Does defective hypoxia signalling cause type 2 diabetes?

Presently more than 200 Million people are sufferingfrom type 2 diabetes (1). Considerable progress hasbeen achieved in the understanding of the pathoge-netic role of insulin resistance (2, 3). However, less isknown with regard to a dysregulation of islet cellfunction. Three pathogenetic mechanisms have beenidentied. They include alterations in glucose sensing,insulin secretion, and insulin signalling (Fig. 1).Genetic alterations of insulin secretion are found inpatients with Maturity Onset Diabetes of the Young(MODY). Five out of six mutations leading to MODYinvolve transcription factors that regulate insulinsignalling (4).However, several questions in the pathogenetic eld oftype 2 diabetes remain unsolved.1. Are genes other than those causing MODY involvedin the pathogenesis of type 2 diabetes?2. Is there a key player, regulating various genesinvolved in insulin secretion, insulin signalling andglucose sensing?3. Does the deeper understanding of the pathogenesisof type 2 diabetes provide new targets of thetreatment of the disease?To examine this issue Gunton and co-workers (5)compared the gene expression prole of pancreatic isletsfrom patients with type 2 diabetes and non-affectedcontrols using oligonucleotide microarrays and real-time PCR. Apart from expected changes in genes knownto be involved in the pathogenesis of type 2 diabetesmellitus, there was a marked downregulation of thegene for hypoxia-inducible factor-1b (HIF-1b)alsocalled aryl hydrocarbon receptor nuclear translocator(ARNT). The microarray data were conrmed by real-time PCR.Experimental downregulation of ARNT in theinsulin-secreting insulinoma cell line Min6 usingsiRNA resulted in a marked reduction of genes involvedin glucose-stimulated insulin secretion such asHepatocyte Nuclear Factors (HNF) 4a and 1a. More-over, genes involved in glucose metabolism and insulinsecretion were signicantly decreased as a consequenceof ARNT suppression.To examine the role of ARNT in vivo,Guntonandco-workers created a mouse with a targeted deletionof pancreatic ARNT (b-ARNT) (5). Female b-ARNTmice had an abolished glucose-stimulated insulinrelease, whereas male animals had a milderphenotype showing slightly higher serum glucoseconcentrations but a normalin vivo insulin secretionin response to glucose. However, in isolated islets thesecretion of insulin was attenuated when glucoseconcentrations of 8.3 mM and above were applied.However, total b-cell mass and total insulinconcentration was not changed and insulinsecretion was unaltered in response to lowerconcentrations of glucose. One of the MODY genes,HNF4a, was signicantly decreased by more than90% in the islets of the b-ARNT knock out mice. Asin the cellular ARNT knock out, a number of genesinvolved in glucose metabolism, insulin secretion,and insulin receptor were signicantly decreased.Finally, by showing that ARNT is not reduced in thediabetic db/db and ob/ob mice, Gunton and co-workersprove that the downregulation of the gene is not non-specically caused by diabetes, hyperglycaemia, orinsulin resistance (5).ARNT does not appear to be merely a factor that isepigenetically regulated and appears to play animportant role in the genesis of type 2 diabetes.Whether ARNT itself or more essential factors furtherupstream in the cascade are the essential key player,remains to be shown. Would an early correction ofARNT suppression delay the onset of type 2 diabetes?Furthermore, do the results of Gunton and co-workerssuggest an involvement of hypoxia induced processes inthe genesis of type 2 diabetes? These issues may markquestions appearing worth to be investigated in furtherresearch projects.