Diabetes and cancer are two of the most common public health concerns worldwide. The complex interplay of these two conditions is a growing area of research, as patients with diabetes are at increased risk for developing cancer, and vice versa. Furthermore, both patient populations show increased risk of many communicable infectious diseases and their adverse consequences, while vaccination can play a crucial role in their prevention, improving patient outcomes. Vaccination should represent a standard part of care for patients with cancer, diabetes, and both the diseases simultaneously, including people undergoing cancer treatment or in remission. Several international guidelines provide recommendations for vaccinating people with cancer or diabetes, but the two conditions have not been specifically evaluated together. Here we present a multidisciplinary consensus position paper on vaccination in patients with cancer and diabetes. The position paper is the result of a collaborative effort between experts from the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF). The paper provides a comprehensive overview of the current state-of-the-art knowledge on vaccination in patients with cancer and diabetes. It discusses the importance of vaccination in preventing infections, focuses attention on the need to consider the unique challenges faced by patients with cancer and diabetes when it comes to vaccine administration, and highlights the need for coordinated care to optimize treatment outcomes. Overall, the consensus position paper provides healthcare professionals caring for patients with cancer and diabetes recommendations on the use of various vaccines, including influenza, COVID-19, HZV, and HPV vaccines, as well as guidance on how to address common concerns and challenges related to vaccine administration.

The gut is traditionally recognized as the central organ for the digestion and absorption of nutrients, however, it also functions as a significant endocrine organ, secreting a variety of hormones such as glucagon-like peptide 1, serotonin, somatostatin, and glucocorticoids. These gut hormones, produced by specialized intestinal epithelial cells, are crucial not only for digestive processes but also for the regulation of a wide range of physiological functions, including appetite, metabolism, and immune responses. While gut hormones can exert systemic effects, they also play a pivotal role in maintaining local homeostasis within the gut. This review discusses the role of the gut as an endocrine organ, emphasizing the stimuli, the newly discovered functions, and the clinical significance of gut-secreted hormones. Deciphering the emerging role of gut hormones will lead to a better understanding of gut homeostasis, innovative treatments for disorders in the gut, as well as systemic diseases.

Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.

Pegvisomant, the first and currently only clinically available growth hormone receptor antagonist, is an effective therapeutic option for the medical treatment of acromegaly, a rare disorder characterized by excessive growth hormone secretion. With now over 20 years of real world experience, its safety and efficacy is well-established. However, several aspects of its clinical use are still controversially discussed. The high cost of pegvisomant has limited its use in several countries, and recent studies have reported a lower efficacy than the initial clinical trials. A reported increase in tumor volume under therapy varies between studies and has been attributed to either actual growth or re-expansion after cessation of somatostatin receptor ligand therapy. Furthermore, different combinations of pegvisomant and other therapeutic agents aiming at reduction of acromegaly disease activity have been proposed to increase or retain effectiveness while lowering side effects and cost. This review aims to assess current clinical data on the safety and efficacy of pegvisomant while also addressing controversies surrounding its use.

To investigate the changes of circulating levels of all proglucagon-derived peptides (PGDPs) in individuals with overweight or obesity receiving liraglutide (3 mg) or naltrexone/bupropion (32/360 mg), and to explore the association between induced changes in postprandial PGDP levels and body composition, as well as metabolic variables, after 3 and 6 months on treatment.

Seventeen patients with obesity or with overweight and co-morbidities, but without diabetes, were assigned to receive once-daily oral naltrexone/bupropion 32/360 mg (n = 8) or once-daily subcutaneous liraglutide 3 mg (n = 9). Participants were assessed before treatment initiation and after 3 and 6 months on treatment. At the baseline and 3-month visits, participants underwent a 3-hour mixed meal tolerance test to measure fasting and postprandial levels of PGDPs, C-peptide, hunger and satiety. Clinical and biochemical indices of metabolic function, magnetic resonance-assessed liver steatosis and ultrasound-assessed liver stiffness were measured at each visit.

Both medications improved body weight and composition, carbohydrate and lipid metabolism, and liver fat and function. Naltrexone/bupropion produced a weight-independent increase in the levels of proglucagon (P < .001) and decreases in glucagon-like peptide-2 (GLP-2), glucagon and the major proglucagon fragment (P ≤ .01), whereas liraglutide markedly upregulated total glucagon-like peptide-1 (GLP-1) levels in a weight-independent manner (P = .04), and similarly downregulated the major proglucagon fragment, GLP-2 and glucagon (P < .01). PGDP levels at the 3-month visit were positively and independently correlated with improvements in fat mass, glycaemia, lipaemia and liver function, and negatively with reductions in fat-free mass, at both the 3- and 6-month visits.

PGDP levels in response to liraglutide and naltrexone/bupropion are associated with improvements in metabolism. Our study provides support for the administration of the downregulated members of the PGDP family as replacement therapy (e.g. glucagon), in addition to the medications currently in use that induced their downregulation (e.g. GLP-1), and future studies should explore whether the addition of other PGDPs (e.g. GLP-2) could offer additional benefits.

To evaluate the treatment effect Fand pharmacoeconomic value of Dugaglutide in women with type 2 diabetes.

Women (n=96) with type 2 diabetes recruited from June 2019 to December 2021 were randomized into two equal groups. The control group was treated with Liraglutide, and the observation group was treated with Dulaglutide, both for 24 weeks. The blood glucose levels, biochemical index, insulin resistance index (HOMA-IR), cost-effect ratio (CER), and drug safety were determined and compared between the two groups.

Blood glucose levels, the biochemical index, and HOMA-IR were lower in both groups after the treatment (P < 0.05), and there was no statistical difference in the blood glucose levels, biochemical index and HOMA-IR between the two groups (P > 0.05). The CER levels did not differ statistically between the two groups (P > 0.05). Both the cost and the incidence of drug side effects during solution injection were lower in the observation group than in the control group after 24 weeks of treatment (P < 0.05).

Both Dulaglutide and Liraglutide can reduce blood glucose levels, improve biochemical index, and HOMA-IR levels in women with type 2 diabetes. Dulaglutide is more cost-effective and safe.

https://www.chictr.org.cn/index.aspx, identifier ChiCTR1900026514.

The intestinal L cell secretes a diversity of biologically active hormones, most notably the glucagon-like peptides, GLP-1 and GLP-2. The highly successful introduction of GLP-1-based drugs into the clinic for the treatment of patients with type 2 diabetes and obesity, and of a GLP-2 analog for patients with short bowel syndrome, has led to the suggestion that stimulation of the endogenous secretion of these peptides may serve as a novel therapeutic approach in these conditions. Situated in the intestinal epithelium, the L cell demonstrates complex relationships with not only circulating, paracrine, and neural regulators, but also ingested nutrients and other factors in the lumen, most notably the microbiota. The integrated input from these numerous secretagogues results in a variety of temporal patterns in L cell secretion, ranging from minutes to 24 hours. This review combines the findings of traditional, physiological studies with those using newer molecular approaches to describe what is known and what remains to be elucidated after 5 decades of research on the intestinal L cell and its secreted peptides, GLP-1 and GLP-2.

The incretin hormone glucagon-like peptide-1 (GLP-1) has received enormous attention during the past three decades as a therapeutic target for the treatment of obesity and type 2 diabetes. Continuous improvement of the pharmacokinetic profile of GLP-1R agonists, starting from native hormone with a half-life of ~2-3 min to the development of twice daily, daily and even once-weekly drugs highlight the pharmaceutical evolution of GLP-1-based medicines. In contrast to GLP-1, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) received little attention as a pharmacological target, because of conflicting observations that argue activation or inhibition of the GIP receptor (GIPR) provides beneficial effects on systemic metabolism. Interest in GIPR agonism for the treatment of obesity and diabetes was recently propelled by the clinical success of unimolecular dual-agonists targeting the receptors for GIP and GLP-1, with reported significantly improved body weight and glucose control in patients with obesity and type II diabetes. Here we review the biology and pharmacology of GLP-1 and GIP and discuss recent advances in incretin-based pharmacotherapies.

The enteroendocrine system coordinates the physiological response to food intake by regulating rates of digestion, nutrient absorption, insulin secretion, satiation and satiety. Gut hormones with important anorexigenic and/or insulinotropic roles include glucagon-like peptide 1 (GLP-1), peptide YY (PYY_3-36), cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP). High BMI or obesogenic diets do not markedly disrupt this enteroendocrine system, which represents a critical target for inducing weight loss and treating co-morbidities in individuals with obesity.

To present an overview of exendin(9-39)NH₂ usage as a scientific tool in humans and provide recommendations for dosage and infusion regimes.

We systematically searched the literature on exendin(9-39)NH₂ and included for review 44 clinical studies reporting use of exendin(9-39)NH₂ in humans.

Exendin(9-39)NH₂ binds to the orthosteric binding site of the glucagon-like peptide-1 (GLP-1) receptor with high affinity. The plasma elimination half-life of exendin(9-39)NH₂ after intravenous administration is ~30 minutes, requiring ~2.5 hours of constant infusion before steady-state plasma concentrations can be expected. Studies utilizing infusions with exendin(9-39)NH₂ in humans have applied varying regimens (priming with a bolus or constant infusion) and dosages (continuous infusion rate range 30-900 pmol/kg/min) with subsequent differences in effects. Administration of exendin(9-39)NH₂ in healthy individuals, patients with diabetes, obese patients, and patients who have undergone bariatric surgery significantly increases fasting and postprandial levels of glucose and glucagon, but has inconsistent effects on circulating concentrations of insulin and C-peptide, gastric emptying, appetite sensations, and food intake. Importantly, exendin(9-39)NH₂ induces secretion of all L cell products (ie, in addition to GLP-1, also peptide YY, glucagon-like peptide-2, oxyntomodulin, and glicentin) complicating use of exendin(9-39)NH₂ as a tool to study the isolated effect of GLP-1.

Exendin(9-39)NH₂ is selective for the GLP-1 receptor, with numerous and complex whole-body effects. To obtain GLP-1 receptor blockade in humans, we recommend an initial high-dose infusion, followed by a continuous infusion rate aiming at a ratio of exendin(9-39)NH₂ to GLP-1 of 2000:1. Highlights Exendin(9-39)NH₂ is a competitive antagonist of the human GLP-1 receptor. Exendin(9-39)NH₂ has been used as a tool to delineate human GLP-1 physiology since 1998. Exendin(9-39)NH₂ induces secretion of GLP-1 and other L cell products. Reported effects of exendin(9-39)NH₂ on insulin levels and food intake are inconsistent. Here, we provide recommendations for the use of exendin(9-39)NH₂ in clinical studies.

Long-chain triglycerides (LCTs) intake strongly stimulates GIP secretion from enteroendocrine K cells and induces obesity and insulin resistance partly due to GIP hypersecretion. In this study, we found that medium-chain triglycerides (MCTs) inhibit GIP secretion after single LCT ingestion and clarified the mechanism underlying MCT-induced inhibition of GIP secretion. MCTs reduced the CCK effect after single LCT ingestion in wild-type (WT) mice, and a CCK agonist completely reversed MCT-induced inhibition of GIP secretion. In vitro studies showed that medium-chain fatty acids (MCFAs) inhibit long-chain fatty acid (LCFA)-stimulated CCK secretion and increase in intracellular Ca²⁺ concentrations through inhibition of GPR120 signaling. Long-term administration of MCTs reduced obesity and insulin resistance in high-LCT diet-fed WT mice, but not in high-LCT diet-fed GIP-knockout mice. Thus, MCT-induced inhibition of GIP hypersecretion reduces obesity and insulin resistance under high-LCT diet feeding condition.

The importance of fasting glucagon-like peptide-1 (GLP-1) in altered metabolic outcomes has been questioned.

This work aimed to assess whether fasting GLP-1 differs in children and adolescents with overweight/obesity compared to a population-based reference, and whether concentrations predict cardiometabolic risk (CMR) factors.

Analyses were based on The Danish Childhood Obesity Data- and Biobank, a cross-sectional study including children and adolescents, aged 6 to 19 years, from an obesity clinic group (n = 1978) and from a population-based group (n = 2334). Fasting concentrations of plasma total GLP-1 and quantitative CMR factors were assessed. The effects of GLP-1 as a predictor of CMR risk outcomes were examined by multiple linear and logistic regression modeling.

The obesity clinic group had higher fasting GLP-1 concentrations (median 3.3 pmol/L; interquartile range, 2.3-4.3 pmol/L) than the population-based group (2.8 pmol/L; interquartile range, 2.1-3.8 pmol/L; P < 2.2E-16). Body mass index SD score (SDS), waist circumference, and total body fat percentage were significant predictors of fasting GLP-1 concentrations in boys and girls. Fasting GLP-1 concentrations were positively associated with homeostasis model assessment of insulin resistance, fasting values of insulin, high-sensitivity C-reactive protein, C-peptide, triglycerides, alanine transaminase (ALT), glycated hemoglobin A1c, and SDS of diastolic and systolic blood pressure. A 1-SD increase in fasting GLP-1 was associated with an increased risk of insulin resistance (odds ratio [OR] 1.59), dyslipidemia (OR 1.16), increased ALT (OR 1.14), hyperglycemia (OR 1.12) and hypertension (OR 1.12).

Overweight/obesity in children and adolescents is associated with increased fasting plasma total GLP-1 concentrations, which was predictive of higher CMR factors.

This review is aimed at examining whether the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) is higher in Caucasian, adult, treatment-naïve patients with acromegaly (ACRO) than in the reference population independently of diabetes presence and to evaluate the impact of treatment [surgery and somatostatin analogues (SSAs)] on its assessment.

We systematically reviewed in PubMed and Web of Science from July 1985 to December 2019, registered with the code number CRD42020148737. The inclusion criteria comprised studies conducted in Caucasian adult treatment-naïve patients with active ACRO in whom HOMA-IR or basal insulin and glucose were reported. Three reviewers screened eligible publications, extracted the outcomes, and assessed the risk of biases.

Of 118 originally selected studies, 15 met the inclusion criteria. HOMA-IR was higher in ACRO than the reference population, with mean difference and (95% confidence intervals) of 2.04 (0.65-3.44), even in ACRO patients without diabetes, 1.89 (1.06-2.73). HOMA-IR significantly decreased after treatment with either surgery or SSAs - 2.53 (- 3.24- - 1.81) and - 2.30 (- 3.05- - 1.56); respectively. However, the reduction of HOMA-IR due to SSAs did not improve basal glucose.

HOMA-IR in treatment-naïve ACRO patients is higher than in the reference population, even in patients without diabetes. This finding, confirms that insulin resistance is an early event in ACRO. Our results also suggest that HOMA-IR is not an adequate tool for assessing insulin resistance in those patients treated with SSAs.

Therapeutic approaches to the treatment of type 2 diabetes mellitus that are designed to increase insulin secretion either directly target β-cells or indirectly target gastrointestinal enteroendocrine cells (EECs), which release hormones that modulate insulin secretion (for example, incretins). Given that β-cells and EECs both express a large array of G protein-coupled receptors (GPCRs) that modulate insulin secretion, considerable research and development efforts have been undertaken to design therapeutic drugs targeting these GPCRs. Among them are GPCRs specific for free fatty acid ligands (lipid GPCRs), including free fatty acid receptor 1 (FFA1, otherwise known as GPR40), FFA2 (GPR43), FFA3 (GPR41) and FFA4 (GPR120), as well as the lipid metabolite binding glucose-dependent insulinotropic receptor (GPR119). These lipid GPCRs have demonstrated important roles in the control of islet and gut hormone secretion. Advances in lipid GPCR pharmacology have led to the identification of a number of synthetic agonists that exert beneficial effects on glucose homeostasis in preclinical studies. Yet, translation of these promising results to the clinic has so far been disappointing. In this Review, we present the physiological roles, pharmacology and clinical studies of these lipid receptors and discuss the challenges associated with their clinical development for the treatment of type 2 diabetes mellitus.

Somatostatin (SS) inhibits glucagon-like peptide-1 (GLP-1) secretion in a paracrine manner. We hypothesized that blocking somatostatin subtype receptor 2 (SSTR2) and 5 (SSTR5) would improve glycemia by enhancing GLP-1 secretion. In the perfused mouse small intestine, the selective SSTR5 antagonist (SSTR5a) stimulated glucose-induced GLP-1 secretion to a larger degree than the SSTR2 antagonist (SSTR2a). In parallel, mice lacking the SSTR5R showed increased glucose-induced GLP-1 secretion. Both antagonists improved glycemia in vivo in a GLP-1 receptor-dependent (GLP-1R-dependent) manner, as the glycemic improvements were absent in mice with impaired GLP-1R signaling and in mice treated with a GLP-1R-specific antagonist. SSTR5a had no direct effect on insulin secretion in the perfused pancreas, whereas SSTR2a increased insulin secretion in a GLP-1R-independent manner. Adding a dipeptidyl peptidase 4 inhibitor (DPP-4i) in vivo resulted in additive effects on glycemia. However, when glucose was administered intraperitoneally, the antagonist was incapable of lowering blood glucose. Oral administration of SSTR5a, but not SSTR2a, lowered blood glucose in diet-induced obese mice. In summary, we demonstrate that selective SSTR antagonists can improve glucose control primarily through the intestinal GLP-1 system in mice.

To examine how circulating glucagon-like peptide-1 (GLP-1) concentrations during liraglutide treatment relate to its therapeutic actions on glucose and weight, and to study the effects of liraglutide on other proglucagon-derived peptides (PGDPs), including endogenous GLP-1, glucagon-like peptide-2, glucagon, oxyntomodulin, glicentin and major proglucagon fragment, which also regulate metabolic and weight control.

Adults who were overweight/obese (body mass index 27-40 kg/m² ) with prediabetes were randomized to liraglutide (1.8 mg/day) versus placebo for 14 weeks. We used specific assays to measure exogenous (liraglutide, GLP-1 agonist [GLP-1A]) and endogenous (GLP-1E) GLP-1, alongside five other PGDP concentrations during a mixed meal tolerance test (MMTT) completed at baseline and at week 14 (liraglutide, n = 16; placebo, n = 19). Glucose during MMTT, steady-state plasma glucose (SSPG) concentration for insulin resistance and insulin secretion rate (ISR) were previously measured. MMTT area-under-the-curve (AUC) was calculated for ISR, glucose and levels of PGDPs.

Participants on liraglutide versus placebo had significantly (P ≤ .004) decreased weight (mean -3.6%, 95% CI [-5.2% to -2.1%]), SSPG (-32% [-43% to -22%]) and glucose AUC (-7.0% [-11.5% to -2.5%]) and increased ISR AUC (30% [16% to 44%]). GLP-1A AUC at study end was significantly (P ≤ .04) linearly associated with % decrease in weight (r = -0.54) and SSPG (r = -0.59) and increase in ISR AUC (r = 0.51) in the liraglutide group. Treatment with liraglutide significantly (P ≤ .005) increased exogenous GLP-1A AUC (median 310 vs. 262 pg/mL × 8 hours at baseline but decreased endogenous GLP-1E AUC [13.1 vs. 24.2 pmol/L × 8 hours at baseline]), as well as the five other PGDPs. Decreases in the PGDPs processed in the intestines are independent of weight loss, indicating a probable direct effect of GLP-1 receptor agonists to decrease their endogenous production in contrast to weight loss-dependent changes in glucagon and major proglucagon fragment that are processed in pancreatic alpha cells.

Circulating GLP-1A concentrations, reflecting liraglutide levels, predict improvement in weight, insulin action and secretion in a linear manner. Importantly, liraglutide also downregulates other PGDPs, normalization of the levels of which may provide additional metabolic and weight loss benefits in the future.

Chagas disease is caused by the parasite, Trypanosoma cruzi that causes chronic cardiac and digestive dysfunction. Megacolon, an irreversible dilation of the left colon, is the main feature of the gastrointestinal form of Chagas disease. Patients have severe constipation, a consequence of enteric neuron degeneration associated with chronic inflammation. Dysmotility, infection, neuronal loss and a chronic exacerbated inflammation, all observed in Chagas disease, can affect enteroendocrine cells (EEC) expression, which in turn, could influence the inflammatory process. In this study, we investigated the distribution and chemical coding of EEC in the dilated and non-dilated portion of T. cruzi-induced megacolon and in non-infected individuals (control colon). Using immunohistochemistry, EECs were identified by applying antibodies to chromogranin A (CgA), glucagon-like peptide 1 (GLP-1), 5-hydroxytryptamine (5-HT), peptide YY (PYY) and somatostatin (SST). Greater numbers of EEC expressing GLP-1 and SST occurred in the dilated portion compared to the non-dilated portion of the same patients with Chagas disease and in control colon, but numbers of 5-HT and PYY EEC were not significantly different. However, it was noticeable that EEC in which 5-HT and PYY were co-expressed were common in control colon, but were rare in the non-dilated and absent in the dilated portion of chagasic megacolon. An increase in the number of CgA immunoreactive EEC in chagasic patients reflected the increases in EEC numbers summarised above. Our data suggests that the denervation and associated chronic inflammation are accompanied by changes in the number and coding of EEC that could contribute to disorders of motility and defence in the chagasic megacolon.

Acromegaly is a rare, chronic and severe disease. Drug therapy including somatostatin analogues (SAs), dopamine receptor agonists and growth hormone receptor antagonists (pegvisomant, PEG) are commonly used to treat patients who do not respond to surgery. The use of combination therapy with PEG and SAs has become more common over the last decade. We performed this study to accurately evaluate the effect of combination therapy of SAs with PEG on acromegalic patients.

PubMed, EMBASE, The Cochrane Library, ClinicalTrials.gov, Scopus, Web of Science, Chinese Biomedical Literature Database and Trip database were searched for relevant studies. Prospective clinical trials treating acromegaly with the co-administration of SAs and PEG were included. We performed a meta-analysis by using Stata 12.1. Sensitivity analysis was conducted to explore heterogeneity.

Nine studies were included in this meta-analysis. The overall rate of serum insulin-like growth factor 1 (IGF-1) normalization was 66% (95% CI: 52-78%; I² = 62.59%). The combination therapy did not significantly change patients' fasting plasma glucose (ES: 0.011 mmol*L^- 1; 95% CI: - 0.374 to 0.397 mmol*L^- 1; P = 0.954) or glycosylated haemoglobin (ES: - 0.074%; 95% CI: - 0.166 to 0.315%; P = 0.544) while decreasing the fasting plasma insulin (ES: - 21.487 pmol*L^-1; 95% CI: - 35.713 to - 7.260 pmol*L^-1; P = 0.003). Elevation of liver enzyme levels was found in 14% (95% CI: 8 to 21%) of the patients. There was no significant difference for serious adverse events and treatment discontinuation due to adverse event between SAs monotherapy group and combination therapy group.

Combined therapy of SAs and PEG effectively normalized IGF-1 levels in most of the patients whose IGF-1 level was greater than the upper limit of normal after high dose SAs monotherapy. The therapy also decreased significantly FPI levels with a neutral effect on glucose parameters in acromegaly patients. Moreover, elevated liver enzyme levels were observed in a small number of patients, which suggests a need for liver function monitoring.

We have our protocol registered in PROSPERO. (Registration number: CRD42019115549 ).

Total parenteral nutrition (TPN) is a life-saving therapy administered to millions of patients. However, it is associated with significant adverse effects, namely liver injury, risk of infections, and metabolic derangements. In this review, the underlying causes of TPN-associated adverse effects, specifically gut atrophy, dysbiosis of the intestinal microbiome, leakage of the epithelial barrier with bacterial invasion, and inflammation are first described. The role of the bile acid receptors farnesoid X receptor and Takeda G protein-coupled receptor, of pleiotropic hormones, and growth factors is highlighted, and the mechanisms of insulin resistance, namely the lack of insulinotropic and insulinomimetic signaling of gut-originating incretins as well as the potentially toxicity of phytosterols and pro-inflammatory fatty acids mainly released from soybean oil-based lipid emulsions, are discussed. Finally, novel approaches in the design of next generation lipid delivery systems are proposed. Propositions include modifying the physicochemical properties of lipid emulsions, the use of lipid emulsions generated from sustainable oils with favorable ratios of anti-inflammatory n-3 to pro-inflammatory n-6 fatty acids, beneficial adjuncts to TPN, and concomitant pharmacotherapies to mitigate TPN-associated adverse effects.

25 years ago, the future of treating obesity and diabetes focused on end organs known to be involved in energy balance and glucose regulation, including the brain, muscle, adipose tissue, and pancreas. Today, the most effective therapies are focused around the gut. This includes surgical options, such as vertical sleeve gastrectomy and Roux-en-Y gastric bypass, that can produce sustained weight loss and diabetes remission but also extends to pharmacological treatments that simulate or amplify various signals that come from the gut. The purpose of this Review is to discuss the wealth of approaches currently under development that seek to further leverage the gut as a source of novel therapeutic opportunities with the hope that we can achieve the effects of surgical interventions with less invasive and more scalable solutions.

The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity.

In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases.

Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders.

DPP-4 inhibitors, used for treatment of type 2 diabetes, act by increasing the concentrations of intact glucagon-like peptide-1 (GLP-1), but at the same time, they inhibit secretion of GLP-1, perhaps by a negative feedback mechanism. We hypothesized that GLP-1 secretion is feedback regulated by somatostatin (SS) from neighboring D-cells, and blocking this feedback circuit results in increased GLP-1 secretion. We used a wide range of experimental techniques, including gene expression analysis, immunohistochemical approaches, and the perfused mouse intestine to characterize the paracrine circuit controlling GLP-1 and SS. We show that 1) antagonizing the SS receptor (SSTr) 2 and SSTr5 led to increased GLP-1 and SS secretion in the mouse, 2) SS exhibits strong tonic inhibition of GLP-1 secretion preferentially through SSTr5, and 3) the secretion of S was GLP-1 receptor dependent. We conclude that SS is a tonic inhibitor of GLP-1 secretion, and interventions in the somatostain-GLP-1 paracrine loop lead to increased GLP-1 secretion.

In horses a number of small intestinal diseases is potentially life threatening. Among them are Equine Grass Sickness (EGS), which is characterised by enteric neurodegeneration of unknown aetiology, as well as reperfusion injury of ischaemic intestine (I/R), and post-operative ileus (POI), common after colic surgery. The perfusion of isolated organs is successfully used to minimize animal testing for the study of pathophysiology in other scenarios. However, extracorporeal perfusion of equine ileum sourced from horses slaughtered for meat production has not yet been described. Therefore the present study evaluated the potential of such a model for the investigation of small intestinal diseases in an ex vivo and cost-efficient system avoiding experiments in live animals.

Nine ileum specimens were sourced from horses aged 1-10 years after routine slaughter at a commercial abattoir. Ileum perfusion with oxygenated autologous blood and plasma was successfully performed for 4 h in a warm isotonic bath (37.0-37.5 °C). Ileum specimens had good motility and overall pink to red mucosa throughout the experiment; blood parameters indicated good tissue vitality: 82 ± 34 mmHg mean arterial partial pressure of oxygen (pO₂) compared to 50 ± 17 mmHg mean venous pO_2, 48 ± 10 mmHg mean arterial partial pressure of carbon dioxide (pCO₂) compared to 66 ± 7 mmHg venous pCO₂ and 9.8 ± 2.8 mmol/L mean arterial lactate compared to 11.6 ± 2.7 mmol/L venous lactate. There was a mild increase in ileum mass reaching 105 ± 7.5% of the pre-perfusion mass after 4 hours. Histology of haematoxylin and eosin stained biopsy samples taken at the end of perfusion showed on average 99% (±1%) histologically normal neurons in the submucosal plexus and 76.1% (±23.9%) histologically normal neurons in the myenteric plexus and were not significantly different to control biopsies.

Extracorporeal, normothermic perfusion of equine ileum over 4 h using autologous oxygenated blood/plasma perfusate showed potential as experimental model to test whether haematogenous or intestinal exposure to neurotoxins suspected in the pathogenesis of EGS can induce neuronal damage typical for EGS. Also, this model may allow investigations into the effect of pharmaceuticals on I/R injury, as well as into the pathogenesis of equine POI.

Pasireotide long-acting release (LAR) is a somatostatin multireceptor ligand, and in the current consensus criteria pasireotide LAR is considered the second-line medical treatment for acromegaly. We present in this article our recommendations to define the position of pasireotide LAR in the treatment of acromegaly and provide recommendations for the management of pasireotide-induced hyperglycemia.

Our recommendations are based on our experiences with the pasireotide LAR and pegvisomant (PEGV) combination study and the available basic or clinical articles published in peer-reviewed international journals on pasireotide LAR and acromegaly.

In accordance with the current consensus criteria, we recommend pasireotide LAR monotherapy as a second-line therapy in young patients who show tumor growth during first-generation somatostatin receptor ligand (SRL) therapy and in patients who show tumor growth during PEGV therapy. In addition, we recommend pasireotide LAR monotherapy in patients with headache not responsive to first-generation SRL therapy and in patients who experience side effects or are intolerant to PEGV monotherapy. In contrast to the current consensus criteria, we recommend considering combination therapy with pasireotide LAR and PEGV as third-line treatment in patients without diabetes at low PEGV dosages (≤80 mg/week) and in patients with tumor growth or symptoms of active acromegaly during first-generation SRL and PEGV combination therapy. With respect to pasireotide-induced hyperglycemia, we recommend a more liberal strategy of blood glucose monitoring during pasireotide treatment.

In contrast to the current consensus criteria, we recommend a more reluctant use of pasireotide LAR therapy for the treatment of acromegaly.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are secreted postprandially and contribute importantly to postprandial glucose tolerance. In this study, we assessed the individual and combined contributions of endogenous GIP and GLP-1 to the postprandial changes in glucose and glucoregulatory hormones using the novel GIP receptor antagonist GIP(3-30)NH₂ and the well-established GLP-1 receptor antagonist exendin(9-39)NH₂ During 4-h oral glucose tolerance tests (75 g) combined with an ad libitum meal test, 18 healthy men received on four separate days in randomized, double-blinded order intravenous infusions of A) GIP(3-30)NH₂ (800 pmol/kg/min) plus exendin(9-39)NH₂ (0-20 min: 1,000 pmol/kg/min; 20-240 min: 450 pmol/kg/min), B) GIP(3-30)NH₂, C) exendin(9-39)NH₂, and D) saline, respectively. Glucose excursions were significantly higher during A than during B, C, and D, while glucose excursions during B were higher than during C and D. Insulin secretion (assessed by C-peptide/glucose ratio) was reduced by 37 ± 16% (A), 30 ± 17% (B), and 8.6 ± 16% (C) compared with D (mean ± SD). A and C resulted in higher glucagon levels and faster gastric emptying. In conclusion, endogenous GIP affects postprandial plasma glucose excursions and insulin secretion more than endogenous GLP-1, but the hormones contribute additively to postprandial glucose regulation in healthy individuals.

Bariatric surgery is widely used to treat obesity and improves type 2 diabetes beyond expectations from the degree of weight loss. Elevated post-prandial concentrations of glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin are widely reported, but the importance of GLP-1 in post-bariatric physiology remains debated. Here, we show that GLP-1 is a major driver of insulin secretion after bariatric surgery, as demonstrated by blocking GLP-1 receptors (GLP1Rs) post-gastrectomy in lean humans using Exendin-9 or in mice using an anti-GLP1R antibody. Transcriptomics and peptidomics analyses revealed that human and mouse enteroendocrine cells were unaltered post-surgery; instead, we found that elevated plasma GLP-1 and PYY correlated with increased nutrient delivery to the distal gut in mice. We conclude that increased GLP-1 secretion after bariatric surgery arises from rapid nutrient delivery to the distal gut and is a key driver of enhanced insulin secretion.

The incretin hormone glucagon-like peptide-1 (GLP-1) has been subject to substantial pharmaceutical research regarding the treatment of type 2 diabetes mellitus. However, quantification of GLP-1 levels remains complicated due to the low circulation concentration and concurrent existence of numerous metabolites, homologous peptides, and potentially introduced GLP-1 receptor agonists. Surface plasmon resonance (SPR) facilitates real-time monitoring allowing a more detailed characterisation of the interaction compared with conventional enzyme-linked immunosorbent assays (ELISA). In this paper, we describe the development of the first SPR assays for characterisation of anti-GLP-1 antibodies for ELISA purposes. Binding responses were obtained on covalently immobilised anti-GLP-1 antibodies at 12°C, 25°C, and 40°C and fitted to a biomolecular (1:1) interaction model showing association rates of 1.01 × 10³ to 4.54 × 10³  M^-1  s^-1 and dissociation rates of 3.56 × 10^-5 to 1.56 × 10^-3  s^-1 leading to affinities of 35.2 to 344 nM, depending on the temperature. Determination of thermodynamic properties revealed an enthalpy driven interaction (ΔH < ΔS < 0) with higher affinities at lower temperatures due to the formation and stabilisation of hydrogen bonds within the binding site primarily composed of polar amino acids (ΔC_p  < 0). Pair-wise epitope mapping was performed on captured anti-GLP-1 antibodies followed by subsequent interaction with GLP-1 (7-36) and other anti-GLP-1 antibodies. A global evaluation of every binding response led to an epitope map elucidating the potential of various anti-GLP-1 antibody pairs for sandwich ELISA and hence pinpointing the optimal antibody combinations. The SPR assays proved capable of providing vital information for ELISA development endorsing it as a useful optimisation tool.

Somatostatin analogs (SSAs) effectivelycontrol growth hormone secretion in first and second line treatmentof acromegaly. Their effect onglucose metabolism is still debated.

to address the following questions: 1) Do SSAs affect fasting plasma glucose (FPG), fasting plasma insulin (FPI), glycosylated hemoglobin (HbA1c), glucose load (2h-OGTT), HOMA-I, HOMA-β, triglycerides (TGD), weight (W) or body mass index (BMI)? 2) Do lanreotide (LAN) and octreotide LAR (OCT) affect metabolism differently? 3)Does their effect depend on disease control?

We performed a meta-analysis of prospective interventional trialstreating acromegaly with SSAs. Inclusion criteria: all studies reporting glyco-metabolic outcomes before and after SSAs with a minimum 6-month follow-up.

The inclusion criteria were met by 47 studies treating 1297 subjects (631 F). SSA treatment effectively lowered FPI (effect size [ES] -6.67 mU/L, 95%CI: -8.38 to -4.95mU/L; p<0.001), HOMA-I (ES -1.57, CI: -2.42 to -0.72; p<0.001), HOMA-β (ES -47.45, CI: -73.15 to -21.76; p<0.001) and TGD (ES -0.37 mmol/L, CI: -0.47 to -0.27 mmol/L; p<0.001). SSAs worsened 2h-OGTT (ES 0.59 mmol/L, CI: 0.05 to 1.13 mmol/L; p=0.032), but not FPG. A mild but significant increase in HbA1c (ES 0.12%, CI: 0.00to 0.25%; p=0.044) was found in OCT treated subjects.

SSA treatment in acromegaly patients-while improving disease control- reduces insulin levels, increases after load glucose and, ultimately, increases HbA1c levels without affecting FPG. The findings suggest that clinicians treating acromegaly with SSAs should consider targeting post-prandial glucose.

Long-chain acyl-CoA synthetase (ACSL)-dependent upper small intestinal lipid metabolism activates pre-absorptive pathways to regulate metabolic homeostasis, but whether changes in the upper small intestinal microbiota alter specific fatty acid-dependent pathways to impact glucose homeostasis remains unknown. We here first find that upper small intestinal infusion of Intralipid, oleic acid, or linoleic acid pre-absorptively increases glucose tolerance and lowers glucose production in rodents. High-fat feeding impairs pre-absorptive fatty acid sensing and reduces upper small intestinal Lactobacillus gasseri levels and ACSL3 expression. Transplantation of healthy upper small intestinal microbiota to high-fat-fed rodents restores L. gasseri levels and fatty acid sensing via increased ACSL3 expression, while L. gasseri probiotic administration to non-transplanted high-fat-fed rodents is sufficient to restore upper small intestinal ACSL3 expression and fatty acid sensing. In summary, we unveil a glucoregulatory role of upper small intestinal L. gasseri that impacts an ACSL3-dependent glucoregulatory fatty acid-sensing pathway.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are now a widely used, safe and efficacious class of antidiabetic drugs, which were developed prospectively using a rational drug design approach based on a thorough understanding of the endocrinology and degradation of glucagon-like peptide-1 (GLP-1). GLP-1 is an intestinal hormone with potent insulinotropic and glucagonostatic effects and can normalise blood glucose levels in patients with type 2 diabetes, but the native peptide is not therapeutically useful because of its inherent metabolic instability. Using the GLP-1/DPP-4 system and type 2 diabetes as an example, this review summarises how knowledge of a peptide's biological effects coupled with an understanding of the pathways involved in its metabolic clearance can be exploited in a rational, step-by-step manner to develop a therapeutic agent, which is effective and well tolerated, and any side effects are minor and largely predictable. Other peptides with metabolic effects which can also be degraded by DPP-4 will be reviewed, and their potential role as additional mediators of the effects of DPP-4 inhibitors will be assessed.

To assess the efficacy and safety of pasireotide long-acting release (PAS-LAR) alone or in combination with pegvisomant by switching patients with acromegaly who were well controlled with long-acting somatostatin analogues (LA-SSAs) and pegvisomant to PAS-LAR with or without pegvisomant.

Sixty-one patients with acromegaly were enrolled in a prospective open-label study. We included patients with an insulin-like growth factor I (IGF-I) ≤1.2 × upper limit of normal (ULN) during treatment with LA-SSAs and pegvisomant. At baseline, the pegvisomant dose was reduced by 50% up to 12 weeks. When IGF-I remained ≤1.2 × ULN after 12 weeks, patients were switched to PAS-LAR 60 mg monotherapy. When IGF-I was >1.2 × ULN, patients were switched to PAS-LAR 60 mg, and they continued with the 50% reduced pegvisomant dose.

At baseline, mean IGF-I was 0.97 × ULN, and the median pegvisomant dose was 80 mg/wk. At 12 weeks, mean IGF-I increased to 1.59 × ULN, and IGF-I levels ≤1.2 ULN were observed in 24.6% of participants. At 24 weeks, IGF-I levels were reduced into the reference range in 73.8% of patients. Between baseline and 24 weeks, the pegvisomant dose was reduced by 66.1%. PAS-LAR was well tolerated, but hyperglycemia was the most frequent adverse event. The frequency of diabetes increased from 32.8% at baseline to 68.9% at 24 weeks.

Switching to PAS-LAR, either as monotherapy or combination with pegvisomant, can control IGF-I levels in most patients. PAS-LAR demonstrated a pegvisomant-sparing effect of 66% compared with the combination with LA-SSAs. Hyperglycemia was the most important safety issue.

Therapeutic engineering of glucagon-like peptide 1 (GLP-1) has enabled development of new medicines to treat type 2 diabetes. These injectable analogs achieve robust glycemic control by increasing concentrations of "GLP-1 equivalents" (∼50 pmol/L). Similar levels of endogenous GLP-1 occur after gastric bypass surgery, and mechanistic studies indicate glucose lowering by these procedures is driven by GLP-1. Therefore, because of the remarkable signaling and secretory capacity of the GLP-1 system, we sought to discover mechanisms that increase GLP-1 pharmacologically. To study active GLP-1, glucose-dependent insulinotropic polypeptide receptor (Gipr)-deficient mice receiving background dipeptidyl peptidase 4 (DPP4) inhibitor treatment were characterized as a model for evaluating oral agents that increase circulating GLP-1. A somatostatin receptor 5 antagonist, which blunts inhibition of GLP-1 release, and agonists for TGR5 and GPR40, which stimulate GLP-1 secretion, were investigated alone and in combination with the DPP4 inhibitor sitagliptin; these only modestly increased GLP-1 (∼5-30 pmol/L). However, combining molecules to simultaneously intervene at multiple regulatory nodes synergistically elevated active GLP-1 to unprecedented concentrations (∼300-400 pmol/L), drastically reducing glucose in Gipr null and Lepr^db/db mice in a GLP-1 receptor-dependent manner. Our studies demonstrate that complementary pathways can be engaged to robustly increase GLP-1 without invasive surgical or injection regimens.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted postprandially from enteroendocrine K cells, but despite therapeutically interesting effects, GIP physiology in humans remains incompletely understood. Progress in this field could be facilitated by a suitable GIP receptor antagonist. For the first time in humans, we investigated the antagonistic properties of the naturally occurring GIP(3-30)NH₂ in in vivo and in in vitro receptor studies.

In transiently transfected COS-7 cells, GIP(3-30)NH₂ was evaluated with homologous receptor binding and receptor activation (cAMP accumulation) studies at the glucagon-like peptide 1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucagon, secretin and growth hormone-releasing hormone (GHRH) receptors. Ten healthy men (eligibility criteria: age 20-30 years, HbA_1c less than 6.5% [48 mmol/mol] and fasting plasma glucose [FPG] less than 7 mmol/l) were included in the clinical study. Data were collected as plasma and serum samples from a cubital vein cannula. As primary outcome, insulin secretion and glucose requirements were evaluated together with in a randomised, four-period, crossover design by infusing GIP(3-30)NH₂ (800 pmol kg^-1 min^-1), GIP (1.5 pmol kg^-1 min^-1), a combination of these or placebo during hyperglycaemic clamp experiments. The content of the infusions were blinded to the study participants and experimental personnel. No study participants dropped out.

GIP(3-30)NH₂ neither bound, stimulated nor antagonised a series of related receptors in vitro. The elimination plasma half-life of GIP(3-30)NH₂ in humans was 7.6 ± 1.4 min. Markedly larger amounts of glucose were required to maintain the clamp during GIP infusion compared with the other days. GIP-induced insulin secretion was reduced by 82% (p < 0.0001) during co-infusion with GIP(3-30)NH₂, and the need for glucose was reduced to placebo levels. There were no effects of GIP(3-30)NH₂ alone or of GIP with or without GIP(3-30)NH₂ on plasma glucagon, GLP-1, somatostatin, triacylglycerols, cholesterol, glycerol or NEFA. GIP(3-30)NH₂ administration was well tolerated and without side effects.

We conclude that GIP(3-30)NH₂ is an efficacious and specific GIP receptor antagonist in humans suitable for studies of GIP physiology and pathophysiology.

ClinicalTrials.gov registration no. NCT02747472.

The study was funded by Gangstedfonden, the European Foundation for the Study of Diabetes, and Aase og Ejnar Danielsens fond.

The gut microbiota alters energy homeostasis. In parallel, metformin regulates upper small intestinal sodium glucose cotransporter-1 (SGLT1), but whether changes of the microbiota or SGLT1-dependent pathways in the upper small intestine mediate metformin action is unknown. Here we report that upper small intestinal glucose sensing triggers an SGLT1-dependent pathway to lower glucose production in rodents. High-fat diet (HFD) feeding reduces glucose sensing and SGLT1 expression in the upper small intestine. Upper small intestinal metformin treatment restores SGLT1 expression and glucose sensing while shifting the upper small intestinal microbiota partly by increasing the abundance of Lactobacillus. Transplantation of upper small intestinal microbiota from metformin-treated HFD rats to the upper small intestine of untreated HFD rats also increases the upper small intestinal abundance of Lactobacillus and glucose sensing via an upregulation of SGLT1 expression. Thus, we demonstrate that metformin alters upper small intestinal microbiota and impacts a glucose-SGLT1-sensing glucoregulatory pathway.

The clinical application of dipeptidyl peptidase IV inhibitors (DPP4i) increasing active glucagon-like peptide-1 (AGLP-1) levels has been linked to pancreatitis, pancreatic tumors, and cardiovascular events. However, DPP4 mutations in humans or the long-term outcomes of high glucagon-like peptide-1 (GLP-1) level exposure have not been reported. A trio family with a proband showing an extremely high AGLP-1 level [defined here as hyperglipemia (hyper-glucagon-like peptide-1-emia)] were conducted whole-exome sequencing for potential pathogenic genetic defects. One novel DPP4 mutation, p.V486M (c.1456 G>A), was identified in the proband and showed damaged enzymatic activity of DPP4. Ex vivo functional study further showed that the serum from the proband markedly enhanced insulin production of primary rat islet cells. Furthermore, V486M variant and another eight DPP4 variants were identified in our in-home database and seven showed decreased enzymatic activities than wild-type DPP4, consistent with their alterations in their protein expression levels. Of note, the levels of glucose, lipids, and tumor markers (especially for CA15-3 and CA125), increased gradually in the proband during a 4-year follow-up period, although no abnormal physical symptoms or imaging results were observed at present. The other two old carriers in the pedigree both had type 2 diabetes, and one of them also had hyperlipidemia and myocarditis. We first identified hyperglipemia in a female subject harboring a loss-of-function DPP4 mutation with decreased DPP4 activity. Other sporadic DPP4 mutations verified the low-frequent occurrence of genetic inhibition of DPP4 activity, at least in the Chinese population studied. These results may provide new evidence for evaluation of the potential long-term effects of DPP4i and GLP-1 analogs.