Review on monogenic diabetes
ABSTRACT The goal of this review is to provide an update on the different forms of monogenic diabetes, including maturity-onset diabetes of the young (MODY) and neonatal diabetes (permanent and transient neonatal diabetes).
Monogenic diabetes accounts for approximately 1-2% of diabetes cases and results from mutations that primarily reduce β-cell function. Individuals with islet autoantibody negative youth-onset forms of diabetes should be evaluated for either glucokinase-MODY or transcription factors MODY. The mild-fasting hyperglycemia found in glucokinase-MODY typically does not necessitate pharmacological treatment, whereas patients with MODY caused by transcription factor mutations can often be successfully treated with low-dose sulfonylurea. Neonatal diabetes is defined as diabetes onset within the first 6 months of life and most individuals with permanent neonatal diabetes can be treated with high-dose sulfonylurea.
The discovery of the genetic cause of monogenic diabetes has greatly advanced our understanding and management of these uncommon forms of diabetes.
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ABSTRACT: Glucokinase plays important tissue-specific roles in human physiology, where it acts as a sensor of blood glucose levels in the pancreas, and a few other cells of the gut and brain, and as the rate-limiting step in glucose metabolism in the liver. Liver-specific expression is driven by one of the two tissue-specific promoters, and has an absolute requirement for insulin. The sequences that mediate regulation by insulin are incompletely understood. To better understand the liver-specific expression of the human glucokinase gene we compared the structures of this gene from diverse mammals. Much of the sequence located between the 5' pancreatic beta-cell-specific and downstream liver-specific promoters of the glucokinase genes is composed of repetitive DNA elements that were inserted in parallel on different mammalian lineages. The transcriptional activity of the liver-specific promoter 5' flanking sequences were tested with and without downstream intronic sequences in two human liver cells lines, HepG2 and L-02. While glucokinase liver-specific 5' flanking sequences support expression in liver cell lines, a sequence located about 2000 bases 3' to the liver-specific mRNA start site represses gene expression. Enhanced reporter gene expression was observed in both cell lines when cells were treated with fetal calf serum, but only in the L-02 cells was expression enhanced by insulin. Our results suggest that the normal liver L-02 cell line may be a better model to understand the regulation of the liver-specific expression of the human glucokinase gene. Our results also suggest that sequences downstream of the liver-specific mRNA start site have important roles in the regulation of liver-specific glucokinase gene expression.PLoS ONE 09/2012; 7(9):e45824. DOI:10.1371/journal.pone.0045824 · 3.53 Impact Factor
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ABSTRACT: Diabetes mellitus is a common endocrinopathy in companion animals, characterised by hyperglycaemia, glycosuria and weight loss, resulting from an absolute or relative deficiency in the pancreatic hormone insulin. There are breed differences in susceptibility to diabetes mellitus in dogs, with the Samoyed breed being overrepresented, while Boxers are relatively absent in the UK population of diabetic dogs, suggesting that genetic factors play an important role in determining susceptibility to the disease. A number of genes, linked with susceptibility to diabetes mellitus in humans, are associated with an increased risk of diabetes mellitus in dogs, some of which appear to be relatively breed-specific. Diabetes mellitus in dogs has been associated with major histocompatibility complex (MHC) class II genes (dog leucocyte antigen; DLA), with similar haplotypes and genotypes being identified in the most susceptible breeds. A region containing a variable number of tandem repeats (VNTR) and several polymorphisms have been identified in the canine insulin gene, with some alleles associated with susceptibility or resistance to diabetes mellitus in a breed-specific manner. Polymorphisms in the canine CTLA4 promoter and in other immune response genes are associated with susceptibility to diabetes mellitus in a number of pedigree breeds. Genome wide association studies are currently underway that should shed further light on the genetic factors responsible for the breed profile seen in the diabetic dog population.The Veterinary Journal 12/2012; 195(2). DOI:10.1016/j.tvjl.2012.11.013 · 2.17 Impact Factor