Carolyn Fiona Deacon

Aims: 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. Methods: 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. Results: 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. Conclusions: 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. ClinicalTrials.gov (NCT03893526).

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 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.

Sodium‐glucose co‐transporter‐2 inhibitors (SGLT2is) lower blood glucose and are used for treatment of type 2 diabetes. However, SGLT2is 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 SGLT2is 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 the direct effects of SGLT2 inhibition on glucagon secretion are conflicting. By contrast, alpha‐cell sodium‐glucose co‐transporter‐1 (SGLT1) expression has been found more consistently and appears to be more prominent, pointing to an underappreciated role for this transporter. Nevertheless, the selectivity of most SGLT2is 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 shown in experiments with glucose clamping where SGLT2i‐associated increases in plasma glucagon 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 because the increase in EGP occurs before any rise in plasma glucagon.

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.

Aim: To assess the effects of Roux‐en‐Y gastric bypass surgery (RYGB)‐related changes in glucagon‐like peptide‐1 (GLP‐1) on cerebral resting‐state functioning in obese women. Materials and Methods: In nine obese females aged 40‐54 years in the fasted state, we studied the effects of RYGB and GLP‐1 on five a priori selected networks implicated in food‐ and reward‐related processes as well as environment monitoring (default mode, right frontoparietal, basal ganglia, insula/anterior cingulate and anterior cingulate/orbitofrontal networks). Results: Before surgery, GLP‐1 receptor blockade (using exendin9‐39) was associated with increased right caudate nucleus (basal ganglia network) and decreased right middle frontal (right frontoparietal network) connectivity compared with placebo. RYGB resulted in decreased right orbitofrontal (insula/anterior cingulate network) connectivity. In the default mode network, after surgery, GLP‐1 receptor blockade had a larger effect on connectivity in this region than GLP‐1 receptor blockade before RYGB (all P _FWE < .05). Results remained similar after correction for changes in body weight. Default mode and right frontoparietal network connectivity changes were related to changes in body mass index and food scores after RYGB. Conclusions: These findings suggest GLP‐1 involvement in resting‐state networks related to food and reward processes and monitoring of the internal and external environment, pointing to a potential role for GLP‐1–induced changes in resting‐state connectivity in RYGB‐mediated weight loss and appetite control.

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.

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/m ² ) 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 < .01) and lipase (+19 U/L [7‐30], P < .01) increased during liraglutide treatment. Pancreatic volume did not change from baseline to steady state of treatment (+0.2 cm ³ [−8‐8], P = .96) and no change in pancreatic cellular infiltration was found ( P = .22). During titration of liraglutide, FLT uptake in pancreatic tissue increased numerically (+0.08 [0.00‐0.17], P = .0507). Conclusions: Six weeks of treatment with liraglutide did not affect pancreatic volume, oedema or cellularity in obese men without diabetes.