The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion

Abstract

Mutations in the gene encoding hepatocyte nuclear factor-4α (HNF-4α) result in maturity-onset diabetes of the young (MODY). To determine the contribution of HNF-4α to the maintenance of glucose homeostasis by the β cell in vivo, we derived a conditional knockout of HNF-4α using the Cre-loxP system. Surprisingly, deletion of HNF-4α in β cells resulted in hyperinsulinemia in fasted and fed mice but paradoxically also in impaired glucose tolerance. Islet perifusion and calcium-imaging studies showed abnormal responses of the mutant β cells to stimulation by glucose and sulfonylureas. These phenotypes can be explained in part by a 60% reduction in expression of the potassium channel subunit Kir6.2. We demonstrate using cotransfection assays that the Kir6.2 gene is a transcriptional target of HNF-4α. Our data provide genetic evidence that HNF-4α is required in the pancreatic β cell for regulation of the pathway of insulin secretion dependent on the ATPdependent potassium channel.

Gene Variants Associated with Transient Neonatal Diabetes Mellitus in the Very Low Birth Weight Infant

“…In contrast, numerous previous publications have shown that HNF4A gene mutations most often result in hyperinsulinemic hypoglycemia in the neonatal period [9], followed by a decline in β-cell function, leading to MODY1 at a later stage, suggesting a dual role of the transcription factor at different stages of life. The role of HNF4A in insulin secretion has been studied in transgenic mice in which HNF4A is deleted specifically in β-cells by crossing HNF4alpha loxP/loxP mice with mice expressing a Cre recombinase under the insulin promoter [16,17]. One study [16] showed that conditional deletion of HNF4A leads to lower blood glucose values associated with increased insulin levels in fasted and fed states in both neonates and 3- to 5-month-old mice.…”

“…The role of HNF4A in insulin secretion has been studied in transgenic mice in which HNF4A is deleted specifically in β-cells by crossing HNF4alpha loxP/loxP mice with mice expressing a Cre recombinase under the insulin promoter [16,17]. One study [16] showed that conditional deletion of HNF4A leads to lower blood glucose values associated with increased insulin levels in fasted and fed states in both neonates and 3- to 5-month-old mice. Interestingly, this increased insulin secretion in a basal state was lost when the mice were challenged with intraperitoneal glucose.…”

“…Interestingly, this increased insulin secretion in a basal state was lost when the mice were challenged with intraperitoneal glucose. Thus, these mice were glucose intolerant and had a markedly impaired first-phase insulin response to glucose both in vivo and in vitro [16] . Though the basal elevation of insulin was not found in every study [17], the impaired response to an acute glucose challenge was constant in all studies, indicating that, depending on subtle differences in the genetic background, the phenotype of the gene defect could vary but would become apparent in the presence of increased insulin demand, such as during puberty, which would explain the diagnosis of the disease in young adulthood in most patients.…”

“…The p.Glu23Lys variant that was identified predisposes an individual to type 2 diabetes later in life [26,27] by slightly increasing KATP channel activity at physiological nucleotide concentrations in β-cells [28,29] and, thus, slightly decreasing insulin secretion [27,30]. Whether the p.Pro190Leu variant in HNF4A also influences the expression of KCNJ11 , as observed in studies of mice conditionally knocked out for HNF4A [16], could not be verified in our patient.…”

The orphan nuclear receptors at their 25-year reunion

“…Mouse models have shown that it is required in the pancreas for glucose-stimulated insulin secretion and beta cell expansion (Gupta et al 2005, 2007). HNF4α has pleiotropic roles in other enterohepatic tissues, most prominently in the liver, where it is required for the maturation, maintenance and differentiated functions of hepatocytes (Sladek et al 1990; Chen et al 1994b).…”