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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 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 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.

Objective Incretins are known to influence lipid metabolism in the intestine when administered as pharmacologic agents. The aggregate influence of endogenous incretins on chylomicron production and clearance is less clear, particularly in light of opposing effects of co-secreted hormones. Here, we tested the hypothesis that physiological levels of incretins may impact on production or clearances rates of chylomicrons and VLDL. Design and methods A group of 22 overweight/obese men was studied to determine associations between plasma levels of glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) after a fat-rich meal and the production and clearance rates of apoB48- and apoB100-containing triglyceride-rich lipoproteins. Subjects were stratified by above- and below-median incretin response (area under the curve). Results Stratification yielded subgroups that differed about two-fold in incretin response. There were neither differences in apoB48 production rates in chylomicrons or VLDL fractions nor in apoB100 or triglyceride kinetics in VLDL between men with above- vs below-median incretin responses. The men with above-median GLP-1 and GLP-2 responses exhibited higher postprandial plasma and chylomicron triglyceride levels, but this could not be related to altered kinetic parameters. No differences were found between incretin response subgroups and particle clearance rates. Conclusion We found no evidence for a regulatory effect of endogenous incretins on contemporaneous chylomicron or VLDL metabolism following a standardised fat-rich meal. The actions of incretins at pharmacological doses may not be reflected at physiological levels of these hormones.

Sodium-glucose transporter-2 inhibitors (SGLT2i) lower blood glucose and are used for treatment of type-2-diabetes. However, SGLT2i have been associated with increases in endogenous glucose production (EGP) by mechanisms that have been proposed to result from SGLT2i-mediated increases in circulating glucagon concentrations, but the relative importance of this effect is debated, and mechanisms possibly coupling SGLT2i to increased plasma glucagon are unclear. A direct effect on alpha-cell activity has been proposed, but data on alpha-cell SGLT2 expression are inconsistent, and studies investigating direct effects of SGLT2 inhibition on glucagon secretion are conflicting. In contrast, alpha-cell SGLT1 expression has been found more consistently and seems to be more prominent, pointing to an underappreciated role for this transporter. Nevertheless, the selectivity of most SGLT2i does not support interference with SGLT1 during therapy. Paracrine effects mediated by secretion of glucagonotropic/-static molecules from beta- and/or delta-cells have also been suggested to be involved in SGLT2i-induced increase in plasma glucagon, but studies are few and arrive at different conclusions. It is also possible that the effect on glucagon is secondary to drug-induced increases in urinary glucose excretion and lowering of blood glucose, as demonstrated in experiments with glucose clamping where SGLT2i-associated increases in plasma glucagon is are prevented. However, regardless of the mechanisms involved, the current balance of evidence does, not support that SGLT2 plays a crucial role for alpha-cell physiology or that SGLT2i-induced glucagon secretion is important for the associated increased EGP, particularly since the increase in EGP occurs before any rise in plasma glucagon. This article is protected by copyright. All rights reserved.

Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post-hoc analysis of a 3-year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase-4 inhibitor increases active glucagon-like peptide-1 (GLP-1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase-4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP-1.We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.Postprandial plasma glucose increased by 57% (incremental area under the curve 0-240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6-2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP-1 and C-peptide concentrations increased after sacubitril/valsartan, but insulin and glucose-dependent insulinotropic polypeptide did not change.The glucose-lowering effects of long-term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero-pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study.gov (NCT03893526).

Dipeptidyl peptidase 4 inhibitors (DPP4i) have been available for treating type 2 diabetes mellitus since 2006. Although they are a diverse group, DPP4i are all small, orally available molecules that interact with the catalytic site of DPP4 without disturbing any of its other known functions, including its effects on the immune system. DPP4i have no intrinsic glucose-lowering activity, so their efficacy as anti-diabetic agents is related directly to their ability to inhibit DPP4 activity and is mediated through the effects of the substrates they protect. Of these, the incretin hormone, glucagon-like peptide 1, is probably the most important. As the effects of glucagon-like peptide 1 are glucose-dependent, the risk of hypoglycaemia with DPP4i is low. Class effects, which are directly related to the mechanism of action, are common to all DPP4i; these include their overall good safety profile and tolerability, as well as their efficacy in improving glycaemic control, but also, potentially, a small increased risk of acute pancreatitis. Compound-specific effects are those related to their differing chemistries and/or pharmacokinetic profiles. These compound-specific effects could affect the way in which individual DPP4i are used therapeutically and potentially explain off-target adverse effects, such as hospitalization for heart failure, which is seen only with one DPP4i. Overall, DPP4i have a favourable therapeutic profile and are safe and effective in the majority of patients with type 2 diabetes mellitus.

Context Inhibitors of the protease neprilysin (NEP) are used for treating heart failure, but are also linked to improvements in metabolism. NEP may cleave proglucagon-derived peptides, including the glucose and amino acid (AA)-regulating hormone glucagon. Studies investigating NEP inhibition on glucagon metabolism are warranted. Objective This work aims to investigate whether NEP inhibition increases glucagon levels. Methods Plasma concentrations of glucagon and AAs were measured in eight healthy men during a mixed meal with and without a single dose of the NEP inhibitor/angiotensin II type 1 receptor antagonist, sacubitril/valsartan (194 mg/206 mg). Long-term effects of sacubitril/valsartan (8 weeks) were investigated in individuals with obesity (n = 7). Mass spectrometry was used to investigate NEP-induced glucagon degradation, and the derived glucagon fragments were tested pharmacologically in cells transfected with the glucagon receptor (GCGR). Genetic deletion or pharmacological inhibition of NEP with or without concomitant GCGR antagonism was tested in mice to evaluate effects on AA metabolism. Results In healthy men, a single dose of sacubitril/valsartan significantly increased postprandial concentrations of glucagon by 228%, concomitantly lowering concentrations of AAs including glucagonotropic AAs. Eight-week sacubitril/valsartan treatment increased fasting glucagon concentrations in individuals with obesity. NEP cleaved glucagon into 5 inactive fragments (in vitro). Pharmacological NEP inhibition protected both exogenous and endogenous glucagon in mice after an AA challenge, while NEP-deficient mice showed elevated fasting and AA-stimulated plasma concentrations of glucagon and urea compared to controls. Conclusion NEP cleaves glucagon, and inhibitors of NEP result in hyperglucagonemia and may increase postprandial AA catabolism without affecting glycemia.

Background Glucose-dependent insulinotropic polypeptide (GIP) has been suggested to stimulate the secretion of pancreatic polypeptide (PP), an islet hormone thought to regulate gut motility, appetite, and glycemia. Objective To determine whether human GIP1-42 (hGIP) stimulates PP secretion. Method As glycemia modulates the secretion of PP, we measured plasma PP concentrations from 2 studies in healthy men (n = 10) and in patients with type 2 diabetes (T2D) (n = 12), where hGIP1-42 had been administered intravenously during fasting glycemia, hyperglycemia (12 mmol/L), and insulin-induced hypoglycemia (targets: 2.5 mmol/L [healthy]; 3.5 mmol/L [T2D]). Porcine GIP1-42 (pGIP) was also infused intra-arterially in isolated porcine pancreata (n = 4). Results Mean fasting plasma glucose concentrations were approximately 5 mmol/L (healthy) and approximately 8 mmol/L (T2D). At fasting glycemia, PP concentrations were higher during intravenous hGIP1-42 infusion compared with saline in healthy men (mean [standard error of the mean, SEM], net incremental areas under the curves (iAUCs)[0-30min], 403 [116] vs –6 [57] pmol/L × min; P = 0.004) and in patients with T2D (905 [177] vs –96 [86] pmol/L × min; P = 0.009). During hyperglycemic clamping, mean [SEM] PP concentrations were significantly higher during hGIP1-42 infusion compared with saline in patients with T2D (771 [160] vs –183 [117] pmol/L × min; P = 0.001), but not in healthy individuals (–8 [86] vs –57 [53] pmol/L × min; P = 0.69). When plasma glucose levels were declining in response to exogenous insulin, mean [SEM] PP concentrations were higher during hGIP1-42 infusion compared with saline in healthy individuals (294 [88] vs –82 [53] pmol/L × min; P = 0.0025), but not significantly higher in patients with T2D (586 [314] vs –120 [53]; P = 0.070). At target hypoglycemia, PP levels surged in both groups during both hGIP1-42 and saline infusions. In isolated pancreata, pGIP1-42 increased mean [SEM] PP output in the pancreatic venous effluent (baseline vs infusion, 24[5] vs 79 [16] pmol/min x min; P = 0.044). Conclusion GIP1-42 increases plasma PP secretion in healthy individuals, patients with T2D, and isolated porcine pancreata. Hyperglycemia blunts the stimulatory effect of hGIP1-42 in healthy individuals, but not in patients with T2D.

The focus of this article is on the analysis of the release and postrelease fate of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Their actions are dealt with to the extent that they are linked to their secretion. For both hormones, their posttranslational processing is analyzed in detail, because of its importance for the understanding of the molecular heterogeneity of the hormones. Methods of analysis, in particular regarding measurements in plasma from in vivo experiments, are discussed in detail in relation to the molecular heterogeneity of the hormones, and the importance of the designations "total" versus "intact hormones" is explained. Both hormones are substrates for the ubiquitous enzyme, dipeptidyl peptidase-4, which inactivates the peptides with dramatic consequences for their physiological spectrum of activities. The role of endogenous and exogenous antagonists of the receptors is discussed in detail because of their importance for the elucidation of the physiology and pathophysiology of the hormones. Regarding the actual secretion, the most important factors are discussed, including gastric emptying rate and the influence of the different macronutrients. Additional factors discussed are the role of bile, paracrine regulation, the role of the microbiota, pharmaceuticals, and exercise. Finally, the secretion during pathological conditions is discussed. © 2019 American Physiological Society. Compr Physiol 9:1339-1381, 2019.

Neurotensin (NT) is released from enteroendocrine cells and lowers food intake in rodents. We evaluated postprandial NT secretion in humans after surgeries associated with accelerated small intestinal nutrient delivery, and after Roux-en-Y gastric bypass (RYGB) when glucagon-like peptide-1 (GLP-1) signalling and dipeptidyl peptidase 4 (DPP-4) were inhibited, and during pharmacological treatments influencing entero-pancreatic functions.We measured NT concentrations in plasma from meal studies: (I) after truncal vagotomy with pyloroplasty (TVP), cardia resection +TVP (CTVP), and matched controls (n = 10); (II) after RYGB, sleeve gastrectomy (SG), and in matched controls (n = 12); (III) after RYGB (n = 11) with antagonism of GLP-1 signalling using exendin(9-39) and DPP-4 inhibition using sitagliptin; (IV) after RYGB (n = 11) during a run-in period and subsequent treatment with, sitagliptin, liraglutide (GLP-1 receptor agonist), verapamil (calcium antagonist), acarbose (alpha glucosidase inhibitor), and pasireotide (somatostatin analogue), respectively.(I) NT secretion was similar after TVP/CTVP (p = 0.9), but increased vs. controls (p 0.0001). (II) NT secretion was increased after RYGB vs. SG and controls (p 0.0001). NT responses were similar in SG and controls (p = 0.3), but early postprandial NT concentrations were higher after SG (p 0.05). (III) Exendin (9-39) and sitagliptin did not change NT responses vs placebo (p 0.2), but responses were lower during sitagliptin vs. exendin(9-39) (p = 0.03). (IV) Pasireotide suppressed NT secretion (p = 0.004). Sitagliptin tended to lower NT secretion (p = 0.08). Liraglutide, verapamil, and acarbose had no effect (p 0.9).Neurotensin secretion is increased after surgeries associated with accelerated gastric emptying and lowered by pasireotide.

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.

Plasma concentrations of the two pancreatic enzymes, amylase and lipase, are increased within the normal physiological range after initiation of glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment. An association between the use of GLR-1RA and incidence of acute pancreatitis or pancreatic cancer has not been found - neither in rodent studies nor in preclinical studies or in the large cardiovascular outcome trials with GLP-1RAs. The increased concentrations of pancreatic enzymes have been suggested to be explained by increased DNA or protein synthesis found in rodent and acinar cell studies. However, whether this translates into humans is unknown. We therefore investigated the effect of liraglutide, a GLP-1RA, on pancreatic volume, edema and DNA synthesis reflected by 18F-flourothymidine (FLT)-uptake using state-of-the-art positron emission tomography (PET)-magnetic resonance imaging (MRI) before initiation, after four weeks during titration of liraglutide and after six weeks during steady state on maximum dose of liraglutide 3.0 mg in 14 obese men (age 38 ± 3 years, BMI 32 ± 1 kg/m2) without diabetes. Plasma concentrations of amylase and lipase were assessed in parallel. Amylase (+7 U/L [95% confidence intervals, 3 - 11] p In conclusion, six weeks of treatment with liraglutide did not affect pancreatic volume, edema or cellularity in obese individuals. Increased DNA synthesis reflected by FLT-uptake in the pancreas seen after four weeks of liraglutide treatment may be responsible for the increase in pancreatic enzymes. Disclosure M.S. Svane: None. H.H. Johannesen: None. C. Martinussen: None. K.N. Bojsen-Moller: None. M.L. Hansen: None. A.E. Hansen: None. C.F. Deacon: Employee; Spouse/Partner; Merck & Co., Inc. Stock/Shareholder; Spouse/Partner; Merck & Co., Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novartis AG, Novo Nordisk A/S. B. Hartmann: None. S.H. Keller: None. T.L. Klausen: None. A. Loft: None. A. Kjaer: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. J.O. Löfgren: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp.

AIM To investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA), liraglutide, on pancreatic volume, oedema, cellularity and DNA synthesis in humans. MATERIALS AND METHODS We performed an open-label study in 14 obese men (age 38 ± 11 years, body mass index 32 ± 4 kg/m2 ) without diabetes. Subjects were examined at baseline, during titration (week 4) of liraglutide towards 3.0 mg/day, and 2 weeks after steady-state treatment (week 6) of a final dose of liraglutide. The primary endpoint was pancreatic volume determined by magnetic resonance imaging. Secondary endpoints included pancreatic oedema and cellularity, positron emission tomography-based [18 F]fluorothymidine (FLT) uptake (DNA synthesis) and plasma pancreatic enzymes. RESULTS Plasma amylase (+7 U/L [95% confidence intervals 3-11], P

ContextThe mechanisms regulating the postprandial suppression of ghrelin secretion remain unclear, but recent observations in rats indicate that an increase in duodenal osmolarity is associated with a reduction in ghrelin levels. Several hormones have been implicated in the regulation of ghrelin.ObjectiveWe hypothesized that intraduodenal infusion of a hyperosmolar solution would lower plasma ghrelin concentrations.Design, Setting, Participants, and InterventionsEighteen healthy young men were studied after an overnight fast on two occasions in a randomized double-blinded fashion. A nasoduodenal catheter was positioned and isoosmolar (300 mOsm/L) or hyperosmolar (1500 mOsm/L) saline was infused intraduodenally (4 mL/min, t = 0 to 45 minutes). Venous blood was sampled at t = −45, −30, −15, 0, 15, 30, 45, 60, 75, 90, 120, and 180 minutes.Main Outcome MeasuresPlasma concentrations of ghrelin, glucagonlike peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glucagon, pancreatic polypeptide (PP), neurotensin (NT), peptide YY (PYY), motilin, and glucose.ResultsGhrelin concentrations were suppressed with hyperosmolar when compared with isoosmolar saline, and remained lower until t = 180 minutes. CCK, NT, GLP-1, PYY, and glucagon all increased during hyperosmolar, but not isoosmolar, saline infusion (P < 0.01 for all), whereas GIP, PP, and motilin levels were not affected by either infusion.ConclusionsPlasma ghrelin concentrations are lowered, whereas CCK, GLP-1, PYY, NT, and glucagon concentrations are augmented, by hyperosmolar duodenal content in healthy individuals. These observations have implications for the evaluation of studies comparing the effects of different types and loads of nutrients and chemicals on gut hormone secretion.

The aim of the study was to assess whether a simple substitution of carbohydrate in the conventionally recommended diet with protein and fat would result in a clinically meaningful reduction in postprandial hyperglycaemia in subjects with type 2 diabetes mellitus (T2DM). In all, sixteen subjects with T2DM treated with metformin only, fourteen male, with a median age of 65 (43–70) years, HbA1cof 6·5 % (47 mmol/l) (5·5–8·3 % (37–67 mmol/l)) and a BMI of 30 (sd4·4) kg/m2participated in the randomised, cross-over study. A carbohydrate-reduced high-protein (CRHP) diet was compared with an iso-energetic conventional diabetes (CD) diet. Macronutrient contents of the CRHP/CD diets consisted of 31/54 % energy from carbohydrate, 29/16 % energy from protein and 40/30 % energy from fat, respectively. Each diet was consumed on 2 consecutive days in a randomised order. Postprandial glycaemia, pancreatic and gut hormones, as well as satiety, were evaluated at breakfast and lunch. Compared with the CD diet, the CRHP diet reduced postprandial AUC of glucose by 14 %, insulin by 22 % and glucose-dependent insulinotropic polypeptide by 17 % (allPPP=0·004) and satiety scores by 7 % (P=0·035), respectively. A moderate reduction in carbohydrate with an increase in fat and protein in the diet, compared with an energy-matched CD diet, greatly reduced postprandial glucose excursions and resulted in increased satiety in patients with well-controlled T2DM.

The first clinical study to investigate effects of dipeptidyl peptidase-4 (DPP-4) inhibition was published in 2002, and since then, numerous randomized controlled trials (RCTs) have shown that DPP-4 inhibitors are efficacious, safe and well-tolerated. This review will focus upon RCTs which have investigated DPP-4 inhibitors in patient groups which are often under-represented or excluded from typical phase 3 clinical trials. Large cardiovascular (CV) safety outcome trials in patients with established CV disease have confirmed that DPP-4 inhibitors are not associated with any additional CV risk in these already-at-high-risk individuals, while raising awareness of any uncommon adverse events, such as heart failure hospitalization seen in one of the trials. Studies in patients with kidney disease have shown DPP-4 inhibitors to be efficacious without increasing the risk of hypoglycaemia, irrespective of the degree of renal impairment, while data from the large CV trials as well as smaller RCTs have even pointed towards potential renoprotective effects such individuals. The use of DPP-4 inhibitors with insulin when therapy requires intensification may be beneficial without affecting the incidence or severity of hypoglycaemia, with these effects also being replicated in patients with chronic kidney disease, for whom other agents may not be suitable. Attention is now turning towards exploring the potential utility of DPP-4 inhibitors in other circumstances, including for in-hospital management of hyperglycaemia and in other metabolic disorders. Together, these RCTs raise the possibility that in the future, DPP-4 inhibitors may have a broader use which may extend beyond glycaemic control in the typical type 2 diabetes mellitus (T2DM) patient seen in general practice and may encompass conditions other than T2DM.

In humans, glucagon-like peptide-1 (GLP-1) is rapidly degraded by dipeptidyl peptidase-4 to a relatively stable metabolite, GLP-1(9–36)NH2, which allows measurement of GLP-1 secretion. However, little is known about the kinetics of the GLP-1 metabolite in mice. We hypothesised that the GLP-1 metabolite is rapidly degraded in this species by neutral endopeptidase(s) (NEP[s]). We administered glucose, mixed meal or water orally to 256 mice, and took blood samples before and 2, 6, 10, 20, 30, 60 or 90 min after stimulation. To study the metabolism of the GLP-1 metabolite, i.v. GLP-1(9–36)NH2 (800 fmol) or saline (154 mmol/l NaCl) was administered to 160 mice, some of which had a prior injection of a selective NEP 24.11 ± inhibitor (candoxatril, 5 mg/kg) or saline. Blood was collected before and 1, 2, 4 and 12 min after GLP-1/saline injection. Plasma GLP-1 levels were analysed using a customised single-site C-terminal ELISA, two different two-site ELISAs and MS. GLP-1 secretion profiles after oral glucose administration differed markedly when assayed by C-terminal ELISA compared with sandwich ELISAs, with the former showing a far higher peak value and AUC. In mice injected with GLP-1(9–36)NH2, immunoreactive GLP-1 plasma levels peaked at approximately 75 pmol/l at 1 min when measured with sandwich ELISAs, returning to baseline (~20 pmol/l) after 12 min, but remained elevated using the C-terminal ELISA (~90 pmol/l at 12 min). NEP 24.11 inhibition by candoxatril significantly attenuated GLP-1(9–36)NH2 degradation in vivo and in vitro. MS identified GLP-1 fragments consistent with NEP 24.11 degradation. In mice, the GLP-1 metabolite is eliminated within a few minutes owing to endoproteolytic cleavage by NEP 24.11. Therefore, accurate measurement of GLP-1 secretion in mice requires assays for NEP 24.11 metabolites. Conventional sandwich ELISAs are inadequate because of endoproteolytic cleavage of the dipeptidyl peptidase-4-generated metabolite.

Background and aims: Incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are affected early on in the pathogenesis of metabolic syndrome and type 2 diabetes. Epidemiologic studies consistently link high fructose consumption to insulin resistance but whether fructose consumption impairs the incretin response remains unknown. Methods and results: As many as 66 obese (BMI 26-40 kg/m(2)) male subjects consumed fructose-sweetened beverages containing 75 g fructose/day for 12 weeks while continuing their usual lifestyle. Glucose, insulin, GLP-1 and GIP were measured during oral glucose tolerance test (OGTT) and triglycerides (TG), GLP-1, GIP and PYY during a mixed meal test before and after fructose intervention. Fructose intervention did not worsen glucose and insulin responses during OGTT, and GLP-1 and GIP responses during OGTT and fat-rich meal were unchanged. Postprandial TG response increased significantly, p = 0.004, and we observed small but significant increases in weight and liver fat content, but not in visceral or subcutaneous fat depots. However, even the subgroups who gained weight or liver fat during fructose intervention did not worsen their glucose, insulin, GLP-1 or PYY responses. A minor increase in GIP response during OGTT occurred in subjects who gained liver fat (p = 0.049). Conclusion: In obese males with features of metabolic syndrome, 12 weeks fructose intervention 75 g/day did not change glucose, insulin, GLP-1 or GIP responses during OGTT or GLP-1, GIP or PYY responses during a mixed meal. Therefore, fructose intake, even accompanied with mild weight gain, increases in liver fat and worsening of postprandial TG profile, does not impair glucose tolerance or gut incretin response to oral glucose or mixed meal challenge. (C) 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

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 patients with type 2 diabetes, the lost insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is more apparent after continuous versus bolus administration. To test whether the difference might be explained by rapid tachyphylaxis in response to elevated concentrations of GIP, and whether patients with type 2 diabetes and their relatives are more susceptible to tachyphylaxis than healthy subjects.In a two-way crossover design, insulinotropic responses to repeated bolus injection (50 pmol/kg body weight at 30 and 120 min) and continuous infusion of GIP (2 pmol.kg-1.min-1 from 30 to 180 min) under hyperglycaemic clamp conditions (8.5 mmol/l) was compared in age- gender- and weight-matched patients with type 2 diabetes, first degree relatives of such patients, and healthy subjects.Insulin secretory responses to the first and second GIP bolus were not significantly different in any of the subject groups. Subjects with type 2 diabetes had a significant relative impairment versus healthy subjects with continuous (C-peptide, -13.2 %, p 0.05), but not with repeated bolus administration of GIP (+11.1 %, n.s.). First-degree relatives tended to hyper-secrete insulin with bolus or continuous administrations of GIP.Rapid tachyphylaxis in response to continuous exposure to slightly supraphysiological concentrations of GIP does not explain the reduced insulinotropic response to GIP infusions in patients with type 2 diabetes or their first-degree relatives.

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with insulinotropic and glucagonotropic actions, and is believed to be the more physiologically important incretin hormone in healthy humans. Together with the other incretin hormone, glucagon-like peptide-1 (GLP-1), it plays an important role in regulating glucose homeostasis. Both GLP-1 and GIP are substrates of the enzyme dipeptidyl peptidase-4 (DPP-4), and DPP-4 inhibitors, which potentiate their effects on glycaemic control, are now used to treat type 2 diabetes (T2D). This review describes how post-translational processing of the GIP precursor molecule and post-release degradation of the secretory products give rise to multiple isoforms of GIP, some, but not all of which are biologically active, and discusses how this impacts upon their measurement by immunological- and bioassay-based methods. DPP-4 inhibitors reduce degradation of GIP, and although the insulinotropic effects of GIP are impaired in patients with T2D, they can be at least partially restored if glycaemic control is improved. Therefore, given that studies with incretin receptor antagonists indicate that not all of the glucose-lowering effects of DPP-4 inhibition can be accounted for by GLP-1 alone, evidence supports the notion that GIP may play a role in mediating the anti-hyperglycaemic effects of DPP-4 inhibition, while its glucagonotropic actions at lower glucose levels may contribute to the low risk of hypoglycaemia associated with DPP-4 inhibitors.

Diabetes is an independent risk factor for heart failure. Treatment with a neprilysin inhibitor-angiotensin receptor blocker (sacubitril/valsartan) was demonstrated to improve glycemia and reduce time to initiation of insulin therapy but the underlying mechanism(s) are unknown. We hypothesized that sacubitril/valsartan attenuates neprilysin-dependent degradation of GLP-1, and that combined inhibition of the other enzyme cleaving intact GLP-1, dipeptidyl peptidase 4 (DPP-4), would have synergistic effects on levels of intact GLP-1. In two open-labeled clinical trials, a total of 16 healthy men received a standardized meal (34% carbohydrates, 45% fat, 21% protein) combined with a prior single dose of sacubitril (194mg)/valsartan(206mg), sitagliptin (2x100mg), sacubitril(194mg)/valsartan(206mg) and sitagliptin (2x100mg), or control. Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% and had synergistic effects on intact GLP-1 when combined with sitagliptin. Concentrations of glucose, insulin, and GIP were not significantly changed upon sacubitril/valsartan treatment. Sacubitril/valsartan synergistically protects intact GLP-1 when combined with a DPP-4 inhibitor pointing to a therapeutic potential for the combination in patients with cardiovascular disease and diabetes. Disclosure N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. P.D. Mark: None. L.H. Hansen: None. U.Ø. Andersen: None. B. Hartmann: None. R.D. Carr: Employee; Self; Merck & Co., Inc. Speaker's Bureau; Spouse/Partner; Eli Lilly and Company, Merck & Co., Inc. F. Gustafsson: Advisory Panel; Self; Abbott, Corvia Medical, Inc. Consultant; Self; Bayer AG. Employee; Spouse/Partner; Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation. Speaker's Bureau; Self; Novartis AG, Novo Nordisk A/S. C.F. Deacon: Employee; Spouse/Partner; Merck Sharp & Dohme Corp. Stock/Shareholder; Spouse/Partner; Merck & Co., Inc. Other Relationship; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. J.P. Gøtze: None. P. Plomgaard: None. Funding Rigshopitalet

Dipeptidyl peptidase-4 (DPP-4), also known as the T-cell antigen CD26, is a multi-functional protein which, besides its catalytic activity, also functions as a binding protein and a ligand for a variety of extracellular molecules. It is an integral membrane protein expressed on cells throughout the body, but is also shed from the membrane and circulates as a soluble protein in the plasma. A large number of bioactive molecules can be cleaved by DPP-4 in vitro, but only a few of these have been demonstrated to be physiological substrates. One of these is the incretin hormone, glucagon-like peptide-1 (GLP-1), which plays an important role in the maintenance of normal glucose homeostasis, and DPP-4 has been shown to be the key enzyme regulating its biological activity. This pathway has been targeted pharmacologically through the development of DPP-4 inhibitors, and these are now a successful class of anti-hyperglycaemic agents used to treat type 2 diabetes (T2DM). DPP-4 may additionally influence metabolic control via its proteolytic effect on other regulatory peptides, but it has also been reported to affect insulin sensitivity, potentially mediated through its non-enzymatic interactions with other membrane proteins. Given that altered expression and activity of DPP-4 are associated with increasing body mass index and hyperglycaemia, DPP-4 has been proposed to play a role in linking obesity and the pathogenesis of T2DM by functioning as a local mediator of inflammation and insulin resistance in adipose and hepatic tissue. As well as these broader systemic effects, it has also been suggested that DPP-4 may be able to modulate β-cell function as part of a paracrine system involving GLP-1 produced locally within the pancreatic islets. However, while it is evident that DPP-4 has the potential to influence glycaemic control, its overall significance for the normal physiological regulation of glucose homeostasis in humans and its role in the pathogenesis of metabolic disease remain to be established.

Context Combined inhibition of neprilysin and dipeptidyl peptidase 4 (DPP-4) has been shown to augment plasma concentrations of glucagon-like peptide-1(GLP-1) in animal models, but whether this occurs in humans is unknown. Objective To investigate the effects of inhibition of neprilysin by sacubitril/valsartan alone or in combination with a DPP-4 inhibitor (sitagliptin) on plasma concentrations of GLP-1 in healthy men. Design Two open-labeled crossover studies were performed in human subjects. Setting General community. Participants Nine and 10 healthy young men were included in study 1 and study 2, respectively. Intervention Study participants received a standardized meal (34% carbohydrates, 45% fat, 21% protein; total caloric content, 2106 kJ) combined with a prior dose of either sacubitril/valsartan (194/206 mg) or control in study 1 and in study 2, with a prior dose of sitagliptin (2 ×100 mg, given ∼10 hours apart) either alone or with sacubitril/valsartan (194/206 mg). Main Outcome Measures Plasma concentrations of total and intact GLP-1. Results Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% [total area under the curve (tAUC)0–240min: 3929 ± 344 vs 2348 ± 181 minutes × pmol/L, P = 0.0023] and increased concentrations of intact GLP-1 plasma concentrations more than sitagliptin alone (tAUC0–240min: 1021 ± 114 vs 660 ± 80 minutes × pmol/L, P = 0.01). Plasma concentrations of glucose, insulin, and GIP were not significantly (P > 0.10) changed upon sacubitril/valsartan treatment. Conclusions Sacubitril/valsartan combined with a DPP-4 inhibitor led to markedly higher concentrations of intact GLP-1 than DPP-4 inhibition alone, supporting a role for both neprilysin and DPP-4 in the metabolism of GLP-1 in humans, a finding that may have therapeutic implications.

Degradation-resistant glucagon-like peptide-1 (GLP-1) mimetics and GLP-1 enhancers (inhibitors of dipeptidyl peptidase-4, the enzyme which degrades and inactivates GLP-1) have been used for treatment of type 2 diabetes mellitus since 2005–2006. Cutting-edge research is now focusing on uncovering the secretory mechanisms of the GLP-1-producing cells (L-cells) with the purpose of developing agonists that enhance endogenous hormone secretion. Since GLP-1 co-localizes with other anorectic peptides, cholecystokinin, oxyntomodulin/glicentin and peptide YY, L-cell targeting might cause release of several hormones at the same time, providing additive effects on appetite and glucose regulation. In this review, we explore the role of proglucagon-derived peptides and other L-cell co-localizing hormones, in appetite regulation and the mechanism regulating their secretion.

Post-bariatric hypoglycaemia (PBH) is a rare, but severe, metabolic disorder arising months to years after bariatric surgery. It is characterised by symptomatic postprandial hypoglycaemia, with inappropriately elevated insulin concentrations. The relative contribution of exaggerated incretin hormone signalling to dysregulated insulin secretion and symptomatic hypoglycaemia is a subject of ongoing inquiry. This study was designed to test the hypothesis that PBH and associated symptoms are primarily mediated by glucagon-like peptide-1 (GLP-1). We conducted a double-blinded crossover study wherein eight participants with confirmed PBH were assigned in random order to intravenous infusion of the GLP-1 receptor (GLP-1r) antagonist. Exendin (9-39) (Ex-9), or placebo during an OGTT on two separate days at the Stanford University Clinical and Translational Research Unit. Metabolic, symptomatic and pharmacokinetic variables were evaluated. Results were compared with a cohort of BMI- and glucose-matched non-surgical controls (NSCs). Infusion of Ex-9 decreased the time to peak glucose and rate of glucose decline during OGTT, and raised the postprandial nadir by over 70%, normalising it relative to NSCs and preventing hypoglycaemia in all PBH participants. Insulin AUC and secretion rate decreased by 57% and 71% respectively, and peak postprandial insulin was normalised relative to NSCs. Autonomic and neuroglycopenic symptoms were significantly reduced during Ex-9 infusion. GLP-1r blockade prevented hypoglycaemia in 100% of individuals, normalised beta cell function and reversed neuroglycopenic symptoms, supporting the conclusion that GLP-1 plays a primary role in mediating hyperinsulinaemic hypoglycaemia in PBH. Competitive antagonism at the GLP-1r merits consideration as a therapeutic strategy. ClinicalTrials.gov NCT02550145

Incretin-based therapies are widely used for type 2 diabetes and now also for obesity, but they are associated with elevated plasma levels of pancreatic enzymes and perhaps a modestly increased risk of acute pancreatitis. However, little is known about the effects of the incretin hormone glucagon-like peptide 1 (GLP-1) on the exocrine pancreas. Here, we identify GLP-1 receptors on pancreatic acini and analyze the impact of receptor activation in humans, rodents, isolated acini, and cell lines from the exocrine pancreas. GLP-1 did not directly stimulate amylase or lipase release. However, we saw that GLP-1 induces phosphorylation of the epidermal growth factor receptor and activation of Foxo1, resulting in cell growth with concomitant enzyme release. Our work uncovers GLP-1-induced signaling pathways in the exocrine pancreas and suggests that increases in amylase and lipase levels in subjects treated with GLP-1 receptor agonists reflect adaptive growth rather than early-stage pancreatitis.

Aim To determine whether the addition of sitagliptin to pre-existing therapy with liraglutide changes glycaemic excursions after a mixed meal. Methods A total of 16 patients with type 2 diabetes treated with metformin and liraglutide (1.2 mg/d for ≥2 weeks) were randomized (sealed envelopes), within a cross-over design, to be studied on two occasions, after an overnight fast, with (1) sitagliptin (100 mg orally) and (2) placebo (patients and care givers blinded) administered 60 minutes before a mixed meal, or vice versa. Glucose excursions (incremental area under the curve [AUC]; primary endpoint) and insulin, C-peptide, glucagon and incretin concentrations were measured. The study setting was a metabolic study unit at a specialized diabetes hospital. Results All 16 patients completed the study and were analysed. Glucose (AUCglucose 319 ± 30 [placebo] vs 315 ± 18 mmol.L-1.min-1 [sitagliptin], Δ 7 [95% confidence interval −50 to 63] mmol.L-1.min-1), insulin, C-peptide and glucagon concentrations were not affected significantly by sitagliptin treatment ( P = .60-1.00). Intact glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) concentrations were augmented by sitagliptin, by 78.4% and 90.2%, respectively (both P < .0001). The influence of sitagliptin treatment on incretin plasma concentrations was similar to previously published results obtained in patients with type 2 diabetes on metformin treatment only. Conclusions Sitagliptin, in patients already treated with a GLP-1 receptor agonist (liraglutide), increased intact GLP-1 and GIP concentrations, but with marginal, non-significant effects on glycaemic control. GLP-1 receptors have probably been maximally stimulated by liraglutide. Our findings do not support combination treatment with GLP-1 receptor agonists and DPP-4 inhibitors, but longer-term trials are needed to support clinical recommendations.

Context: The rate of gastric emptying is an important determinant of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) secretion and may influence the magnitude of glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors. Objective: To evaluate the effects of the DPP-4 inhibitor, vildagliptin (VILD), during intraduodenal (ID) glucose infusion at 2 different rates within the physiological range of gastric emptying, in type 2 diabetes. Participants and Design: A total of 16 diet-controlled type 2 diabetic patients were studied on 4 separate days in double-blind, randomized, fashion. On each day, either 5-mg VILD or placebo (PLBO) was given 60 minutes before a 120-minute ID glucose infusion at 2 or 4 kcal/min (ID2 or ID4). Plasma glucose and hormones were measured frequently. Results: Plasma glucose, insulin, C-peptide, glucagon, total GIP, and total and intact GLP-1 concentrations were higher during ID4 than ID2 (P < .01 for each). Compared with PLBO, VILD was associated with higher intact GLP-1, insulin, and C-peptide and lower glucose and total GIP and GLP-1 (P < .01 for each), without affecting glucagon. There were significant interactions between the rate of ID glucose and VILD treatment on plasma glucose, intact and total GLP-1, and GIP (P < .05 for each) but not insulin, C-peptide, or glucagon. The reduction in glucose and the increment in intact GLP-1 after VILD vs PLBO were 3.3- and 3.8-fold greater, respectively, during ID4 compared with ID2. Conclusions/Interpretation: These observations warrant further study to clarify whether type 2 diabetic patients with relatively more rapid gastric emptying have greater glucose lowering during treatment with DPP-4 inhibitors.

Aim To compare directly the clinical effects of vildagliptin and sitagliptin in patients with type 2 diabetes, with a special emphasis on incretin hormones and L-cell feedback inhibition induced by dipeptidyl peptidase (DPP-4) inhibition. Methods A total of 24 patients (12 on a diet/exercise regimen, 12 on metformin) were treated, in randomized order, for 7-9 days, with either vildagliptin (50 mg twice daily = 100 mg/d), sitagliptin (100 mg once daily in those on diet, 50 mg twice daily in those on metformin treatment = 100 mg/d) or placebo (twice daily). A mixed-meal test was performed. Results Intact glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide concentrations were doubled by both DPP-4 inhibitors. Meal-related total GLP-1 responses were reduced by vildagliptin and sitagliptin treatment alike in the majority of patients (vildagliptin: p = 0.0005; sitagliptin: p = 0.019), but with substantial inter-individual variation. L-cell feedback appeared to be more pronounced in those whose intact GLP-1 relative to total GLP-1 increased more, and who had greater reductions in fasting plasma glucose after DPP-4 inhibition. K-cell feedback inhibition overall was not significant. There were no differences in any of the clinical variables (glycaemia, insulin and glucagon secretory responses) between vildagliptin and sitagliptin treatment. Conclusions Vildagliptin and sitagliptin affected incretin hormones, glucose concentrations, insulin and glucagon secretion in a similar manner. Inter-individual variations in L-cell feedback inhibition may indicate heterogeneity in the clinical response to DPP-4 inhibition.

What is the central question of this study? We investigated whether intestinal vagal afferents are necessary for the insulinotropic effect of glucagon-like peptide-1 (GLP-1) infused into a mesenteric artery or a peripheral vein before and after acute truncal vagotomy. What is the main finding and its importance? We found no effect of truncal vagotomy on the insulinotropic effect of exogenous GLP-1 and speculate that high circulating concentrations of GLP-1 after i.v. and i.a. infusion might have overshadowed any neural signalling component. We propose that further investigations into the possible vagal afferent signalling of GLP-1 would best be pursued using enteral stimuli to provide high subepithelial levels of endogenous GLP-1. Glucagon-like peptide 1 (GLP-1) is secreted from the gut in response to luminal stimuli and stimulates insulin secretion in a glucose-dependent manner. As a result of rapid enzymatic degradation of GLP-1 by dipeptidyl peptidase-4, a signalling pathway involving activation of intestinal vagal afferents has been proposed. We conducted two series of experiments in α-chloralose-anaesthetized pigs. In protocol I, pigs (n = 14) were allocated for either i.v. or i.a. (mesenteric) GLP-1 infusions (1 and 2 pmol kg(-1) min(-1) , 30 min) while maintaining permissive glucose concentrations at 6 mmol l(-1) by i.v. glucose infusion. The GLP-1 infusions were repeated after acute truncal vagotomy. In protocol II, pigs (n = 27) were allocated into six groups. Glucagon-like peptide 1 was infused i.v. or i.a. (mesenteric) for 1 h at 3 or 30 pmol kg(-1) min(-1) . During the steady state (21 min into the GLP-1 infusion), glucose (0.2 g kg(-1) , i.v.) was administered over 9 min to stimulate β-cell secretion. Thirty minutes after the glucose infusion, GLP-1 infusions were discontinued. Following a washout period, the vagal trunks were severed in four of six groups (vagal trunks were left intact in two of six groups), whereupon all infusions were repeated. We found no effect of vagotomy on insulin or glucagon secretion during administration of exogenous GLP-1 in any experiment. We speculate that the effect of exogenous GLP-1 overshadowed any effect occurring via the vagus. Within dosage groups, total GLP-1 concentrations were similar, but intact GLP-1 concentrations were much lower when infused via the mesenteric artery because of extensive degradation of GLP-1 in the splanchnic bed. This demonstrates the effectiveness with which intestinal capillary dipeptidyl peptidase-4 protects the systemic circulation from intact GLP-1, consistent with a local role for GLP-1 involving activation of vagal pathways.

Low-abundance regulatory peptides, including metabolically important gut hormones, have shown promising therapeutic potential. Here, we present a streamlined mass spectrometry-based platform for identifying and characterizing low-abundance regulatory peptides in humans. We demonstrate the clinical applicability of this platform by studying a hitherto neglected glucose- and appetite-regulating gut hormone, namely, oxyntomodulin. Our results show that the secretion of oxyntomodulin in patients with type 2 diabetes is significantly impaired, and that its level is increased by more than 10-fold after gastric bypass surgery. Furthermore, we report that oxyntomodulin is co-distributed and co-secreted with the insulin-stimulating and appetite-regulating gut hormone glucagon-like peptide-1 (GLP-1), is inactivated by the same protease (dipeptidyl peptidase-4) as GLP-1 and acts through its receptor. Thus, oxyntomodulin may participate with GLP-1 in the regulation of glucose metabolism and appetite in humans. In conclusion, this mass spectrometry-based platform is a powerful resource for identifying and characterizing metabolically active low-abundance peptides., Highlights • In the pursuit of identifying metabolic peptides in humans we developed a streamlined mass-spectrometry based platform • Our platform was used to investigate a gut derived glucose and appetite regulatory peptide, oxyntomodulin • Levels of oxyntomodulin are reduced in subjects with type 2 diabetes and increased after gastric bypass surgery The human plasma comprises a variety of peptides with importance for metabolic health. Identification of such peptides has been exploited for developing glucose-lowering therapies, such as incretin-based therapy. We therefore developed a mass-spectrometry based platform for identification of peptides in humans and by applying this platform we characterized a peptide hormone oxyntomodulin secreted from the intestine in response to glucose. Our data suggest that oxyntomodulin is down-regulated in subjects with type 2 diabetes and up-regulated after bariatric surgery. In summary, the collected data indicate that oxyntomodulin may co-orchestrate appetite and glucose regulatory effects together with incretin hormones.

GLUTag, NCI-H716, and STC-1 are cell lines that are widely used to study mechanisms underlying secretion of glucagon-like peptide-1 (GLP-1), but the extent to which they resemble native L-cells is unknown. We used validated immunoassays for 14 different hormones to analyze peptide content (lysis samples;n= 9 from different passage numbers) or peptide secretion in response to buffer (baseline), and after stimulation with 50 mM KCl or 10 mM glucose + 10 µM forskolin/3-isobutyl-1-methylxanthine (n= 6 also different passage numbers). All cell lines produced and processed proglucagon into GLP-1, GLP-2, glicentin, and oxyntomodulin in a pattern (prohormone convertase (PC)1/3 dependent) similar to that described for human gut. All three cell lines showed basal secretion of GLP-1 and GLP-2, which increased after stimulation. In contrast to freshly isolated murine L-cells, all cell lines also expressed PC2 and secreted large amounts of pancreatic glucagon. Neurotensin and somatostatin storage was low and secretion was not consistently increased by stimulation. STC-1 cells released more glucose-dependent insulinotropic polypeptide than GLP-1 at baseline (P< 0.01) and KCl elevated its secretion (P< 0.05). Peptide YY, which normally co-localizes with GLP-1 in distal L-cells, was not detected in any of the cell lines. GLUTag and STC-1 cells also expressed vasoactive intestinal peptide, but none expressed pancreatic polypeptide or insulin. GLUTag contained and secreted large amounts of CCK, while NCI-H716 did not store this peptide and STC-1 contained low amounts. Our results show that hormone production in cell line models of the L-cell has limited similarity to the natural L-cells.

Type 2 diabetes (T2DM) is a progressive disease, and pharmacotherapy with a single agent does not generally provide durable glycaemic control over the long term. Sulphonylurea (SU) drugs have a history stretching back over 60 years, and have traditionally been the mainstay choice as second-line agents to be added to metformin once glycaemic control with metformin monotherapy deteriorates; however, they are associated with undesirable side effects, including increased hypoglycaemia risk and weight gain. Dipeptidyl peptidase (DPP)-4 inhibitors are, by comparison, more recent, with the first compound being launched in 2006, but the class now globally encompasses at least 11 different compounds. DPP-4 inhibitors improve glycaemic control with similar efficacy to SUs, but do not usually provoke hypoglycaemia or weight gain, are relatively free from adverse side effects, and have recently been shown not to increase cardiovascular risk in large prospective safety trials. Because of these factors, DPP-4 inhibitors have become an established therapy for T2DM and are increasingly being positioned earlier in treatment algorithms. The present article reviews these two classes of oral antidiabetic drugs (DPP-4 inhibitors and SUs), highlighting differences and similarities between members of the same class, as well as discussing the potential advantages and disadvantages of the two drug classes. While both classes have their merits, the choice of which to use depends on the characteristics of each individual patient; however, for the majority of patients, DPP-4 inhibitors are now the preferred choice.

Enteropancreatic hormone secretion is thought to include a cephalic phase, but the evidence in humans is ambiguous. We studied vagally induced gut hormone responses with and without muscarinic blockade in 10 glucose-clamped healthy men (age: 24.5 ± 0.6 yr, means ± SE; body mass index: 24.0 ± 0.5 kg/m2; HbA1c: 5.1 ± 0.1%/31.4 ± 0.5 mmol/mol). Cephalic activation was elicited by modified sham feeding (MSF, aka “chew and spit”) with or without atropine (1 mg bolus 45 min before MSF + 80 ng·kg−1·min−1 for 2 h). To mimic incipient prandial glucose excursions, glucose levels were clamped at 6 mmol/l on all days. The meal stimulus for the MSF consisted of an appetizing breakfast. Participants (9/10) also had a 6 mmol/l glucose clamp without MSF. Pancreatic polypeptide (PP) levels rose from 6.3 ± 1.1 to 19.9 ± 6.8 pmol/l (means ± SE) in response to MSF and atropine lowered basal PP levels and abolished the MSF response. Neither insulin, C-peptide, glucose-dependent insulinotropic polypeptide (GIP), nor glucagon-like peptide-1 (GLP-1) levels changed in response to MSF or atropine. Glucagon and ghrelin levels were markedly attenuated by atropine prior to and during the clamp: at t = 105 min on the atropine (ATR) + clamp (CLA) + MSF compared with the saline (SAL) + CLA and SAL + CLA + MSF days; baseline-subtracted glucagon levels were −10.7 ± 1.1 vs. −4.0 ± 1.1 and −4.7 ± 1.9 pmol/l (means ± SE), P < 0.0001, respectively; corresponding baseline-subtracted ghrelin levels were 303 ± 36 vs. 39 ± 38 and 3.7 ± 21 pg/ml (means ± SE), P < 0.0001. Glucagon and ghrelin levels were unaffected by MSF. Despite adequate PP responses, a cephalic phase response was absent for insulin, glucagon, GLP-1, GIP, and ghrelin.