Primary Thyroid Dysfunction Is Prevalent in Hidradenitis Suppurativa and Marked by a Signature of Hypothyroid Graves' Disease: A Case-Control Study.

Hidradenitis suppurativa (HS) is a chronic skin disease that can have an association with endocrine disorders. There is conflicting information in the literature regarding the role of the thyroid gland in HS. This study aimed to close this knowledge gap and investigate how thyroid disease is involved in patients with HS. We carried out a case-control study with a total of 160 patients, of whom 108 were patients with HS and 52 were controls matched for age and sex. Parametric and non-parametric methods were used to analyze the results. We calculated structural parameters of thyroid homeostasis to detect subclinical thyroid disease, non-thyroid disease syndrome and other forms. The severity of HS was not associated with thyroid hormone levels and antibodies (p > 0.05). HS patients with or without hypothyroidism had decreased FT4 levels and a decreased thyroid secretory capacity (SPINA-GT). Titers of TSH receptor autoantibodies (TRAb) were significantly higher in smoking HS patients compared to non-smokers (median: 1.18 vs. 1.08; p = 0.042). The rate of subclinical hypothyroidism was significantly higher in HS patients; thus, subclinical hypothyroidism is an important comorbidity of HS (p < 0.05). Further studies are needed to investigate whether the chronic inflammation of HS is a cause of increased rates of (subclinical) hypothyroidism.

Longitudinal data on humoral response and neutralizing antibodies against SARS-CoV-2 Omicron BA.1 and subvariants BA.4/5 and BQ.1.1 after COVID-19 vaccination in cancer patients.

PURPOSE: The SARS-CoV-2 Omicron variant of concern (VOC) and subvariants like BQ.1.1 demonstrate immune evasive potential. Little is known about the efficacy of booster vaccinations regarding this VOC and subvariants in cancer patients. This study is among the first to provide data on neutralizing antibodies (nAb) against BQ.1.1. METHODS: Cancer patients at our center were prospectively enrolled between 01/2021 and 02/2022. Medical data and blood samples were collected at enrollment and before and after every SARS-CoV-2 vaccination, at 3 and 6 months. RESULTS: We analyzed 408 samples from 148 patients (41% female), mainly with solid tumors (85%) on active therapy (92%; 80% chemotherapy). SARS-CoV-2 IgG and nAb titers decreased over time, however, significantly increased following third vaccination (p < 0.0001). NAb (ND50) against Omicron BA.1 was minimal prior and increased significantly after the third vaccination (p < 0.0001). ND50 titers against BQ.1.1 after the third vaccination were significantly lower than against BA.1 and BA.4/5 (p < 0.0001) and undetectable in half of the patients (48%). Factors associated with impaired immune response were hematologic malignancies, B cell depleting therapy and higher age. Choice of vaccine, sex and treatment with chemo-/immunotherapy did not influence antibody response. Patients with breakthrough infections had significantly lower nAb titers after both 6 months (p < 0.001) and the third vaccination (p = 0.018). CONCLUSION: We present the first data on nAb against BQ.1.1 following the third vaccination in cancer patients. Our results highlight the threat that new emerging SARS-CoV-2 variants pose to cancer patients and support efforts to apply repeated vaccines. Since a considerable number of patients did not display an adequate immune response, continuing to exhibit caution remains reasonable.

Screening for Diabetes Mellitus in Patients with Hidradenitis Suppurativa-A Monocentric Study in Germany.

Hidradenitis suppurativa (HS) is a chronic skin disease that is often associated with metabolic disorders. Diabetes mellitus (DM) is a frequent comorbidity in HS. There is currently no established screening for DM in HS patients. The aim of our study was to identify high-risk groups of HS patients that develop DM and to assess the frequency of different types of DM present in HS patients. To do so, we conducted a monocentric study in 99 patients with HS. All patients underwent detailed clinical and laboratory assessments, including the determination of glycated hemoglobin. Among the 20.2% of patients that presented with DM, type 2 was by far the most prevalent (19 out of 20 patients). Moreover, male gender, age, BMI, Hurley stage, modified Hidradenitis Suppurativa Score (mHSS), DLQI and hypertension all correlated with the glycated hemoglobin levels in the HS patients. In the multivariable analysis, Hurley stage III, older age, and higher BMI were significantly associated with DM. Specifically, patients at Hurley stage III were at a 5.3-fold increased risk of having DM type II compared to patients at earlier Hurley stages. Since many of the HS patients had not been diagnosed, our study reveals shortcomings in the screening for DM and suggest that this should be routinely performed in HS patients at high risk to avoid secondary complications.

Digestive, Anorectal, and Urogenital Functions in Patients with Type 2 Diabetes Mellitus, Impaired Glucose Tolerance and Normal Glucose Tolerance: Association with Autonomic Neuropathy.

AIMS: Gastrointestinal disorders, including constipation and fecal incontinence, are common in type 2 diabetes mellitus (T2DM) and may derive from diabetic autonomic neuropathy, severe intestinal bacterial overgrowth, or a dysfunctional anorectal sphincter. The present study aims to characterize the correlation between these conditions. METHODS: Patients with T2DM, prediabetes, and normal glucose tolerance (NGT) were included. The anorectal function was assessed with high-resolution anorectal manometry. Patients were screened for autonomic neuropathy by measuring olfactory, sweat, and erectile dysfunction as well as heart rate variability. Constipation and fecal (in-)continence were evaluated using validated questionnaires. Breath tests were used to assess severe intestinal bacterial overgrowth. RESULTS: We included 59 participants (32 (54.2%) with T2DM, 9 (15.3%) with prediabetes, and 18 (30.5%) NGT). The presence of autonomic neuropathy, severe bacterial overgrowth, and symptoms of constipation and incontinence were comparable. HbA1c was correlated with an increased anorectal resting sphincter pressure (r=0.31, P=0.019) and constipation symptoms (r=0.30, P=0.031). In patients with a long-standing diagnosis of T2DM, significantly higher values for maximum anorectal resting pressure (Δ=+27.81±7.84 mmHg, P=0.0015) and baseline pressure (Δ=20.50±9.74 mmHg, P=0.046) were found compared with NGT, but not with prediabetes. CONCLUSIONS: Long-standing T2DM increases anorectal sphincter activity, and constipation symptoms are associated with higher HbA1c levels. The lack of an association of symptoms with autonomic neuropathy suggests glucotoxicity as the primary mechanism.

Meta-analysis of head-to-head clinical trials comparing incretin-based glucose-lowering medications and basal insulin: An update including recently developed glucagon-like peptide-1 (GLP-1) receptor agonists and the glucose-dependent insulinotropic polypeptide/GLP-1 receptor co-agonist tirzepatide.

OBJECTIVE: To assess comparative efficacy, safety and tolerability of injectable incretin-based glucose-lowering medications (IBGLMs) versus basal insulin treatment in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed an updated meta-analysis of randomized clinical trials of head-to-head comparisons of IBGLMs (short- and long-acting glucagon-like peptide-1 [GLP-1] receptor agonists [GLP-1RAs] and glucose-dependent insulinotropic polypeptide [GIP]/GLP-1 receptor co-agonist tirzepatide) versus basal insulin using a PubMed database search (April 2022). The primary endpoint was difference in reduction of glycated haemoglobin (HbA1c ) versus baseline between pooled IBGLMs (fixed-effects meta-analysis) and their subgroups (random-effects meta-analysis) versus basal insulin treatment (mean differences). Secondary endpoints were fasting plasma glucose, body weight, HbA1c target achievement, hypoglycaemia, blood pressure and lipids. Risk of bias assessment was performed using Jadad scores and the Risk of Bias tool 2.0. RESULTS: In all, 20 studies, representing 47 study arms and 11 843 patients, were eligible. Compared with basal insulin, IGBLMs lowered HbA1c by 0.48 (0.45-0.52)% more than did basal insulin treatment. This effect was driven by pooled long-acting GLP-1RAs (ΔHbA1c -0.25 [-0.38; -0.11]%) and the only GIP/GLP-1 receptor co-agonist, tirzepatide (pooled doses; ΔHbA1c -0.90 [-1.06; -0.75]%), while short-acting GLP-1RAs were equally effective compared with basal insulin (P = 0.90). All IBGLM subgroups achieved significantly lower body weight versus insulin treatment (-4.6 [-4.7; -4.4] kg), in particular tirzepatide (-12.0 [-13.8; -10.1] kg). IBGLMs significantly reduced hypoglycaemia and blood pressure and improved lipid variables. Risk of bias was low. IBGLM treatment was associated with more nausea, vomiting and diarrhoea and study medication discontinuation. CONCLUSIONS: Recently introduced, highly effective IBGLMs were superior to basal insulin treatment, reinforcing the recommendation that IBGLMs should be considered as the first injectable treatment for most patients with type 2 diabetes.

Undifferentiated pleomorphic sarcoma of the breast with neoplastic fever: case report and genomic characterization.

PURPOSE: Primary breast sarcomas are extraordinary rare, in particular undifferentiated pleomorphic sarcoma (UPS). UPS with neoplastic fever (UPS-NF) of the breast has not been reported yet. Here, we present an extended UPS-NF of the breast including its comprehensive molecular workup. METHODS: A 58-year-old female presented with general malaise, fever spikes, weight loss, and a massively swollen left breast. C-reactive protein and blood leucocytes were significantly increased. However, repeated blood cultures and smears were all sterile. Histopathology of the abscess-forming tumor revealed an undifferentiated malignancy with numerous of tumor giant cells as well as spindle-shaped cells with nuclear pleomorphism and hyperchromasia. Immunohistochemistry demonstrated partial, patchy desmin staining and weak heterogonous neuron-specific enolase immunoreactivity of tumor cells, but a focal staining for Melan-A. RESULTS: Neither common melanoma driver mutations nor an ultraviolet mutational signature was detected by whole genome sequencing. Using FISH and RT-PCR we also excluded translocations characteristic for clear cell sarcoma. Thus, the diagnosis of inflammatory UPS-NF of the breast was considered highly probable. Despite a complete mastectomy, the tumor recurred after only three months. This recurrence was treated with a combination of ipilimumab and nivolumab based on the primary tumor's TPS score for PD-L1 of 30%. After an initial response, however, the tumor was progressive again. CONCLUSION: We describe here the first case of UPS-NF of the breast, which shows great clinical and histopathologic resemblances to previously reported UPS-NF of other anatomic localizations.

Attitude towards and perception of individual safety after SARS-CoV-2 vaccination among German cancer patients.

PURPOSE: Refusal to receive SARS-CoV-2 vaccination poses a threat to fighting the COVID-19 pandemic. Little is known about German cancer patients' attitude towards and experience with SARS-CoV-2 vaccination. METHODS: Patients were enrolled between 04-11/2021. They completed a baseline questionnaire (BLQ) containing multiple choice questions and Likert items ranging from 1 ("totally disagree") to 11 ("totally agree") regarding their attitude towards vaccination and COVID-19. A follow-up questionnaire (FUQ) was completed after vaccination. RESULTS: 218 patients (43% female) completed BLQ (110 FUQ; 48% female). Most patients agreed to "definitely get vaccinated" (82%) and disagreed with "SARS-CoV-2 vaccination is dispensable due to COVID-19 being no serious threat" (82%; more dissent among men, p = 0.05). Self-assessment as a member of a risk group (p = 0.03) and fear of COVID-19 (p = 0.002) were more common among women. Fear of side effects was more common among women (p = 0.002) and patients with solid or GI tumors (p = 0.03; p < 0.0001). At FUQ, almost all (91%) reported their vaccination to be well tolerated, especially men (p = 0.001). High tolerability correlated with confidence in the vaccine being safe (r = 0.305, p = 0.003). Most patients would agree to get it yearly (78%). After vaccination, patients felt safe meeting friends/family (91%) or shopping (62%). Vacation (32%) or work (22%) were among others considered less safe (less frequent among men, p < 0.05). CONCLUSION: Acceptance of SARS-CoV-2 vaccination is high and it is well tolerated in this sensitive cohort. However, concerns about vaccine safety remain. Those and gender differences need to be addressed. Our results help identify patients that benefit from pre-vaccination consultation.

Acute effects of linagliptin on intact and total glucagon-like peptide-1 and gastric inhibitory polypeptide levels in insulin-dependent type 2 diabetes patients with and without moderate renal impairment.

AIMS: To investigate the effect of renal impairment on incretin metabolism in patients with type 2 diabetes mellitus (T2DM) before and after treatment with the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin. MATERIALS AND METHODS: Long-standing T2DM patients with normal (estimated glomerular filtration rate [eGFR] >90 mL/min/1.73m2 ) and impaired (eGFR <60 mL/min/1.73m2 ) renal function on stable treatment with insulin were included. Before and after 8 days of treatment with 5 mg linagliptin once daily, patients underwent a 75-g oral glucose tolerance test (OGTT) and total and intact glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), glucose, insulin, C-peptide and glucagon concentrations were measured. The primary outcome was the difference between the study groups in change of intact GLP-1 concentrations. RESULTS: Of 115 patients screened, 29 were analysed (15 [51.7%] with and 14 [48.3%] without renal impairment). Renal function differed significantly between the groups (101 ± 11 vs. 47 ± 13 mL/min/1.73m2 ; P < 0.0001), while glycaemic control was similar (glycated haemoglobin 68 ± 5 vs. 66 ± 5 mmol/mol; P = 0.45). Baseline GLP-1 and GIP levels were comparable. Glucose concentrations during the OGTT were significantly lowered by linagliptin treatment in patients with renal impairment (P = 0.017), but not in those with normal renal function (P = 0.17). Treatment with linagliptin resulted in a significant increase in intact GLP-1 and GIP levels in patients with normal (P = 0.048 and P = 0.0001, respectively) and impaired (P = 0.040 and P = 0.0011, respectively) renal function during the OGTT. However, the primary outcome (difference between the groups in change of intact GLP-1 concentrations) was not significant (P = 0.22). Overall, linagliptin was well tolerated. CONCLUSIONS: Treatment with linagliptin increases intact incretin levels in patients with T2DM. Impaired renal function does not compromise the effects of linagliptin on active or total incretin levels as well as on glucagon secretion. Thus, treatment with linagliptin is suitable for patients with T2DM, independently of renal function.

Low Serological Prevalence of SARS-CoV-2 Antibodies in Cancer Patients at a German University Oncology Center.

BACKGROUND: Coronavirus disease 2019 (COVID-19) cases in Germany, as in most other places in Europe or worldwide, are still highly prevalent. Vaccination rates currently remain low, putting cancer patients at a continued risk of infection with SARS-CoV-2, while prevalence of SARS-CoV-2 antibodies among cancer patients in Germany remains essentially unknown. METHODS: Between August 2020 and February 2021, patients admitted to our hospital were prospectively enrolled in our COVID-19 biobank. Collected sera were analyzed for SARS-CoV-2-IgM/IgG using Elecsys Anti-SARS-CoV-2 assay. RESULTS: One hundred and ten patients with cancer were included in this study. With 71 (65%) patients, most had active cancer treatment, mainly chemotherapy (56%). The most frequent diagnosis was gastrointestinal cancer (54%) with pancreatic cancer being the most common cancer type (24%). Hematologic malignancies were present in 21 patients (17%). Among the cancer patients first diagnosed during the pandemic, the rate of palliative treatment situations tended to be higher (76% vs. 67%, p = 0.17). A history of SARS-CoV-2 infection was documented in 15 (14%) patients; however, SARS-CoV-2 antibodies were detected in 10 (67%) patients only. Of the patients without a history of SARS-CoV-2 infection, none displayed SARS-CoV-2 antibodies. CONCLUSION: In the present single-center experience, a low serological prevalence of SARS-CoV-2 antibodies among cancer patients even after SARS-CoV-2 infection was found. The results support continued strict preventive measures as well as efforts toward faster vaccination, due to a low immunity level in the population.

Rate of atrial fibrillation and flutter induced tachycardiomyopathy in a cohort of hospitalized patients with heart failure and detection of indicators for improved diagnosis.

Background: Atrial fibrillation (AF) and atrial flutter (AFL) induced tachycardiomyopathy (TCM) has been known to cause reversible heart failure (HF) for many years. However, the prevalence of the disease is unknown, and diagnosis is challenging. Therefore, the aim of the present study was (1) to assess the rate of AF/AFL induced TCM and (2) to identify indicators for diagnosis. Methods: Consecutively, all patients with a diagnosis of HF who were hospitalized in our department within 12 months were reviewed. For the main analysis, all patients with HF with reduced ejection fraction (HFrEF) and AF or AFL were included. AF/AFL induced TCM was diagnosed when there was at least a 10% improvement in left ventricular ejection fraction under rhythm or rate control within 3 months. Patients with HFrEF with AF/AFL but without TCM served as control group. Results: A total of 480 patients were included. AF/AFL induced TCM occurred in 26 patients (5.4%) and HFrEF with AF/AFL in 53 patients (11%). Independent indicators of AF/AFL induced TCM were age<79 years [Odds ratio 5.887, confidence interval (CI) 1.999-17.339, p < 0.001], NT-pro-BNP <5,419 pg/mL (Odds ratio 2.327, CI 1.141-4.746, p = 0.004), and a resting heart rate >112 bpm (Odds ratio 2.503, CI 1.288-4.864, p = 0.001). Conclusion: Approximately 5% of all patients hospitalized for HF suffer from AF/AFL induced TCM. Improved discrimination of AF/AFL induced TCM to HFrEF with AF/AFL is possible considering age, NT-pro-BNP level, and resting heart rate >112 beats/minute. Based on these parameters, an earlier diagnosis and improved therapy might be possible.

The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH2 ) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.

Macronutrient intake, appetite, food preferences and exocrine pancreas function after treatment with short- and long-acting glucagon-like peptide-1 receptor agonists in type 2 diabetes.

AIM: To clarify the distinct effects of a long-acting (liraglutide) and a short-acting (lixisenatide) glucagon-like peptide-1 receptor agonist (GLP-1 RA) on macronutrient intake, gastrointestinal side effects and pancreas function. MATERIALS AND METHODS: Fifty participants were randomized to either lixisenatide or liraglutide for a treatment period of 10 weeks. Appetite, satiety, macronutrient intake, gastrointestinal symptoms and variables related to pancreatic function and gastric emptying were assessed at baseline and after treatment. RESULTS: Both GLP-1 RAs reduced macronutrient intake similarly. Weight loss and appetite reduction were not related to the delay in gastric emptying or gastrointestinal side effects (P > .05). Lipase increased significantly with liraglutide treatment (by 18.3 ± 4.1 U/L; P = .0001), but not with lixisenatide (-1.8 ± 2.4 U/L; P = .46). Faecal elastase and serum ß-carotin levels (indicators for exocrine pancreas function) improved in both groups (P < .05). Changes in lipase activities did not correlate with gastrointestinal symptoms (P > .05 for each variable). CONCLUSIONS: Both GLP-1 RAs comparably affected body weight, energy and macronutrient intake. Both treatments were associated with indicators of improved exocrine pancreas function. Reductions in appetite and body weight as a result of treatment with short- or long-acting GLP-1 RAs are not driven by changes in gastric emptying or gastrointestinal side effects.

Cardiovascular Safety and Benefits of Semaglutide in Patients With Type 2 Diabetes: Findings From SUSTAIN 6 and PIONEER 6.

To exclude an excess risk of cardiovascular (CV) events, CV outcomes trials (CVOTs) have assessed the effects of new glucose-lowering therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), in patients with type 2 diabetes and established CV disease or CV risk factors. The CV safety of semaglutide vs. placebo, when added to standard care, was evaluated in the SUSTAIN 6 trial for the formulation administered once-weekly subcutaneously and in PIONEER 6 for the new once-daily oral formulation. In SUSTAIN 6 and PIONEER 6, both powered to demonstrate noninferiority (upper 95% confidence interval [CI] of the hazard ratio [HR] <1.8), there were fewer first major adverse CV events with semaglutide vs. placebo, with HRs of 0.74 (95% CI 0.58-0.95) and 0.79 (0.57-1.11), respectively. In SUSTAIN 6, the results were significant for noninferiority and superiority, although the latter was not prespecified. Surprisingly, CV and all-cause mortality were significantly reduced by oral semaglutide in PIONEER 6. The ongoing SOUL CVOT will further inform about CV outcomes with oral semaglutide vs. placebo (NCT03914326). Findings from SUSTAIN 6 and PIONEER 6 fall within the spectrum reported with other GLP-1RA CVOTs: noninferiority vs. placebo for major CV events was seen with lixisenatide and exenatide extended-release, while superiority was demonstrated with liraglutide, albiglutide, and dulaglutide. Beneficial outcomes have been recognized in international guidelines, which recommend subcutaneous liraglutide, semaglutide, and dulaglutide to reduce the risk of CV events in high-risk patients. Both indirect mechanisms via risk factor modification and direct effects via GLP-1 receptors in the CV system have been proposed to be responsible for CV event reductions. The exact mechanism(s) remains to be characterized, but appears to be mainly linked to anti-atherosclerotic effects. Further research is needed to elucidate the relevant mechanisms for CV benefits of GLP-1RAs.

Day-to-Day Variations in Fasting Plasma Glucose Do Not Influence Gastric Emptying in Subjects With Type 1 Diabetes.

OBJECTIVE: Acute experimental variations in glycemia decelerate (hyperglycemia) or accelerate (hypoglycemia) gastric emptying. Whether spontaneous variations in fasting plasma glucose (FPG) have a similar influence on gastric emptying is yet unclear. RESEARCH DESIGN AND METHODS: Gastric emptying of a mixed meal was prospectively studied three times in 20 patients with type 1 diabetes and 10 healthy subjects with normal glucose tolerance using a 13C-CO2 octanoate breath test with Wagner-Nelson analysis. The velocity of gastric emptying was related to FPG measured before the test (grouped as low, intermediate, or high). In addition, gastric emptying data from 255 patients with type 1 diabetes studied for clinical indications were compared by tertiles of baseline FPG. RESULTS: Despite marked variations in FPG (by 4.8 [95% CI 3.4; 6.2] mmol/L), gastric emptying did not differ among the three prospective examinations in patients with type 1 diabetes (Δ T1/2 between highest and lowest FPG: 1 [95% CI -35; 37] min; P = 0.90). The coefficient of variation for T1/2 determined three times was 21.0%. Similar results at much lower variations in FPG were found in healthy subjects. In the cross-sectional analysis, gastric emptying did not differ between the tertiles of FPG (Δ T1/2 between highest and lowest FPG: 7 [95% CI -10; 23] min; P = 0.66), when FPG varied by 7.2 (6.7; 7.8) mmol/L. However, higher HbA1c was significantly related to slower gastric emptying. CONCLUSIONS: Day-to-day variations in FPG not induced by therapeutic measures do not influence gastric emptying significantly. These findings are in contrast with those obtained after rapidly clamping plasma glucose in the hyper- or hypoglycemic concentrations range and challenge the clinical importance of short-term glucose fluctuations for gastric emptying in patients with type 1 diabetes. Rather, chronic hyperglycemia is associated with slowed gastric emptying.

GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art.

BACKGROUND: GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). SCOPE OF REVIEW: To summarize current knowledge about GLP-1 receptor agonist. MAJOR CONCLUSIONS: At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.

Effects of Lixisenatide Versus Liraglutide (Short- and Long-Acting GLP-1 Receptor Agonists) on Esophageal and Gastric Function in Patients With Type 2 Diabetes.

OBJECTIVE: Short-acting glucagon-like peptide 1 receptor agonists (GLP-1 RAs) decelerate gastric emptying more than long-acting GLP-1 RAs. Delayed gastric emptying is a risk factor for gastroesophageal reflux disease. We aimed to measure esophageal reflux and function as well as gastric emptying and acid secretion during treatment with short-acting (lixisenatide) and long-acting (liraglutide) GLP-1 RAs. RESEARCH DESIGN AND METHODS: A total of 57 subjects with type 2 diabetes were randomized to a 10-week treatment with lixisenatide or liraglutide. Changes from baseline in the number of reflux episodes during 24-h pH registration in the lower esophagus, lower esophagus sphincter pressure, gastric emptying (13C-sodium octanoate acid breath test), and gastric acid secretion (13C-calcium carbonate breath test) were analyzed. RESULTS: Gastric emptying half-time was delayed by 52 min (Δ 95% CI 16, 88) with lixisenatide (P = 0.0065) and by 25 min (3, 46) with liraglutide (P = 0.025). There was no difference in the number of reflux episodes (mean ± SEM 33.7 ± 4.1 vs. 40.1 ± 5.3 for lixisenatide and liraglutide, respectively, P = 0.17) or the extent of gastroesophageal reflux (DeMeester score) (35.1 ± 6.7 vs. 39.7 ± 7.5, P = 0.61), with similar results for the individual GLP-1 RAs. No significant changes from baseline in other parameters of esophageal motility and lower esophageal sphincter function were observed. Gastric acidity decreased significantly by -20.7% (-40.6, -0.8) (P = 0.042) with the GLP-1 RAs. CONCLUSIONS: Lixisenatide exerted a more pronounced influence on gastric emptying after breakfast than liraglutide. Neither lixisenatide nor liraglutide had significant effects on esophageal reflux or motility. Gastric acid secretion appears to be slightly reduced by GLP-1 RAs.

Impact of proton pump inhibitor treatment on pancreatic beta-cell area and beta-cell proliferation in humans.

INTRODUCTION: Gastrin has been shown to promote beta-cell proliferation in rodents, but its effects in adult humans are largely unclear. Proton pump inhibitors (PPIs) lead to endogenous hypergastrinaemia, and improved glucose control during PPI therapy has been reported in patients with diabetes. Therefore, we addressed whether PPI treatment is associated with improved glucose homoeostasis, islet cell hyperplasia or increased new beta-cell formation in humans. PATIENTS AND METHODS: Pancreatic tissue specimens from 60 patients with and 33 patients without previous PPI therapy were examined. The group was subdivided into patients without diabetes (n = 27), pre-diabetic patients (n = 31) and patients with diabetes (n = 35). RESULTS: Fasting glucose and HbA1c levels were not different between patients with and without PPI therapy (P = 0.34 and P = 0.30 respectively). Beta-cell area was higher in patients without diabetes than in patients with pre-diabetes or diabetes (1.33 ± 0.12%, 1.05 ± 0.09% and 0.66 ± 0.07% respectively; P < 0.0001). There was no difference in beta-cell area between patients with and without PPI treatment (1.05 ± 0.08% vs 0.87 ± 0.08%, respectively; P = 0.16). Beta-cell replication was rare and not different between patients with and without PPI therapy (P = 0.20). PPI treatment was not associated with increased duct-cell replication (P = 0.18), insulin expression in ducts (P = 0.28) or beta-cell size (P = 0.63). CONCLUSIONS: These results suggest that in adult humans, chronic PPI treatment does not enhance beta-cell mass or beta-cell function to a relevant extent.