Potential Role of Peroxisome Proliferator-Activated Receptor-α in the Modulation of Glucose-Stimulated Insulin Secretion

Sugden, Mary C.; Holness, Mark J.

doi:10.2337/diabetes.53.2007.s71

Cited by 48 publications

(32 citation statements)

References 114 publications

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“…Given the postulated role of PPAR-␣ in the regulation of ␤-cell lipid metabolism, it is possible that the lower level of PPAR-␣ in the HNF-4␣ mutants partially contributes to the elevated basal insulin levels (17). In support of this hypothesis, PPAR-␣ null mice develop fasting hyperinsulinemic hypoglycemia, suggesting that PPAR-␣ is important for regulated insulin secretion during fasting (18).…”

Section: Resultssupporting

confidence: 58%

Persistent Hyperinsulinemic Hypoglycemia and Maturity-Onset Diabetes of the Young Due to Heterozygous HNF4A Mutations

et al. 2008

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OBJECTIVE-Mutations in the human HNF4A gene encoding the hepatocyte nuclear factor (HNF)-4␣ are known to cause maturity-onset diabetes of the young (MODY), which is characterized by autosomal-dominant inheritance and impaired glucose-stimulated insulin secretion from pancreatic ␤-cells. HNF-4␣ has a key role in regulating the multiple transcriptional factor networks in the islet. Recently, heterozygous mutations in the HNF4A gene were reported to cause transient hyperinsulinemic hypoglycemia associated with macrosomia.RESEARCH DESIGN AND METHODS-Three infants presented with macrosomia and severe hypoglycemia with a positive family history of MODY. The hypoglycemia was confirmed to be due to hyperinsulinism, and all three patients required diazoxide therapy to maintain normoglycemia. Two of the three infants are still requiring diazoxide therapy at 8 and 18 months, whereas one of them had resolution of hyperinsulinemic hypoglycemia at 32 months of age.RESULTS-Sequencing of the HNF4A gene identified heterozygous mutations in all three families. In family 1, a frameshift mutation L330fsdel17ins9 (c.987 1003del17ins9; p.Leu330fs) was present in the proband; a mutation affecting the conserved A nucleotide of the intron 2 branch site (c.264 -21AϾG) was identified in the proband of family 2; and finally a nonsense mutation, Y16X (c.48CϾG, p.Tyr16X), was found in the proband of family 3. (1,2). HNF-4␣ is a transcription factor of the nuclear hormone receptor superfamily and is expressed in liver, kidney, gut, and pancreatic islets (3). It plays a key role in the regulation of pancreatic insulin secretion. Loss-of-function HNF4A mutations have been identified in maturity-onset diabetes of the young (MODY) families in both coding and regulatory regions of the gene, including the P2 promoter region, which is suggested to be the primary transcriptional start site used in ␤-cells (4,5). MODY is characterized by an autosomal-dominant inheritance pattern and impaired glucose-stimulated insulin secretion from pancreatic ␤-cells (4). CONCLUSIONS-HeterozygousThe finding of transient mild hyperinsulinemic hypoglycemia is unexpected, since heterozygous mutations in the HNF4A gene lead to loss of glucose-induced insulin secretion with glucose intolerance in these patients. We now extend the observations of two previous studies (1,2) and report that heterozygous HNF4A mutations can cause macrosomia with severe and persistent hyperinsulinemic hypoglycemia as well as MODY in three families. RESEARCH DESIGN AND METHODSPatient 1. Patient 1 was born at 39 weeks' gestation with a birth weight of 5.9 kg after a vaginal delivery. The delivery was complicated with a prolonged second stage and shoulder dystocia. After delivery, the baby developed severe symptomatic hypoglycemia (jitteriness and irritability with a blood glucose concentration of 0.8 mmol/l). He required a continuous infusion of 25% dextrose delivering 25 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 glucose, as well as an infusion of glucagon to maintain normoglycemia. Biochemical analysis showed an in...

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Section: Resultssupporting

confidence: 58%

Persistent Hyperinsulinemic Hypoglycemia and Maturity-Onset Diabetes of the Young Due to Heterozygous HNF4A Mutations

et al. 2008

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“…It has been demonstrated that another possible modulator of insulin secretion is PPAR␣ (47). PPAR␣ in turn regulates the transcription of CPT-1 and UCP-2 (56).…”

Section: Discussionmentioning

confidence: 99%

“…Islets-It is known that PPAR␣ regulates insulin secretion (47). Expression of PPAR␣ was not modified in rats fed the CSF diet (Fig.…”

Section: Ppar␣ Is Not Modified By Soy Protein In Pancreaticmentioning

confidence: 99%

Pancreatic Insulin Secretion in Rats Fed a Soy Protein High Fat Diet Depends on the Interaction between the Amino Acid Pattern and Isoflavones

Noriega

Tovar²,

González‐Granillo

et al. 2007

Journal of Biological Chemistry

100

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Obesity is frequently associated with the consumption of high carbohydrate/fat diets leading to hyperinsulinemia. We have demonstrated that soy protein (SP) reduces hyperinsulinemia, but it is unclear by which mechanism. Thus, the purpose of the present work was to establish whether SP stimulates insulin secretion to a lower extent and/or reduces insulin resistance, and to understand its molecular mechanism of action in pancreatic islets of rats with diet-induced obesity. Long-term consumption of SP in a high fat (HF) diet significantly decreased serum glucose, free fatty acids, leptin, and the insulin:glucagon ratio compared with animals fed a casein HF diet. Hyperglycemic clamps indicated that SP stimulated insulin secretion to a lower extent despite HF consumption. Furthermore, there was lower pancreatic islet area and insulin, SREBP-1, PPAR␥, and GLUT-2 mRNA abundance in comparison with rats fed the casein HF diet. Euglycemic-hyperinsulinemic clamps showed that the SP diet prevented insulin resistance despite consumption of a HF diet. Incubation of pancreatic islets with isoflavones reduced insulin secretion and expression of PPAR␥. Addition of amino acids resembling the plasma concentration of rats fed casein stimulated insulin secretion; a response that was reduced by the presence of isoflavones, whereas the amino acid pattern resembling the plasma concentration of rats fed SP barely stimulated insulin release. Infusion of isoflavones during the hyperglycemic clamps did not stimulate insulin secretion. Therefore, isoflavones as well as the amino acid pattern seen after SP consumption stimulated insulin secretion to a lower extent, decreasing PPAR␥, GLUT-2, and SREBP-1 expression, and ameliorating hyperinsulinemia observed during obesity.Obesity is a major health problem around the world because of chronic overnutrition and increase in the sedentary life style (1, 2). The development of obesity is accompanied by several metabolic changes including insulin resistance, hyperinsulinemia, dyslipidemia, hyperleptinemia, and hepatic steatosis among others, known as the metabolic syndrome (3, 4). Thus, the search for therapies to prevent the development of metabolic syndrome has increased over the last few years, including pharmacological and dietary therapies (5-11).Previous studies have shown that long term consumption of soy protein diet reduces hyperinsulinemia, which in turn decreases the expression of the sterol regulatory element-binding protein (SREBP) 2 -1c in liver, reducing hepatic steatosis (12). Furthermore, recent evidence showed that soy protein is able to reduce hepatic lipotoxicity even in the presence of hyperinsulinemia and hyperleptinemia by a reduction in the expression of lipogenic genes and an increase in oxidative pathways (13). This evidence suggests that the type of dietary protein may play an important role in preventing the development of the metabolic syndrome.It is not clear whether the effect of consumption of soy protein on serum insulin concentration is associated with changes in...

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“…Since insulin can affect Insig levels [45], it is possible that the low levels of insulin in the rodent fetus [43] can impact upon Insig expression levels. This would not explain why Insig-1 levels are low in the placenta and yolk sac since these tissues come in contact with the maternal circulation, though it has been hypothesized that all tissues are insulin resistant during gestation [46,47]. Also, Insig-1 is stabilized when sterols are present [22,23].…”

Section: Constitutive Processing Of Srebp-2mentioning

confidence: 99%

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

Yao

Jenkins

Horn

et al. 2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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SUMMARYThe requirement for cholesterol is greater in developing tissues (fetus, placenta, and yolk sac) as compared to adult tissues. Here, we compared cholesterol-induced suppression of sterol synthesis rates in the adult liver to the fetal liver, fetal body, placenta, and yolk sac of the Golden Syrian hamster. Sterol synthesis rates were suppressed maximally in non-pregnant adult livers when cholesterol concentrations were increased. In contrast, sterol synthesis rates were suppressed only marginally in fetal livers, fetal bodies, placentas, and yolk sacs when cholesterol concentrations were increased. To begin to elucidate the mechanism responsible for the blunted response of sterol synthesis rates in fetal tissues to exogenous cholesterol, the ratio of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) to Insig-1 was measured in these same tissues since the ratio of SCAP to the Insigs can impact SREBP processing. The fetal tissues had anywhere from a 2-to 6-fold greater ratio of SCAP to Insig-1 than did the adult liver, suggesting constitutive processing of the SREBPs. As expected, the level of mature, nuclear SREBP-2 was not different in the fetal tissues with different levels of cholesterol whereas it was different in adult livers. These findings indicate that the suppression of sterol synthesis to exogenous sterol is blunted in developing tissues and the lack of response appears to be mediated at least partly through relative levels of Insigs and SCAP.

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Potential Role of Peroxisome Proliferator-Activated Receptor-α in the Modulation of Glucose-Stimulated Insulin Secretion

Cited by 48 publications

References 114 publications

Persistent Hyperinsulinemic Hypoglycemia and Maturity-Onset Diabetes of the Young Due to Heterozygous HNF4A Mutations

Persistent Hyperinsulinemic Hypoglycemia and Maturity-Onset Diabetes of the Young Due to Heterozygous HNF4A Mutations

Pancreatic Insulin Secretion in Rats Fed a Soy Protein High Fat Diet Depends on the Interaction between the Amino Acid Pattern and Isoflavones

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

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