Despite greater health education, obesity remains one of the greatest health challenges currently facing the world. The prevalence of obesity among children and adolescents and the rising rates of prediabetes and diabetes are of particular concern. A deep understanding of regulatory pathways and development of new anti-obesity drugs with increased efficacy and safety are of utmost necessity. The 2 major biological players in the regulation of food intake are the gut and the brain as peptides released from the gut in response to meals convey information about the energy needs to brain centers of energy homeostasis. There is evidence that gut hormones not only pass the blood-brain barrier and bind to receptors located in different brain areas relevant for body weight regulation, but some are also expressed in the brain as part of hedonic and homeostatic pathways. Regarding obesity interventions, the only truly effective treatment for obesity is bariatric surgery, the long-term benefits of which may actually involve increased activity of gut hormones including peptide YY3-36 and glucagon-like peptide 1. This review discusses critical gut-hormones involved in the regulation of food intake and energy homeostasis and their effects on peripheral tissues versus central nervous system actions.

Humans have an innate liking for sweetness, which may have an evolutionary basis. Sweetness typically signals the presence of calories and nutrients and thus, universal liking for sweet taste once served to support survival. In the modern food supply, however, sweetness is often delivered via added sugars and sweeteners devoid of other beneficial nutrients. Nonnutritive sweeteners (NNS) provide sweetness with no or few calories, and therefore may offer a potential strategy to maintain food and beverage palatability, while reducing the caloric content. Despite marked increases in NNS use, their metabolic and health effects are not well-characterized, and particularly little is known about their effects when exposure starts early in life. Herein, we critically review existing data on NNS exposure in utero, during lactation, and throughout childhood and adolescence with respect to taste preferences, weight trajectory, and development of chronic disease. We specifically focus on potential mechanisms through which sweetness exposure during early development may affect key metabolic outcomes.

Ghrelin is a pleiotropic hormone, whose effect on growth hormone secretion, through the growth hormone secretagogue (GHS) receptor, is one of its many actions. Relationships between GHS receptor gene variants and human height, both in healthy individuals and in patients with growth disorders have been identified. These include constitutional delay in growth and puberty, idiopathic short stature, and isolated growth hormone deficiency. In this review, we provide an overview of the role of ghrelin in growth.

Enteroendocrine cells (EEC) have been studied extensively for their ability to regulate gastrointestinal motility and insulin release by secretion of peptide hormones. In particular, the L cell-derived incretin glucagon-like peptide 1 has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes. Yet, accumulating data indicates a critical role for EEC and incretins in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC actively sense the lamina propria and luminal environment including the microbiota via receptors and transporters, subsequently mediating signals by secreting hormones and cytokines. Data indicate that immune cells and cytokine-mediated signaling impacts EEC numbers and function during infection and chronic inflammation of the gut, suggesting EEC not only to play a role in these pathologies but also being a target of inflammatory processes. This review presents data on the interrelation of incretins and inflammatory signaling. It focuses on the impact of intestinal inflammation, in particular inflammatory bowel disease, on EEC and the potential role of EEC and incretins in these pathologies. Furthermore, it highlights endoplasmic reticulum unfolded protein response, cytokines and the intestinal microbiota as possible targets of inflammatory and EEC signaling.

Incretins are hormones secreted into the blood stream from the gut mucosa in response to nutrient intake. They have been characterized based on their capacity to lower blood glucose levels. The more potent reduction of blood glucose coupled to a more intensive stimulation of insulin secretion, in response to oral glucose uptake, as compared to intravenous glucose infusion has further been termed the "incretin effect." As a prototype incretin hormone, the biology of glucagon-like peptide 1 (GLP-1) has been intensively studied. GLP-1 actions are mediated through cyclic adenosine monophosphate-coupled membrane receptors. Classical physiological effects involve stimulation of insulin secretion from pancreatic beta cells and reduction of glucagon secretion from pancreatic alpha cells, inhibition of gastric motility, and increase of satiety with reduced food uptake. The understanding of these metabolic functions has led to the notion that incretin hormones, and specifically GLP-1, would represent ideal antidiabetic treatment options. As native GLP-1 is degraded by dipeptidyl peptidase type 4 (DPP-4) within minutes, other pharmacological approaches to exploit GLP-1 actions for the treatment of type 2 diabetes have been developed. These include DPP-4 inhibitors as oral medications and GLP-1 receptor agonists (incretin mimetics) as peptide compounds to be injected.

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. They constitute the largest endocrine system in the human body by secreting multiple peptide hormones to control, for example, postprandial digestion, insulin homeostasis, food intake, and gut motility. For this purpose, most EECs exhibit luminal sensors that detect the GI tract content. Thereafter, they may act either in a classical endocrine fashion, or by paracrine effects on nearby neural and immune cells. This creates a pivotal role for EECs to influence the GI immune system and the enteric nervous system. In this chapter, the anatomical characteristics, development, differentiation and maturation of EECs are described, and their important biological potential illustrated as part of the gut interacting sensory system.

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. By these mechanisms, more than 100 different hormonal peptides are released from the gut. Gut hormones are also widely expressed in extraintestinal cells. These cells may release different fragments of the same prohormone due to cell-specific processing pathways. Moreover, endocrine cells, immune cells, neurons, myocytes, kidney cells, sperm cells and cancer cells secrete gut peptides in different ways, so the same peptide may act for instance as a hormone, a neurotransmitter, a cytokine, a growth factor or a fertility factor. The targets of gastrointestinal hormones are specific G-protein coupled receptors that are expressed in the cell membrane all over the body. Thus, each gut hormone constitutes a regulatory system operating in the whole organism.

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. Islet transplantation was developed in the 1970s as a minimally invasive procedure with initially poor outcomes. However, since the report of the 'Edmonton protocol' in 2000, the functional results of islet transplantation have substantially and constantly improved and are about to match those of whole pancreas transplantation. Islet transplantation is primarily performed alone in nonuremic patients with severe hypoglycemia. Both pancreas transplantation and islet transplantation are able to abolish hypoglycemia and to prevent or slow down the development of secondary complications of diabetes. Pancreas transplantation and islet transplantation should be seen as two complementary, rather than competing, therapeutic approaches for beta-cell replacement that are able to optimize organ donor use and patient care.

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. Moreover, other treatment goals in diabetic patients influence both glycaemic control and quality of life. Lipoproteins, blood pressure, weight control, mental health and lifestyle are important factors that contribute to the frequency of diabetes-associated complications.

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. Glucose-lowering therapies may influence the risk of cancer in people with type 2 diabetes due to these therapies' effects on risk factors that are common to both conditions, including hyperglycaemia and obesity, as well as effects that are specific to the class of drug or drugs. Drugs that reduce circulating insulin levels, such as metformin, may reduce cancer risk, and drugs that increase circulating insulin levels, including exogenous insulin and insulin secretagogues, may increase cancer risk. The influence of glucose-lowering therapies on cancer risk may become an important consideration when selecting glucose-lowering therapies to treat people with type 2 diabetes and a high risk of cancer occurrence or recurrence.

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. Whenever optimal offloading is guaranteed, a neuropathic ulcer will heal, whereas an ulceration compromised by even a minor degree of arterial insufficiency has little chance of healing without revascularization. The population presenting with diabetic foot ulcers has shown a clear shift from neuropathic ulcers to neuro-ischaemic ulcers over the last two decades, underscoring the necessity to adapt management strategies to this condition. Cohort studies (the Eurodiale study group) teach us that the underlying problems are an absence of assessment of PAD, underuse of imaging and late referral for revascularization. Regarding reducing amputation rates in diabetes, a highly preventable complication, the situation is far from being under control. Prevention strategies targeting the high-risk population to avoid ulcer recurrence, optimized management by multidisciplinary foot care teams, integrated care with a clear definition of the patient itinerary and anticipated action to ameliorate ischaemia are promising options for the future.

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. BP control in relation to DN is the main focus of this review, but tight control of the glucose level is equally important. There is an unmet need for new treatment options, and while a few promising candidates exist, their roles in clinical practice have not yet been determined.

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. Anti-VEGF therapies have largely replaced laser photocoagulation for the treatment of diabetic macular edema. The benefit of intravitreal anti-VEGF in diabetic macular edema has been proven in numerous large randomized controlled trials. Moreover, a role of inflammation in DR has been recognized, and several mainly steroid-based, anti-inflammatory agents for intravitreal treatment have been shown to be effective. Despite these recent advances, strict systemic control of glycemia remains the cornerstone of the management of DR, significantly reducing ocular complications. This chapter will provide an overview of current and novel concepts of DR and will allude to promising novel therapeutic options for this sight-threatening disease.

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. Common variants capture only ∼10% of the heritability of type 2 diabetes. Low-frequency and rare variants with large effects have also been identified, but their contribution to 'missing heritability' at the population level is limited. Gene-environment and gene-gene interactions and epigenetics are likely to contribute to the missing heritability of type 2 diabetes. Epigenetic factors (DNA methylations and histone modifications) are especially important because they might mediate the effects of environmental exposures on the risk of type 2 diabetes. Although understanding of the genetics of type 2 diabetes has exhibited great progress in the past few years, a substantial amount of additional work will be required to identify causal variants/genes and molecular mechanisms via which the association signals found confer diabetes risk.

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. As a consequence, interim achievements on this way result in the commercialization of innovative new diabetes technology devices, which help to facilitate the daily life of the affected people with diabetes.