Einleitung, Fragestellung. Der Inkretin-Effekt ist bei Typ 2 Diabetes (T2D) und Chronischer Pankreatitis mit Diabetes mellitus (CPD) reduziert, obwohl die Inkretinhormone Glucose-dependent Insulinotropic Polypeptide (GIP) und Glucagon-like Peptide-1 (GLP-1) unbeeinträchtigt sezerniert werden. Wir wollten untersuchen, ob die Erklärung darin liegt, dass die Rezeptoren für GIP und GLP-1 in endokrinen Inseln/ß-Zellen bei T2D und/oder CPD vermindert exprimiert werden.

AIM:To perform a direct, double-blind, randomised, crossover comparison of subcutaneous and intravenous glucagon-like peptide-1 (GLP-1) in hyperglycaemic subjects with type 2 diabetes naïve to GLP-1-based therapy. MATERIALS AND METHODS:Ten fasted, hyperglycaemic subjects (1 female, age 63 ± 10 years [mean ± SD], glycated haemoglobin 73.5 ± 22.0 mmol/mol [8.9% ± 2.0%], both mean ± SD) received subcutaneous GLP-1 and intravenous saline, or intravenous GLP-1 and subcutaneous saline. Infusion rates were doubled every 120 min (1.2, 2.4, 4.8 and 9.6 pmol·kg-1·min-1 for subcutaneous, and 0.3, 0.6, 1.2 and 2.4 pmol·kg-1·min-1 for intravenous). Plasma glucose, total and intact GLP-1, insulin, C-peptide, glucagon and gastrointestinal symptoms were evaluated over 8 h. The results are presented as mean ± SEM. RESULTS:Plasma glucose decreased more with intravenous (by ~8.0 mmol/L [144 mg/dL]) than subcutaneous GLP-1 (by ~5.6 mmol/L [100 mg/dL]; p < 0.001). Plasma GLP-1 increased dose-dependently, but more with intravenous than subcutaneous for both total (∆max 154.2 ± 3.9 pmol/L vs. 85.1 ± 3.8 pmol/L; p < 0.001), and intact GLP-1 (∆max 44.2 ± 2.2 pmol/L vs. 12.8 ± 2.2 pmol/L; p < 0.001). Total and intact GLP-1 clearance was higher for subcutaneous than intravenous GLP-1 (p < 0.001 and p = 0.002, respectively). The increase in insulin secretion was greater, and glucagon was suppressed more with intravenous GLP-1 (p < 0.05 each). Gastrointestinal symptoms did not differ (p > 0.05 each). CONCLUSIONS:Subcutaneous GLP-1 administration is much less efficient than intravenous GLP-1 in lowering fasting plasma glucose, with less stimulation of insulin and suppression of glucagon, and much less bioavailability, even at fourfold higher infusion rates.

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 (Delta = + 27.81 +/- 7.84 mmHg, P = 0.0015) and baseline pressure (Delta = 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.

Background We previously published an algorithm predicting 24 h basal insulin infusion profiles in insulin pump-treated subjects with type 1 diabetes profiles from six subject characteristics. This algorithm was to be externally validated in an independent environment and patient population. Methods Thirty-two patients with pump-treated type diabetes were switched to their individually algorithm-derived basal insulin infusion profile, and the appropriateness of fasting glycemic control was scrutinized by means of a supervised 24 h fast. Primary endpoint was appropriate fasting glycemic control according to pre-defined criteria in at least 80% of the cohort. Results In 24 out of 32 patients switching to the algorithm-derived basal insulin infusion rate and undergoing a 24-h fasting period, appropriate glycemic control was achieved (=75%, lower than the pre-defined threshold of 80%), two patients discontinued the fast due to hyperglycemia, and six finished the fasting period, however, with inappropriate fasting glycemic control (entirely due to hyperglycemic episodes). There were no obvious differences in baseline characteristics between those with appropriate vs. inappropriate fasting glycemic control on the basal insulin infusion rate provided by the algorithm. Conclusion In conclusion, when testing fasting glycemic control with an algorithm-derived individual basal insulin infusion profile during a 24 h fasting period in a cohort unrelated in terms of the hospital environment and catchment area, the success rate was lower than a pre-defined threshold for concluding utility of this algorithm. Therefore, applying this algorithm in order to initiate or optimize basal insulin infusion profiles in type 1 diabetes cannot be generally recommended.

The role of gut–brain axis functioning gains growing attention in research on the pathophysiology of major depressive disorders. Here, especially consequences of altered microbiota composition on tryptophan metabolism resulting in altered serotonergic neurotransmission in the central nervous system (CNS) have reached a central position. Previous research, however, mainly focused on either microbiota and peripheral serotonin levels or central serotonergic neurotransmission. The present study aimed to combine the analysis of microbiota composition and central serotonergic activity using a valid neurophysiological indicator. We recruited 19 adult patients with type 1 diabetes and depression (D + D; 7 males), 19 patients with type 1 diabetes (D-; 7 male), and 20 healthy participants (HC; 7 males). Next to the analysis of fecal microbiota regarding α- and β-diversity, the loudness dependence of auditory evoked potential (LDAEP) was investigated, a non-invasive measurement of central serotonergic activity. High α-diversity was associated with high LDAEP, i.e., low serotonergic activity, in patients with diabetes and additional depression. Furthermore, relative abundances of bacterial families belonging to Bacteroidetes, Proteobacteria and Firmicutes were shown to have an impact on central serotonergic activity. This finding was supported by a tendency indicating an association of central serotonergic activity with the Bacteroidetes–Firmicutes ratio in both patients’ groups. Together, this data suggests that the guts’ microbiota composition might play an important role in regulating the central serotonergic activity in the brain.

Aim: Glucagon-like peptide-1 receptor agonists improve glycaemic control: some are now available as oral and subcutaneous formulations, and some have indications for reducing cardiovascular risk. The expanded scope for these therapies warrants comprehensive safety evaluations. We report the safety/tolerability of subcutaneous and oral semaglutide from the SUSTAIN and PIONEER clinical trial programmes, respectively.Materials and methods: Adverse events (AEs) from 16 randomized placebo-or active controlled phase IIIa trials in patients with type 2 diabetes (n = 11 159) including once-weekly subcutaneous semaglutide (n = 3150; SUSTAIN trials) or once-daily oral semaglutide (n = 4116; PIONEER trials) were analysed. Data pools were analysed for each programme, with separate analyses of cardiovascular outcomes trials (CVOTs; n = 6480).Results: In the phase IIIa pools, gastrointestinal disorders were reported in 41.9%/39.1% of patients with subcutaneous/oral semaglutide, respectively (most prevalent during initiation/escalation) versus 22.0%/24.8% with comparators. Rates of kidney disorders, acute pancreatitis, malignant neoplasms, hypoglycaemia, diabetic retinopathy, heart failure and other cardiovascular events were similar for semaglutide versus comparators. Cholelithiasis incidence was higher with subcutaneous and oral semaglutide versus placebo. Diabetic retinopathy incidence was higher with subcutaneous semaglutide versus placebo in SUSTAIN 6. Small pulse rate increases occurred with both formulations; there was no increased rate of arrhythmias. Fatal AE incidence was similar between semaglutide and comparators. Versus placebo, CVOTs showed a reduced risk of major adverse cardiovascular events with subcutaneous semaglutide and non-inferiority criteria were met with oral semaglutide.Conclusions: The most common AEs with semaglutide were gastrointestinal disorders, which decreased with continued therapy. These comprehensive safety/ tolerability data may better inform patient selection and guidance in care.

In clinical practice, the distinction between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) can be challenging, leaving patients with “ambiguous” diabetes type. Insulin-treated patients (n=115) previously diagnosed with T2DM had to be re-classified based on clinical phenotype and laboratory results, and were operationally defined as having an ambiguous diabetes type. They were compared against patients with definite T1DM and T2DM regarding 12 clinical and laboratory features typically different between diabetes types. Characteristics of patients with ambiguous diabetes type, representing approximately 6% of all patients with T1DM or T2DM seen at our specialized clinic, fell in between those of patients with definite T1DM and T2DM, both regarding individual features and with respect to a novel classification based on multi-variable regression analysis (P<0.0001). In conclusion, a substantial proportion of diabetes patients in a tertiary care centre presented with an “ambiguous” diabetes type. Their clinical characteristics fall in between those of definite T1DM or T2DM patients.

Tirzepatide is a unimolecular co-agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor-activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP-1 and GIP, their receptors, and previous results of co-targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP-1 and GIP receptor activation, tirzepatide does not seem to have a classical co-activating mode of action in humans. Rather, in vitro studies of the human GLP-1 and GIP receptors reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.

Fragestellung Menschen mit Typ 2 Diabetes (T2DM) weisen ein erhöhtes Risiko für einen postprandialen Abfall des systolischen Blutdrucks (≥20mmHg, genannt postprandiale Hypotension [PPH]) auf, einen unabhängigen Risikofaktor für eine gesteigerte Mortalität. Eine Studie unserer Arbeitsgruppe zeigte, dass intraduodenale Metformingabe Auswirkungen auf die Blutdruckregulation, Glucagon-Like Peptide 1 (GLP-1) Spiegel und die Magenentleerung hat. Es erfolgte daher die Untersuchung der postprandialen Auswirkungen einer oralen Metformintherapie auf Blutdruck, Herzfrequenz, GLP-1, Laktat und Magenentleerung bei Menschen mit diätetisch eingestelltem T2DM.

Aims To evaluate the efficacy and safety of oral semaglutide versus comparators by patient characteristic subgroups in patients with type 2 diabetes. Materials and Methods Change from baseline in glycated haemoglobin (HbA1c) and body weight, and achievement of HbA1c <7.0% with oral semaglutide 7 mg, oral semaglutide 14 mg, flexibly dosed oral semaglutide (flex) and comparators were assessed across baseline subgroups (age, race, ethnicity, diabetes duration, body mass index and HbA1c) from the PIONEER programme. Treatment differences were analysed using a mixed model for repeated measurements for continuous variables and a logistic regression model for the binary endpoint. Pooled safety data were analysed descriptively. Results Changes from baseline in HbA1c and body weight, and the odds of achieving HbA1c <7.0%, were greater with oral semaglutide 14 mg/flex (n = 1934) and higher or similar with oral semaglutide 7 mg (n = 823) versus comparators (n = 2077) across most subgroups. Changes in HbA1c with oral semaglutide 14 mg/flex were greater for patients with higher baseline HbA1c (HbA1c >9.0%: -1.7% to -2.6%; HbA1c <8.0%: -0.7% to -1.2%). In some trials, Asian patients experienced greater HbA1c reductions with oral semaglutide 14 mg/flex (-1.5% to -1.8%) than other racial groups (-0.6% to -1.6%). The overall incidence of adverse events (AEs) with oral semaglutide was similar to that with comparators and was consistent across subgroups. More gastrointestinal AEs were observed with oral semaglutide, versus comparators, across subgroups. Conclusions Oral semaglutide demonstrated consistently greater HbA1c and body weight reductions across a range of patient characteristics, with greater HbA1c reductions seen at higher baseline HbA1c levels.

Cardiovascular outcomes trials (CVOTs) with novel drugs to treat type 2 diabetes have uniformly chosen the composite "major adverse cardiovascular events (MACE)" as their primary endpoint, but they also report hazard ratios for individual cardiovascular outcomes (myocardial infarction, stroke, cardiovascular death, all-cause death, hospitalization for heart failure). We wanted to scrutinize the power to identify significant differences with respect to individual as compared to composite outcomes. We estimated post hoc the statistical power to detect significant differences of 10-25% for published studies, comparing the proportions of patients with an event (two-sided log-rank tests). For MACE, the power to detect a 15% difference ranged from 82.3 to 100.0% for larger trials, but was only 69.1 and 50.5 for smaller, preliminary trials (SUSTAIN-6 and PIONEER-6). For individual endpoints, the power, as a rule, was substantially lower. In conclusion, cardiovascular outcomes trials had appropriate power to detect significant reductions in hazard ratios with respect to the primary endpoint, but not for individual cardiovascular outcomes. This was particularly the case for small, preliminary studies. Our results call for caution when comparing results regarding individual endpoints between CVOTs, if the aim is to identify heterogeneity within or between medication classes.

To investigate whether upper gastrointestinal (GI) disease has any effect on the exposure of oral semaglutide, an important consideration given that its absorption occurs primarily in the stomach.

Background Individuals with type 1 diabetes and those with depression show differences in the composition of the gut microbiome from that of healthy people. However, these differences have not yet been studied in patients with both diseases. Therefore, we compared the gut microbiome of people with type 1 diabetes with or without depression with matched healthy controls. Methods A case-control study was conducted in 20 adults with type 1 diabetes (group A), 20 adults with type 1 diabetes and depression (group B), and 20 healthy adults (group C). Gut microbiota composition was determined by sequencing of the V3-V4 region of the bacterial 16S rDNA and alpha and beta diversity was compared between the groups. Results Groups A and B both showed higher alpha diversity than the healthy control group ( P < 0.001) but alpha diversity did not differ significantly between groups A and B. Participants having type 1 diabetes with ( P < 0.05) or without comorbid depression ( P < 0.001) differed regarding beta diversity from healthy controls but not between each other. Group B (diabetes with depression) had significantly higher abundance of Megaspaera than groups A and C. Both diabetes groups had a higher abundance of Christensenellaceae, Succinivibrionaceae , and Rhodospirillaceae than the healthy group but similar between-group abundances. Conclusions While differences in alpha and beta diversity and in some bacterial taxa occurred only between participants with diabetes and healthy controls, specific characteristics regarding the abundance of Megasphaera were observed in people with diabetes and comorbid depression. In summary, the study findings indicate a possible involvement of bacterial groups in depression in people with diabetes. The results suggest replication studies in larger samples to verify these findings.

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/1.73m(2)) and impaired (eGFR <60 mL/min/1.73m(2)) 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/1.73m(2); 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.

Introduction Breath tests utilising (13) C-labelled substrates for the assessment of gastric emptying have been applied widely. Wagner-Nelson analysis is a pharmacokinetic model that can be utilised to generate a gastric emptying curve from the % (13) CO (2) measured in breath samples. We compared Wagner-Nelson analysis with (i) scintigraphy and (ii) conventional breath test modelling to quantify gastric emptying in type 2 diabetes. Methods Thirteen patients (age 68.1 & PLUSMN;1.5 years, body mass index 31.0 & PLUSMN;0.9 kg/m (2) , HbA1c 6.3 +/- 0.2%) consumed a mashed potato meal comprising 65 g powdered potato, 20 g glucose, 250 ml water, an egg yolk labelled with 100 mu L (13) C-octanoic acid and 20MBq (99m) Tc-calcium phytate. Scintigraphic data were acquired and breath samples collected for 4 hours after the meal. Gastric emptying curves were derived based on each technique; the 50% emptying time and intragastric retention at 60 min were also calculated. Results With Wagner-Nelson analysis, a K (el) =0.60 (the elimination constant) best approximated the scintigraphic gastric emptying curve. There was a relationship between the T50 calculated with scintigraphy and by both Wagner-Nelson K (el) =0.60 (r (2) =0.45, P < 0.05) and conventional analysis (r (2) =0.44, P < 0.05). There was no significant difference in the 50% gastric emptying time for scintigraphy (68.5 +/- 4.8 min) and Wagner-Nelson K (el) =0.60 (71.3 & PLUSMN;4.5 min), however, the 50% gastric emptying time calculated by conventional analysis was much greater at 164.7 +/- 6.0 min (P < 0.001). Conclusion In type 2 diabetes, gastric emptying of a mashed potato meal measured using a (13) C-octanoic acid breath test analysed with Wagner-Nelson K (el) =0.60 closely reflects measurements obtained with scintigraphy, whereas, in absolute terms, the conventional breath test analysis does not.

Acute bacterial skin and skin structures infections (ABSSSIs) are associated with high morbidity, costs and mortality in patients with diabetes mellitus. Their appropriate management should include several figures and a well-organized approach. This review aims to highlight the interplay between diabetes and ABSSSIs and bring out the unmet clinical needs in this area. Pathogenetic mechanisms underlying the increased risk of ABSSSIs in diabetes mellitus are multifactorial: high glucose levels play a crucial pathogenetic role in the tissue damage and delayed clinical cure. Moreover, the presence of diabetes complications (neuropathy, vasculopathy) further complicates the management of ABSSSIs in patients with diabetes. Multidrug resistance organisms should be considered in this population based on patient risk factors and local epidemiology and etiological diagnosis should be obtained whenever possible. Moreover, drug-drug interactions and drug-related adverse events (such as nephrotoxicity) should be considered in the choice of antibiotic therapy. Reducing unnecessary hospitalizations and prolonged length of hospital stay is of primary importance now, more than ever. To achieve these objectives, a better knowledge of the interplay between acute and chronic hyperglycemia, multidrug resistant etiology, and short and long-term outcome is needed. Of importance, a multidisciplinary approach is crucial to achieve full recovery of these patients.

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/1.73m(2)) and impaired (eGFR <60 mL/min/1.73m(2)) 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/1.73m(2); 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.

A patient was admitted for the treatment of recurrent postprandial hypoglycaemia after Roux-en-Y gastric bypass. Diazoxide was initiated after dietary recommendations had failed to relieve symptoms. The patient was discharged after the drug was administered with good acute tolerance. One week after initiation of therapy she developed lymphadenopathy and pancytopenia. There was no clinical evidence of an infection. After discontinuing diazoxide, the symptoms subsided. Our case report describes rare haemotological adverse drug reactions under diazoxide.