Abstract
Recently it has been shown that dominant mutations in the human hepatocyte nuclear factor 1alpha (HNF1alpha) gene, encoding for a homeoprotein that is expressed in liver, kidney, pancreas and intestine, result in maturity onset diabetes of the young type 3 (MODY3). HNF1alpha-null mice are diabetic, but at the same time suffer from a renal Fanconi syndrome characterized by urinary glucose loss. Here we show that MODY3 patients are also characterized by a reduced tubular reabsorption of glucose. The renal murine defect is due to reduced expression of the low affinity/high capacity glucose cotransporter (SGLT2). Our results show that HNF1alpha directly controls SGLT2 gene expression. Together these data indicate that HNF1alpha plays a key role in glucose homeostasis in mammals.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Absorption
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Adult
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Animals
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Biological Transport
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Blood Glucose / metabolism
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Blotting, Northern
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DNA Primers / chemistry
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DNA-Binding Proteins*
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Diabetes Mellitus, Type 1 / genetics
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Diabetes Mellitus, Type 1 / metabolism*
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Female
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Genomic Library
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Glucose / metabolism*
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Hepatocyte Nuclear Factor 1
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Hepatocyte Nuclear Factor 1-alpha
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Hepatocyte Nuclear Factor 1-beta
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Humans
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Kidney Tubules, Proximal / metabolism*
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Luciferases / metabolism
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Male
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Mice
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Mice, Knockout
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Middle Aged
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Monosaccharide Transport Proteins / genetics*
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Monosaccharide Transport Proteins / metabolism
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Mutation
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Nuclear Proteins*
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Promoter Regions, Genetic
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Reverse Transcriptase Polymerase Chain Reaction
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Sodium-Glucose Transporter 2
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Transcription Factors / genetics*
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Transcription Factors / physiology*
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Transfection
Substances
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Blood Glucose
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DNA Primers
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DNA-Binding Proteins
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HNF1A protein, human
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HNF1B protein, human
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Hepatocyte Nuclear Factor 1-alpha
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Hnf1a protein, mouse
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Hnf1b protein, mouse
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Monosaccharide Transport Proteins
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Nuclear Proteins
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SLC5A2 protein, human
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Slc5a2 protein, mouse
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Sodium-Glucose Transporter 2
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Transcription Factors
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Hepatocyte Nuclear Factor 1
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Hepatocyte Nuclear Factor 1-beta
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Luciferases
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Glucose