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)

A mouse model of thiamin-responsive megaloblastic anemia (diabetes mellitus, deafness, megaloblastic anemia) lacking functional Slc19a2 has been generated and unexpectedly found to have a male-specific sterility phenotype. We describe here the characterization of the testis-specific effects of absence of the high-affinity thiamin transporter, Tht1. Null males were found to have hypoplastic testes secondary to germ cell depletion. Morphologic and expression analysis revealed that under conditions of standard thiamin intake, tissues affected in the syndrome (pancreatic beta-cell, hematopoietic cells, auditory nerve) maintained normal function but pachytene stage spermatocytes underwent apoptosis. Under conditions of thiamin challenge, the apoptotic cell loss extended to earlier stages of germ cells but spared Sertoli cells and Leydig cells. Injection of high-dose thiamin was effective in reversing the spermatogenic failure, suggesting that the absence of the thiamin carrier could be overcome by diffusion-mediated transport at supranormal thiamin concentrations. These observations demonstrated that male germ cells, particularly those with high thiamin transporter expression beyond the blood-testis barrier, were more susceptible to apoptosis triggered by intracellular thiamin deficiency than any other tissue type. The findings described here highlight an unexpected and critical role for thiamin transport and metabolism in spermatogenesis.
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PMID:Male infertility due to germ cell apoptosis in mice lacking the thiamin carrier, Tht1. A new insight into the critical role of thiamin in spermatogenesis. 1473 78

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder with features that include megaloblastic anemia, mild thrombocytopenia and leukopenia, sensorineural deafness and diabetes mellitus. In this disease, the active thiamine uptake into cells is disturbed. Treatment with pharmacological doses of thiamine ameliorates the megaloblastic anemia and diabetes mellitus. Previous studies have demonstrated that the disease is caused by mutations in the SLC19A2 gene encoding a high-affinity thiamine transporter. We present a 5-yr-old-boy with TRMA and, because of its rarity, we review the literature.
Pediatr Diabetes 2002 Dec
PMID:TRMA syndrome (thiamine-responsive megaloblastic anemia): a case report and review of the literature. 1501 49

More than 20 syndromes among the significant and increasing number of degenerative diseases of neuronal tissues are known to be associated with diabetes mellitus, increased insulin resistance and obesity, disturbed insulin sensitivity, and excessive or impaired insulin secretion. This review briefly presents such syndromes, including Alzheimer disease, ataxia-telangiectasia, Down syndrome/trisomy 21, Friedreich ataxia, Huntington disease, several disorders of mitochondria, myotonic dystrophy, Parkinson disease, Prader-Willi syndrome, Werner syndrome, Wolfram syndrome, mitochondrial disorders affecting oxidative phosphorylation, and vitamin B(1) deficiency/inherited thiamine-responsive megaloblastic anemia syndrome as well as their respective relationship to malignancies, cancer, and aging and the nature of their inheritance (including triplet repeat expansions), genetic loci, and corresponding functional biochemistry. Discussed in further detail are disturbances of glucose metabolism including impaired glucose tolerance and both insulin-dependent and non-insulin-dependent diabetes caused by neurodegeneration in humans and mice, sometimes accompanied by degeneration of pancreatic beta-cells. Concordant mouse models obtained by targeted disruption (knock-out), knock-in, or transgenic overexpression of the respective transgene are also described. Preliminary conclusions suggest that many of the diabetogenic neurodegenerative disorders are related to alterations in oxidative phosphorylation (OXPHOS) and mitochondrial nutrient metabolism, which coincide with aberrant protein precipitation in the majority of affected individuals.
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PMID:Neurodegenerative disorders associated with diabetes mellitus. 1517 61

Mutations in the gene coding for the high-affinity thiamine transporter Slc19a2 underlie the clinical syndrome known as thiamine-responsive megaloblastic anemia (TRMA) characterized by anemia, diabetes, and sensorineural hearing loss. To create a mouse model of this disease, a mutant line was created with targeted disruption of the gene. Cochlear function is normal in these mutants when maintained on a high-thiamine diet. When challenged with a low-thiamine diet, Slc19a2-null mice showed 40-60 dB threshold elevations by auditory brainstem response (ABR), but only 10-20 dB elevation by otoacoustic emission (OAE) measures. Wild-type mice retain normal hearing on either diet. Cochlear histological analysis showed a pattern uncommon for sensorineural hearing loss: selective loss of inner hair cells after 1-2 weeks on low thiamine and significantly greater inner than outer hair cell loss after longer low-thiamine challenges. Such a pattern is consistent with the observed discrepancy between ABR and OAE threshold shifts. The possible role of thiamine transport in other reported cases of selective inner hair cell loss is considered.
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PMID:Deletion of SLC19A2, the high affinity thiamine transporter, causes selective inner hair cell loss and an auditory neuropathy phenotype. 1664 88

To study the clinical and hematologic features of pernicious anemia in Chinese, we describe 181 Chinese with megaloblastic anemia and low serum cobalamin, in association with either classic Schilling test results (82 patients) or the presence of serum antibody to intrinsic factor (99 patients), encountered in a regional hospital in Hong Kong from May 1994 to May 2005. The median age was 75 years (range, 32-95 yr) and the male to female ratio was 1:1.5. The chief presenting feature was anemia, and fewer than 10% of patients presented predominantly with neurologic deficit. Gastric biopsies of 109 patients showed glandular atrophy in 73, endocrine cell hyperplasia in 5, polyps in 14, adenocarcinoma in 1, and chronic gastritis in the rest. Gastric adenocarcinoma occurred in 1.7% of patients after a median follow-up of 35 months (range, 0.5-132 mo). Diabetes mellitus occurred in 24% of patients and thyroid disease in 7%. No specific ABO blood group was associated with pernicious anemia. Serum antibody to intrinsic factor (73%) occurred more frequently than serum antibody to gastric parietal cell (65%) (p=0.353). The frequency of serum antibody to gastric parietal cell was higher in male (78%) than in female patients (53%) (p=0.018). Pernicious anemia is a major cause of megaloblastic anemia in Chinese.
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PMID:Pernicious anemia in Chinese: a study of 181 patients in a Hong Kong hospital. 1672 Dec 55

The micronutrient thiamine is required for normal growth and development of human tissues, and is accumulated into cells through the activity of plasma membrane thiamine transporters, e.g. hTHTR1 (human thiamine transporter 1). Recent genetic evidence has linked mutations in hTHTR1 with the manifestation of TRMA (thiamine-responsive megaloblastic anaemia), a condition also associated with diabetes mellitus, sensorineural deafness and retinal disorders. To examine how mutations in hTHTR1 impair thiamine accumulation, we have investigated the targeting and functional properties of several different hTHTR1 mutants in human cell lines derived from epithelia relevant to thiamine absorption or tissues implicated in TRMA pathology. These constructs encompassed two newly identified point mutations (P51L and T158R) and two truncations of hTHTR1 identical with those found in TRMA kindreds (W358X and Delta383fs). Our results reveal a spectrum of mutant phenotypes, underlining that TRMA can result from decreased thiamine transport activity underpinned by changes in hTHTR1 expression levels, cellular targeting and/or protein transport activity.
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PMID:Targeting and intracellular trafficking of clinically relevant hTHTR1 mutations in human cell lines. 1733 Oct 69

Thiamine-responsive megaloblastic anaemia (TRMA) is a rare autosomal recessive condition, characterized by megaloblastic anaemia, non-autoimmune diabetes mellitus, and sensorineural hearing loss. We describe three infants with TRMA from two consanguineous Pakistani families, who were not known to be related but originated from the same area in Pakistan. All children were homozygous, and the parents were heterozygous for a c.196G>T mutation in the SLC19A2 gene on chromosome 1q23.3, which encodes a high-affinity thiamine transporter. The result is an abnormal thiamine transportation and vitamin deficiency in the cells. Thiamine in high doses (100-200 mg/d) reversed the anaemia in all our patients. Two patients discontinued insulin treatment successfully after a short period, while the third patient had to continue with insulin. The hearing loss persisted in all three children. The diagnosis of TRMA should be suspected in patients with syndromic diabetes including hearing loss and anaemia, even if the latter is only very mild and, particularly, in the case of consanguinity.
Pediatr Diabetes 2007 Aug
PMID:Thiamine-responsive megaloblastic anaemia: a cause of syndromic diabetes in childhood. 1765 67

Thiamine responsive megaloblastic anemia syndrome (TRMA), an autosomal recessive disorder caused by the deficiency of thiamine transporter protein, is the association of diabetes mellitus, anemia and deafness. Pharmacological dose thiamine normalizes hematological abnormalities and their effects on the course of diabetes mellitus. We report on 8 years follow up of two siblings with TRMA. They presented in the prepubertal period with diabetic ketoacidosis due to lack of thiamine supplementation for 2 months. Their insulin requirements fell rapidly and disappeared with thiamine therapy. Hematological parameters normalized within 30 days. The diabetic picture is responsive to thiamine treatment in patients with TRMA. Insulin dependent diabetes may occur throughout the pubertal period. If thiamine supplementation is not sufficient, ketoacidosis may develop in patients during the prepubertal period.
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PMID:Thiamine withdrawal can lead to diabetic ketoacidosis in thiamine responsive megaloblastic anemia: report of two siblings. 1855 72

Reported here is a 2-year-old girl who was diagnosed to have thiamine-responsive megaloblastic anemia during evaluations for her bilateral neurosensorial deafness. Besides reporting a new mutation on the gene SLC19A2 for the first time in the literature, we highlight the recognition of this syndrome--when megaloblastic anemia and diabetes mellitus coexists--and the role of thiamine replacement for the treatment of both disorders.
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PMID:A novel mutation in the SLC19A2 gene in a Turkish female with thiamine-responsive megaloblastic anemia syndrome. 1861 93

This report describes a female child with thiamine responsive megaloblastic anemia syndrome (Rogers syndrome), presenting with anemia and diabetes mellitus responding to thiamine. She also had retinitis pigmentosa. The anemia improved and blood sugar was controlled with daily oral thiamine. Previously unreported olfactory abnormalities, as described in Wolfram syndrome, were also present in our patient.
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PMID:Thiamine responsive megaloblastic anemia. 1924 38


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