Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene).

Abstract

Diabetes resulting from heterozygosity for an inactivating mutation of the homeodomain transcription factor insulin promoter factor 1 (IPF-1) is due to a genetic defect of ␤-cell function referred to as maturity-onset diabetes of the young 4. IPF-1 is required for the development of the pancreas and mediates glucose-responsive stimulation of insulin gene transcription. To quantitate islet cell responses in a family harboring a Pro63fsdelC mutation in IPF-1, we performed a five-step (1-h intervals) hyperglycemic clamp on seven heterozygous members (NM) and eight normal genotype members (NN). During the last 30 min of the fifth glucose step, glucagon-like peptide 1 (GLP-1) was also infused (1.5 pmol · kg -1 · min -1 ). Fasting plasma glucose levels were greater in the NM group than in the NN group (9.2 vs. 5.9 mmol/l, respectively; P < 0.05). Fasting insulin levels were similar in both groups (72 vs. 105 pmol/l for NN vs. NM, respectively). First-phase insulin and C-peptide responses were absent in individuals in the NM group, who had markedly attenuated insulin responses to glucose alone compared with the NN group. At a glucose level of 16.8 mmol/l above fasting level, GLP-1 augmented insulin secretion equivalently (fold increase) in both groups, but the insulin and C-peptide responses to GLP-1 were sevenfold less in the NM subjects than in the NN subjects. In both groups, glucagon levels fell during each glycemic plateau, and a further reduction occurred during the GLP-1 infusion. Sigmoidal dose-response curves of glucose clearance versus insulin levels during the hyperglycemic clamp in the two small groups showed both a left shift and a lower maximal response in the NM group compared with the NN group, which is consistent with an increased insulin sensitivity in the NM subjects. A sharp decline occurred in the doseresponse curve for suppression of nonesterified fatty acids versus insulin levels in the NM group. We conclude that the Pro63fsdelC IPF-1 mutation is associated with a severe impairment of ␤-cell sensitivity to glucose and an apparent increase in peripheral tissue sensitivity to insulin and is a genetically determined cause of ␤-cell dysfunction. Diabetes 49:1856-1864, 2000 T ype 2 diabetes is a highly prevalent and heterogeneous disorder of glucose homeostasis characterized by an imbalance between insulin synthesis and secretion by the endocrine pancreatic ␤-cells and peripheral tissue sensitivity to insulin. Diabetes has long been recognized as a genetic disorder with complex modes of inheritance. Recent advances reveal the genetic basis for a monogenic type of diabetes referred to as maturity-onset diabetes of the young (MODY), which is characterized by diagnosis at <25 years of age, autosomal dominant inheritance, and lack of a requirement for insulin therapy for at least 5 years after initial diagnosis (1). To date, five MODY genes have been identified, four of which encode endocrine pancreatic transcription factors (2-5) and one that encodes the pancreatic and hepatic glycolytic enzyme glucokina...

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

“…Pdx1 haploinsufficiency does not appear to physically or functionally impinge upon pancreas development in Pdx1+/− mice [12,13], however, such mice exhibit strikingly impaired glucose tolerance and glucose-stimulated insulin secretion with age [56,57]. Similarly impaired β cell function in the setting of Pdx1 deficiency has been observed in several other animal models (rat, fish, and sand rat [58][59][60][61][62]), as well as in humans with single allelic mutations in Ipf1 (where the development of impaired glucose responsiveness and frank diabetes occurs) [17][18][19][20][21]. The sand rat (Psammomys obesus) is a particularly an interesting case, as Pdx1 is not normally found in islets from these animals; however, gene transfer experiments show that repletion of Pdx1 in these islets greatly enhances insulin content and glucose-stimulated insulin transcription [62].…”

“…Pdx1 also appears to be crucial for the function of the mature β cell. Heterozygous missense and frameshift mutations of the Ipf1 gene in humans (while not impairing pancreas formation) result in defective insulin secretion and the development of a form of diabetes known as maturity onset diabetes of the young 4 (MODY4) [17][18][19][20][21]. Similarly, studies of animal models of insulin resistance suggest that the down regulation of pdx1 expression in the β cell may underlie the pathogenesis of β cell failure and type 2 diabetes [22][23][24].…”

Foxa2 (HNF3β) Controls Multiple Genes Implicated in Metabolism-Secretion Coupling of Glucose-induced Insulin Release

“…Naturally occurring mutations in the human HNF4␣, HNF1␣, PDX1, and HNF1␤ genes have been associated with four monogenic forms of MODY caused by impaired glucose-induced insulin secretion (12,13,37). However, genetic analysis has failed to link the FOXA2 mutations to MODY pedigrees (14,15).…”

Experimental Models of Transcription Factor-Associated Maturity-Onset Diabetes of the Young

“…Homozygosity for a mutation in the PDX-1/IPF-1 gene results in failure of pancreas formation, whereas heterozygosity for an inactivating mutation and missense mutations in this gene are associated with MODY4 and late-onset type 2 diabetes in humans, respectively (33,34). The primary defect in MODY4 is impaired glucose-stimulated insulin secretion (35). Targeted disruption of PDX-1 in mice results in pancreatic aplasia (32), whereas mice with ␤-cell-specific deletion of PDX-1 develop diabetes (36).…”