|
1
|
Samanta A, Ray G. Hepatic glycogen storage disease: Deciphering the genotype-phenotype conundrum. World J Clin Pediatr 2025; 14:103415. [DOI: 10.5409/wjcp.v14.i3.103415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 03/08/2025] [Accepted: 03/17/2025] [Indexed: 06/16/2025] Open
Abstract
Glycogen storage diseases (GSDs) are a group of inherited disorders caused by genetic defects in various enzymes involved in glycogen production or breakdown. Hepatic GSDs often have overlapping clinical features, making subtyping or prognostication difficult. With the availability and advancement of next-generation sequencing, definitive molecular diagnosis is now available for most patients, with newer variants being increasingly identified. Molecular diagnosis could help in systematic follow-up, anticipating complications and prognostications. However, the mutations reported in the published literature display wide variations across racial and geographical groups. Hence, natural history, long-term outcome, and genotype-phenotypic correlation studies in patients with various hepatic GSDs are needed for a deeper understanding. Considering the emerging evidence of genetic profiling of patients with hepatic GSDs, including the recent study by Vanduangden et al, this editorial aims to review the various clinical subtypes, the spectrum of genetic mutations, and genotype-phenotype correlations for various hepatic GSDs.
Collapse
Affiliation(s)
- Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Gautam Ray
- Department of Pediatric Gastroenterology, Institute of Postgraduate Medical and Research, Kolkata 700020, West Bengal, India
| |
Collapse
|
|
2
|
Derks TGJ, Overduin RJ, Grünert SC, Rossi A. State of the Art and Consensus Statements by Healthcare Providers, Patients, and Caregivers on Continuous Glucose Monitoring in Liver Glycogen Storage Diseases. J Inherit Metab Dis 2025; 48:e70040. [PMID: 40360288 PMCID: PMC12074895 DOI: 10.1002/jimd.70040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 04/23/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025]
Abstract
Continuous glucose monitoring (CGM) is increasingly used although not officially registered for the management of people living with liver glycogen storage diseases (GSDs). The aims of this study were twofold: (a) to investigate the current experiences of healthcare providers (HCPs), patients, and caregivers using CGM to monitor glucose concentrations in liver GSDs, and (b) to formulate consensus statements. Two web-based questionnaires were distributed, one for HCPs and one for patients and/or their caregivers. The questionnaires collected data on demographics and epidemiology, current use of CGM, and opinions and statements about CGM in GSDs. For the statements, respondents rated their agreement on a 5-point Likert scale, and the consensus level was set at 75%. One Hundred Fourteen HCPs (including 87 physicians and 26 dietitians) from 28 countries responded, representing care of approximately 3800 liver GSD patients. Additionally, 148 GSD patients and/or their caregivers from 21 countries responded, mainly representing GSD Ia (n = 50), GSD Ib (n = 56), GSD III (n = 14), and GSD IX (n = 18). The median age to consider starting to use CGM was 6 and 2 months for HCPs and GSD families, respectively. Out of 16 statements common to the two questionnaires, HCPs and patients/caregivers reached consensus on 12 statements in both groups. Use of CGM is considered standard of care by both HCPs and GSD families, but reimbursement of CGM devices is challenging. Compared to diabetes mellitus, CGM should be applied differently in liver GSDs. Consensus guidelines are warranted on the use of CGM in liver GSDs, both in routine healthcare and in clinical trials.
Collapse
Affiliation(s)
- Terry G. J. Derks
- Department of Metabolic DiseasesBeatrix Children's Hospital, University Medical Center Groningen, University of GroningenGroningenthe Netherlands
- UMCG Center of Expertise for Carbohydrate, Fatty Acid Oxidation and Ketone Bodies DisordersUniversity Medical Center GroningenGroningenthe Netherlands
| | - Ruben J. Overduin
- Department of Metabolic DiseasesBeatrix Children's Hospital, University Medical Center Groningen, University of GroningenGroningenthe Netherlands
- UMCG Center of Expertise for Carbohydrate, Fatty Acid Oxidation and Ketone Bodies DisordersUniversity Medical Center GroningenGroningenthe Netherlands
| | - Sarah C. Grünert
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of MedicineMedical Center‐University of FreiburgFreiburgGermany
| | - Alessandro Rossi
- Department of Metabolic DiseasesBeatrix Children's Hospital, University Medical Center Groningen, University of GroningenGroningenthe Netherlands
- UMCG Center of Expertise for Carbohydrate, Fatty Acid Oxidation and Ketone Bodies DisordersUniversity Medical Center GroningenGroningenthe Netherlands
- Department of Translational Medicine, Section of PediatricsUniversity of Naples “Federico II”NaplesItaly
| |
Collapse
|
|
3
|
Toyoda Y, Shigesawa R, Merriman TR, Matsuo H, Takada T. GLUT2/SLC2A2 is a bi-directional urate transporter. J Biol Chem 2025; 301:108485. [PMID: 40209957 PMCID: PMC12143617 DOI: 10.1016/j.jbc.2025.108485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 03/31/2025] [Indexed: 04/12/2025] Open
Abstract
Recent genetic studies showed an association between solute carrier 2A2 (SLC2A2), which encodes glucose transporter 2 (GLUT2), and serum urate concentrations; however, urate transport activity of GLUT2 has not been studied contrary to its function as a sugar transporter. Here, we hypothesized that GLUT2 acts also as a urate transporter, which led us to conduct cell-based functional analyses using HEK-derived 293A cells. We found that radiolabeled [8-14C]-urate was incorporated into GLUT2-expressing cells more compared to control cells and this elevated cellular activity was almost completely inhibited by GLUT2 inhibitors, demonstrating that GLUT2 is a urate transporter. Regarding the concentration dependence of GLUT2-mediated urate transport, no saturable properties were observed within an experimentally achievable range (0-500 μM), suggesting that GLUT2 mediates the robust transport of urate. Moreover, the GLUT2-mediated urate transport was not inhibited by 10 mM glucose; GLUT2-mediated sugar transport was hardly affected by 500 μM urate. As these concentrations of urate and glucose were relevant to their maximum levels in healthy humans, our results suggest that GLUT2 maintains its urate transport ability under physiological conditions. Furthermore, using a cell-based urate efflux assay system, we successfully demonstrated that urate secretion was accelerated in GLUT2-expressing cells than in control cells. Therefore, GLUT2 may also function as a urate exporter. The present study revealed that GLUT2 is a bi-directional urate transporter. Our findings contribute to a deeper understanding of urate-handling systems in the body. To elucidate the physiological role of GLUT2 as a urate transporter, further studies are required.
Collapse
Affiliation(s)
- Yu Toyoda
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan; Department of Pharmacy, The University of Tokyo Hospital, Bunkyo, Tokyo, Japan
| | - Ryuichiro Shigesawa
- Department of Pharmacy, The University of Tokyo Hospital, Bunkyo, Tokyo, Japan
| | - Tony R Merriman
- Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Hirotaka Matsuo
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
| | - Tappei Takada
- Department of Pharmacy, The University of Tokyo Hospital, Bunkyo, Tokyo, Japan.
| |
Collapse
|
|
4
|
Reyes-Apodaca M, Consuelo-Sánchez A, Vázquez-Frias R, Rodríguez-Espino BA, Medeiros M. Integral kidney function assessment in pediatric patients with glycogen storage diseases. Front Pediatr 2025; 13:1543164. [PMID: 40356781 PMCID: PMC12066456 DOI: 10.3389/fped.2025.1543164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 04/07/2025] [Indexed: 05/15/2025] Open
Abstract
Introduction Glycogen storage diseases (GSDs) are a group of hereditary metabolic disorders with variable clinical manifestations, depending on the enzyme and organ affected. Renal dysfunction, including hyperfiltration, proteinuria, and renal tubular acidosis (RTA), is a known complication, particularly in GSD types of Ia and Ib. Methods This cross-sectional study evaluated renal function in 17 pediatric patients with different GSD types using an integral kidney assessment (IKA). The comprehensive evaluation included biochemical and urinary analyses, glomerular filtration rate calculations, and acidification tests. Results The median age at first renal evaluation was 33 months, and nutritional management was often suboptimal at this stage. Through IKA, renal alterations were identified in 47% of the patients. Hyperfiltration was present in 40% of GSD type I patients, while lactic acidosis was noted in 30% of these cases. Two siblings with GSD XI presented with proximal RTA and Fanconi syndrome, highlighting severe tubular involvement. Distal RTA was documented in one non-adherent GSD Ia patient, underscoring the importance of metabolic control. Discussion This study emphasizes the heterogeneity of renal manifestations among different GSD subtypes. Hyperfiltration, particularly in GSD I, may result from altered energy metabolism and compensatory mechanisms within the renal tubules. Proximal tubular damage in GSD XI reflects glycogen and monosaccharide accumulation within renal epithelial cells. Adherence to dietary and medical interventions is critical for mitigating renal complications and ensuring growth and development in GSD patients. Annual kidney evaluations are recommended for early detection of renal dysfunction, enabling timely initiation of therapeutic strategies such as alkali therapy and angiotensin-converting enzyme inhibitors.
Collapse
Affiliation(s)
- Magali Reyes-Apodaca
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Nephrology and Bone Mineral Metabolism Research and Diagnostic Unit, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | - Alejandra Consuelo-Sánchez
- Department of Gastroenterology and Nutrition, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | - Rodrigo Vázquez-Frias
- Department of Gastroenterology and Nutrition, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
- Research Management Assistant Office, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | - Benjamín Antonio Rodríguez-Espino
- Nephrology and Bone Mineral Metabolism Research and Diagnostic Unit, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | - Mara Medeiros
- Research Direction Office, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
- Pharmacology Department, National Autonomous University of Mexico, Mexico City, Mexico
| |
Collapse
|
|
5
|
Demko J, Saha B, Takagi E, Manis A, Weber R, Koepsell H, Pearce D. Coordinated Regulation of Renal Glucose Reabsorption and Gluconeogenesis by mTORC2 and Potassium. J Am Soc Nephrol 2025:00001751-990000000-00621. [PMID: 40208690 DOI: 10.1681/asn.0000000703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 04/03/2025] [Indexed: 04/11/2025] Open
Abstract
Key Points
The insulin-regulated kinase, mammalian target of rapamycin complex 2 (mTORC2), coordinates regulation of sodium-glucose cotransport and gluconeogenesis in the kidney proximal tubule.Dietary potassium can bypass mTORC2 to regulate sodium-glucose cotransport and gluconeogenesis in mTORC2 knockout mice.The transcription factor forkhead box O4 may have an unexpected role in mediating mTORC2 effects on renal tubule glucose homeostasis.
Background
The kidney is uniquely responsible for reabsorption of filtered glucose and gluconeogenesis. Insulin stimulates glucose transport and suppresses gluconeogenesis in the proximal tubule; however, the signaling mechanisms and coordinated regulation of these processes are poorly understood. The kinase complex mammalian target of rapamycin complex 2 (mTORC2) is critical for regulation of growth, metabolism, solute transport, and electrolyte homeostasis in response to a wide array of inputs. In this study, we examined its role in the regulation of renal glucose reabsorption and gluconeogenesis.
Methods
Rictor, an essential component of mTORC2, was knocked out using the Pax8-LC1 system to generate inducible tubule–specific Rictor knockout (KO) mice. A second Rictor KO model was generated using Cre-loxP technology and a proximal tubule–specific promoter. Animals were fasted and refed on normal- or high-potassium (K+) diets. Metabolic parameters, including glucose homeostasis and kidney function, were assessed. Kidneys and livers were harvested for molecular analysis of gluconeogenic enzymes, glucose transporters, and mTORC2-regulated signaling targets.
Results
On a normal-K+ diet, mTORC2 KO mice had marked glycosuria despite normal blood glucose. Immunofluorescence microscopy and immunostaining of plasma membrane protein fractions showed lower proximal tubule apical membrane sodium-glucose cotransporter 2 and sodium-glucose cotransporter 1 in the fed state of KO mice. Metabolic testing showed elevated fasting insulin, impaired pyruvate tolerance, and elevated hemoglobin A1c. In addition, renal gluconeogenic enzymes were increased, consistent with abnormal renal gluconeogenesis in KO mice. These effects correlated with reduced downstream phosphorylation of Akt and the transcription factor forkhead box O4, identifying a novel role of forkhead box O4 in the kidney tubules. Interestingly, high dietary K+ rapidly lowered glycosuria and gluconeogenesis, despite persistent reduction in mTORC2 substrate phosphorylation.
Conclusions
Renal tubule mTORC2 is critical for coordinated regulation of sodium-glucose cotransporter membrane localization and renal gluconeogenesis. In the absence of mTORC2, dietary K+ promotes glucose reabsorption and suppresses gluconeogenesis independent of insulin signaling.
Collapse
Affiliation(s)
- John Demko
- Division of Nephrology, Department of Medicine, University of California at San Francisco, San Francisco, California
| | - Bidisha Saha
- Division of Nephrology, Department of Medicine, University of California at San Francisco, San Francisco, California
| | - Enzo Takagi
- Division of Nephrology, Department of Medicine, University of California at San Francisco, San Francisco, California
| | - Anna Manis
- Division of Nephrology, Department of Medicine, University of California at San Francisco, San Francisco, California
| | - Robert Weber
- Division of Endocrinology, Department of Medicine, University of California at San Francisco, San Francisco, California
| | - Hermann Koepsell
- Institute of Anatomy and Cell Biology, University of Würzberg, Würzberg, Germany
| | - David Pearce
- Division of Nephrology, Department of Medicine, University of California at San Francisco, San Francisco, California
- Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California
| |
Collapse
|
|
6
|
Torun Bayram M, Kavukcu S. Renal glucosuria in children. World J Clin Pediatr 2025; 14:91622. [DOI: 10.5409/wjcp.v14.i1.91622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 10/10/2024] [Accepted: 11/13/2024] [Indexed: 12/20/2024] Open
Abstract
The kidneys play a critical role in maintaining glucose homeostasis. Under normal renal tubular function, most of the glucose filtered from the glomeruli is reabsorbed in the proximal tubules, leaving only trace amounts in the urine. Glycosuria can occur as a symptom of generalized proximal tubular dysfunction or when the reabsorption threshold is exceeded or the glucose threshold is reduced, as seen in familial renal glycosuria (FRG). FRG is characterized by persistent glycosuria despite normal blood glucose levels and tubular function and is primarily associated with mutations in the sodium/glucose cotransporter 5A2 gene, which encodes the sodium-glucose cotransporter (SGLT) 2. Inhibiting SGLTs has been proposed as a novel treatment strategy for diabetes, and since FRG is often considered an asymptomatic and benign condition, it has inspired preclinical and clinical studies using SGLT2 inhibitors in type 2 diabetes. However, patients with FRG may exhibit clinical features such as lower body weight or height, altered systemic blood pressure, diaper dermatitis, aminoaciduria, decreased serum uric acid levels, and hypercalciuria. Further research is needed to fully understand the pathophysiology, molecular genetics, and clinical manifestations of renal glucosuria.
Collapse
Affiliation(s)
- Meral Torun Bayram
- Division of Nephrology, Department of Pediatrics, Dokuz Eylül University, School of Medicine, Inciralti-Balcova 35340, Izmir, Türkiye
| | - Salih Kavukcu
- Division of Nephrology, Department of Pediatrics, Dokuz Eylül University, School of Medicine, Inciralti-Balcova 35340, Izmir, Türkiye
| |
Collapse
|
|
7
|
Shimokawa M, Kajio Y, Kawanishi K, Kawanishi K, Shiomi M, Morikawa T, Sasai F, Baba M, Kang D, Takaki T, Suzuki T, Koiwa F, Honda K, Honda H. Acute Tubular Injury and Fanconi Syndrome Associated With Red Yeast Rice Supplement. Kidney Int Rep 2025; 10:956-959. [PMID: 40225362 PMCID: PMC11993213 DOI: 10.1016/j.ekir.2024.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 12/02/2024] [Accepted: 12/16/2024] [Indexed: 04/15/2025] Open
Affiliation(s)
- Mayu Shimokawa
- Department of Anatomy, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan
- Internal Medicine (Nephrology), Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Yuki Kajio
- Department of Nephrology, Showa University Graduate School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan
| | - Keishu Kawanishi
- Department of Anatomy, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan
- Internal Medicine (Nephrology), Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Kunio Kawanishi
- Department of Anatomy, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan
| | - Mika Shiomi
- Department of Nephrology, Showa University Graduate School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan
| | - Tomoki Morikawa
- Department of Nephrology, Showa University Graduate School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan
| | - Fumihiko Sasai
- Internal Medicine (Nephrology), Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Masaki Baba
- Department of Diagnostic Pathology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Dedong Kang
- Department of Anatomy, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan
| | - Takashi Takaki
- Department of Anatomy, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan
- Center for Electron Microscopy, Showa University School of Medicine, Hatanodai, Tokyo, Japan
| | - Taihei Suzuki
- Department of Nephrology, Showa University Graduate School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan
| | - Fumihiko Koiwa
- Internal Medicine (Nephrology), Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Kazuho Honda
- Department of Anatomy, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan
| | - Hirokazu Honda
- Department of Nephrology, Showa University Graduate School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan
| |
Collapse
|
|
8
|
Hodrob T, Abusalameh A, Ismail I, Dweikat I, Rmeilah SA, Sultan M, Libdeh BA, Libdeh AASA, Shweiki S, Damseh N. Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome. Clin Genet 2025; 107:335-340. [PMID: 39548873 DOI: 10.1111/cge.14648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 11/01/2024] [Accepted: 11/04/2024] [Indexed: 11/18/2024]
Abstract
This study aims to investigate the clinical, biochemical, and genetic characteristics of Fanconi-Bickel syndrome (FBS) in a cohort of 20 individuals from Palestine and to identify novel pathogenic variants. A retrospective analysis was conducted on medical records from Al-Makassed Hospital's pediatric department spanning 2015 to 2023. Individuals diagnosed with FBS via molecular genetic testing were included in the study. Among the 20 genetically confirmed FBS patients, hepatomegaly was prevalent in 95%, whereas 70% exhibited both developmental delay and hypophosphatemic rickets, and 68.4% experienced growth retardation. Hypertriglyceridemia (HTG) was universal. Elevated liver enzymes and alkaline phosphatase were common, along with hypophosphatemia (95%) and urinary abnormalities. Genetic analysis revealed five distinct SLC2A2 pathogenic variants, including three previously unreported variants: p.Gln23Arg (c.68A > G), p.Thr353Arg (c.1058_1059delinsGG), and an exon 7 deletion. This study presents the largest single-center cohort of FBS patients, expanding our understanding of the disorder's phenotypic and genotypic spectrum. Despite FBS generally carrying a favorable prognosis, timely diagnosis remains crucial to prevent severe complications.
Collapse
Affiliation(s)
- Tamer Hodrob
- Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine
| | | | - Ibrahim Ismail
- Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine
| | - Imad Dweikat
- Metabolic Department, Arab American University, Jenin, Palestine
| | - Sarah Abu Rmeilah
- Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine
- Department of Pediatrics and Genetics, Al Makassed Hospital, East Jerusalem, Palestine
| | - Mutaz Sultan
- Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine
- Department of Pediatrics and Genetics, Al Makassed Hospital, East Jerusalem, Palestine
| | - Bassam Abu Libdeh
- Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine
- Department of Pediatrics and Genetics, Al Makassed Hospital, East Jerusalem, Palestine
| | - Abd-Al-Salam Abu Libdeh
- Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine
- Department of Pediatrics and Genetics, Al Makassed Hospital, East Jerusalem, Palestine
| | - Shaher Shweiki
- Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine
- Department of Pediatrics and Genetics, Al Makassed Hospital, East Jerusalem, Palestine
| | - Nadirah Damseh
- Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine
- Department of Pediatrics and Genetics, Al Makassed Hospital, East Jerusalem, Palestine
| |
Collapse
|
|
9
|
Farias FHG, Mhlanga-Mutangadura T, Guo J, Hansen L, Johnson GS, Katz ML. FAN1 Deletion Variant in Basenji Dogs with Fanconi Syndrome. Genes (Basel) 2024; 15:1469. [PMID: 39596669 PMCID: PMC11593659 DOI: 10.3390/genes15111469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 11/29/2024] Open
Abstract
Background: Fanconi syndrome is a disorder of renal proximal tubule transport characterized by metabolic acidosis, amino aciduria, glucosuria, and phosphaturia. There are acquired and hereditary forms of this disorder. A late-onset form of Fanconi syndrome in Basenjis was first described in 1976 and is now recognized as an inherited disease in these dogs. In part because of the late onset of disease signs, the disorder has not been eradicated from the breed by selective mating. A study was therefore undertaken to identify the molecular genetic basis of the disease so that dogs could be screened prior to breeding in order to avoid generating affected offspring. Methods: Linkage analysis within a large family of Basenjis that included both affected and unaffected individuals was performed to localize the causative variant within the genome. Significant linkage was identified between chromosome 3 (CFA3) makers and the disease phenotype. Fine mapping restricted the region to a 2.7 Mb section of CFA3. A whole genome sequence of a Basenji affected with Fanconi syndrome was generated, and the sequence data were examined for the presence of potentially deleterious homozygous variants within the mapped region. Results: A homozygous 317 bp deletion was identified in the last exon of FAN1 of the proband. 78 Basenjis of known disease status were genotyped for the deletion variant. Among these dogs, there was almost complete concordance between genotype and phenotype. The only exception was one dog that was homozygous for the deletion variant but did not exhibit signs of Fanconi syndrome. Conclusions: These data indicate that the disorder is very likely the result of FAN1 deficiency. The mechanism by which this deficiency causes the disease signs remains to be elucidated. FAN1 has endonuclease and exonuclease activity that catalyzes incisions in regions of double-stranded DNA containing interstrand crosslinks. FAN1 inactivation may cause Fanconi syndrome in Basenjis by sensitization of kidney proximal tubule cells to toxin-mediated DNA crosslinking, resulting in the accumulation of genomic and mitochondrial DNA damage in the kidney. Differential exposure to environmental toxins that promote DNA crosslink formation may explain the wide age-at-onset variability for the disorder in Basenjis.
Collapse
Affiliation(s)
- Fabiana H. G. Farias
- Canine Genetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA; (F.H.G.F.); (T.M.-M.); (J.G.); (L.H.)
| | - Tendai Mhlanga-Mutangadura
- Canine Genetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA; (F.H.G.F.); (T.M.-M.); (J.G.); (L.H.)
| | - Juyuan Guo
- Canine Genetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA; (F.H.G.F.); (T.M.-M.); (J.G.); (L.H.)
| | - Liz Hansen
- Canine Genetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA; (F.H.G.F.); (T.M.-M.); (J.G.); (L.H.)
| | - Gary S. Johnson
- Canine Genetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA; (F.H.G.F.); (T.M.-M.); (J.G.); (L.H.)
| | - Martin L. Katz
- Canine Genetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA; (F.H.G.F.); (T.M.-M.); (J.G.); (L.H.)
- Neurodegenerative Diseases Research Laboratory, Department of Ophthalmology, University of Missouri, Columbia, MO 65212, USA
| |
Collapse
|
|
10
|
Szmuilowicz ED, Fruzyna E, Madden N, Bolden JR, Kozek A, Vucko E, Ghossein C, Barish G. Management of Dysglycemia in a Pregnancy Complicated by Fanconi-Bickel Syndrome. AACE Clin Case Rep 2024; 10:224-228. [PMID: 39734506 PMCID: PMC11680753 DOI: 10.1016/j.aace.2024.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 07/10/2024] [Accepted: 07/23/2024] [Indexed: 12/31/2024] Open
Abstract
Background/Objective Fanconi-Bickel Syndrome (FBS) is an inherited disorder of glucose metabolism resulting from functional loss of glucose transporter 2 characterized by fasting hypoglycemia oscillating with postprandial hyperglycemia. Dysglycemia treatment strategies during FBS pregnancy have not been reported, and insulin therapy carries significant risk due to fasting hypoglycemia in FBS. We report for the first time: (1) glycemic profiles obtained via continuous glucose monitoring (CGM), (2) CGM-guided strategies for cornstarch and nutritional therapy for fasting hypoglycemia and postprandial hyperglycemia, respectively, and (3) placental glucose transporter 2 isoform expression in a pregnant individual with FBS. Case Report A 27-year-old woman with FBS presented at 6 weeks gestation for management of fasting hypoglycemia and postprandial hyperglycemia. Cornstarch therapy for fasting hypoglycemia and nutritional therapy for postprandial hyperglycemia were iteratively adjusted across gestation based on CGM-derived glycemic patterns. Pregnancy-specific glycemic targets were successfully achieved, and she delivered a healthy term infant. Glucose transporter 2 isoform was not detected in placental tissue. Discussion We report for the first time glycemic patterns across gestation in a pregnant individual with FBS. Glycemic targets were achieved through stepwise optimization of nutritional and cornstarch therapy, both guided by CGM data. Our approach obviated the need for insulin therapy, which carries amplified risk in FBS. Conclusion Fasting hypoglycemia and postprandial hyperglycemia can be effectively treated through CGM-guided adjustment of both nutritional and glucose polymer therapies in FBS pregnancy. More broadly, our case highlights a novel application for CGM in the management of uncommon glucose metabolism disorders during pregnancy.
Collapse
Affiliation(s)
- Emily D. Szmuilowicz
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Ellen Fruzyna
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Nigel Madden
- Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Janelle R. Bolden
- Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Anne Kozek
- Division of Pediatric Genetics, Genomics and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
| | - Erika Vucko
- Division of Pediatric Genetics, Genomics and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
| | - Cybele Ghossein
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Grant Barish
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Division of Endocrinology, Diabetes, and Metabolism, Jesse Brown VA Medical Center, Chicago, Illinois
| |
Collapse
|
|
11
|
Overduin RJ, Grünert SC, Besouw MTP, Bolhuis MS, Groen J, Schreuder AB, Woidy M, Murko S, Santer R, Derks TGJ. Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin. J Inherit Metab Dis 2024; 47:1018-1027. [PMID: 38802119 DOI: 10.1002/jimd.12752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/30/2024] [Accepted: 05/06/2024] [Indexed: 05/29/2024]
Abstract
Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen. SGLT2 inhibitors act on apical glucose reabsorption of renal proximal tubular cells. The purpose of this study was to retrospectively describe the first experiences with repurposing the SGLT2 inhibitor empagliflozin to treat the generalized tubulopathy in Fanconi-Bickel syndrome. A case series was conducted of seven persons from five families (five males, two females; three children, who were 14y5m, 2y9m, and 1y6m old) with genetically confirmed Fanconi-Bickel syndrome, off-label treated with empagliflozin. Median (range) age at start of empagliflozin was 27 years (1y6m - 61y) and duration of follow-up under empagliflozin treatment was 169 days (57-344). Under empagliflozin (up to 25 mg/d), biochemical parameters of tubular cell integrity (urinary N-acetyl-glucosaminidase) and/or tubular functions (including urinary α1-microglobulin) improved in all persons with Fanconi-Bickel syndrome, albeit to varying degrees. Clinically, supplementations (i.e., phosphate, alkali, carnitine, and alfacalcidol) could be completely discontinued in the three children, whereas results in the four adult patients were more variable and not as significant. Empagliflozin was well-tolerated and no symptomatic hypoglycemia was observed. In conclusion, SGLT2 inhibitors such as empagliflozin shift the metabolic block in Fanconi-Bickel syndrome, that is, they intervene specifically in the underlying pathophysiology and can thus attenuate renal proximal tubulopathy, especially when started in early childhood.
Collapse
Affiliation(s)
- Ruben J Overduin
- Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Sarah C Grünert
- Department of General Pediatrics, Adolescent Medicine and Neonatology, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Martine T P Besouw
- Department of Pediatric Nephrology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Mathieu S Bolhuis
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Joost Groen
- Department of Laboratory Medicine University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Andrea B Schreuder
- Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Mathias Woidy
- Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany
| | - Simona Murko
- Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany
| | - René Santer
- Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany
| | - Terry G J Derks
- Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| |
Collapse
|
|
12
|
Mishra K, Kakhlon O. Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs). Biomolecules 2024; 14:1096. [PMID: 39334863 PMCID: PMC11430448 DOI: 10.3390/biom14091096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 09/30/2024] Open
Abstract
Glycogen storage disorders (GSDs) are a group of inherited metabolic disorders characterized by defects in enzymes involved in glycogen metabolism. Deficiencies in enzymes responsible for glycogen breakdown and synthesis can impair mitochondrial function. For instance, in GSD type II (Pompe disease), acid alpha-glucosidase deficiency leads to lysosomal glycogen accumulation, which secondarily impacts mitochondrial function through dysfunctional mitophagy, which disrupts mitochondrial quality control, generating oxidative stress. In GSD type III (Cori disease), the lack of the debranching enzyme causes glycogen accumulation and affects mitochondrial dynamics and biogenesis by disrupting the integrity of muscle fibers. Malfunctional glycogen metabolism can disrupt various cascades, thus causing mitochondrial and cell metabolic dysfunction through various mechanisms. These dysfunctions include altered mitochondrial morphology, impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and defective mitophagy. The oxidative burden typical of GSDs compromises mitochondrial integrity and exacerbates the metabolic derangements observed in GSDs. The intertwining of mitochondrial dysfunction and GSDs underscores the complexity of these disorders and has significant clinical implications. GSD patients often present with multisystem manifestations, including hepatomegaly, hypoglycemia, and muscle weakness, which can be exacerbated by mitochondrial impairment. Moreover, mitochondrial dysfunction may contribute to the progression of GSD-related complications, such as cardiomyopathy and neurocognitive deficits. Targeting mitochondrial dysfunction thus represents a promising therapeutic avenue in GSDs. Potential strategies include antioxidants to mitigate oxidative stress, compounds that enhance mitochondrial biogenesis, and gene therapy to correct the underlying mitochondrial enzyme deficiencies. Mitochondrial dysfunction plays a critical role in the pathophysiology of GSDs. Recognizing and addressing this aspect can lead to more comprehensive and effective treatments, improving the quality of life of GSD patients. This review aims to elaborate on the intricate relationship between mitochondrial dysfunction and various types of GSDs. The review presents challenges and treatment options for several GSDs.
Collapse
Affiliation(s)
- Kumudesh Mishra
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem 9112001, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerem, Jerusalem 9112102, Israel
| | - Or Kakhlon
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem 9112001, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerem, Jerusalem 9112102, Israel
| |
Collapse
|
|
13
|
Caspi I, Tremmel DM, Pulecio J, Yang D, Liu D, Yan J, Odorico JS, Huangfu D. Glucose Transporters Are Key Components of the Human Glucostat. Diabetes 2024; 73:1336-1351. [PMID: 38775784 PMCID: PMC11262048 DOI: 10.2337/db23-0508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 04/16/2024] [Indexed: 07/21/2024]
Abstract
Mouse models are extensively used in metabolic studies. However, inherent differences between the species, notably their blood glucose levels, hampered data translation into clinical settings. In this study, we confirmed GLUT1 to be the predominantly expressed glucose transporter in both adult and fetal human β-cells. In comparison, GLUT2 is detected in a small yet significant subpopulation of adult β-cells and is expressed to a greater extent in fetal β-cells. Notably, GLUT1/2 expression in INS+ cells from human stem cell-derived islet-like clusters (SC-islets) exhibited a closer resemblance to that observed in fetal islets. Transplantation of primary human islets or SC-islets, but not murine islets, lowered murine blood glucose to the human glycemic range, emphasizing the critical role of β-cells in establishing species-specific glycemia. We further demonstrate the functional requirements of GLUT1 and GLUT2 in glucose uptake and insulin secretion through chemically inhibiting GLUT1 in primary islets and SC-islets and genetically disrupting GLUT2 in SC-islets. Finally, we developed a mathematical model to predict changes in glucose uptake and insulin secretion as a function of GLUT1/2 expression. Collectively, our findings illustrate the crucial roles of GLUTs in human β-cells, and identify them as key components in establishing species-specific glycemic set points. ARTICLE HIGHLIGHTS
Collapse
Affiliation(s)
- Inbal Caspi
- Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY
- Developmental Biology Program, Sloan Kettering Institute, New York, NY
| | - Daniel M. Tremmel
- Transplantation Division, Department of Surgery, University of Wisconsin-Madison, Madison, WI
| | - Julian Pulecio
- Developmental Biology Program, Sloan Kettering Institute, New York, NY
| | - Dapeng Yang
- Developmental Biology Program, Sloan Kettering Institute, New York, NY
| | - Dingyu Liu
- Developmental Biology Program, Sloan Kettering Institute, New York, NY
- Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Jielin Yan
- Developmental Biology Program, Sloan Kettering Institute, New York, NY
- Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Jon S. Odorico
- Transplantation Division, Department of Surgery, University of Wisconsin-Madison, Madison, WI
| | - Danwei Huangfu
- Developmental Biology Program, Sloan Kettering Institute, New York, NY
| |
Collapse
|
|
14
|
Chen APF, Russell G, Ashour A, Yacoub A. Presentation and Management of Acute Mania in Fanconi-Bickel Syndrome, A Metabolic Genetic Disorder. Case Rep Psychiatry 2024; 2024:5593846. [PMID: 38605735 PMCID: PMC11008969 DOI: 10.1155/2024/5593846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/17/2023] [Accepted: 03/13/2024] [Indexed: 04/13/2024] Open
Abstract
Fanconi-Bickel syndrome (FBS) is a rare metabolic disorder caused by decreased glucose transporter 2 (GLUT2) function due to several known mutations in the SLC2A2 gene. As of 2020, 144 cases of FBS have been described in the literature. Metabolic and somatic sequelae include dysglycemia and accumulation of glycogen in the kidney and liver. However, there are no descriptions in the literature of possible neuropsychiatric manifestations of FBS. This case report is to our knowledge the first in this regard, describing a patient with FBS who was admitted to our psychiatric inpatient unit while experiencing acute mania. We conceptualize the case as a novel psychiatric presentation of acute mania in FBS, which may inform our understanding of bipolar disorder pathophysiology because of the hypothesized functional changes in neural pathways involving the paraventricular thalamus induced by decreased GLUT2 activity in FBS.
Collapse
Affiliation(s)
- Allen P. F. Chen
- Medical Scientist Training Program, Renaissance School of Medicine, Stony Brook, NY, USA
| | - Geoffrey Russell
- Department of Psychiatry, Renaissance School of Medicine, Stony Brook, NY, USA
| | - Amnie Ashour
- The Division of General Surgery at New York-Presbyterian, Brooklyn, NY, USA
| | - Adeeb Yacoub
- Department of Psychiatry, Renaissance School of Medicine, Stony Brook, NY, USA
| |
Collapse
|
|
15
|
Abarca-Barriga HH, Laso-Salazar MC, Orihuela-Tacuri D, Chirinos-Saire J, Venero-Nuñez A. Importance about use of high-throughput sequencing in pediatric: case report of a patient with Fanconi-Bickel syndrome. BMC Pediatr 2024; 24:161. [PMID: 38454379 PMCID: PMC10921798 DOI: 10.1186/s12887-024-04641-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 02/13/2024] [Indexed: 03/09/2024] Open
Abstract
BACKGROUND Fanconi-Bickel syndrome is characterized by hepatorenal disease caused by anomalous glycogen storage. It occurs due to variants in the SLC2A2 gene. We present a male patient of 2 years 7 months old, with failure to thrive, hepatomegaly, metabolic acidosis, hypophosphatemia, hypokalemia, hyperlactatemia. RESULTS Exome sequencing identified the homozygous pathogenic variant NM_000340.2(SLC2A2):c.1093 C > T (p.Arg365Ter), related with Fanconi-Bickel syndrome. He received treatment with bicarbonate, amlodipine, sodium citrate and citric acid solution, enalapril, alendronate and zolendronate, and nutritional management with uncooked cornstarch, resulting in an improvement of one standard deviation in weight and height. CONCLUSIONS The importance of knowing the etiology in rare genetic disease is essential, not only to determine individual and familial recurrence risk, but also to establish the treatment and prognosis; in this sense, access to a new genomic technology in low- and middle-income countries is essential to shorten the diagnostic odyssey.
Collapse
Affiliation(s)
- Hugo Hernán Abarca-Barriga
- Instituto de Investigaciones de Ciencias Biomédicas, Universidad Ricardo Palma, Av. Benavides 5440, Santiago de Surco, Lima, Perú.
- Servicio de Genética & Errores Innatos del Metabolismo, Instituto Nacional de Salud del Niño- Breña, Lima, Perú.
| | - María Cristina Laso-Salazar
- Equipo Funcional de Genética y Biología Molecular, Instituto Nacional de Enfermedades Neoplásicas, Lima, Perú
| | - Diego Orihuela-Tacuri
- Servicio de Genética & Errores Innatos del Metabolismo, Instituto Nacional de Salud del Niño- Breña, Lima, Perú
| | - Jenny Chirinos-Saire
- Servicio de Genética & Errores Innatos del Metabolismo, Instituto Nacional de Salud del Niño- Breña, Lima, Perú
| | | |
Collapse
|
|
16
|
Du T, Xia Y, Sun C, Gong Z, Liang L, Gong Z, Wang R, Lu D, Zhang K, Yang Y, Sun Y, Sun M, Sun Y, Xiao B, Qiu W. Clinical, genetic profile and therapy evaluation of 11 Chinese pediatric patients with Fanconi-Bickel syndrome. Orphanet J Rare Dis 2024; 19:75. [PMID: 38365697 PMCID: PMC10874070 DOI: 10.1186/s13023-024-03070-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 02/03/2024] [Indexed: 02/18/2024] Open
Abstract
BACKGROUND Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction. METHODS Clinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed. RESULTS Hepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3-) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3- and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from - 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient. CONCLUSIONS Early diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.
Collapse
Affiliation(s)
- Taozi Du
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Yu Xia
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Chengkai Sun
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Zhuwen Gong
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Lili Liang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Zizhen Gong
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Ruifang Wang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Deyun Lu
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Kaichuang Zhang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Yi Yang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Yuning Sun
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Manqing Sun
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Yu Sun
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
- Department of Clinical Genetics Centre, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China
| | - Bing Xiao
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China.
- Department of Clinical Genetics Centre, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China.
| | - Wenjuan Qiu
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, 200092, Shanghai, China.
| |
Collapse
|
|
17
|
Klip A, De Bock K, Bilan PJ, Richter EA. Transcellular Barriers to Glucose Delivery in the Body. Annu Rev Physiol 2024; 86:149-173. [PMID: 38345907 DOI: 10.1146/annurev-physiol-042022-031657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2024]
Abstract
Glucose is the universal fuel of most mammalian cells, and it is largely replenished through dietary intake. Glucose availability to tissues is paramount for the maintenance of homeostatic energetics and, hence, supply should match demand by the consuming organs. In its journey through the body, glucose encounters cellular barriers for transit at the levels of the absorbing intestinal epithelial wall, the renal epithelium mediating glucose reabsorption, and the tight capillary endothelia (especially in the brain). Glucose transiting through these cellular barriers must escape degradation to ensure optimal glucose delivery to the bloodstream or tissues. The liver, which stores glycogen and generates glucose de novo, must similarly be able to release it intact to the circulation. We present the most up-to-date knowledge on glucose handling by the gut, liver, brain endothelium, and kidney, and discuss underlying molecular mechanisms and open questions. Diseases associated with defects in glucose delivery and homeostasis are also briefly addressed. We propose that the universal problem of sparing glucose from catabolism in favor of translocation across the barriers posed by epithelia and endothelia is resolved through common mechanisms involving glucose transfer to the endoplasmic reticulum, from where glucose exits the cells via unconventional cellular mechanisms.
Collapse
Affiliation(s)
- Amira Klip
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada;
| | - Katrien De Bock
- Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland
| | - Philip J Bilan
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada;
| | - Erik A Richter
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
18
|
Haeri MR. Diabetes and diabesity in the view of proteomics, drug, and plant-derived remedies. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2023; 28:77. [PMID: 38152069 PMCID: PMC10751518 DOI: 10.4103/jrms.jrms_487_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 07/08/2023] [Accepted: 07/31/2023] [Indexed: 12/29/2023]
Abstract
Diabetes and obesity are highly prevalent in the world. Proteomics is a promising approach to better understanding enzymes, proteins, and signaling molecules involved in diabetes processes which help recognize the basis of the disease better and find suitable new treatments. This study aimed to summarize the molecular mechanisms from the beginning of insulin secretion in response to stimuli to the pathology of the insulin signaling pathway and, finally, the mechanisms of drugs/chemicals remedies that affect this process. The titles and subtitles of this process were determined, and then for each of them, the articles searched in PubMed and ScienceDirect were used. This review article starts the discussion with the molecular basis of insulin biosynthesis, secretion, insulin's mechanism of action, and molecular aspect of diabetes and diabesity (a new term showing the relation between diabetes and obesity) and ends with the drug and plant-derived intervention for hyperglycemia.
Collapse
Affiliation(s)
- Mohammad Reza Haeri
- Department of Clinical Biochemistry, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran
- Reference Laboratory, Qom University of Medical Sciences, Qom, Iran
| |
Collapse
|
|
19
|
Gümüş E, Özen H. Glycogen storage diseases: An update. World J Gastroenterol 2023; 29:3932-3963. [PMID: 37476587 PMCID: PMC10354582 DOI: 10.3748/wjg.v29.i25.3932] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/15/2023] [Accepted: 04/30/2023] [Indexed: 06/28/2023] Open
Abstract
Glycogen storage diseases (GSDs), also referred to as glycogenoses, are inherited metabolic disorders of glycogen metabolism caused by deficiency of enzymes or transporters involved in the synthesis or degradation of glycogen leading to aberrant storage and/or utilization. The overall estimated GSD incidence is 1 case per 20000-43000 live births. There are over 20 types of GSD including the subtypes. This heterogeneous group of rare diseases represents inborn errors of carbohydrate metabolism and are classified based on the deficient enzyme and affected tissues. GSDs primarily affect liver or muscle or both as glycogen is particularly abundant in these tissues. However, besides liver and skeletal muscle, depending on the affected enzyme and its expression in various tissues, multiorgan involvement including heart, kidney and/or brain may be seen. Although GSDs share similar clinical features to some extent, there is a wide spectrum of clinical phenotypes. Currently, the goal of treatment is to maintain glucose homeostasis by dietary management and the use of uncooked cornstarch. In addition to nutritional interventions, pharmacological treatment, physical and supportive therapies, enzyme replacement therapy (ERT) and organ transplantation are other treatment approaches for both disease manifestations and long-term complications. The lack of a specific therapy for GSDs has prompted efforts to develop new treatment strategies like gene therapy. Since early diagnosis and aggressive treatment are related to better prognosis, physicians should be aware of these conditions and include GSDs in the differential diagnosis of patients with relevant manifestations including fasting hypoglycemia, hepatomegaly, hypertransaminasemia, hyperlipidemia, exercise intolerance, muscle cramps/pain, rhabdomyolysis, and muscle weakness. Here, we aim to provide a comprehensive review of GSDs. This review provides general characteristics of all types of GSDs with a focus on those with liver involvement.
Collapse
Affiliation(s)
- Ersin Gümüş
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hacettepe University Faculty of Medicine, Ihsan Dogramaci Children’s Hospital, Ankara 06230, Turkey
| | - Hasan Özen
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hacettepe University Faculty of Medicine, Ihsan Dogramaci Children’s Hospital, Ankara 06230, Turkey
| |
Collapse
|
|
20
|
Xi L, Zhai G, Liu Y, Gong Y, Lu Q, Zhang Z, Liu H, Jin J, Zhu X, Yin Z, Xie S, Han D. Attenuated glucose uptake promotes catabolic metabolism through activated AMPK signaling and impaired insulin signaling in zebrafish. Front Nutr 2023; 10:1187283. [PMID: 37305084 PMCID: PMC10250679 DOI: 10.3389/fnut.2023.1187283] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/04/2023] [Indexed: 06/13/2023] Open
Abstract
Glucose metabolism in fish remains a controversial area of research as many fish species are traditionally considered glucose-intolerant. Although energy homeostasis remodeling has been observed in fish with inhibited fatty acid β-oxidation (FAO), the effects and mechanism of the remodeling caused by blocked glucose uptake remain poorly understood. In this study, we blocked glucose uptake by knocking out glut2 in zebrafish. Intriguingly, the complete lethality, found in Glut2-null mice, was not observed in glut2-/- zebrafish. Approxiamately 30% of glut2-/- fish survived to adulthood and could reproduce. The maternal zygotic mutant glut2 (MZglut2) fish exhibited growth retardation, decreased blood and tissue glucose levels, and low locomotion activity. The decreased pancreatic β-cell numbers and insulin expression, as well as liver insulin receptor a (insra), fatty acid synthesis (chrebp, srebf1, fasn, fads2, and scd), triglyceride synthesis (dgat1a), and muscle mechanistic target of rapamycin kinase (mtor) of MZglut2 zebrafish, suggest impaired insulin-dependent anabolic metabolism. Upregulated expression of lipolysis (atgl and lpl) and FAO genes (cpt1aa and cpt1ab) in the liver and proteolysis genes (bckdk, glud1b, and murf1a) in muscle were observed in the MZglut2 zebrafish, as well as elevated levels of P-AMPK proteins in both the liver and muscle, indicating enhanced catabolic metabolism associated with AMPK signaling. In addition, decreased amino acids and elevated carnitines of the MZglut2 zebrafish supported the decreased protein and lipid content of the whole fish. In summary, we found that blocked glucose uptake impaired insulin signaling-mediated anabolism via β-cell loss, while AMPK signaling-mediated catabolism was enhanced. These findings reveal the mechanism of energy homeostasis remodeling caused by blocked glucose uptake, which may be a potential strategy for adapting to low glucose levels.
Collapse
Affiliation(s)
- Longwei Xi
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Gang Zhai
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Yulong Liu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Yulong Gong
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
| | - Qisheng Lu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Zhimin Zhang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
| | - Haokun Liu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Junyan Jin
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoming Zhu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Zhan Yin
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
- Hubei Hongshan Laboratory, Huazhong Agriculture University, Wuhan, China
- The Innovative Academy of Seed Design, Chinese Academy of Sciences, Wuhan, China
| | - Shouqi Xie
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
- The Innovative Academy of Seed Design, Chinese Academy of Sciences, Wuhan, China
| | - Dong Han
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
- Hubei Hongshan Laboratory, Huazhong Agriculture University, Wuhan, China
| |
Collapse
|
|
21
|
Unno K, Taguchi K, Takagi Y, Hase T, Meguro S, Nakamura Y. Mouse Models with SGLT2 Mutations: Toward Understanding the Role of SGLT2 beyond Glucose Reabsorption. Int J Mol Sci 2023; 24:ijms24076278. [PMID: 37047250 PMCID: PMC10094282 DOI: 10.3390/ijms24076278] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/22/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023] Open
Abstract
The sodium–glucose cotransporter 2 (SGLT2) mainly carries out glucose reabsorption in the kidney. Familial renal glycosuria, which is a mutation of SGLT2, is known to excrete glucose in the urine, but blood glucose levels are almost normal. Therefore, SGLT2 inhibitors are attracting attention as a new therapeutic drug for diabetes, which is increasing worldwide. In fact, SGLT2 inhibitors not only suppress hyperglycemia but also reduce renal, heart, and cardiovascular diseases. However, whether long-term SGLT2 inhibition is completely harmless requires further investigation. In this context, mice with mutations in SGLT2 have been generated and detailed studies are being conducted, e.g., the SGLT2−/− mouse, Sweet Pee mouse, Jimbee mouse, and SAMP10-ΔSglt2 mouse. Biological changes associated with SGLT2 mutations have been reported in these model mice, suggesting that SGLT2 is not only responsible for sugar reabsorption but is also related to other functions, such as bone metabolism, longevity, and cognitive functions. In this review, we present the characteristics of these mutant mice. Moreover, because the relationship between diabetes and Alzheimer’s disease has been discussed, we examined the relationship between changes in glucose homeostasis and the amyloid precursor protein in SGLT2 mutant mice.
Collapse
|
|
22
|
Battal A, Dogan A, Uyar A, Demir A, Keleş ÖF, Celik I, Baloglu MC, Aslan A. Exploring of the ameliorative effects of Nerium (Nerium oleander L.) ethanolic flower extract in streptozotocin induced diabetic rats via biochemical, histological and molecular aspects. Mol Biol Rep 2023; 50:4193-4205. [PMID: 36897524 DOI: 10.1007/s11033-023-08332-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 01/17/2023] [Indexed: 03/11/2023]
Abstract
BACKGROUND Nerium oleander L. is ethnopharmacologically used for diabetes. Our aim was to investigate the ameliorative effects of ethanolic Nerium flower extract (NFE) in STZ-induced diabetic rats. METHODS Seven random groups including control group, NFE group (50 mg/kg), diabetic group, glibenclamide group and NFE treated groups (25 mg/kg, 75 mg/kg, and 225 mg/kg) were composed of forty-nine rats. Blood glucose level, glycated hemoglobin (HbA1c), insulin level, liver damage parameters and lipid profile parameters were investigated. Antioxidant defense system enzyme activities and reduced glutathione (GSH) and malondialdehyde (MDA) contents and immunotoxic and neurotoxic parameters were determined in liver tissue. Additionally, the ameliorative effects of NFE were histopathologically examined in liver. mRNA levels of SLC2A2 gene encoding glucose transporter 2 protein were measured by quantitative real time PCR. RESULTS NFE caused decrease in glucose level and HbA1c and increase in insulin and C-peptide levels. Additionally, NFE improved liver damage biomarkers and lipid profile parameters in serum. Moreover, lipid peroxidation was prevented and antioxidant enzyme activities in liver were regulated by NFE treatment. Furthermore, anti-immunotoxic and anti-neurotoxic effects of NFE were determined in liver tissue of diabetic rats. Histopathogically, significant liver damages were observed in the diabetic rats. Histopathological changes were decreased partially in the 225 mg/kg NFE treated group. SLC2A2 gene expression in liver of diabetic rats significantly reduced compared to healthy rats and NFE treatment (25 mg/kg) caused increase in gene expression. CONCLUSION Flower extract of Nerium plant may have an antidiabetic potential due to its high phytochemical content.
Collapse
Affiliation(s)
- Abdulhamit Battal
- Department of Pharmaceutical Biotechnology, Van Yüzüncü Yıl University, Van, Turkey.
| | - Abdulahad Dogan
- Department of Biochemistry, Van Yüzüncü Yıl University, Van, Turkey
| | - Ahmet Uyar
- Departement of Pathology, Mustafa Kemal University, Hatay, Turkey
| | - Abdulbaki Demir
- Department of Molecular Biology and Genetics, Van Yüzüncü Yıl University, Van, Turkey
| | - Ömer Faruk Keleş
- Departement of Pathology, Van Yüzüncü Yıl University, Van, Turkey
| | - Ismail Celik
- Department of Molecular Biology and Genetics, Van Yüzüncü Yıl University, Van, Turkey
| | | | - Ali Aslan
- Department of Pharmacology, Van Yüzüncü Yıl University, Van, Turkey.,Department of Biology, Kyrgyz-Turkish Manas University, Bishkek, Kyrgyzstan
| |
Collapse
|
|
23
|
Ahmad M, Abramovich I, Agranovich B, Nemirovski A, Gottlieb E, Hinden L, Tam J. Kidney Proximal Tubule GLUT2-More than Meets the Eye. Cells 2022; 12:cells12010094. [PMID: 36611887 PMCID: PMC9818791 DOI: 10.3390/cells12010094] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/06/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
Tubulopathy plays a central role in the pathophysiology of diabetic kidney disease (DKD). Under diabetic conditions, the kidney proximal tubule cells (KPTCs) are exposed to an extensive amount of nutrients, most notably glucose; these nutrients deteriorate KPTCs function and promote the development and progression of DKD. Recently, the facilitative glucose transporter 2 (GLUT2) in KPTCs has emerged as a central regulator in the pathogenesis of DKD. This has been demonstrated by identifying its specific role in enhancing glucose reabsorption and glucotoxicity, and by deciphering its effect in regulating the expression of the sodium-glucose transporter 2 (SGLT2) in KPTCs. Moreover, reduction/deletion of KPTC-GLUT2 has been recently found to ameliorate DKD, raising the plausible idea of considering it as a therapeutic target against DKD. However, the underlying molecular mechanisms by which GLUT2 exerts its deleterious effects in KPTCs remain vague. Herein, we review the current findings on the proximal tubule GLUT2 biology and function under physiologic conditions, and its involvement in the pathophysiology of DKD. Furthermore, we shed new light on its cellular regulation during diabetic conditions.
Collapse
Affiliation(s)
- Majdoleen Ahmad
- Obesity and Metabolism Laboratory, Faculty of Medicine, The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Ifat Abramovich
- Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 3525422, Israel
| | - Bella Agranovich
- Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 3525422, Israel
| | - Alina Nemirovski
- Obesity and Metabolism Laboratory, Faculty of Medicine, The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Eyal Gottlieb
- Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 3525422, Israel
| | - Liad Hinden
- Obesity and Metabolism Laboratory, Faculty of Medicine, The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
- Correspondence: (L.H.); (J.T.); Tel.: +972-2-675-7650 (L.H.); +972-2-675-7645 (J.T.)
| | - Joseph Tam
- Obesity and Metabolism Laboratory, Faculty of Medicine, The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
- Correspondence: (L.H.); (J.T.); Tel.: +972-2-675-7650 (L.H.); +972-2-675-7645 (J.T.)
| |
Collapse
|
|
24
|
Lal MK, Sharma E, Tiwari RK, Devi R, Mishra UN, Thakur R, Gupta R, Dey A, Lal P, Kumar A, Altaf MA, Sahu DN, Kumar R, Singh B, Sahu SK. Nutrient-Mediated Perception and Signalling in Human Metabolism: A Perspective of Nutrigenomics. Int J Mol Sci 2022; 23:ijms231911305. [PMID: 36232603 PMCID: PMC9569568 DOI: 10.3390/ijms231911305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/03/2022] [Accepted: 09/21/2022] [Indexed: 11/16/2022] Open
Abstract
The interaction between selective nutrients and linked genes involving a specific organ reveals the genetic make-up of an individual in response to a particular nutrient. The interaction of genes with food opens opportunities for the addition of bioactive compounds for specific populations comprising identical genotypes. The slight difference in the genetic blueprints of humans is advantageous in determining the effect of nutrients and their metabolism in the body. The basic knowledge of emerging nutrigenomics and nutrigenetics can be applied to optimize health, prevention, and treatment of diseases. In addition, nutrient-mediated pathways detecting the cellular concentration of nutrients such as sugars, amino acids, lipids, and metabolites are integrated and coordinated at the organismal level via hormone signals. This review deals with the interaction of nutrients with various aspects of nutrigenetics and nutrigenomics along with pathways involved in nutrient sensing and regulation, which can provide a detailed understanding of this new leading edge in nutrition research and its potential application to dietetic practice.
Collapse
Affiliation(s)
- Milan Kumar Lal
- Division of Crop Physiology, Biochemistry and Post-Harvest Technology, ICAR-Central Potato Research Institute, Shimla 171001, India
| | - Eshita Sharma
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar 143005, India
| | - Rahul Kumar Tiwari
- Division of Plant Protection, ICAR-Central Potato Research Institute, Shimla 171001, India
| | - Rajni Devi
- Department of Microbiology, Punjab Agricultural University, Ludhiana 141004, India
| | | | - Richa Thakur
- Division of Silviculture and Forest Management, Himalayan Forest Research Institute, Conifer Campus, Shimla 171001, India
| | - Rucku Gupta
- Department of horticulture, Sher-e-Kashmir University of Agricultural Science and Technology of Jammu, Jammu 181101, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, India
| | - Priyanka Lal
- Department of Agricultural Economics and Extension, School of Agriculture, Lovely Professional University, Jalandhar GT Road (NH1), Phagwara 144402, India
| | - Awadhesh Kumar
- Division of Crop Physiology and Biochemistry, ICAR-National Rice Research Institute, Cuttack 754006, India
| | | | - Durgesh Nandini Sahu
- State Key Laboratory of Agricultural Genomics, BGI-Shenzhen, Shenzhen 518083, China
| | - Ravinder Kumar
- Division of Plant Protection, ICAR-Central Potato Research Institute, Shimla 171001, India
| | - Brajesh Singh
- Division of Crop Physiology, Biochemistry and Post-Harvest Technology, ICAR-Central Potato Research Institute, Shimla 171001, India
- Correspondence: (B.S.); (S.K.S.)
| | - Sunil Kumar Sahu
- State Key Laboratory of Agricultural Genomics, BGI-Shenzhen, Shenzhen 518083, China
- Correspondence: (B.S.); (S.K.S.)
| |
Collapse
|
|
25
|
Sharari S, Kabeer B, Mohammed I, Haris B, Pavlovski I, Hawari I, Bhat AA, Toufiq M, Tomei S, Mathew R, Syed N, Nisar S, Maacha S, Grivel JC, Chaussabel D, Ericsson J, Hussain K. Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi-Bickel Syndrome. Biomedicines 2022; 10:biomedicines10092114. [PMID: 36140215 PMCID: PMC9495670 DOI: 10.3390/biomedicines10092114] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/14/2022] [Accepted: 08/15/2022] [Indexed: 12/04/2022] Open
Abstract
Fanconi−Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized by the accumulation of glycogen mainly in the liver. It is inherited in an autosomal recessive manner due to mutations in the SLC2A2 gene. SLC2A2 encodes for the glucose transporter GLUT2 and is expressed in tissues that are involved in glucose homeostasis. The molecular mechanisms of dysglycemia in FBS are still not clearly understood. In this study, we report two cases of FBS with classical phenotypes of FBS associated with dysglycemia. Genomic DNA was extracted and analyzed by whole-genome and Sanger sequencing, and patient PBMCs were used for molecular analysis. One patient had an exonic SLC2A2 mutation (c.1093C>T in exon 9, R365X), while the other patient had a novel intronic SLC2A2 mutation (c.613-7T>G). Surprisingly, the exonic mutation resulted in the overexpression of dysfunctional GLUT2, resulting in the dysregulated expression of other glucose transporters. The intronic mutation did not affect the coding sequence of GLUT2, its expression, or glucose transport activity. However, it was associated with the expression of miRNAs correlated with type 1 diabetes mellitus, with a particular significant overexpression of hsa-miR-29a-3p implicated in insulin production and secretion. Our findings suggest that SLC2A2 mutations cause dysglycemia in FBS either by a direct effect on GLUT2 expression and/or activity or, indirectly, by the dysregulated expression of miRNAs implicated in glucose homeostasis.
Collapse
Affiliation(s)
- Sanaa Sharari
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar
- Department of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha 26999, Qatar
| | | | - Idris Mohammed
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar
- Department of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha 26999, Qatar
| | - Basma Haris
- Department of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha 26999, Qatar
| | | | - Iman Hawari
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar
- Department of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha 26999, Qatar
| | | | | | - Sara Tomei
- Research Branch, Sidra Medicine, Doha 26999, Qatar
| | | | - Najeeb Syed
- Research Branch, Sidra Medicine, Doha 26999, Qatar
| | - Sabah Nisar
- Research Branch, Sidra Medicine, Doha 26999, Qatar
| | - Selma Maacha
- Research Branch, Sidra Medicine, Doha 26999, Qatar
| | | | | | - Johan Ericsson
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar
- School of Medicine and Medical Science, University College Dublin, Belfield, 4 D4 Dublin, Ireland
| | - Khalid Hussain
- Department of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha 26999, Qatar
- Correspondence:
| |
Collapse
|
|
26
|
Massese M, Tagliaferri F, Dionisi-Vici C, Maiorana A. Glycogen storage diseases with liver involvement: a literature review of GSD type 0, IV, VI, IX and XI. Orphanet J Rare Dis 2022; 17:241. [PMID: 35725468 PMCID: PMC9208159 DOI: 10.1186/s13023-022-02387-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 06/06/2022] [Indexed: 12/31/2022] Open
Abstract
Background Glycogen storage diseases (GSDs) with liver involvement are classified into types 0, I, III, IV, VI, IX and XI, depending on the affected enzyme. Hypoglycemia and hepatomegaly are hallmarks of disease, but muscular and renal tubular involvement, dyslipidemia and osteopenia can develop. Considering the paucity of literature available, herein we provide a narrative review of these latter forms of GSDs. Main body Diagnosis is based on clinical manifestations and laboratory test results, but molecular analysis is often necessary to distinguish the various forms, whose presentation can be similar. Compared to GSD type I and III, which are characterized by a more severe impact on metabolic and glycemic homeostasis, GSD type 0, VI, IX and XI are usually known to be responsive to the nutritional treatment for achieving a balanced metabolic homeostasis in the pediatric age. However, some patients can exhibit a more severe phenotype and an important progression of the liver and muscular disease. The effects of dietary adjustments in GSD type IV are encouraging, but data are limited. Conclusions Early diagnosis allows a good metabolic control, with improvement of quality of life and prognosis, therefore we underline the importance of building a proper knowledge among physicians about these rare conditions. Regular monitoring is necessary to restrain disease progression and complications.
Collapse
Affiliation(s)
- Miriam Massese
- Division of Metabolism, Department of Pediatric Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.,Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Francesco Tagliaferri
- Division of Metabolism, Department of Pediatric Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.,SCDU of Pediatrics, Azienda Ospedaliero-Universitaria Maggiore Della Carità, University of Piemonte Orientale, Novara, Italy
| | - Carlo Dionisi-Vici
- Division of Metabolism, Department of Pediatric Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy
| | - Arianna Maiorana
- Division of Metabolism, Department of Pediatric Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.
| |
Collapse
|
|
27
|
Sarhan OM, Al Farhan A, Abdallah S, Al Ghwanmah H, Boqari D, Omar H, Al Faddagh A, Al Kanani H, Al Kawai F. Pediatric metanephric adenoma with Fanconi-Bickel syndrome: a case report and review of literature. Surg Case Rep 2022; 8:86. [PMID: 35511306 PMCID: PMC9072611 DOI: 10.1186/s40792-022-01435-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 04/19/2022] [Indexed: 11/14/2022] Open
Abstract
Background Metanephric adenoma (MA) is a rare benign renal tumor that resembles renal cell carcinoma and Wilms’ tumor in radiological as well as pathological appearance. It can present at any age or gender, and it is extremely rare in the pediatric age group with less than 50 reported cases. Fanconi–Bickel syndrome (FBS) is a rare autosomal recessive disorder of carbohydrate metabolism. Herein, we report a rare incidence of MA in a boy with a genetically confirmed FBS who underwent a nephron-sparing surgery. Case presentation A 21-month-old boy was referred to the pediatric urology clinic for further evaluation of an incidentally discovered left renal mass. His laboratory investigations showed normal renal function, hypophosphatemia, high blood glucose level, markedly elevated serum alkaline phosphatase, and low serum vitamin D. Blood picture showed signs of polycythemia and urinalysis showed glucosuria and aminoaciduria. Genetic testing was positive for Fanconi–Bickel syndrome. Radiological investigations were carried out with abdominal ultrasound and computerized tomography (CT) with intravenous contrast documented a sharply marginated peripheral hypoechoic hypovascular homogeneously enhancing mass at the upper pole of the left kidney measuring 2.0 × 1.8 × 2.0 cm. The child was admitted and started on supportive treatment until his medical condition was stabilized, then underwent elective open left partial nephrectomy via a left upper transverse abdominal transperitoneal incision. The excised renal mass was sent for histopathological assessment and was found to be a tumor composed of tightly packed tubules with no mitotic figures or necrosis and scanty cytoplasm consistent with MA. After good hydration and tumor resection, his polycythemia gradually improved. The patient was discharged home in a good condition with his proper replacement therapies. His follow-up abdominal ultrasound after 12 months showed no signs of recurrence. Conclusions Metanephric adenoma is extremely rare in the pediatric age group, especially in those who have a FBS. The only way to diagnose and treat this tumor is by surgical resection as most patients are asymptomatic. A nephron-sparing surgery is better for this age group in which the future renal function is considered.
Collapse
Affiliation(s)
- Osama M Sarhan
- Urology Department, Faculty of Medicine, Mansoura Urology and Nephrology Center, Mansoura University, Mansoura, Egypt. .,Urology Department, King Fahad Specialist Hospital, Dammam, 31444, Saudi Arabia.
| | - Ahmed Al Farhan
- Urology Department, King Fahad Specialist Hospital, Dammam, 31444, Saudi Arabia
| | - Salma Abdallah
- Department of Pediatrics, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Hamzah Al Ghwanmah
- Urology Department, King Fahad Specialist Hospital, Dammam, 31444, Saudi Arabia
| | - Deena Boqari
- Pathology Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Helmy Omar
- Urology Department, King Fahad Specialist Hospital, Dammam, 31444, Saudi Arabia
| | | | - Hanan Al Kanani
- Department of Pediatrics, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Fouad Al Kawai
- Urology Department, King Fahad Specialist Hospital, Dammam, 31444, Saudi Arabia
| |
Collapse
|
|
28
|
GLUT3 inhibitor discovery through in silico ligand screening and in vivo validation in eukaryotic expression systems. Sci Rep 2022; 12:1429. [PMID: 35082341 PMCID: PMC8791944 DOI: 10.1038/s41598-022-05383-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 01/06/2022] [Indexed: 12/30/2022] Open
Abstract
The passive transport of glucose and related hexoses in human cells is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT3 is a high-affinity glucose transporter primarily responsible for glucose entry in neurons. Changes in its expression have been implicated in neurodegenerative diseases and cancer. GLUT3 inhibitors can provide new ways to probe the pathophysiological role of GLUT3 and tackle GLUT3-dependent cancers. Through in silico screening of an ~ 8 million compounds library against the inward- and outward-facing models of GLUT3, we selected ~ 200 ligand candidates. These were tested for in vivo inhibition of GLUT3 expressed in hexose transporter-deficient yeast cells, resulting in six new GLUT3 inhibitors. Examining their specificity for GLUT1-5 revealed that the most potent GLUT3 inhibitor (G3iA, IC50 ~ 7 µM) was most selective for GLUT3, inhibiting less strongly only GLUT2 (IC50 ~ 29 µM). None of the GLUT3 inhibitors affected GLUT5, three inhibited GLUT1 with equal or twofold lower potency, and four showed comparable or two- to fivefold better inhibition of GLUT4. G3iD was a pan-Class 1 GLUT inhibitor with the highest preference for GLUT4 (IC50 ~ 3.9 µM). Given the prevalence of GLUT1 and GLUT3 overexpression in many cancers and multiple myeloma’s reliance on GLUT4, these GLUT3 inhibitors may discriminately hinder glucose entry into various cancer cells, promising novel therapeutic avenues in oncology.
Collapse
|
|
29
|
Maiorana A, Lepri FR, Novelli A, Dionisi-Vici C. Hypoglycaemia Metabolic Gene Panel Testing. Front Endocrinol (Lausanne) 2022; 13:826167. [PMID: 35422763 PMCID: PMC9001947 DOI: 10.3389/fendo.2022.826167] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/21/2022] [Indexed: 12/31/2022] Open
Abstract
A large number of inborn errors of metabolism present with hypoglycemia. Impairment of glucose homeostasis may arise from different biochemical pathways involving insulin secretion, fatty acid oxidation, ketone bodies formation and degradation, glycogen metabolism, fructose and galactose metabolism, branched chain aminoacids and tyrosine metabolism, mitochondrial function and glycosylation proteins mechanisms. Historically, genetic analysis consisted of highly detailed molecular testing of nominated single genes. However, more recently, the genetic heterogeneity of these conditions imposed to perform extensive molecular testing within a useful timeframe via new generation sequencing technology. Indeed, the establishment of a rapid diagnosis drives specific nutritional and medical therapies. The biochemical and clinical phenotypes are critical to guide the molecular analysis toward those clusters of genes involved in specific pathways, and address data interpretation regarding the finding of possible disease-causing variants at first reported as variants of uncertain significance in known genes or the discovery of new disease genes. Also, the trio's analysis allows genetic counseling for recurrence risk in further pregnancies. Besides, this approach is allowing to expand the phenotypic characterization of a disease when pathogenic variants give raise to unexpected clinical pictures. Multidisciplinary input and collaboration are increasingly key for addressing the analysis and interpreting the significance of the genetic results, allowing rapidly their translation from bench to bedside.
Collapse
Affiliation(s)
- Arianna Maiorana
- Division of Metabolism, Department of Pediatrics Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy
- *Correspondence: Arianna Maiorana,
| | - Francesca Romana Lepri
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unity, Ospedale Pediatrico Bambino Gesù, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy
| | - Antonio Novelli
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unity, Ospedale Pediatrico Bambino Gesù, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy
| | - Carlo Dionisi-Vici
- Division of Metabolism, Department of Pediatrics Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy
| |
Collapse
|
|
30
|
Chen H, Lyu JJ, Huang Z, Sun XM, Liu Y, Yuan CJ, Ye L, Yu D, Wu J. Case Report: Fanconi-Bickel Syndrome in a Chinese Girl With Diabetes and Severe Hypokalemia. Front Pediatr 2022; 10:897636. [PMID: 35757134 PMCID: PMC9218529 DOI: 10.3389/fped.2022.897636] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/06/2022] [Indexed: 11/24/2022] Open
Abstract
Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive carbohydrate metabolism disorder. The main symptoms of FBS are hepatomegaly, nephropathy, postprandial hyperglycemia, fasting hypoglycemia, and growth retardation. Hypokalemia is a rare clinical feature in patients with FBS. In this study, we present a neonate suffering from FBS. She presented with hypokalemia, dysglycaemia, glycosuria, hepatomegaly, abnormality of liver function, and brain MRI. Trio whole-exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variants. A compound heterozygous mutation (NM_000340.2; p. Trp420*) of SLC2A2 was identified. Here, we report a patient with FBS in a consanguineous family with diabetes, severe hypokalemia, and other typical FBS symptoms. Patients with common clinical features may be difficult to diagnose just by phenotypes in the early stage of life, but WES could be an important tool. We also discuss the use of insulin in patients with FBS and highlight the importance of a continuous glucose monitoring system (CGMS), not only in diagnosis but also to avoid hypoglycemic events.
Collapse
Affiliation(s)
- Hongbo Chen
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Juan-Juan Lyu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Zhuo Huang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Xiao-Mei Sun
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Ying Liu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Chuan-Jie Yuan
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Li Ye
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Dan Yu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Jin Wu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| |
Collapse
|
|
31
|
Sharari S, Aouida M, Mohammed I, Haris B, Bhat AA, Hawari I, Nisar S, Pavlovski I, Biswas KH, Syed N, Maacha S, Grivel JC, Saifaldeen M, Ericsson J, Hussain K. Understanding the Mechanism of Dysglycemia in a Fanconi-Bickel Syndrome Patient. Front Endocrinol (Lausanne) 2022; 13:841788. [PMID: 35663312 PMCID: PMC9159359 DOI: 10.3389/fendo.2022.841788] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 04/07/2022] [Indexed: 11/28/2022] Open
Abstract
Fanconi-Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized mainly by the accumulation of glycogen in the liver and kidney. It is inherited as an autosomal recessive disorder caused by mutations in the SLC2A2 gene, which encodes for GLUT2. Patients with FBS have dysglycemia but the molecular mechanisms of dysglycemia are still not clearly understood. Therefore, we aimed to understand the underlying molecular mechanisms of dysglycemia in a patient with FBS. Genomic DNA was isolated from a peripheral blood sample and analyzed by whole genome and Sanger sequencing. CRISPR-Cas9 was used to introduce a mutation that mimics the patient's mutation in a human kidney cell line expressing GLUT2 (HEK293T). Mutant cells were used for molecular analysis to investigate the effects of the mutation on the expression and function of GLUT2, as well as the expression of other genes implicated in dysglycemia. The patient was found to have a homozygous nonsense mutation (c.901C>T, R301X) in the SLC2A2 gene. CRISPR-Cas9 successfully mimicked the patient's mutation in HEK293T cells. The mutant cells showed overexpression of a dysfunctional GLUT2 protein, resulting in reduced glucose release activity and enhanced intracellular glucose accumulation. In addition, other glucose transporters (SGLT1 and SGLT2 in the kidney) were found to be induced in the mutant cells. These findings suggest the last loops (loops 9-12) of GLUT2 are essential for glucose transport activity and indicate that GLUT2 dysfunction is associated with dysglycemia in FBS.
Collapse
Affiliation(s)
- Sanaa Sharari
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
- Department of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha, Qatar
| | - Mustapha Aouida
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Idris Mohammed
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
- Department of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha, Qatar
| | - Basma Haris
- Department of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha, Qatar
| | | | - Iman Hawari
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
- Department of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha, Qatar
| | - Sabah Nisar
- Department of Research, Sidra Medicine, Doha, Qatar
| | | | - Kabir H. Biswas
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Najeeb Syed
- Department of Research, Sidra Medicine, Doha, Qatar
| | - Selma Maacha
- Department of Research, Sidra Medicine, Doha, Qatar
| | | | - Maryam Saifaldeen
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Johan Ericsson
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
- School of Medicine and Medical Science, University College Dublin, Belfield, Ireland
| | - Khalid Hussain
- Department of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha, Qatar
- *Correspondence: Khalid Hussain,
| |
Collapse
|
|
32
|
Scully KJ, Wolfsdorf J, Dedekian M. Acquired growth hormone deficiency in Fanconi-Bickel syndrome. BMJ Case Rep 2021; 14:e246212. [PMID: 34728514 PMCID: PMC8565550 DOI: 10.1136/bcr-2021-246212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2021] [Indexed: 11/04/2022] Open
Abstract
Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disease, resulting from mutations in the SLC2A2 gene, causing impaired glucose transporter 2 protein transporter protein function, impaired glucose and galactose utilisation, hepatorenal glycogen accumulation and organ dysfunction. Clinical features include failure to thrive, hepatomegaly, rickets, short stature and delayed puberty. Therapy includes electrolyte supplementation and uncooked cornstarch. We present a 15-year-old boy diagnosed with FBS in infancy. Growth velocity was normal on standard treatment until age 8.5 years, at which time growth failure led to a diagnosis of acquired growth hormone (GH) deficiency. Initiation of recombinant human GH (rhGH) replacement of 0.25 μg/kg/week resulted in marked improvement in growth velocity and height. While short stature is expected in FBS, growth velocity that falls below the normal range despite adequate therapy should prompt further evaluation. Our case suggests that acquired GH deficiency can arise in FBS and benefits from rhGH therapy.
Collapse
Affiliation(s)
- Kevin J Scully
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Joseph Wolfsdorf
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Michael Dedekian
- Division of Pediatric Endocrinology, Maine Medical Center, Portland, Maine, USA
| |
Collapse
|
|
33
|
Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems. Sci Rep 2021; 11:13751. [PMID: 34215797 PMCID: PMC8253845 DOI: 10.1038/s41598-021-93063-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/14/2021] [Indexed: 01/07/2023] Open
Abstract
Glucose is an essential energy source for cells. In humans, its passive diffusion through the cell membrane is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT2 transports both glucose and fructose with low affinity and plays a critical role in glucose sensing mechanisms. Alterations in the function or expression of GLUT2 are involved in the Fanconi-Bickel syndrome, diabetes, and cancer. Distinguishing GLUT2 transport in tissues where other GLUTs coexist is challenging due to the low affinity of GLUT2 for glucose and fructose and the scarcity of GLUT-specific modulators. By combining in silico ligand screening of an inward-facing conformation model of GLUT2 and glucose uptake assays in a hexose transporter-deficient yeast strain, in which the GLUT1-5 can be expressed individually, we identified eleven new GLUT2 inhibitors (IC50 ranging from 0.61 to 19.3 µM). Among them, nine were GLUT2-selective, one inhibited GLUT1-4 (pan-Class I GLUT inhibitor), and another inhibited GLUT5 only. All these inhibitors dock to the substrate cavity periphery, close to the large cytosolic loop connecting the two transporter halves, outside the substrate-binding site. The GLUT2 inhibitors described here have various applications; GLUT2-specific inhibitors can serve as tools to examine the pathophysiological role of GLUT2 relative to other GLUTs, the pan-Class I GLUT inhibitor can block glucose entry in cancer cells, and the GLUT2/GLUT5 inhibitor can reduce the intestinal absorption of fructose to combat the harmful effects of a high-fructose diet.
Collapse
|
|
34
|
Sanchez Caballero L, Gorgogietas V, Arroyo MN, Igoillo-Esteve M. Molecular mechanisms of β-cell dysfunction and death in monogenic forms of diabetes. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 359:139-256. [PMID: 33832649 DOI: 10.1016/bs.ircmb.2021.02.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Monogenetic forms of diabetes represent 1%-5% of all diabetes cases and are caused by mutations in a single gene. These mutations, that affect genes involved in pancreatic β-cell development, function and survival, or insulin regulation, may be dominant or recessive, inherited or de novo. Most patients with monogenic diabetes are very commonly misdiagnosed as having type 1 or type 2 diabetes. The severity of their symptoms depends on the nature of the mutation, the function of the affected gene and, in some cases, the influence of additional genetic or environmental factors that modulate severity and penetrance. In some patients, diabetes is accompanied by other syndromic features such as deafness, blindness, microcephaly, liver and intestinal defects, among others. The age of diabetes onset may also vary from neonatal until early adulthood manifestations. Since the different mutations result in diverse clinical presentations, patients usually need different treatments that range from just diet and exercise, to the requirement of exogenous insulin or other hypoglycemic drugs, e.g., sulfonylureas or glucagon-like peptide 1 analogs to control their glycemia. As a consequence, awareness and correct diagnosis are crucial for the proper management and treatment of monogenic diabetes patients. In this chapter, we describe mutations causing different monogenic forms of diabetes associated with inadequate pancreas development or impaired β-cell function and survival, and discuss the molecular mechanisms involved in β-cell demise.
Collapse
Affiliation(s)
- Laura Sanchez Caballero
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Vyron Gorgogietas
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Maria Nicol Arroyo
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Mariana Igoillo-Esteve
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/.
| |
Collapse
|
|
35
|
Iafusco F, Maione G, Rosanio FM, Mozzillo E, Franzese A, Tinto N. Cystic Fibrosis-Related Diabetes (CFRD): Overview of Associated Genetic Factors. Diagnostics (Basel) 2021; 11:diagnostics11030572. [PMID: 33810109 PMCID: PMC8005125 DOI: 10.3390/diagnostics11030572] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 03/19/2021] [Indexed: 12/21/2022] Open
Abstract
Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population and is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that encodes for a chloride/bicarbonate channel expressed on the membrane of epithelial cells of the airways and of the intestine, as well as in cells with exocrine and endocrine functions. A common nonpulmonary complication of CF is cystic fibrosis-related diabetes (CFRD), a distinct form of diabetes due to insulin insufficiency or malfunction secondary to destruction/derangement of pancreatic betacells, as well as to other factors that affect their function. The prevalence of CFRD increases with age, and 40–50% of CF adults develop the disease. Several proposed hypotheses on how CFRD develops have emerged, including exocrine-driven fibrosis and destruction of the entire pancreas, as well as contrasting theories on the direct or indirect impact of CFTR mutation on islet function. Among contributors to the development of CFRD, in addition to CFTR genotype, there are other genetic factors related and not related to type 2 diabetes. This review presents an overview of the current understanding on genetic factors associated with glucose metabolism abnormalities in CF.
Collapse
Affiliation(s)
- Fernanda Iafusco
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy; (F.I.); (G.M.)
- CEINGE Advanced Biotechnology, 80131 Naples, Italy
| | - Giovanna Maione
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy; (F.I.); (G.M.)
- CEINGE Advanced Biotechnology, 80131 Naples, Italy
| | - Francesco Maria Rosanio
- Regional Center of Pediatric Diabetology, Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, 80131 Naples, Italy; (F.M.R.); (E.M.); (A.F.)
| | - Enza Mozzillo
- Regional Center of Pediatric Diabetology, Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, 80131 Naples, Italy; (F.M.R.); (E.M.); (A.F.)
| | - Adriana Franzese
- Regional Center of Pediatric Diabetology, Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, 80131 Naples, Italy; (F.M.R.); (E.M.); (A.F.)
| | - Nadia Tinto
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy; (F.I.); (G.M.)
- CEINGE Advanced Biotechnology, 80131 Naples, Italy
- Correspondence:
| |
Collapse
|
|
36
|
Eghbali M, Fatemi KS, Salehpour S, Abiri M, Saei H, Talebi S, Olyaei NA, Yassaee VR, Modarressi MH. Whole-Exome Sequencing Uncovers Novel Causative Variants and Additional Findings in Three Patients Affected by Glycogen Storage Disease Type VI and Fanconi-Bickel Syndrome. Front Genet 2021; 11:601566. [PMID: 33505429 PMCID: PMC7831547 DOI: 10.3389/fgene.2020.601566] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 12/07/2020] [Indexed: 01/08/2023] Open
Abstract
Glycogen storage diseases (GSDs) are the heterogeneous group of disorders caused by mutations in at least 30 different genes. Different types of GSDs, especially liver GSDs, take overlapping symptoms and can be clinically indistinguishable. This survey evaluated the use of whole-exome sequencing (WES) for the genetic analysis of the liver GSD-suspected patients in three unrelated families. An in-house filtering pipeline was used to assess rare pathogenic variants in GSD-associated genes, autosomal recessive/mendelian disorder genes (carrier status for genetic counseling subjects), and the ACMG's list of 59 actionable genes. For the interpretation of the causative variants and the incidental/secondary findings, ACMG guidelines were applied. Additionally, we have explored PharmGKB class IA/IB pharmacogenetic variants. The segregation analysis was performed using Sanger sequencing for the novel causative variants. Bioinformatics analysis of the exome data in three individuals revealed three novel homozygous causative variants in the GSD-associated genes. The first variant, c.298_307delATGATCAACC in PYGL gene has related to HERS disease (GSD VI). Both variants of c.1043dupT and c.613-1G > C in SLC2A2 gene have been associated with Fanconi-Bickel syndrome (GSDXI). Eight pathogenic/likely pathogenic medical actionable findings in Mendelian disease genes and 10 pharmacogenetic variants with underlying drug response phenotypes have been identified. No known/expected pathogenic variants were detected in the ACMG's list of 59 actionable genes. The logical filtering steps can help in finding other medical actionable secondary/incidental findings as well as effectively identifying the causative variants in heterogeneous conditions such as GSDs. Three novel variants related to GSD genes recognized in liver GSD-suspected patients with early infantile and childhood-age onset.
Collapse
Affiliation(s)
- Maryam Eghbali
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kiyana Sadat Fatemi
- Dr. Zenali’s Medical Genetics Laboratory, Kawsar Human Genetics Research Center, Tehran, Iran
| | - Shadab Salehpour
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Pediatric Endocrinology and Metabolism, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Abiri
- Shahid Akbarabadi Clinical Research Development Unit, Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hassan Saei
- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Saeed Talebi
- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nasrin Alipour Olyaei
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Reza Yassaee
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | |
Collapse
|