Maternal serum levels of prokineticin-1 related to pregnancy complications and metformin use in women with polycystic ovary syndrome: a post hoc analysis of two prospective, randomised, placebo-controlled trials.

OBJECTIVE: Serum prokineticin-1 (s-PROK1) in the second and third trimester of pregnancy is positively correlated to preeclampsia, intrauterine growth restriction (IUGR) and preterm delivery. Women with polycystic ovary syndrome (PCOS) are prone to these adverse pregnancy outcomes. However, the contribution of PROK1 to the development of pregnancy complications and the effect of metformin and hyperandrogenism on s-PROK1 in PCOS have not been studied previously. DESIGN: This work is a post hoc analysis of two prospective, randomised, placebo-controlled trials. SETTING: Pregnant women with PCOS were included from 11 study centres in Norway. PARTICIPANTS: From 313 women, 264 participated in the present study after exclusions due to dropouts or insufficient serum samples. INTERVENTION: Women with PCOS were randomly administered with metformin or placebo, from first trimester to delivery. PRIMARY AND SECONDARY OUTCOME MEASURES: s-PROK1 was analysed using ELISA at gestational week 19 and related to pregnancy complications, fasting insulin levels, homoeostatic model assessment for insulin resistance (HOMA-IR), testosterone, or androstenedione levels, metformin use, PCOS phenotype and hyperandrogenism. RESULTS: Maternal s-PROK1 in the second trimester did not predict pregnancy-induced hypertension, pre-eclampsia or late miscarriage/preterm delivery in women with PCOS. However, s-PROK1 was lower in women who used metformin before inclusion, both in those randomised to metformin and to placebo, compared with those who did not. s-PROK1 was also lower in those who used metformin both at conception and during pregnancy compared with those who used metformin from inclusion or did not use metformin at all. s-PROK1 was lower in hyperandrogenic compared with normo-androgenic women with PCOS. CONCLUSIONS: Maternal s-PROK1 in the second trimester did not predict pregnancy complications in PCOS. Those who used metformin at conception and/or during pregnancy had lower s-PROK1. PCOS women with hyperandrogenism exhibited lower s-PROK1 compared with normo-adrogenic phenotypes. TRIAL REGISTRATION NUMBER: NCT03259919 and NCT00159536.

Future therapies for obesity.

Obesity is a chronic disease associated with increased morbidity and mortality. Bariatric surgery can lead to sustained long-term weight loss (WL) and improvement in multiple obesity-related complications, but it is not scalable at the population level. Over the past few years, gut hormone-based pharmacotherapies for obesity and type 2 diabetes mellitus (T2DM) have rapidly evolved, and combinations of glucagon-like peptide 1 (GLP1) with other gut hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) as dual or triple agonists are under investigation to enhance and complement the effects of GLP1 on WL and obesity-related complications. Tirzepatide, a dual agonist of GLP1 and GIP receptors, marks a new era in obesity pharmacotherapy in which a combination of gut hormones could approach the WL achieved with bariatric surgery. In this review, we discuss emerging obesity treatments with a focus on gut hormone combinations and the concept of a multimodal approach for obesity management.

Gut hormone co-agonists for the treatment of obesity: from bench to bedside.

The discovery and development of so-called gut hormone co-agonists as a new class of drugs for the treatment of diabetes and obesity is considered a transformative breakthrough in the field. Combining action profiles of multiple gastrointestinal hormones within a single molecule, these novel therapeutics achieve synergistic metabolic benefits. The first such compound, reported in 2009, was based on balanced co-agonism at glucagon and glucagon-like peptide-1 (GLP-1) receptors. Today, several classes of gut hormone co-agonists are in development and advancing through clinical trials, including dual GLP-1-glucose-dependent insulinotropic polypeptide (GIP) co-agonists (first described in 2013), and triple GIP-GLP-1-glucagon co-agonists (initially designed in 2015). The GLP-1-GIP co-agonist tirzepatide was approved in 2022 by the US Food and Drug Administration for the treatment of type 2 diabetes, providing superior HbA1c reductions compared to basal insulin or selective GLP-1 receptor agonists. Tirzepatide also achieved unprecedented weight loss of up to 22.5%-similar to results achieved with some types of bariatric surgery-in non-diabetic individuals with obesity. In this Perspective, we summarize the discovery, development, mechanisms of action and clinical efficacy of the different types of gut hormone co-agonists, and discuss potential challenges, limitations and future developments.

[Gastrointestinal hormones: their increasing pharmacotherapeutic relevance in metabolic diseases]. / Gastrointestinale Hormone ­ zunehmende arzneitherapeutische Bedeutung bei Stoffwechselerkrankungen.

Gastrointestinal hormones play an important role in the endocrine communication between the intestine, the pancreas, the liver and the brain. Glucagon-like peptide­1 receptor agonists (GLP-1RA) are established therapeutic agents in the treatment of type­2 diabetes. Multiple agonists acting as ligands on various gastrointestinal hormone receptors are a novel pharmacological development. In addition to glucagon-like peptide 1 (GLP-1), these multiple agonists also have glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptors as target structures for their pharmacological action. The multiple agonist action is designed to increase glycaemic effects as well as the effects on body weight. This article provides an overview of GLP-1RA and the multiple agonists. Among the dual agonists, the GIP/GLP-1-agonist tirzeptide has been approved for the treatment of type­2 diabetes, and clinical studies with tirzepatide as a treatment for obesity are ongoing. The currently available data on studies with GLP-1/glucagon agonists and triple agonists are also summarized.

From Entero-Endocrine Cell Biology to Surgical Interventional Therapies for Type 2 Diabetes.

The physiological roles of the enteroendocrine system in relation to energy and glucose homeostasis regulation have been extensively studied in the past few decades. Considerable advances were made that enabled to disclose the potential use of gastro-intestinal (GI) hormones to target obesity and type 2 diabetes (T2D). The recognition of the clinical relevance of these discoveries has led the pharmaceutical industry to design several hormone analogues to either to mitigate physiological defects or target pharmacologically T2D.Amongst several advances, a major breakthrough in the field was the unexpected observation that enteroendocrine system modulation to T2D target could be achieved by surgically induced anatomical rearrangement of the GI tract. These findings resulted from the widespread use of bariatric surgery procedures for obesity treatment, which despite initially devised to induce weight loss by limiting the systemic availably of nutrients, are now well recognized to influence GI hormone dynamics in a manner that is highly dependent on the type of anatomical rearrangement produced.This chapter will focus on enteroendocrine system related mechanisms leading to improved glycemic control in T2D after bariatric surgery interventions.

The new place of enterohormones in intestinal failure.

PURPOSE OF REVIEW: Since the approval of teduglutide, a glucagon-like peptide-2 (GLP-2) analog, for the treatment of patients with short bowel syndrome (SBS) associated with intestinal failure, enterohormone therapy has received significant interest and is becoming the first choice of treatment in selected patients. As such, it is paramount to assess and understand the new place of hormonal therapy in the algorithm of treatments in SBS-intestinal failure. RECENT FINDINGS: Specialized intestinal failure units have recently reported their outcomes with teduglutide to evaluate if they are consistent with the phase III trials results. SBS-intestinal failure patients are very heterogenous including their response to this treatment, hence the importance of real-life studies beyond the context of clinical trials. Moreover, it is essential to find a consensus on criteria identifying candidate patients for teduglutide. In addition, the impact of teduglutide on quality of life and its cost-effectiveness are emerging as well as new enterohormone treatments are being studied whether it is long action GLP-2 analog or other ileocolonic break hormones like glucagon-like peptide-1 analog. SUMMARY: Hormonotherapy is currently modifying the natural history of patients with SBS-intestinal failure by decreasing their need for parenteral support and possibly even complications associated with long-term parenteral support. Enterohormone treatment is now the cornerstone in SBS-intestinal failure and should be offered as a first-line therapy to selected patients.

Potential Therapeutic Effects of Gut Hormones, Ghrelin and Obestatin in Oral Mucositis.

Chemotherapy and/or head and neck radiotherapy are frequently associated with oral mucositis. Oral pain, odynophagia and dysphagia, opioid use, weight loss, dehydration, systemic infection, hospitalization and introduction of a feeding tube should be mentioned as the main determinated effect of oral mucositis. Oral mucositis leads to a decreased quality of life and an increase in treatment costs. Moreover, oral mucositis is a life-threatening disease. In addition to its own direct life-threatening consequences, it can also lead to a reduced survival due to the discontinuation or dose reduction of anti-neoplasm therapy. There are numerous strategies for the prevention or treatment of oral mucositis; however, their effectiveness is limited and does not correspond to expectations. This review is focused on the ghrelin and obestatin as potentially useful candidates for the prevention and treatment of chemo- or/and radiotherapy-induced oral mucositis.

Incretin-based therapy for the treatment of bone fragility in diabetes mellitus.

Bone fractures are common comorbidities of type 2 diabetes mellitus (T2DM). Bone fracture incidence seems to develop due to increased risk of falls, poor bone quality and/or anti-diabetic medications. Previously, a relation between gut hormones and bone has been suspected. Most recent evidences suggest indeed that two gut hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), may control bone remodeling and quality. The GIP receptor is expressed in bone cells and knockout of either GIP or its receptor induces severe bone quality alterations. Similar alterations are also encountered in GLP-1 receptor knock-out animals associated with abnormal osteoclast resorption. Some GLP-1 receptor agonist (GLP-1RA) have been approved for the treatment of type 2 diabetes mellitus and although clinical trials may not have been designed to investigate bone fracture, first results suggest that GLP-1RA may not exacerbate abnormal bone quality observed in T2DM. The recent design of double and triple gut hormone agonists may also represent a suitable alternative for restoring compromised bone quality observed in T2DM. However, although most of these new molecules demonstrated weight loss action, little is known on their bone safety. The present review summarizes the most recent findings on peptide-based incretin therapy and bone physiology.

Gut hormone polyagonists for the treatment of type 2 diabetes.

Chemical derivatives of the gut-derived peptide hormone glucagon-like peptide 1 (GLP-1) are among the best-in-class pharmacotherapies to treat obesity and type 2 diabetes. However, GLP-1 analogs have modest weight lowering capacity, in the range of 5-10%, and the therapeutic window is hampered by dose-dependent side effects. Over the last few years, a new concept has emerged: combining the beneficial effects of several key metabolic hormones into a single molecular entity. Several unimolecular GLP-1-based polyagonists have shown superior metabolic action compared to GLP-1 monotherapies. In this review article, we highlight the history of polyagonists targeting the receptors for GLP-1, GIP and glucagon, and discuss recent progress in expanding of this concept to now allow targeted delivery of nuclear hormones via GLP-1 and other gut hormones, as a novel approach towards more personalized pharmacotherapies.

Gut as an emerging organ for the treatment of diabetes: focus on mechanism of action of bariatric and endoscopic interventions.

Increasing worldwide prevalence of type 2 diabetes mellitus and its accompanying pathologies such as obesity, arterial hypertension and dyslipidemia represents one of the most important challenges of current medicine. Despite intensive efforts, high percentage of patients with type 2 diabetes does not achieve treatment goals and struggle with increasing body weight and poor glucose control. While novel classes of antidiabetic medications such as incretin-based therapies and gliflozins have some favorable characteristics compared to older antidiabetics, the only therapeutic option shown to substantially modify the progression of diabetes or to achieve its remission is bariatric surgery. Its efficacy in the treatment of diabetes is well established, but the exact underlying modes of action are still only partially described. They include restriction of food amount, enhanced passage of chymus into distal part of small intestine with subsequent modification of gastrointestinal hormones and bile acids secretion, neural mechanisms, changes in gut microbiota and many other possible mechanisms underscoring the importance of the gut in the regulation of glucose metabolism. In addition to bariatric surgery, less-invasive endoscopic methods based on the principles of bariatric surgery were introduced and showed promising results. This review highlights the role of the intestine in the regulation of glucose homeostasis focusing on the mechanisms of action of bariatric and especially endoscopic methods of the treatment of diabetes. A better understanding of these mechanisms may lead to less invasive endoscopic treatments of diabetes and obesity that may complement and widen current therapeutic options.

Bariatric surgery - time to replace with GLP-1?

Obesity with a body mass index (BMI) over 30 kg/m2 represents a significant risk for increased morbidity and mortality, with reduced life expectancy of about 10 years. Until now, surgical treatment has been the only effective longterm intervention. The currently standardized method of bariatric surgery, gastric bypass, means that many gastrointestinal peptide hormones are activated, yielding net reductions in appetite and food intake. Among the most important gut peptide hormones in this perspective is glucagon-like peptide-1 (GLP-1), which rises sharply after gastric bypass. Consistent with outcomes of this surgery, GLP-1 suppresses appetite and reduces food intake. This implies that GLP-1 has the potential to achieve a similar therapeutic outcome as gastric bypass. GLP-1 analogs, which are used for the treatment of type 2 diabetes mellitus, also lead to significant weight loss. Altered hormonal profiles after gastric bypass therefore indicate a logical connection between gut peptide hormone levels, weight loss and glucose homeostasis. Furthermore, combinations of GLP-1 with other gut hormones such as peptide YY (PYY) and cholecystokinin (CCK) may be able to reinforce GLP-1 driven reduction in appetite and food intake. Pharmacological intenvention in obesity by use of GLP-1 analogs (exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, taspoglutide) and inhibitors of dipeptidyl peptidase-IV (DPP-IV) degradation that inactivate GLP-1 (sitagliptin, vildagliptin), leading to reduced appetite and weight with positive effects on metabolic control, are realistically achievable. This may be regarded as a low-risk therapeutic alternative to surgery for reducing obesity-related risk factors in the obese with lower BMIs.

Biological Activity and Antidiabetic Potential of C-Terminal Octapeptide Fragments of the Gut-Derived Hormone Xenin.

Xenin is a peptide that is co-secreted with the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), from intestinal K-cells in response to feeding. Studies demonstrate that xenin has appetite suppressive effects and modulates glucose-induced insulin secretion. The present study was undertaken to determine the bioactivity and antidiabetic properties of two C-terminal fragment xenin peptides, namely xenin 18-25 and xenin 18-25 Gln. In BRIN-BD11 cells, both xenin fragment peptides concentration-dependently stimulated insulin secretion, with similar efficacy as the parent peptide. Neither fragment peptide had any effect on acute feeding behaviour at elevated doses of 500 nmol/kg bw. When administered together with glucose to normal mice at 25 nmol/kg bw, the overall insulin secretory effect was significantly enhanced in both xenin 18-25 and xenin 18-25 Gln treated mice, with better moderation of blood glucose levels. Twice daily administration of xenin 18-25 or xenin 18-25 Gln for 21 days in high fat fed mice did not affect energy intake, body weight, circulating blood glucose or body fat stores. However, circulating plasma insulin concentrations had a tendency to be elevated, particularly in xenin 18-25 Gln mice. Both treatment regimens significantly improved insulin sensitivity by the end of the treatment period. In addition, sustained treatment with xenin 18-25 Gln significantly reduced the overall glycaemic excursion and augmented the insulinotropic response to an exogenous glucose challenge on day 21. In harmony with this, GIP-mediated glucose-lowering and insulin-releasing effects were substantially improved by twice daily xenin 18-25 Gln treatment. Overall, these data provide evidence that C-terminal octapeptide fragments of xenin, such as xenin 18-25 Gln, have potential therapeutic utility for type 2 diabetes.

PATHOPHYSIOLOGICAL ASPECTS OF PLEIOTROPIC EFFECTS OF GASTROINTESTINAL HORMONES.

The unique properties and a great therapeutic potential of incretin drugs allowed them to win a firm place in modern algorithms of treatment of type 2 diabetes in an unprecedented short period of time. Due to discovery of the incretin effect and introduction of the increrin mimetics into clinical practice, an interest of the researchers was growing to study the plelotropic effects of gastrointestinal hormones. In experimental and clinical studies in recent years there has been shown the cytoprotective and cytoproliferative effects of a number of intestinal hormones, namely giucagon-like peptide-1 (GLP-1), ghrelin, and obestatin when administered systemicallyThis review presents an analysis of the currently available results of fundamental and clinical research on the plelotropic potential of the gastrointestinal peptides, and also determines the relevance of further research on the metabolic effects of bariatric surgery.

Can Bayliss and Starling gut hormones cure a worldwide pandemic?

Bayliss and Starling first coined the term 'hormone' with reference to secretin, a substance they found that was produced by the gut, but released into the blood stream to act at a distance. The intestine is now known as the largest endocrine organ in the body, and it produces numerous hormones with a wide range of functions. These include controlling appetite and energy homeostasis. Obesity is one of the greatest health threats facing the world today. At present, the only successful treatment is surgery. Bariatric procedures such as the Roux-en-Y bypass work by elevating gut hormones that induce satiety. Significant research has gone into producing versions of these hormones that can be delivered therapeutically to treat obesity. This review looks at the role of gut hormones in obesity, and the development of gut hormone-derived obesity treatments.

Structural aspects of gut peptides with therapeutic potential for type 2 diabetes.

Gut hormones represent a niche subset of pharmacologically active agents that are rapidly gaining importance in medicine. Due to their exceptional specificity for their receptors, these hormones along with their analogues have attracted considerable pharmaceutical interest for the treatment of human disorders including type 2 diabetes. With the recent advances in the structural biology, a significant amount of structural information for these hormones is now available. This Minireview presents an overview of the structural aspects of these hormones, which have roles in physiological processes such as insulin secretion, as well as a discussion on the relevant structural modifications used to improve these hormones for the treatment of type 2 diabetes.

Bowels control brain: gut hormones and obesity.

Peptide hormones are released from the gastrointestinal tract in response to nutrients and communicate information regarding the current state of energy balance to the brain. These hormones regulate appetite, energy expenditure and glucose homeostasis. They can act either via the circulation at target peripheral tissues, by activation of the vagus nerve or by acting on key brain regions implicated in energy homeostasis such as the hypothalamus and brainstem. This review gives an overview of the main gut hormones implicated in the regulation of food intake and how some of these are being targeted to develop anti obesity treatments.

The pharmacological treatment and management of obesity.

Obesity is a pandemic with many complications that increase the societal disease burden and cost of health care, and decrease longevity and quality of life. Currently, 1 in 3 adults in the United States is obese. Physicians must therefore regularly confront obesity and its consequent diseases, and develop strategies for effective treatment and management. This article summarizes current lifestyle modifications, pharmacological treatment, and surgical options for the management of obesity and discusses the benefits, limitations, and risks of each. As insights are gained into the pathophysiology of a gut-brain neurochemical feedback axis governing satiety and feeding behavior, targets for new pharmacotherapies are being developed. In particular, gut hormone analogs are an attractive antiobesity therapy because they appear to lack the adverse effects historically associated with central nervous system-acting agents.

Medical management of pediatric intestinal failure.

The outcome for children with congenital enteropathies or massive surgical resections has improved significantly over the past two decades. Advances in understanding of the pathophysiology of intractable diarrhea and of the mutations causing many of the congenital enteropathies have enabled initiation of preventive measures for intractable diarrhea, and have enabled clinicians to provide focused treatment of immune-mediated congenital diarrheal illnesses. Children with surgical short bowel syndrome also face an improved outcome because of improvements in the composition of parenteral nutrition (TPN) and in enteral alimentation strategies. It is now recognized that, through adaptation, small intestinal surface area and absorptive function may improve over time to facilitate emancipation from parenteral nutrition. Beyond provision of enteral nutrition, ancillary therapies such as judicious use of acid suppression, antibiotics, prokinetic agents, and soluble fiber seem to accelerate the rate of adaptation in young children. In the future, trophic hormones such as epidermal growth factor (EGF) or glucagon-like peptide 2 (GLP-2) may become routine members of the therapeutic armamentarium for surgical short bowel syndrome, thus further improving outcomes.

Therapeutic potential of gut peptides.

A great deal of research interest is directed toward understanding the control of appetite and regulation of metabolism. It seems as if an epidemic of obesity is sweeping the world, and type II diabetes (T2DM) is following in its wake. The regulation of energy homeostasis is an area that straddles neurobiology, classical endocrinology and metabolism. It is currently one of the most exciting and rapidly advancing topics in medical research, and is also one of the most frustrating areas. The availability of highly palatable, calorie-dense food, together with the low requirement for physical activity in our modern environment, are major factors contributing to the obesity epidemic. If energy intake exceeds energy use, the excess calories are stored as body fat. Knowledge of the homeostatic system that controls body weight has increased dramatically over the last years and has revealed new potential targets for the treatment of obesity. One therapeutic approach is the development of agents based on the gastrointestinal hormones that control food intake and appetite. This review discusses several gut hormones and ligands for their receptors as potential anti-obesity treatments.

Can colorectal cancer be prevented or treated by oral hormone replacement therapy?

Guanylyl cyclase C (GCC) is the receptor specifically expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin and diarrheagenic bacterial heat-stable enterotoxins. This tissue-specific receptor coordinates lineage-dependent regulation of epithelial homeostasis, and its disruption contributes to intestinal tumorigenesis. It coordinates regenerative and metabolic circuits by restricting the cell cycle and proliferation and programming metabolic transitions central to organizing the dynamic crypt-surface axis. Further, mice deficient in GCC signaling are more susceptible to colon cancer induced by Apc mutations or the carcinogen azoxymethane. Moreover, guanylin and uroguanylin are gene products most commonly lost, early, in colon cancer in animals and humans. The role of GCC as a tumor suppressing receptor regulating proliferation and metabolism, together with the universal loss of guanylin and uroguanylin in tumorigenesis, suggests a model in which colorectal cancer is a paracrine hormone deficiency syndrome. In that context, activation of GCC reverses the tumorigenic phenotype by limiting growth of colorectal cancer cells by restricting progression through the G1/S transition and reprogramming metabolic circuits from glycolysis to oxidative phosphorylation, limiting bioenergetic support for rapid proliferation. These observations suggest a pathophysiological hypothesis in which GCC is a lineage-dependent tumor suppressing receptor coordinating proliferative homeostasis whose dysregulation through hormone loss contributes to neoplasia. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral supplementation with GCC ligands.