Impaired Processing of Prohormones Associated with Abnormalities of Glucose Homeostasis and Adrenal Function

O’Rahilly, Stephen; Gray, Helen; Humphreys, P; Krook, Anna; Polonsky, Kenneth S.; White, Anne; Gibson, S.; Taylor, Kevin; Carr, Cornelia S

doi:10.1056/nejm199511233332104

Cited by 228 publications

(167 citation statements)

References 30 publications

(31 reference statements)

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“…This patient had a history of insulin resistance and hormone disorders associated with elevated plasma concentrations of intact proinsulin and 64,65 split proinsulin which was compatible with a defect in PC3 processing at the B chain/C peptide junction. The patient also exhibited defects in the processing of the ACTH precursor (POMC); however, there was no evidence for aberrant processing of proglucagon [19]. Circulating proIAPP was not estimated but the results from our study would suggest that processing of IAPP (like that of proglucagon) would be unaffected in this patient.…”

Section: Discussionmentioning

confidence: 54%

“…Proglucagon on the hand is processed in the ~ cells solely by PC2 [18]. Interestingly, a patient with a primary defect of PC3 activity has been described [19]. This patient had a history of insulin resistance and hormone disorders associated with elevated plasma concentrations of intact proinsulin and 64,65 split proinsulin which was compatible with a defect in PC3 processing at the B chain/C peptide junction.…”

Section: Discussionmentioning

confidence: 99%

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Processing of pro‐islet amyloid polypeptide (proIAPP) by the prohormone convertase PC2

et al. 1996

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Islet amyloid polypeptide (lAPP), 'amylin', is the component peptide of islet amyloid formed in Type 2 diabetes. IAPP is expressed in islet /]-cells and is derived from a larger precursor, proIAPP, by proteolysis. An in vitro translation/ translocation system was used to separately examine processing of human proIAPP by the/I-cell endopeptidases PC2, PC3 or furin. ProIAPP was converted to mature IAPP by PC2 but there was little conversion by furin or PC3. These data are consistent with processing of proIAPP in/]-cell secretory granules. Abnormal cellular proteolysis associated with type 2 diabetes could contribute to lAPP amyloidosis.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Processing of pro‐islet amyloid polypeptide (proIAPP) by the prohormone convertase PC2

et al. 1996

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“…In the early 1990s, a patient referred to the Addenbrooke's Hospital Endocrine Clinic had severe obesity from a young age but also a range of additional unexplained endocrine disturbances. 27 Through a combination of biochemistry and genetics, we eventually discovered that she had a primary defect in the ability to process certain peptide prohormones. We found compound heterozygous mutations in the prohormone convertase 1 (PC1) gene (now referred to as PC1/3) 28 to be responsible.…”

Section: Discussionmentioning

confidence: 99%

Human obesity as a heritable disorder of the central control of energy balance

O’Rahilly

Farooqi

2008

Int J Obes

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In the spirit of celebration associated with the 20th anniversary of the Pennington Biomedical Research Center, we have seized the opportunity of taking a highly personal and not at all comprehensive 'whistle-stop tour' of a large body of evidence that, we feel, supports the following conclusions: (1) that body fat stores are regulated by biological control processes in humans as they are in lower animals; (2) that there are major inherited influences on the efficiency whereby such control processes operate in humans; (3) that the precise nature of those genetic and biological influences and how they interact with environmental factors are beginning to be understood; (4) that most of the genes discovered thus far have their principal impact on hunger, satiety and food intake; (5) that while there is understandable resistance to the notion that genes can influence a human behavior such as the habitual ingestion of food, the implications of these discoveries are essentially benign. Indeed, we hope that they may eventually lead to improved treatment for patients and, in addition, help to inculcate a more enlightened attitude to the obese with a reduction in their experience of social and economic discrimination.

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“…Investigation revealed partial adrenocorticotrophin deficiency. Circulating proinsulin levels were massively elevated but true insulin was undetected, yet the proinsulin gene sequence was normal (6). Pro-opiomelanocortin (POMC) levels were also hugely elevated suggesting a generalised defect in prohormone conversion and, following the characterisation of the genomic structure of the PC1 gene we went on to find two loss of function mutations in the neuroendocrine convertase PC1 (7).…”

Section: Prohormone Convertase 1 (Pc1)mentioning

confidence: 99%

Insights into obesity and insulin resistance from the study of extreme human phenotypes

O’Rahilly

2002

European Journal of Endocrinology

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The detailed study of rare, extreme human phenotypes has a long and distinguished history in endocrinology. Such individuals have often acted as 'experiments of nature' providing important novel information regarding endocrine physiology and mechanistic insights relevant to the study of more common endocrine disorders. This review presents a personal experience of the study of two such extreme phenotypes, obesity and severe insulin resistance.

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Impaired Processing of Prohormones Associated with Abnormalities of Glucose Homeostasis and Adrenal Function

Cited by 228 publications

References 30 publications

Processing of pro‐islet amyloid polypeptide (proIAPP) by the prohormone convertase PC2

Processing of pro‐islet amyloid polypeptide (proIAPP) by the prohormone convertase PC2

Human obesity as a heritable disorder of the central control of energy balance

Insights into obesity and insulin resistance from the study of extreme human phenotypes

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