Generation of cortisol from cortisone by type 1 11β‐hydroxysteroid dehydrogenase (HSD11B1; Figure 6.4)
The biological importance of these modifying enzymes is exemplified by rare mutations in the genes that encode them, presenting with endocrine over‐activity or under‐activity.
The development of the pancreas and, in particular, the specification and function of β‐cells, which secrete insulin, relies on a considerable number of transcription factors. Pancreas duodenal homeobox factor 1 [PDX1, also called insulin promoter factor 1 (IPF1)] and several members of the hepatocyte nuclear factor (HNF) family are critical; inactivating mutations cause monogenic diabetes mellitus at an early age, also called ‘maturity‐onset diabetes of the young’ (MODY) (Table 11.3). Evidence suggests these individuals never accrue a full complement of β‐cells, which also fail to function properly. Interestingly, it is emerging that more subtle under‐functioning of these transcription factors, for instance, due to genetic variations in their regulatory enhancers and promoters, is associated with type 2 diabetes.
Figure 3.20 Nuclear hormone receptor–DNA interactions. (a) Steroid hormone receptors form homodimers bound to palindromic hexanucleotide target DNA sequences that comprise the hormone response element (HRE). (b) Thyroid hormone receptor (TR), similar to receptors for retinoic acid and calcitriol, forms heterodimers with the retinoid X receptor. (c) Once occupied by tri‐iodothyronine (T3), DNA‐bound TR recruits co‐activator proteins which, in turn, bridge to, activate and stabilize the multiple components of the transcription initiation complex at the basal promoter of the target gene.
Table 3.3 Defects in nuclear hormone signalling
| Mutations in genes encoding | Clinical effects |
|---|---|
| Androgen (AR) | Partial or complete androgen insensitivity syndromes |
| Glucocorticoid (GR) | Generalized inherited glucocorticoid resistance |
| Oestrogen (ER) | Oestrogen resistance |
| Thyroid hormone (TR) | Thyroid hormone resistance |
| Vitamin D (VDR) | Vitamin D (calcitriol)‐resistant rickets |
Table 3.4 Examples of important transcription factors required for the development and function of endocrine cell types and organs
| Organ or cell type | Transcription factor |
|---|---|
| Adrenal gland | SF‐1 (NR5A1), DAX1 (NR0B1), CITED2 |
| Enteroendocrine cells | NEUROG3 (NGN3) |
| Gonad | WT1, SRY, SOX9, SF‐1, DAX1 |
| Pancreas/islets of Langerhans | PDX1, PTF1A, SOX9, HLXB9, NGN3, PAX6, PAX4, RFX6, NKX2.2, NKX6.1, NeuroD1 (also see Table 13.3) |
| Parathyroid gland | TBX1 (part of Di George syndrome; see Figure 4.4), GATA3 |
| Pituitary | PIT1, PROP1, HESX1, PITX2, SF‐1, DAX1, LHX3, LHX4 |
| Thyroid gland | PAX8, FOXE1, NKX2.1 |
Alternative names for some transcription factors are given in parentheses
Hormones act by binding to receptors and triggering intracellular responses
Tissue distribution of the receptor determines where a hormone exerts its effect
The two major subdivisions of hormone receptor are classified by their cellular site of action: cell surface or nuclear
Peptide hormones and catecholamines act via cell‐surface receptors and generate fast responses in seconds or minutes
Steroid and thyroid hormones act via nuclear receptors to alter the expression of target genes, with subsequent translation into protein; the response is slow, most commonly over hours
Mutations in genes encoding any part of the cascade from hormone to hormone receptor and downstream signalling cascade can cause under or over‐activity, or, potentially, tumour formation
CHAPTER 4 Investigations in endocrinology and diabetes
Key topics
Pre‐analytical requirements for accurate endocrine testing
Cell and molecular biology as diagnostic tools
Learning objectives
To understand how circulating hormones are measured
To understand how other laboratory investigations are applied to clinical endocrinology and diabetes
To understand the molecular biology that underpins genetic diagnoses
To understand the options available for imaging the endocrine system
This chapter details how clinical endocrinology and diabetes is investigated