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Diabetes is associated with significantly accelerated rates of several debilitating microvascular complications such as nephropathy, retinopathy, and neuropathy, and macrovascular complications such as atherosclerosis and stroke. While several studies have been devoted to the evaluation of genetic factors related to type 1 and type 2 diabetes and associated complications, much less is known about epigenetic changes that occur without alterations in the DNA sequence. Environmental factors and nutrition have been implicated in diabetes and can also affect epigenetic states. Exciting research has shown that epigenetic changes in chromatin can affect gene transcription in response to environmental stimuli, and changes in key chromatin histone methylation patterns have been noted under diabetic conditions. Reports also suggest that epigenetics may be involved in the phenomenon of metabolic memory observed in clinic trials and animal studies. Further exploration into epigenetic mechanisms can yield new insights into the pathogenesis of diabetes and its complications and uncover potential therapeutic targets and treatment options to prevent the continued development of diabetic complications even after glucose control has been achieved. diabetes; metabolic memory; hyperglycemia; diabetic kidney disease doi: 10.1152/ajprenal.00200.2010.

Homologous chromosomes must pair and establish stable connections during prophase I of meiosis to segregate reliably from each other at anaphase I. In most organisms, the stable connections, called chiasmata, arise from crossovers. In Drosophila males, homologs pair and segregate without crossing oven Chiasmata are replaced by a homolog conjunction complex that includes the Stromalin in Meiosis (SNM) and Modifier of Mdg4 in Meiosis (MNM) proteins. MNM is one of 31 alternative splice products of mod(mdg4), all of which share a common 402-amino-acid N terminus and differ at their C termini. Previous data demonstrated that an MNM-specific exon is required for homolog conjunction, but did not address whether the N-terminal common region, which includes a BTB domain that can mediate coalescence of protein-DNA complexes, is also required. Here we describe a mutation in the common region of mod(mdg4), Z3-3401, that causes qualitatively similar phenotypes as the MNM-specific alleles but disrupts X-Y segregation much more drastically than autosomal segregation. The mutant MNM protein in Z3-3401 is expressed throughout prophase I in spermatocytes but the protein is confined to the cytoplasm, suggesting that the Z3-3401 mutation disrupts a signal required for nuclear localization or retention. Z3-3401 fails to complement a large battery of lethal and semilethal alleles in the common region for meiotic nondisjunction, including an allele containing an amino acid substitution at a conserved residue in the BTB/POZ domain, consistent with a general requirement for the mod(mdg4) common region in homolog segregation.

Homologous chromosomes must pair and establish stable connections during prophase I of meiosis to segregate reliably from each other at anaphase I. In most organisms, the stable connections, called chiasmata, arise from crossovers. In Drosophila males, homologs pair and segregate without crossing over. Chiasmata are replaced by a homolog conjunction complex that includes the Stromalin in Meiosis (SNM) and Modifier of Mdg4 in Meiosis (MNM) proteins. MNM is one of 31 alternative splice products of mod(mdg4), all of which share a common 402-amino-acid N terminus and differ at their C termini. Previous data demonstrated that an MNM-specific exon is required for homolog conjunction, but did not address whether the N-terminal common region, which includes a BTB domain that can mediate coalescence of protein-DNA complexes, is also required. Here we describe a mutation in the common region of mod(mdg4), Z3-3401, that causes qualitatively similar phenotypes as the MNM-specific alleles but disrupts X-Y segregation much more drastically than autosomal segregation. The mutant MNM protein in Z3-3401 is expressed throughout prophase I in spermatocytes but the protein is confined to the cytoplasm, suggesting that the Z3-3401 mutation disrupts a signal required for nuclear localization or retention. Z3- 3401 fails to complement a large battery of lethal and semilethal alleles in the common region for meiotic nondisjunction, including an allele containing an amino acid substitution at a conserved residue in the BTB/POZ domain, consistent with a general requirement for the mod(mdg4) common region in homolog segregation. [ABSTRACT FROM AUTHOR]

The incidence of diabetes and related complications like nephropathy is growing rapidly and has become a major health care issue. Changes in the environment and nutritional habits have been implicated as major players. Furthermore, it is becoming increasingly clear that epigenetic factors may modulate the connections between genes and the environment. While diabetes in itself is treatable to a large extent, it is still associated with significantly increased risk for complications including chronic kidney and cardiovascular diseases. Current treatments have added preventative approaches so as to avoid future diabetic complications. Unfortunately, diabetic patients are often plagued with the continued development of various complications even after achieving glucose control. This has been suggested to be attributable to a mysterious phenomenon termed 'metabolic memory' of the prior glycemic state. Recent studies have suggested that epigenetic changes to chromatin can affect gene expression in response to various stimuli, and changes in key biochemical pathways and epigenetic histone and DNA methylation patterns in chromatin have been observed in a diabetic milieu. These accumulating data suggest that metabolic or hyperglycemic memory may be due to epigenetic changes in specific target tissues altering gene expression without changing the genetic code itself. While the genetics of diabetes has long been the focus of scientific research, much less is known about the role of epigenetics and the related molecular pathways that might affect the development of diabetes and the associated complications. Further studies of epigenetic mechanisms are therefore timely and could provide valuable new insights into the pathology of diabetic complications and also uncover much needed new therapeutic targets., (Copyright © 2011 S. Karger AG, Basel.)