Endocrine Development

The gastrointestinal (GI) tract exhibits an enormous surface area that consists mostly of absorptive enterocytes. Enteroendocrine cells (EECs) are found scattered along the GI tract between absorptive enterocytes and other secretory cells, and comprise around 1% of the epithelial cell population. Interestingly, they develop from the same crypt stem cell as the other absorptive or secretory cells of the gut. EECs differentiate along the crypt villus axis and are renewed every 4-6 days, and hence possess a high plasticity...

Gastrointestinal hormones are released from enteroendocrine cells in the digestive tract. More than 30 hormone genes are expressed, which make the gut the largest endocrine organ in the body. At present, it is feasible to conceive the hormones under 5 headings: the structural homology groups most hormones into 9 families, each of which is assumed to originate from a single gene. Today's hormone gene often has multiple phenotypes due to alternative splicing, tandem organization or differentiated maturation of the prohormone...

Pancreas and islet transplantation are 2 types of beta-cell replacement therapies for type 1 diabetes mellitus. Since 1966, when pancreas transplantation was first performed, it has evolved to become a highly efficient procedure with high success rates, thanks to advances in surgical technique and immunosuppression. Pancreas transplantation is mostly performed as simultaneous pancreas-kidney transplantation in patients with end-stage nephropathy secondary to diabetes. In spite of its efficiency, pancreas transplantation is still a major surgical procedure burdened by high morbidity, which called for the development of less invasive and hazardous ways of replacing beta-cell function in the past...

The quality of glycaemic control in diabetes mellitus relies on accurate individualization of available treatment options. Treatment targets depend on the type and duration of diabetes, the patients' abilities and characteristics and the individual risk for acute and/or late-stage complications. These complications include hypoglycaemia, which can be severe and life threatening, hyperglycaemia, which is a main factor for the development of cardiovascular disease, and macrovascular and microvascular disease, both of which are hallmark features of diabetes-associated constraints...

Diabetes and cancer are common conditions, affecting 384 million and 33 million people worldwide, respectively. Therefore, there is great potential for overlap, with people with diabetes also developing cancer and vice versa. However, people with diabetes may be at increased risk of developing cancer when compared with the general population. This is due to both shared risk factors associated with the two diseases and the metabolic derangements associated with diabetes, such as hyperglycaemia, insulin resistance, hyperinsulinaemia and oxidative stress...

Diabetes, a major public health concern, is increasing in prevalence worldwide. A diabetic patient has an up to 25% lifetime risk of developing a foot ulcer condition that predisposes that patient to lower-extremity amputation. The underlying pathology is diabetic peripheral neuropathy and peripheral arterial disease (PAD) associated with deformities of foot anatomy due to motor neuropathy. Trauma, often secondary to ill-fitting shoes, precipitates skin breakdown, whereas PAD determines the prognosis for healing...

Diabetic nephropathy (DN) is a major complication of both type 1 and type 2 diabetes. DN is the most common cause of end-stage renal disease, and it markedly enhances the risk of cardiovascular events. An elevated urinary albumin excretion rate, increased blood pressure (BP), and a continual loss of renal function are characteristics of DN. Screening for microalbuminuria is central to diabetes care, and antihypertensive agents are used for the primary prevention and treatment of DN. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers play central roles and have protective properties beyond their BP-lowering effects...

Although diabetic retinopathy (DR) remains a leading cause of vision loss, the last decade has brought significant advances in the diagnosis and treatment of this common complication of diabetes mellitus. First, optical coherence tomography allows for noninvasive imaging of the retina, in particular, the macula, with very high resolution, thus facilitating the management of diabetic macular edema. In addition, recent advances in the understanding of the pathophysiology of DR, in particular, the key role of cytokines, such as vascular endothelial growth factor (VEGF), have led to the development of anti-VEGF antibodies for intraocular use...

Genetic and environmental factors as well as their interactions contribute to the pathogenesis of type 2 diabetes. Linkage analysis, candidate gene approaches, genome-wide association studies, and sequencing have been used in the identification of common, low-frequency and rare variants for type 2 diabetes. Genome-wide association studies have identified >80 common variants for type 2 diabetes, with small effect sizes (risk of type 2 diabetes increased by 5-40%). Almost all of these variants regulate insulin secretion, and only a few regulate insulin sensitivity...

Diabetes technology is an evolving field. The research started with the development of blood glucose meters for patient self-testing and the introduction of insulin pen injection devices. Modern devices employ new technological features, such as the use of computer simulations and mathematical algorithms, connectivity and signal transfer, and the use of modern (space research-derived) materials. With these innovations, the goal to develop an artificial pancreas by closing the loop between a continuous glucose sensor and a continuous insulin-delivering device via insulin delivery algorithms is coming closer to reality...

Individuals with higher-than-normal blood sugar levels used to be diagnosed as having either type 1 or type 2 diabetes. We now know that a wide range of different factors can cause diabetes, including single gene defects, which account for at least 1% of all diabetes cases and up to 4% of cases in the pediatric population. However, misdiagnosis remains common due to the considerable clinical overlap between the different diabetes forms. Monogenic diabetes onset can occur shortly after birth, as observed in neonatal diabetes mellitus, or any time later in life...

This chapter deals with novel therapeutic approaches, predominantly for type 2 diabetes. Incretin-based therapies utilize the effects of glucagon-like peptide-1 (GLP-1), which stimulates insulin and inhibits glucagon secretion in a glucose-dependent manner. Incretin-based therapies comprise injectable GLP-1 receptor agonists and orally active dipeptidyl peptidase-IV inhibitors. Both have a low hypoglycaemia risk. GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, dulaglutide, albiglutide) reduce glycated haemoglobin levels more effectively than oral antidiabetic agents do and lead to weight loss as well as a slight decrease in systolic blood pressure...

An array of oral agents is available for the treatment of hyperglycaemia in type 2 diabetes. This systematic inventory focuses on 'old' oral agents, including metformin, sulfonylureas (SUs), thiazolidinediones, alpha glucosidase inhibitors, and meglitinides. Twelve meta-analyses and six randomized controlled trials that used patient-relevant outcomes as primary endpoints were critically reviewed. Guidelines recommend the use of metformin or an SU as the first-line pharmacotherapeutic options. Beneficial effects of metformin have been demonstrated for 'any diabetes-related endpoint' and 'all-cause mortality' in small study groups of overweight and obese patients with newly manifested type 2 diabetes...

Based on the Hyperglycemia and Adverse Pregnancy Outcome study, new universal screening recommendations and cut-offs for gestational diabetes mellitus (GDM) have been proposed. In addition to the immediate perinatal risk, GDM carries an increased risk of metabolic disease in the mother and child. Maternal obesity has even been shown to be associated with increased all-cause mortality in offspring. In addition to known risk factors, excessive gestational weight gain, increased fat consumption, a low vitamin D level, psychological stress and negative mood are risk factors for GDM...

X-linked adrenoleukodystrophy (X-ALD) is the most frequent inherited monogenic demyelinating disease. It is often lethal and currently lacks a satisfactory therapy. The disease is caused by loss of function of the ABCD1 gene, a peroxisomal ATP-binding cassette transporter, resulting in the accumulation of very-long-chain fatty acids (VLCFA) in organs and plasma. Recent findings on pathomechanisms of the peroxisomal neurometabolic disease X-ALD have provided important clues on therapeutic targets. Here we describe the impact of chronic redox imbalance caused by the excess VLCFA on mitochondrial biogenesis and respiration, and explore the consequences on the protein quality control systems essential for cell survival, such as the proteasome and autophagic flux...

Gene therapy for rare inherited neurologic diseases has entered the clinics. One strategy relies upon the replacement of brain microglia using hematopoietic stem cell gene therapy with lentiviral vectors. Therapeutic success using this approach has been obtained in X-linked adrenoleukodystrophy and metachromatic leukodystrophy. The other strategy relies upon the intracerebral administration of adeno-associated virus vectors encoding lysosomal enzymes. Therapeutic trials are ongoing in Batten's disease, metachromatic leukodystrophy, and Sanfilippo type A and B diseases...

Reports published in the 1990s of men with estrogen deficiency caused by defective aromatase or estrogen resistance due to a defective estrogen receptor α confirmed the crucial role of estrogen in bone maturation, closure of the epiphyses and cessation of statural growth. Based on these findings, it became reasonable to postulate that selective inhibition of estrogen synthesis with aromatase inhibitors could increase adult height by delaying bone maturation and prolonging the period of growth in males. To date, aromatase inhibitors have been employed in rare pediatric conditions associated with sex steroid excess, and in randomized controlled trials involving boys with short stature and/or constitutional delay of puberty...

Reproductive hormones play a role at all stages of life and affect most tissues of the body. Gonadotropin-releasing hormone (GnRH) synthesized in the hypothalamus stimulates the secretion of gonadotropins which in turn stimulate gonadal sex hormone production and gamete formation. This hypothalamic-pituitary-gonadal (HPG) axis has, therefore, been the target for the development of numerous drugs which regulate it at various points. These include sex steroid agonists and antagonists, inhibitors of sex steroid biosynthesis, and GnRH agonists and antagonists, which have found extensive applications in treating numerous conditions such as precocious puberty, delayed puberty, prostate cancer, benign prostatic hyperplasia, endometriosis, uterine fibroids and also in in vitro fertilization protocols...

Fibroblast growth factor receptor 3 (FGFR3) is an important regulator of bone formation. Gain-of-function mutations in the FGFR3 gene result in chondrodysplasias which include achondroplasia (ACH), the most common form of dwarfism, in which skull, appendicular and axial skeletons are affected. The skeletal phenotype of patients with ACH showed defective proliferation and differentiation of the chondrocytes in the growth plate cartilage. Both endochondral and membranous ossification processes are disrupted during development...

After the introduction of recombinant human growth hormone (rhGH) in 1985, a myriad of children and adults have benefited from its growth-promoting and metabolic effects. Nowadays, current therapeutic regimens rely on daily subcutaneous GH injections that could be burdensome and inconvenient to pediatric patients. As expected with any long-term parenteral pharmacological treatment, these daily regimens may promote nonadherence, poor compliance, treatment abandonment and/or suboptimal clinical outcomes. In order to improve patient and caregiver acceptance of proposed regimens, simplified dosing schedules could potentially aid in reducing poor compliance and maximize the therapeutic end results...