Functional Effects of Polymorphisms in the Human Gene Encoding 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1): A Sequence Variant at the Translation Start of 11β-HSD1 Alters Enzyme Levels

Abstract Regeneration of active glucocorticoids within liver and adipose tissue by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be of pathophysiological importance in obesity and metabolic syndrome and is a therapeutic target in type 2 diabetes. Polymorphisms in HSD11B1, the gene encoding 11β-HSD1, have been associated with metabolic phenotype in humans, including type 2 diabetes and hypertension. Here, we have tested the functional consequences of two single nucleotide polymorphisms located in contexts that potentially affect tissue levels of 11β-HSD1. We report no effect of allelic variation at rs846910, a polymorphism within the 5′-flanking region of the gene on HSD11B1 promoter activity in vitro. However, compared with the common G allele, the A allele of rs13306421, a polymorphism located two nucleotides 5′ to the translation initiation site, gave higher 11β-HSD1 expression and activity in vitro and was translated at higher levels in in vitro translation reactions, possibly associated with a lower frequency of “leaky scanning.” These data suggest that this polymorphism may have direct functional consequences on levels of 11β-HSD1 enzyme activity in vivo. However, the rs13306421 A sequence variant originally reported in other ethnic groups may be of low prevalence because it was not detected in a population of 600 European Caucasian women.

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11?-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes

Diabetologia ◽

10.1007/s00125-003-1284-4 ◽

2004 ◽

Vol 47 (1) ◽

pp. 1-11 ◽

Cited By ~ 78

Author(s):

T. M. Stulnig ◽

W. Waldh�usl

Keyword(s):

Type 2 Diabetes ◽

Hydroxysteroid Dehydrogenase

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Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disorders

Orvosi Hetilap ◽

10.1556/oh.2013.29558 ◽

2013 ◽

Vol 154 (8) ◽

pp. 283-293 ◽

Cited By ~ 2

Author(s):

Karolina Feldman ◽

István Likó ◽

Zsolt Nagy ◽

Ágnes Szappanos ◽

Vince Kornél Grolmusz ◽

...

Keyword(s):

Enzyme Activity ◽

Hydroxysteroid Dehydrogenase ◽

Chromosome 1 ◽

Gene Encoding ◽

Local Synthesis ◽

Dehydrogenase Enzyme ◽

Clinical Disorders ◽

Polymorphic Variants

Glucocorticoids play an important role in the regulation of carbohydrate and amino acid metabolism, they modulate the function of the immune system, and contribute to stress response. Increased and decreased production of glucocorticoids causes specific diseases. In addition to systemic hypo- or hypercortisolism, alteration of local synthesis and metabolism of cortisol may result in tissue-specific hypo- or hypercortisolism. One of the key enzymes participating in the local synthesis and metabolism of cortisol is the 11β-hydroxysteroid dehydrogenase enzyme. Two isoforms, type 1 and type 2 enzymes are located in the endoplasmic reticulum and catalyze the interconversion of hormonally active cortisol and inactive cortisone. The type 1 enzyme mainly works as an activator, and it is responsible for the generation of cortisol from cortisone in liver, adipose tissue, brain and bone. The gene encoding this enzyme is located on chromosome 1. The authors review the physiological and pathophysiological processes related to the function of the type 1 11β-hydroxysteroid dehydrogenase enzyme. They summarize the potential significance of polymorphic variants of the enzyme in clinical diseases as well as knowledge related to inhibitors of enzyme activity. Although further studies are still needed, inhibition of the enzyme activity may prove to be an effective tool for the treatment of several diseases such as obesity, osteoporosis and type 2 diabetes. Orv. Hetil., 2013, 154, 283–293.

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Genome-Wide Screening, Cloning, Chromosomal Assignment, and Expression of Full-Length Human Endogenous Retrovirus Type K

Journal of Virology ◽

10.1128/jvi.73.11.9187-9195.1999 ◽

1999 ◽

Vol 73 (11) ◽

pp. 9187-9195 ◽

Cited By ~ 69

Author(s):

Ralf R. Tönjes ◽

Frank Czauderna ◽

Reinhard Kurth

Keyword(s):

Human Genome ◽

Endogenous Retrovirus ◽

Full Length ◽

In Vitro Translation ◽

Type K ◽

Genome Wide ◽

A Genome

ABSTRACT The human genome harbors 25 to 50 proviral copies of the endogenous retrovirus type K (HERV-K), some of which code for the characteristic retroviral proteins Gag, Pol, and Env. For a genome-wide cloning approach of full-length and intact HERV-K proviruses, a human P1 gene library was screened with a gag-specific probe. Both HERV-K type 1 and 2 clones were isolated. Sixteen HERV-K type 2 proviral genomes were characterized by direct coupled in vitro transcription-in vitro translation assays to analyze the coding potential of isolatedgag, pol, and env amplicons from individual P1 clones. After determination of long terminal repeat (LTR) sequences and adjacent chromosomal integration sites by inverse PCR techniques, two HERV-K type 2 proviruses displaying long retroviral open reading frames (ORFs) were assigned to chromosomes 7 (C7) and 19 (C19) by using a human-rodent monochromosomal cell hybrid mapping panel. HERV-K(C7) shows an altered (YIDD-to-CIDD) motif in the reverse transcriptase domain. HERV-K(C19) is truncated in the 5′ LTR and harbors a defective protease gene due to a point mutation. Direct amplification of proviral structures from single chromosomes by using chromosomal flanking primers was performed by long PCR for HERV-K(C7) and HERV-K(C19) and for type 1 proviruses HERV-K10 and HERV-K18 from chromosomes 5 and 1, respectively. HERV-K18, in contrast to HERV-K10, bears no intact gag ORF and shows close homology to HERV-K/IDDMK1,222. In transfection experiments, HERV-K(C7) and HERV-K cDNA-based expression vectors yielded the proteins Gag and cORF whereas HERV-K10 vectors yielded Gag alone. The data suggest that the human genome does not contain an entire, intact proviral copy of HERV-K.

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Animal models of catheter-induced intimal hyperplasia in type 1 and type 2 diabetes and the effects of pharmacologic intervention

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y08-098 ◽

2009 ◽

Vol 87 (1) ◽

pp. 37-50 ◽

Cited By ~ 8

Author(s):

D.B. McNamara ◽

S.N. Murthy ◽

A.N. Fonseca ◽

C.V. Desouza ◽

P.J. Kadowitz ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Animal Models ◽

Vascular Injury ◽

Intimal Hyperplasia ◽

In Vivo Studies ◽

Impaired Insulin

Diabetes is a complex disorder characterized by impaired insulin formation, release or action (insulin resistance), elevated blood glucose, and multiple long-term complications. It is a common endocrine disorder of humans and is associated with abnormalities of carbohydrate and lipid metabolism. There are two forms of diabetes, classified as type 1 and type 2. In type 1 diabetes, hyperglycemia is due to an absolute lack of insulin, whereas in type 2 diabetes, hyperglycemia is due to a relative lack of insulin and insulin resistance. More than 90% of people with diabetes have type 2 with varied degrees of insulin resistance. Insulin resistance is often associated with impaired insulin secretion, and hyperglycemia is a common feature in both types of diabetes, but failure to make a distinction between the types of diabetes in different animal models has led to confusion in the literature. This is particularly true in relation to cardiovascular disease in the presence of diabetes and especially the response to vascular injury, in which there are major differences between the two types of diabetes. Animal models do not completely mimic the clinical disease seen in humans. Animal models are at best analogies of the pathologic process they are designed to represent. The focus of this review is an analysis of intimal hyperplasia following catheter-induced vascular injury, including factors that may complicate comparisons between different animal models or between in vitro and in vivo studies. We examine the variables, pitfalls, and caveats that follow from the manner of induction of the injury and the diabetic state of the animal. The efficacy of selected antidiabetic drugs in inhibiting the development of the hyperplastic response is also discussed.

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Association studies between the HSD11B2 gene (encoding human 11beta-hydroxysteroid dehydrogenase type 2), type 1 diabetes mellitus and diabetic nephropathy

Acta Endocrinologica ◽

10.1530/eje.0.1460553 ◽

2002 ◽

pp. 553-558 ◽

Cited By ~ 10

Author(s):

GG Lavery ◽

CL McTernan ◽

SC Bain ◽

TA Chowdhury ◽

M Hewison ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Type 1 Diabetes Mellitus ◽

Association Studies ◽

Hydroxysteroid Dehydrogenase ◽

Salt Sensitivity ◽

Gene Encoding

OBJECTIVE: Mutations in the HSD11B2 gene (encoding human 11beta-hydroxysteroid dehydrogenase type 2) explain the syndrome of apparent mineralocorticoid excess where cortisol acts as a mineralocorticoid. A microsatellite marker within the HSD11B2 gene associates with salt sensitivity and hypertension--phenotypes characterising diabetic nephropathy. Here, we evaluate the HSD11B2 gene as a susceptibility locus for diabetic nephropathy. DESIGN: 150 patients with type 1 diabetes and nephropathy (DN), 145 patients with type 1 diabetes with a long duration of non-nephropathy (LDNN) and 151 normal controls were studied. METHODS: We determined allele frequencies for the (CA)n repeat marker within intron I of the HSD11B2 gene. Duration of type 1 diabetes, diabetic status and renal function were recorded. RESULTS: 11 alleles (138-158) for the marker were observed. Allele 152 was significantly increased in controls compared with LDNN (70.5% vs 57.6%, P(c)<0.05 where P(c) is the P value corrected for multiple comparisons) but no difference was observed between DN and LDNN subjects. Allele 154 was significantly increased in the LDNN compared with the DN subjects (15.9% vs 7.0%, P(c)<0.01) but no difference was observed between DN and controls. A greater proportion of subjects carried at least 1 allele <152 in DN compared with control subjects (47.3% vs 28.5%, P(c)<0.01), but no difference was observed in LDNN compared with control and DN subjects. CONCLUSIONS: Weak associations are reported between the HSD11B2 gene, type 1 diabetes mellitus and nephropathy. The increased frequency of HSD11B2 short alleles in the diabetic groups may reflect reduced renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity and may, in part, explain the enhanced salt sensitivity observed in patients with type 1 diabetes.

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Arachidonic Acid Has Anti-Inflammatory and Anti-Diabetic Actions In Vitro and In Vivo

Current Developments in Nutrition ◽

10.1093/cdn/nzaa052_016 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 747-747

Author(s):

Undurti Das

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Arachidonic Acid ◽

Acid Treatment ◽

Wistar Rats ◽

Anti Inflammatory

Abstract Objectives To evaluate the effect of arachidonic acid (AA) in the pathobiology of chemical-induced type 1 and type 2 diabetes mellitus in experimental animals. Methods In vitro studies were performed using RIN 5F cells and animal studies in 3–4 week old Wistar rats. Alloxan and streptozotocin (STZ) were used to induce type 1 diabetes and STZ employed to induce type 2 diabetes mellitus. RIN5F cell proliferation was measured using MTT assay. Establishment of alloxan and STZ-induced diabetes in animals was confirmed by measuring plasma glucose levels. Plasma insulin, IL-6, TNF levels were measured by ELISA. Expression of cyclo-oxygenase-2, lipoxiygenase, NF-kB and IkB genes was performed in pancreatic and adipose tissues. Results Alloxan and STZ-induced cytotoxicity to RIN5F cells was inhibited by arachidonic acid that was not blocked by both COX and LOX enzymes. Alloxan and STZ-induced type 1 diabetes mellitus and STZ-induced type 2 diabetes was prevented by arachidonic acid treatment. Plasma levels of glucose, insulin, IL-6 and TNF and expressions of NF-kB, IkB, COX-2, LOX in pancrreatic and adipose tissues and lipocalin-2 in adipose tissue were restored to normal by arachidonic acid treatment. AA treatment enhanced plasma lipoxin A4 (LXA4) levels. LXA4 also prevented both type 1 and type 2 diabetes induction by STZ. Conclusions AA prevented the development of both type 1 and type 2 diabetes mellitus in Wistar rats and protected pancreatic beta cells form the cytotoxicity of alloxan and STZ. AA showed strong anti-inflammatory actions. AA seems to bring about its anti-inflammatory and anti-diabetic actions by enhancing LXA4 formation. Funding Sources None.

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