Development of 11&amp;#946; -HSD1 Inhibitors for the Treatment of Type 2 Diabetes

Hale, Clarence; Wang, Minghan

doi:10.2174/138955708784567421

Cited by 37 publications

(18 citation statements)

References 46 publications

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“…This mechanism is an important regulator of GR hormone activity (Remer et al, 2008). Although research in this field is very active towards the development of drugs for the control of obesity and metabolic diseases in humans (Hale and Wang, 2008), very little information is available in farm animals. An association between a single nucleotide polymorphism (SNP) in the HSD11B1 gene and production traits has been described in two pig populations, although these effects may be not be due to the causative mutation (Otieno et al, 2005).…”

Section: Genetics and The Hpa Axismentioning

confidence: 99%

Breeding for robustness: the role of cortisol

Mormède

Foury

Terenina

et al. 2011

Animal

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Robustness in farm animals was defined by Knap as 'the ability to combine a high production potential with resilience to stressors, allowing for unproblematic expression of a high production potential in a wide variety of environmental conditions'. The importance of robustness-related traits in breeding objectives is progressively increasing towards the production of animals with a high production level in a wide range of climatic conditions and production systems, together with a high level of animal welfare. Current strategies to increase robustness include selection for 'functional traits', such as skeletal and cardiovascular integrity, disease resistance and mortality in various stages. It is also possible to use global evaluation of sensitivity to the environment (e.g. reaction norm analysis or canalization), but these techniques are difficult to implement in practice. The hypothalamic-pituitaryadrenocortical (HPA) axis is the most important stress-responsive neuroendocrine system. Cortisol (or corticosterone) released by the adrenal cortices exerts a large range of effects on metabolism, the immune system, inflammatory processes and brain function, for example. Large individual variations have been described in the HPA axis activity with important physiopathological consequences. In terms of animal production, higher cortisol levels have negative effects on growth rate and feed efficiency and increase the fat/lean ratio of carcasses. On the contrary, cortisol has positive effects on traits related to robustness and adaptation. For instance, newborn survival was shown to be directly related to plasma cortisol levels at birth, resistance to bacteria and parasites are increased in animals selected for a higher HPA axis response to stress, and tolerance to heat stress is better in those animals that are able to mount a strong stress response. Intense selection for lean tissue growth during the last decades has concomitantly reduced cortisol production, which may be responsible for the negative effects of selection on piglet survival. One strategy to improve robustness is to select animals with higher HPA axis activity. Several sources of genetic polymorphism have been described in the HPA axis. Hormone production by the adrenal cortices under stimulation by adrenocorticotropin hormone is a major source of individual differences. Several candidate genes have been identified by genomic studies and are currently under investigation. Bioavailability of hormones as well as receptor and post-receptor mechanisms are also subject to individual variation. Integration of these different sources of genetic variability will allow the development of a model for marker-assisted selection to improve animal robustness without negative side effects on production traits.

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Section: Genetics and The Hpa Axismentioning

confidence: 99%

Breeding for robustness: the role of cortisol

Mormède

Foury

Terenina

et al. 2011

Animal

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“…A large variety of 11 β-HSD1 inhibitor classes have been synthesized [174][175][176], and some are under investigation by the pharmaceutical industry to treat type 2 diabetes and obesity [177]. The modulation of 11 β-HSD type 1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia, and obesity.…”

Section: Sodium-dependent Glucose Cotransporter-2 Inhibitorsmentioning

confidence: 99%

Diabetes Mellitus: New Challenges and Innovative Therapies

Sena¹,

Bento²,

Pereira³

et al. 2013

New Strategies to Advance Pre/Diabetes Care: Integrative Approach by PPPM

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Diabetes mellitus is a widespread disease prevalence and incidence of which increases worldwide. The introduction of insulin therapy represented a major breakthrough in type 1 diabetes; however, frequent hyper-and hypoglycemia seriously affects the quality of life of these patients. New therapeutic approaches, such as whole pancreas transplant or pancreatic islet transplant, stem cell, gene therapy and islets encapsulation are discussed in this review. Regarding type 2 diabetes, therapy has been based on drugs that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (alpha-glucosidase inhibitors) or improve insulin action (thiazolidinediones). This review is also focused on the newer therapeutically approaches such as incretin-based therapies, bariatric surgery, stem cells and other emerging therapies that promise to further extend the options available. Gene-based therapies are among the most promising emerging alternatives to conventional treatments. Some of these therapies rely on genetic modification of non-differentiated cells to express pancreatic endocrine developmental factors, promoting differentiation of nonendocrine cells into β-cells, enabling synthesis and secretion of insulin in a glucose-regulated manner. Alternative therapies based on gene silencing using vector systems to deliver interference RNA to cells (i.e. against VEGF in diabetic retinopathy) are also a promising therapeutic option for the treatment of several diabetic complications. In conclusion, treatment of diabetes faces now a new era that is characterized by a variety of innovative therapeutic approaches that will improve quality-life and allow personalized therapyplanning in the near future.

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“…Glucocorticoid action is linked to the development of obesity and insulin resistance. Recently, inhibition of HSD11B1 has been proposed as a strategy to suppress glucocorticoid action in a tissue-specific manner [48]. There is also preliminary evidence supporting an association of HSD11B1 with osteoporosis in postmenopausal women [49].…”

Section: Antigen Identification Using a Human Liver Cdna Expression Lmentioning

confidence: 99%

Antigenically dominant proteins within the human liver mitochondrial proteome identified by monoclonal antibodies

Yang

Liu

et al. 2011

Sci. China Life Sci.

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Analysis of the mitochondrial proteome would provide valuable insight into the function of this important organelle, which plays key roles in energy metabolism, apoptosis, free radical production, thermogenesis, and calcium signaling. It could also increase our understanding about the mechanisms that promote mitochondrial disease. To identify proteins that are antigenically dominant in human liver mitochondria, we generated >240 hybridoma cell lines from native mitochondrial proteins after cell fusion, screening, and cloning. Antibodies that recognized mitochondrial proteins were identified by screening human liver cDNA expression libraries. In this study, we identified 6 major antigens that were recognized by at least 2 different monoclonal antibodies (mAbs). The proteins that were antigenically dominant were: acetyl-Coenzyme A acyltransferase 2 (mitochondrial 3-oxoacyl-Coenzyme A thiolase), aldehyde dehydrogenase 1 family member A1, carbamoyl phosphate synthetase 1, dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase complex), enoyl coenzyme A hydratase 1, and hydroxysteroid (11-beta) dehydrogenase 1. We also determined the subcellular localizations of these enzymes within the mitochondria using immunohistocytochemistry. We believe that these well-characterized antibodies will provide a valuable resource for the Human Liver Proteome Project (HLPP), and will make studies aimed at investigating liver mitochondrial function far easier to perform in future. Our results provide strong evidence that, (i) depletion of dominant proteins from liver mitochondrial samples is possible and, (ii) the approaches adopted in this study can be used to explore or validate protein-protein interactions in this important organelle.

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Development of 11β -HSD1 Inhibitors for the Treatment of Type 2 Diabetes

Cited by 37 publications

References 46 publications

Breeding for robustness: the role of cortisol

Breeding for robustness: the role of cortisol

Diabetes Mellitus: New Challenges and Innovative Therapies

Antigenically dominant proteins within the human liver mitochondrial proteome identified by monoclonal antibodies

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