Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have carried out a detailed sequence and functional analysis of a novel human facilitative glucose transporter, designated GLUT10, located in the Type 2 diabetes-linked region of human chromosome 20q12-13.1. The GLUT10 gene is located between D20S888 and D20S891 and is encoded by 5 exons spanning 26.8 kb of genomic DNA. The human GLUT10 cDNA encodes a 541 amino acid protein that shares between 31 and 35% amino acid identity with human GLUT1-8. The predicted amino acid sequence of GLUT10 is nearly identical in length to the recently described GLUT9 homologue, but is longer than other known members of the GLUT family. In addition, we have cloned the mouse cDNA homolog of GLUT10 that encodes a 537 amino acid protein that shares 77.3% identity with human GLUT10. The amino acid sequence probably has 12 predicted transmembrane domains and shares characteristics of other mammalian glucose transporters. Human and mouse GLUT10 retain several sequence motifs characteristic of mammalian glucose transporters including VP497ETKG in the cytoplasmic C-terminus, G73R[K,R] between TMD2 and TMD3 (PROSITE PS00216), VD92RAGRR between TMD8 and TMD9 (PROSITE PS00216), Q242QLTG in TMD7, and tryptophan residues W430 (TMD10) and W454 (TMD11), that correspond to trytophan residues previously implicated in GLUT1 cytochalasin B binding and hexose transport. Neither human nor mouse GLUT10 retains the full P[E,D,N]SPR motif after Loop6 but instead is replaced with P186AG[T,A]. A PROSITE search also shows that GLUT10 has lost the SUGAR TRANSPORT 2 pattern (PS00217), a result of the substitution G113S in TMD4, while all other known human GLUTs retain the glycine and the pattern match. The significance of this substitution is unknown. Sites for N-linked glycosylation are predicted at N334ATG between TMD8 and TMD9 and N526STG in the cytoplasmic C-terminus. Northern hybridization analysis identified a single 4.4-kb transcript for GLUT10 in human heart, lung, brain, liver, skeletal muscle, pancreas, placenta, and kidney. By RT-PCR analysis, GLUT10 mRNA was also detected in fetal brain and liver. When expressed in Xenopus oocytes, human GLUT10 exhibited 2-deoxy-D-glucose transport with an apparent Km of approximately 0.3 mM. D-Glucose and D-galactose competed with 2-deoxy-D-glucose and transport was inhibited by phloretin. The gene localization and functional properties suggest a role for GLUT10 in glucose metabolism and Type 2 diabetes.
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PMID:Sequence and functional analysis of GLUT10: a glucose transporter in the Type 2 diabetes-linked region of chromosome 20q12-13.1. 1159 15

The SLC2A10 gene encodes the GLUT10 facilitative glucose transporter, which is expressed in high amounts in liver and pancreas. The gene is mapped to chromosome 20q12-q13.1, a region that has been shown to be linked to type 2 diabetes. The gene was examined in 61 Danish type 2 diabetic patients, and a total of six variants (-27C-->T, Ala206Thr, Ala272Ala, IVS2 + 10G-->A, IVS4 + 18T-->G, and IVS4 + 26G-->A) were identified and investigated in an association study, which included 503 type 2 diabetic patients and 510 glucose-tolerant control subjects. None of the variants were associated with type 2 diabetes. Interestingly, carriers of the codon 206 Thr allele had 18% lower fasting serum insulin levels (P = 0.002) and 20% lower insulinogenic index (P = 0.03) than homozygous carriers of the Ala allele. These results suggest that variation in the coding region of SLC2A10 does not contribute substantially to the pathogenesis of type 2 diabetes in the examined study population. However, the codon 206 polymorphism may be related to the interindividual variation in fasting and oral glucose-induced serum insulin levels.
Diabetes 2003 Sep
PMID:Genetic variation of the GLUT10 glucose transporter (SLC2A10) and relationships to type 2 diabetes and intermediary traits. 1294 88

Arterial tortuosity syndrome (ATS) is an autosomal recessive disorder characterized by tortuosity, elongation, stenosis and aneurysm formation in the major arteries owing to disruption of elastic fibers in the medial layer of the arterial wall. Previously, we used homozygosity mapping to map a candidate locus in a 4.1-Mb region on chromosome 20q13.1 (ref. 2). Here, we narrowed the candidate region to 1.2 Mb containing seven genes. Mutations in one of these genes, SLC2A10, encoding the facilitative glucose transporter GLUT10, were identified in six ATS families. GLUT10 deficiency is associated with upregulation of the TGFbeta pathway in the arterial wall, a finding also observed in Loeys-Dietz syndrome, in which aortic aneurysms associate with arterial tortuosity. The identification of a glucose transporter gene responsible for altered arterial morphogenesis is notable in light of the previously suggested link between GLUT10 and type 2 diabetes. Our data could provide new insight on the mechanisms causing microangiopathic changes associated with diabetes and suggest that therapeutic compounds intervening with TGFbeta signaling represent a new treatment strategy.
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PMID:Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. 1657 59

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disease, characterized by widespread arterial involvement with elongation, tortuosity, and aneurysms of the large and middle-sized arteries. Recently, SLC2A10 mutations were identified in this condition. This gene encodes the glucose transporter GLUT10 and was previously suggested as a candidate gene for diabetes mellitus type 2. A total of 12 newly identified ATS families with 16 affected individuals were clinically and molecularly characterized. In addition, extensive cardiovascular imaging and glucose tolerance tests were performed in both patients and heterozygous carriers. All 16 patients harbor biallelic SLC2A10 mutations of which nine are novel (six missense, three truncating mutations, including a large deletion). Haplotype analysis suggests founder effects for all five recurrent mutations. Remarkably, patients were significantly older than those previously reported in the literature (P=0.04). Only one affected relative died, most likely of an unrelated cause. Although the natural history of ATS in this series was less severe than previously reported, it does indicate a risk for ischemic events. Two patients initially presented with stroke, respectively at age 8 months and 23 years. Tortuosity of the aorta or large arteries was invariably present. Two adult probands (aged 23 and 35 years) had aortic root dilation, seven patients had localized arterial stenoses, and five had long stenotic stretches of the aorta. Heterozygous carriers did not show any vascular anomalies. Glucose metabolism was normal in six patients and eight heterozygous individuals of five families. As such, overt diabetes is not related to SLC2A10 mutations associated with ATS.
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PMID:Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. 1793 13

GLUT4 is necessary for acute insulin- and contraction-induced skeletal muscle glucose uptake, but its role in chronic muscle loading (overload)-induced glucose uptake is unknown. Our goal was to determine whether GLUT4 is required for overload-induced glucose uptake. Overload was induced in mouse plantaris muscle by unilateral synergist ablation. After 5 days, muscle weights and ex vivo [3H]-2-deoxy-d-glucose uptake were assessed. Overload-induced muscle glucose uptake and hypertrophic growth were not impaired in muscle-specific GLUT4 knockout mice, demonstrating that GLUT4 is not necessary for these processes. To assess which transporters mediate overload-induced glucose uptake, chemical inhibitors were used. The facilitative GLUT inhibitor cytochalasin B, but not the sodium-dependent glucose cotransport inhibitor phloridzin, prevented overload-induced uptake demonstrating that GLUTs mediate this effect. To assess which GLUT, hexose competition experiments were performed. Overload-induced [3H]-2-deoxy-d-glucose uptake was not inhibited by d-fructose, demonstrating that the fructose-transporting GLUT2, GLUT5, GLUT8, and GLUT12 do not mediate this effect. To assess additional GLUTs, immunoblots were performed. Overload increased GLUT1, GLUT3, GLUT6, and GLUT10 protein levels twofold to fivefold. Collectively, these results demonstrate that GLUT4 is not necessary for overload-induced muscle glucose uptake or hypertrophic growth and suggest that GLUT1, GLUT3, GLUT6, and/or GLUT10 mediate overload-induced glucose uptake.
Diabetes 2017 06
PMID:GLUT4 Is Not Necessary for Overload-Induced Glucose Uptake or Hypertrophic Growth in Mouse Skeletal Muscle. 2827 80

Psoriasis is characterized by hyperproliferation and defective differentiation of keratinocytes (KCs). Patients with psoriasis are at a high risk of developing diabetes and cardiovascular diseases. The debate on the genetic origin of psoriasis pathogenesis remains unresolved due to lack of suitable in vitro human models mimicking the disease phenotypes. In this study, we provide the first human induced pluripotent stem cell (iPSC) model for psoriasis carrying the genetic signature of the patients. iPSCs were generated from patients with psoriasis (PsO-iPSCs) and healthy donors (Ctr-iPSCs) and were efficiently differentiated into mature KCs. RNA sequencing of KCs derived from Ctr-iPSCs and PsO-iPSCs identified 361 commonly upregulated and 412 commonly downregulated genes. KCs derived from PsO-iPSCs showed dysregulated transcripts associated with psoriasis and KC differentiation, such as HLA-C, KLF4, chemokines, type I interferon-inducible genes, solute carrier family, IVL, DSG1, and HLA-DQA1, as well as transcripts associated with insulin resistance, such as IRS2, GDF15, GLUT10, and GLUT14. Our data suggest that the KC abnormalities are the main driver triggering psoriasis pathology and highlights the substantial contribution of genetic predisposition in the development of psoriasis and insulin resistance.
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PMID:Keratinocytes Derived from Patient-Specific Induced Pluripotent Stem Cells Recapitulate the Genetic Signature of Psoriasis Disease. 3199 98