Gender and neurogenin3 influence the pathogenesis of ketosis-prone diabetes.

Ketosis-prone diabetes (KPD) is a phenotypically defined form of diabetes characterized by male predominance and severe insulin deficiency. Neurogenin3 (NGN3) is a proendocrine gene, which is essential for the fate of pancreatic beta cells. Mice lacking ngn3 develop early insulin-deficient diabetes. Thus, we hypothesized that gender and variants in NGN3 could predispose to KPD. We have studied clinical and metabolic parameters according to gender in patients with KPD (n = 152) and common type 2 diabetes (T2DM) (n = 167). We have sequenced NGN3 in KPD patients and screened gene variants in T2DM and controls (n = 232). In KPD, male gender was associated with a more pronounced decrease in beta-cell insulin secretory reserve, assessed by fasting C-peptide [mean (ng/ml) +/- s.d., M: 1.1 +/- 0.6, F: 1.5 +/- 0.9; p = 0.02] and glucagon-stimulated C-peptide [mean (ng/ml) +/- s.d., M: 2.2 +/- 1.1, F: 3.1 +/- 1.7; p = 0.03]. The rare affected females were in an anovulatory state. We found two new variants in the promoter [-3812T/C (af: 2%) and -3642T/C (af: 1%)], two new coding variants [S171T (af: 1%) and A185S (af: 1%)] and the variant already described [S199F (af: 69%)]. These variants were not associated with diabetes. Clinical investigation revealed an association between 199F and hyperglycaemia assessed by glycated haemoglobin [HbA1c (%, +/-s.d.) S199: 12.6 +/- 1.6, S199F: 12.4 +/- 1.4 and 199F: 14.1 +/- 2.2; p = 0.01]. In vitro, the P171T, A185S and S199F variants did not reveal major functional alteration in the activation of NGN3 target genes. In conclusion, male gender, anovulatory state in females and NGN3 variations may influence the pathogenesis of KPD in West Africans. This has therapeutic implications for potential tailored pharmacological intervention in this population.

Regulation of liver carnitine palmitoyltransferase I gene expression by hormones and fatty acids.

This brief review focuses on the transcriptional regulation of liver carnitine palmitoyltransferase I (L-CPT I) by pancreatic and thyroid hormones and by long-chain fatty acids (LCFA). Both glucagon and 3,3',5-tri-iodothyronine (T(3)) enhanced the transcription of the gene encoding L-CPT I, whereas insulin had the opposite effect. Interestingly, the transcriptional effect of T(3) required, in addition to the thyroid-responsive element, the co-operation of a sequence located in the first intron of L-CPT I gene. Non-esterified fatty acids rather than acyl-CoA ester or intra-mitochondrial metabolite were responsible for the transcriptional effect on the gene encoding L-CPT I. It was shown that LCFA and peroxisome proliferators stimulated L-CPT I gene transcription by distinct mechanisms. Peroxisome proliferator stimulated L-CPT I gene transcription through a peroxisome-proliferator-responsive element (PPRE) located at -2846 bp, whereas LCFA induced L-CPT I gene transcription through a peroxisome-proliferator-activated receptor alpha (PPARalpha)-independent mechanism owing to a sequence located in the first intron of the gene.

Long-chain fatty acids regulate liver carnitine palmitoyltransferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptor alpha (PPARalpha)-independent pathway.

Liver carnitine palmitoyltransferase I (L-CPT I) catalyses the transfer of long-chain fatty acid (LCFA) for translocation across the mitochondrial membrane. Expression of the L-CPT I gene is induced by LCFAs as well as by lipid-lowering compounds such as clofibrate. Previous studies have suggested that the peroxisome-proliferator-activated receptor alpha (PPARalpha) is a common mediator of the transcriptional effects of LCFA and clofibrate. We found that free LCFAs rather than acyl-CoA esters are the signal metabolites responsible for the stimulation of L-CPT I gene expression. Using primary culture of hepatocytes we found that LCFAs failed to stimulate L-CPT I gene expression both in wild-type and PPARalpha-null mice. These results suggest that the PPARalpha-knockout mouse does not represent a suitable model for the regulation of L-CPT I gene expression by LCFAs in the liver. Finally, we determined that clofibrate stimulates L-CPT I through a classical direct repeat 1 (DR1) motif in the promoter of the L-CPT I gene while LCFAs induce L-CPT I via elements in the first intron of the gene. Our results demonstrate that LCFAs can regulate gene expression through PPARalpha-independent pathways and suggest that the regulation of gene expression by dietary lipids is more complex than previously proposed.