOMA-IR (PGS003470). We replicated 11 loci that have been previously associated with HOMA-IR and 24 loci that have been associated with HOMA-%B, at nominal statistical significance. We also identified a novel locus associated with beta cell function near gene, tagged by rs61552983 ( = 4.38 × 10). Moreover, our best performing PGS (Q-PGS4; Adj R = 0.233 ± 0.014; = 1.55 x 10) performed better than PGS003470 (Adj R = 0.194 ± 0.014; = 5.45 x 10) in predicting HOMA2-IR in our dataset. This is the first GWAS on HOMA2 and the first GWAS conducted in the Middle East focusing on IR and beta cell function. Herein, we report a novel locus in that is implicated in beta cell dysfunction. Inclusion of under-represented populations in GWAS has potentials to provide important insights into the genetic architecture of IR and beta cell function.
Topics: Humans; Insulin Resistance; Genome-Wide Association Study; Female; Male; Middle Aged; Multifactorial Inheritance; Diabetes Mellitus, Type 2; Adult; Qatar; Polymorphism, Single Nucleotide; Insulin-Secreting Cells; Aged; Body Mass Index; Cohort Studies; Genetic Predisposition to Disease
PubMed: 38938516
DOI: 10.3389/fendo.2024.1384103 -
Stem Cell Research & Therapy Jun 2024Diabetes mellitus, a significant global public health challenge, severely impacts human health worldwide. The organoid, an innovative in vitro three-dimensional (3D)... (Review)
Review
Diabetes mellitus, a significant global public health challenge, severely impacts human health worldwide. The organoid, an innovative in vitro three-dimensional (3D) culture model, closely mimics tissues or organs in vivo. Insulin-secreting islet organoid, derived from stem cells induced in vitro with 3D structures, has emerged as a potential alternative for islet transplantation and as a possible disease model that mirrors the human body's in vivo environment, eliminating species difference. This technology has gained considerable attention for its potential in diabetes treatment. Despite advances, the process of stem cell differentiation into islet organoid and its cultivation demonstrates deficiencies, prompting ongoing efforts to develop more efficient differentiation protocols and 3D biomimetic materials. At present, the constructed islet organoid exhibit limitations in their composition, structure, and functionality when compared to natural islets. Consequently, further research is imperative to achieve a multi-tissue system composition and improved insulin secretion functionality in islet organoid, while addressing transplantation-related safety concerns, such as tumorigenicity, immune rejection, infection, and thrombosis. This review delves into the methodologies and strategies for constructing the islet organoid, its application in diabetes treatment, and the pivotal scientific challenges within organoid research, offering fresh perspectives for a deeper understanding of diabetes pathogenesis and the development of therapeutic interventions.
Topics: Humans; Organoids; Islets of Langerhans; Animals; Islets of Langerhans Transplantation; Diabetes Mellitus; Cell Differentiation
PubMed: 38937834
DOI: 10.1186/s13287-024-03780-7 -
British Journal of Cancer Jun 2024Pancreatoduodenectomy is the only cure for cancers of the pancreas and the periampullary region but has considerable operative complications and uncertain prognosis. Our...
BACKGROUND
Pancreatoduodenectomy is the only cure for cancers of the pancreas and the periampullary region but has considerable operative complications and uncertain prognosis. Our goal was to analyse temporal improvements and provide contemporary population-based benchmarks for outcomes following pancreatoduodenectomy.
METHODS
We empanelled a cohort comprising all patients in Sweden with pancreatic or periampullary cancer treated with pancreatoduodenectomy from 1964 to 2016 and achieved complete follow-up through 2016. We analysed postoperative deaths and disease-specific net survival.
RESULTS
We analysed 5923 patients with cancer of the pancreas (3876), duodenum (444), bile duct (504), or duodenal papilla (963) who underwent classic (3332) or modified (1652) Whipple's procedure or total pancreatectomy (803). Postoperative deaths declined from 17.2% in the 1960s to 1.6% in the contemporary time period (2010-2016). For all four cancer types, median, 1-year and 5-year survival improved substantially over time. Among patients operated between 2010 and 2016, 5-year survival was 29.0% (95% confidence interval (CI): 25.5, 33.0) for pancreatic cancer, 71.2% (95% CI: 62.9, 80.5) for duodenal cancer, 30.8% (95% CI: 23.0, 41.3) for bile duct cancer, and 62.7% (95% CI: 55.5, 70.8) for duodenal papilla cancer.
CONCLUSION
There is a continuous and substantial improvement in the benefit-harm ratio after pancreatoduodenectomy for cancer.
PubMed: 38937622
DOI: 10.1038/s41416-024-02757-w -
Communications Biology Jun 2024The prevalent RNA alternative splicing (AS) contributes to molecular diversity, which has been demonstrated in cellular function regulation and disease pathogenesis....
The prevalent RNA alternative splicing (AS) contributes to molecular diversity, which has been demonstrated in cellular function regulation and disease pathogenesis. However, the contribution of AS in pancreatic islets during diabetes progression remains unclear. Here, we reanalyze the full-length single-cell RNA sequencing data from the deposited database to investigate AS regulation across human pancreatic endocrine cell types in non-diabetic (ND) and type 2 diabetic (T2D) individuals. Our analysis demonstrates the significant association between transcriptomic AS profiles and cell-type-specificity, which could be applied to distinguish the clustering of major endocrine cell types. Moreover, AS profiles are enabled to clearly define the mature subset of β-cells in healthy controls, which is completely lost in T2D. Further analysis reveals that RNA-binding proteins (RBPs), heterogeneous nuclear ribonucleoproteins (hnRNPs) and FXR1 family proteins are predicted to induce the functional impairment of β-cells through regulating AS profiles. Finally, trajectory analysis of endocrine cells suggests the β-cell identity shift through dedifferentiation and transdifferentiation of β-cells during the progression of T2D. Together, our study provides a mechanism for regulating β-cell functions and suggests the significant contribution of AS program during diabetes pathogenesis.
Topics: Diabetes Mellitus, Type 2; Humans; Alternative Splicing; Single-Cell Analysis; Insulin-Secreting Cells; Sequence Analysis, RNA; Transcriptome; RNA-Binding Proteins; Islets of Langerhans
PubMed: 38937540
DOI: 10.1038/s42003-024-06475-0