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Aim: To investigate the effect of dipeptidyl peptidase‐4 inhibitors (DPP4‐Is) and glucagon‐like peptide‐1 receptor agonists (GLP1‐RAs) on diabetic foot ulcer (DFU) and DFU‐related outcomes (lower limb amputation [LLA], DFU‐related hospitalization and mortality). Methods: We performed a cohort study with data from the Clinical Practice Research Datalink Aurum database with linkage to hospital data. We included people with type 2 diabetes starting treatment with metformin. Then we propensity score matched new users of DPP4‐Is and sulphonylureas (N = 98 770), and new users of GLP1‐RAs and insulin (N = 25 422). Cox proportional hazards models estimated the hazard ratios (HRs) for the outcomes. Results: We observed a lower risk of DFU with both DPP4‐I use versus sulphonylurea use (HR 0.88, 95% confidence interval [CI]: 0.79‐0.97) and GLP1‐RA use versus insulin use (HR 0.44, 95% CI: 0.32‐0.60) for short‐term exposure (≤ 400 days) and HR 0.74 (95% CI: 0.60‐0.92) for long‐term exposure (>400 days). Furthermore, the risks of hospitalization and mortality were lower with both DPP4‐I use and GLP1‐RA use. The risk of LLA was lower with GLP1‐RA use. The results remained consistent across several sensitivity analyses. Conclusions: Incretin‐based therapy was associated with a lower risk of DFU and DFU‐related outcomes. This suggests benefits for the use of this treatment in people at risk of DFU. [ABSTRACT FROM AUTHOR]

Introdroduction: Obesity and its associated metabolic conditions have become a significant global health problem in recent years, with many people living with obesity fulfilling criteria for pharmacological treatment. The development of the glucagon‐like peptide‐1 receptor agonists for chronic weight management has triggered new interest in the incretins and other hormones as targets for obesity, and investigations into dual and triple co‐agonists. Methods: The objective of this narrative review was to summarize the available data on approved and emerging incretin‐based agents for the treatment of obesity. Results: In clinical trials of currently available agents in people with overweight or obesity, weight loss of between 6% and 21% of baseline body weight has been observed, with between 23% and 94% of participants achieving 10% or higher weight loss, depending on the study and the agent used. Favourable outcomes have also been seen with regard to cardiovascular risk and outcomes, diabetes prevention, metabolic dysfunction‐associated steatotic liver disease/steatohepatitis and prevention of weight regain after metabolic surgery. Limitations associated with these agents include high costs, the potential for weight regain once treatment is stopped, the potential loss of lean body mass and gastrointestinal adverse events; potential issues with respect to gallbladder and biliary diseases require further investigation. Conclusions: Many dual and triple co‐agonists are still in development, and more data are needed to assess the efficacy, safety and tolerability of these emerging therapies versus the established incretin‐based therapies; however, data are promising, and further results are eagerly awaited. [ABSTRACT FROM AUTHOR]

The objective is to review the newer pharmacological interventions for obesity, specifically single, dual and triple incretin receptor agonists that are either available or in the pipeline for treatment of obesity. The three incretin receptor targets are glucagon like peptide‐1 (GLP‐1), glucose‐dependent insulinotropic peptide (GIP) and glucagon. There are several approved single or dual incretin agonists which can be administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and other experimental dual or triple incretin agonists. Analogues of amylin, peptide YY and oxyntomodulin, as well as the combination of a GLP1R agonist and GIPR antagonist also are in development. Oral semaglutide (administered daily) is approved for type 2 diabetes mellitus and is on track for regulatory review for obesity. The review includes specifically perspectives on the effects of these mechanisms and pharmacological agents on gastric emptying, which contribute to satiation and weight loss, in addition to the established evidence on effects on central mechanisms controlling appetite. In the future, it is anticipated that small molecule GLP‐1 receptor agonists (e.g., oral danuglipron) will be developed for treating obesity. These pharmacological agents are having significant impact on glycaemic control and obesity and on their co‐morbidities. [ABSTRACT FROM AUTHOR]

The article examines whether the Incretin hype should be the same for older adults. Topics discussed include lifestyle interventions that have demonstrated significant improvements in physical function, the classes of incretins that are increasingly valid and widely covered in persons with diabetes, and actions that can help in the identification of the right candidate for these medications.

Summary: Background: Obesity has reached epidemic proportions, with >40% of the US population affected. Although traditionally managed by lifestyle modification, and less frequently by bariatric therapies, there are significant pharmacological advancements. Aims: To conduct a narrative review of the neurohormonal and physiological understanding of weight gain and obesity, and the development, clinical testing, indications, expected clinical outcomes, and associated risks of current FDA‐approved and upcoming anti‐obesity medications (AOMs). Methods: We conducted a comprehensive review in PubMed for articles on pathophysiology and complications of obesity, including terms 'neurohormonal', 'obesity', 'incretin', and 'weight loss'. Next, we searched for clinical trial data of all FDA‐approved AOMs, including both the generic and trade names of orlistat, phentermine/topiramate, bupropion/naltrexone, liraglutide, and semaglutide. Additional searches were conducted for tirzepatide and retatrutide ‐ medications expecting regulatory approval. Searches included combinations of terms related to mechanism of action, indications, side effects, risks, and future directions. Results: We reviewed the pathophysiology of obesity, including specific role of incretins and glucagon. Clinical data supporting the use of various FDA‐approved medications for weight loss are presented, including placebo‐controlled or, when available, head‐to‐head trials. Beneficial metabolic effects, including impact on liver disease, adverse effects and risks of medications are discussed, including altered gastrointestinal motility and risk for periprocedural aspiration. Conclusion: AOMs have established efficacy and effectiveness for weight loss even beyond 52 weeks. Further pharmacological options, such as dual and triple incretins, are probable forthcoming additions to clinical practice for combating obesity and its metabolic consequences such as metabolic dysfunction‐associated steatotic liver disease. [ABSTRACT FROM AUTHOR]

Aims: Alongside its metabolic implications, obesity and associated diabetes impair female reproductive function, causing infertility and polycystic ovarian syndrome (PCOS). Recently, gut hormones and their receptors have been identified in various reproductive organs indicating their potential regulatory effects on reproductive function. This review aims to give an overview of their potential effects. Methods: This review focuses on literature that outlines modifications during obesity, diabetes and related infertility with an emphasis on gut hormones and their therapeutic potential. Results: Evidence suggests that bariatric surgery has positive effects on fertility and PCOS where major alterations in metabolism occurs through restoration of gut hormone levels. This is thought to be due to the indirect effect weight loss and regulation of blood glucose has on the hypothalamic–pituitary–ovarian and hypothalamic–pituitary–adrenal axis influencing reproduction. Conclusions: Further research is required to elucidate the cellular mechanisms involved in the direct effects of gut hormone receptor activation on reproductive tissues. Current observations suggest a therapeutic role for gut hormones in infertility/PCOS associated with metabolic pathophysiology. [ABSTRACT FROM AUTHOR]

Objective: Prandial hyperinsulinemia after Roux‐en‐Y gastric bypass surgery (GB), and to lesser degree after sleeve gastrectomy (SG), has been attributed to rapid glucose flux from the gut and increased insulinotropic gut hormones. However, β‐cell sensitivity to exogenous incretin is reduced after GB. This study examines the effect of GB versus SG on prandial glycemia and β‐cell response to increasing concentrations of endogenous incretins. Methods: Glucose kinetics, insulin secretion rate (ISR), and incretin responses to 50‐g oral glucose ingestion were compared between ten nondiabetic participants with GB versus nine matched individuals with SG and seven nonoperated normal glucose tolerant control individuals (CN) with and without administration of 200 mg of sitagliptin. Results: Fasting glucose and hormonal levels were similar among three groups. Increasing plasma concentrations of endogenous incretins by two‐ to three‐fold diminished prandial glycemia and increased β‐cell secretion in all three groups (p < 0.05), but insulin secretion per insulin sensitivity (i.e., disposition index) was increased only in GB (p < 0.05 for interaction). However, plot of the slope of ISR (from premeal to peak values) versus plasma glucagon‐like peptide‐1 concentration was smaller after GB compared with SG and CN. Conclusions: After GB, increasing incretin activity augments prandial β‐cell response whereas the β‐cell sensitivity to increasing plasma concentrations of endogenous incretin is diminished. [ABSTRACT FROM AUTHOR]

Aims: The contribution of endogenous glucagon‐like peptide (GLP)‐1 to β‐cell function after Roux‐en‐Y gastric bypass surgery (RYGB) is well established in normoglycaemic individuals, but not in those with postoperative hyperglycaemia. We, therefore, studied the effect of GLP‐1 on β‐cell function in individuals with varying degrees of type 2 diabetes mellitus (T2D) control after RYGB. Materials and Methods: Glucose, insulin secretion rates, β‐cell glucose sensitivity and glucagon were measured during an oral glucose tolerance test before (saline only) and at 3, 12 and 24 months after RYGB with and without infusion of the GLP‐1 receptor blocker exendin9−39 (EX9). The cohort was retrospectively classified based on T2D remission (REM) status at the latest study time point: REM (n = 5), persistent T2D (n = 8), or impaired glucose tolerance (n = 16). Results: EX9 blunted the increase in β‐cell glucose sensitivity at 3 months (−44.1%, p <.001) and 12 months (−43.3%, p <.001), but not at 24 months (−12.4%, p =.243). EX9 enhanced postprandial glucagon concentrations by 62.0% at 3 months (p =.008), 46.5% at 12 months (p =.055), and 30.4% at 24 months (p =.017). EX9 counterintuitively decreased glucose concentrations at 3 months in the entire cohort (p <.001) but had no effect on glycaemia at 12 and 24 months in persistent T2D and impaired glucose tolerance; it minimally worsened glycaemia in REM at 12 months. Conclusions: GLP‐1 blockade reversed the improvement in β‐cell function observed after RYGB, but this effect varied temporally and by REM status. GLP‐1 blockade transiently and minimally worsened glycaemia only in REM, and lowered postprandial glucose values at 3 months, regardless of REM status. [ABSTRACT FROM AUTHOR]

Summary: Background: Insulin dysregulation (ID) is diagnosed in horses and ponies using oral glucose (OGTT) and oral sugar (OSTT) tolerance tests. The enteroinsular axis plays a major role in postprandial glucose disposal and insulin response in horses, ponies and foals. The insulin and incretin response to oral carbohydrate challenges has not been characterised in donkeys. Objectives: (a) To characterise OGTT and OSTT, and (b) to assess the plasma incretin response to OGTT and OSTT in healthy donkeys. Study design: In vivo experiments. Methods: Six healthy adult female Andalusian donkeys were challenged with OGTT (1 g/kg glucose, 20% solution by nasogastric tube) and OSTT (0.45 mL/kg corn syrup orally by syringe) with a 1‐week washout. Blood samples were collected for glucose (spectrophotometry), insulin (radioimmunoassay), glucose‐dependent insulinotropic polypeptide (GIP, ELISA) and active glucagon‐like peptide‐1 (aGLP‐1, ELISA) determination over 6 hours. Curves were analysed and proxies calculated. Results: Glucose and insulin concentrations peaked at 180 minutes in OGTT, but at 300 and 150 minutes in OSTT, respectively. Plasma GIP concentrations increased in the OGTT and OSTT (peaked at 180 and 360 minutes, respectively), but aGLP‐1 increased only in OGTT (240 minutes). Main limitations: Single breed, narrow age and sample, diet, season and not having donkeys with evidence of ID to provide clinical validation. Conclusions: Donkeys have a functional enteroinsular axis that is activated by enteral carbohydrates. Donkeys have evident endocrine differences with horses, supporting the validation of the OSTT and OGTT to assess insulin sensitivity in this species to avoid extrapolation from horses. [ABSTRACT FROM AUTHOR]

Aims: β‐cell stress and dysfunction may contribute to islet autoimmunity and progression to clinical type 1 diabetes. We present a protocol of three randomised controlled trials assessing the effects of glucagon‐like peptide 1 (GLP − 1) analogue liraglutide in three early stages of type 1 diabetes. Methods: We will test 10‐ to 30‐year‐old people with multiple islet autoantibodies for their glucose metabolism and randomise participants with stage 1 (multiple islet autoantibodies and normoglycaemia), stage 2 (multiple islet autoantibodies and dysglycaemia) and early stage 3 (clinical diagnosis) type 1 diabetes, 10−14 persons in each, to a 6‐month intervention with liraglutide or placebo with 6‐month follow‐up in the stage 2 and stage 3 trials and 18‐month follow‐up in the stage 1 trial. Primary efficacy outcome in the stage 1 and stage 2 trials is a first‐phase insulin response in an intravenous glucose tolerance test and C‐peptide area under the curve in a 2‐h mixed‐meal tolerance test in the stage 3 trial. In addition, safety and tolerability of liraglutide treatment will be assessed. Conclusions: Most prevention trials of type 1 diabetes have targeted the immune system. Treatment with GLP‐1 analogue liraglutide supports the pancreatic β‐cells, which should likewise attenuate islet autoimmunity. Our innovative study design allows simultaneous investigation of an intervention in three groups of people who represent various early stages of type 1 diabetes and maximises the eligibility to participate. Trial registration: NCT02611232 (stage 1 trial), NCT02898506 (stage 2 trial), NCT02908087 (stage 3 trial). [ABSTRACT FROM AUTHOR]

Aim: To conduct an adjusted indirect treatment comparison (aITC) of the efficacy of tirzepatide 5/10/15 mg versus semaglutide 2 mg in patients with type 2 diabetes. Materials and Methods: The primary analysis was a Bucher aITC of the change from baseline at week 40 in HbA1c (%) and body weight (kg). Aggregate data from the SURPASS‐2 study that met the HbA1c inclusion criterion of the SUSTAIN FORTE study and from SUSTAIN FORTE metformin‐only treated patients were used for primary analysis. Results: The SURPASS‐2 refined population comprised 238/245/240 and 240 participants for tirzepatide 5/10/15 mg and semaglutide 1 mg, respectively. The SUSTAIN FORTE metformin‐only population comprised 222 and 227 participants for semaglutide 1 and 2 mg, respectively. In this aITC, tirzepatide 10 and 15 mg significantly reduced HbA1c versus semaglutide 2 mg with an estimated treatment difference (ETD) of −0.36% (95% confidence interval [CI] −0.63, −0.09) and −0.4% (95% CI −0.67, −0.13), respectively. Tirzepatide 10 and 15 mg significantly reduced body weight versus semaglutide 2 mg with an ETD of −3.15 kg (95% CI −4.84, −1.46) and −5.15 kg (95% CI −6.85, −3.45), respectively. There were no significant differences between tirzepatide 5 mg and semaglutide 2 mg on change from baseline in HbA1c and body weight. Conclusions: In this aITC, HbA1c and weight reductions were significantly greater for tirzepatide 10 and 15 mg versus semaglutide 2 mg and were similar for tirzepatide 5 mg versus semaglutide 2 mg. These findings provide comparative effectiveness insights in the absence of a head‐to‐head clinical trial. [ABSTRACT FROM AUTHOR]

Triglyceride content of the SAT biopsy and plasma lipids SAT triglyceride content was unchanged during infusion of GLP-1 + GIP(3-30)NH SB 2 sb compared with GLP-1 + placebo (Figure 1L). Keywords: GIP; GIP receptor antagonist; GLP-1; incretin hormones; incretins; obesity; type 2 diabetes EN GIP GIP receptor antagonist GLP-1 incretin hormones incretins obesity type 2 diabetes 1882 1887 6 08/04/22 20220901 NES 220901 BACKGROUND In type 2 diabetes (as well as other forms of diabetes), the insulinotropic effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) is markedly reduced or even lost, in contrast to that of exogenous glucagon-like peptide-1 (GLP-1), which retains its insulinotropic effect to a greater degree.1,2 Optimized glycaemic control improves the insulinotropic effect of exogenous GIP in patients with type 2 diabetes, suggesting that diabetic GIP resistance is a reversible phenomenon.3,4 Furthermore, we recently showed that endogenous GIP has insulinotropic properties in type 2 diabetes.5 Several GLP-1 receptor (GLP-1R) agonists (GLP-1RAs) are now approved for the treatment of type 2 diabetes and obesity.6 Previously, GIP was described as an obesity hormone.7,8 In recent years, paradoxically, both GIP receptor (GIPR) agonism and GIPR antagonism have shown anti-obesity effects when combined with GLP-1RAs in preclinical models.9-13 Potentially, the beneficial effects of GIPR agonists arise from functional GIPR antagonism elicited by GIPR internalization.14,15 Several new treatment modalities for type 2 diabetes and obesity combining GLP-1RA with GIPR agonism or GIPR antagonism are emerging.16 However, no human data are currently available describing the combined effects of GLP-1RAs and GIPR antagonism. Peptide infusions Plasma concentrations of total GLP-1 reached a steady state of 55.1 ± 6.0 pmol/L during GLP-1 + GIP(3-30)NH SB 2 sb and 57.0 ± 6.5 pmol/L during GLP-1 + placebo (Figure 1A). [Extracted from the article]

Introduction: Decreased fasting and oral glucose-stimulated incretin hormone concentrations following moderate-intensity continuous endurance training interventions have been reported in glucose-tolerant people, however results are conflicting. The effect of more time-efficient, very low-volume, high-intensity interval training (HIT) on circulating incretin hormone levels has never been studied. Materials and methods: Ten sedentary and overweight-to-obese participants (4 women and 6 men; age 43 ± 6 years (mean ± SD); BMI 30.2 ± 3.2 kg∙m−2; HbA1c 35 ± 5.1 mmol∙mol−1 (5.3 ± 0.3%); VO2max 30 ± 5 ml∙min−1∙kg−1) from the Copenhagen cohort of the METAPREDICT trial underwent 6 weeks of supervised low-volume HIT (3 sessions per week: 7 × 1 min at ∼100% VO2max separated by 1 min of active recovery). We measured glucose, insulin, C-peptide, glucagon, GLP-1 and GIP concentrations during a frequently sampled 75 g oral glucose tolerance test as well as VO2max and body composition before and after the intervention. Results: Training compliance was 100%. Relative VO2max improved after the intervention (median 2.69 ml∙min−1∙kg−1, IQR [0.43; 3.14], p = 0.037) while there were no significant effects on body weight and composition. No significant effects on oral glucose-stimulated glucose and hormone responses or estimates of insulin sensitivity and β-cell function were observed. Conclusion: Low-volume HIT improved aerobic fitness, but neither affected glucose tolerance nor oral glucose-stimulated incretin hormone responses in sedentary and overweight-to-obese people. Highlights Ten sedentary, overweight-to-obese, glucose-tolerant participants underwent 6 weeks of supervised, very low-volume HIT. Aerobic fitness improved. Fasting and oral glucose-stimulated incretin hormone concentrations were not affected. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus and the associated desensitisation of insulin signalling has been identified as a risk factor for progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and others. Glucagon‐like peptide 1 (GLP‐1) is a hormone that has growth factor‐like and neuroprotective properties. Several clinical trials have been conducted, testing GLP‐1 receptor agonists in patients with Alzheimer's disease, Parkinson's disease or diabetes‐induced memory impairments. The trials showed clear improvements in Alzheimer's disease, Parkinson's disease and diabetic patients. Glucose‐dependent insulinotropic polypeptide/gastric inhibitory peptide (GIP) is the 'sister' incretin hormone of GLP‐1. GIP analogues have shown neuroprotective effects in animal models of disease and can improve on the effects of GLP‐1. Novel dual GLP‐1/GIP receptor agonists have been developed that can enter the brain at an enhanced rate. The improved neuroprotective effects of these drugs suggest that they are superior to single GLP‐1 receptor agonists and could provide disease‐modifying care for Alzheimer's disease and Parkinson's disease patients. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc [ABSTRACT FROM AUTHOR]

Summary: Bardet–Biedl syndrome (BBS) is a rare genetic condition, characterized by ciliary protein dysfunction, leading to multi‐organ damage. People with BBS can develop early‐onset severe obesity and associated problems including the metabolic syndrome, type 2 diabetes and coronary heart disease. Weight management can be challenging with the lack of effective medical therapies so far. We report a patient with BBS who underwent successful weight reduction through the use of glucagon‐like peptide‐1 receptor agonists. [ABSTRACT FROM AUTHOR]

Because insulin sensitivity and insulin secretion are inversely related, the decreased insulin secretion may be required for maintenance of normal glucose homeostasis. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic-peptide (GIP) are secreted from the gut by nutrient stimulation and are responsible for the incretin effect that explains about two thirds of postprandial insulin secretion in people with normal glucose tolerance depending on the glucose dose [[1]]. Insulin hypersecretion after GB and SG is linked to the oral route of nutrient administration and may be responsible for late adaptive changes in the incretin effect and the beta-cell sensitivity to incretin hormones after surgery and that it differs from that of nonoperated people with normal glucose tolerance. [Extracted from the article]

Aims: To assess the efficacy, safety and tolerability of ipragliflozin 50 mg once daily added to sitagliptin 50 mg once daily monotherapy in Japanese patients with type 2 diabetes (T2D). Materials and Methods: The results of two clinical trials are reported. In both trials, patients had glycated haemoglobin (HbA1c) levels of 7.0% to 10.0% on sitagliptin 50 mg once daily 2 weeks prior to addition of ipragliflozin or placebo. In one trial (Trial 843), patients were randomized 1:1 to addition of blinded ipragliflozin 50 mg once daily (n = 73) or placebo (n = 70) for 24 weeks; the primary endpoint was efficacy (change in HbA1c at Week 24). In the other trial (Trial 849), open‐label ipragliflozin 50 mg once daily was added for 52 weeks (n = 77); the primary objective was to assess safety/tolerability. Results: In Trial 843, baseline characteristics were similar between groups (mean age 60.5 years, HbA1c 8.0%); after 24 weeks, adding ipragliflozin provided significantly greater reduction in HbA1c compared to placebo: least squares mean difference −0.77% (95% confidence interval −0.98, −0.57; P <0.001). In Trial 843, the incidences of adverse events (AEs) overall and prespecified AEs of clinical interest (symptomatic hypoglycaemia, urinary tract infection, genital infection, hypovolaemia, and polyuria/pollakiuria) were similar between groups. In Trial 849, specific AEs with incidence ≥5% were nasopharyngitis, pollakiuria, back pain, thirst, constipation, influenza and arthralgia; drug‐related AEs reported in ≥2 patients were pollakiuria, thirst and constipation. Conclusions: Ipragliflozin 50 mg once daily added on to sitagliptin 50 mg once daily monotherapy provided significant improvement in glycaemic control and was generally well tolerated in Japanese patients with T2D. ClinicalTrials.gov: NCT02577003, NCT02564211. [ABSTRACT FROM AUTHOR]

Objective: Acromegaly is accompanied by abnormalities in glucose and lipid metabolism which improve upon treatment. Few studies have investigated whether these improvements differ between treatment modalities. This study aimed to compare glucose homeostasis, lipid profiles and postprandial gut hormone response in patients with controlled acromegaly according to actual treatment. Design: Cross‐sectional study at a tertiary care centre. Patients: Twenty‐one patients with acromegaly under stable control (ie insulin growth factor 1 [IGF1] levels below sex‐ and age‐specific thresholds and a random growth hormone level <1.0 µg/L) after surgery (n = 5), during treatment with long‐acting somatostatin analogues (n = 10) or long‐acting somatostatin analogues + pegvisomant (n = 6) were included. Measurements: Glucose, insulin, total cholesterol and high‐density lipoprotein‐cholesterol were measured in fasting serum samples. Glucose, insulin, triglycerides, glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide 1 were measured during a mixed meal test. Insulin sensitivity was evaluated by a hyperinsulinaemic‐euglycaemic clamp. Results: There were no significant differences in glucose tolerance, insulin sensitivity or postprandial gut hormone responses between the three groups. Positive correlations between IGF1 levels and HbA1c, fasting glucose and insulin levels and postprandial area under the curve (AUC) of glucose and insulin and also an inverse association between IGF1 and glucose disposal rate were found in the whole cohort (all p <.05, lowest p =.001 for postprandial AUC glucose with rs = 0.660). Conclusion: In this cross‐sectional study in patients with controlled acromegaly, there were no differences in glucose homeostasis or postprandial substrate metabolism according to treatment modality. However, a lower IGF1 level seems associated with a better metabolic profile. [ABSTRACT FROM AUTHOR]

Aims: To investigate the efficacy, safety and tolerability of sitagliptin 50 mg once daily added to ipragliflozin 50 mg once daily monotherapy in Japanese patients with type 2 diabetes (T2D). Materials and Methods: Japanese patients with T2D and glycated haemoglobin (HbA1c) 7.0% to 10.0% while treated with ipragliflozin 50 mg once daily were randomized 1:1 to additional treatment with sitagliptin 50 mg once daily (N = 70) or matching placebo (N = 71) for 24 weeks. The primary efficacy endpoint was change in HbA1c at Week 24. Secondary efficacy endpoints were changes in 2‐hour post‐meal glucose (PMG), total PMG 0‐ to 2‐hour area under the curve (AUC0‐2h), and fasting plasma glucose (FPG). Results: Baseline characteristics were similar in the two groups (mean age 55.5 years, mean baseline HbA1c 8.0%). After 24 weeks, the addition of sitagliptin provided significantly greater reduction in HbA1c compared to placebo (least squares [LS] mean difference −0.83% [95% confidence interval −1.05, −0.62]; P <0.001). Significant reductions were also observed in all secondary endpoints: LS mean differences from placebo in changes in 2‐hour PMG, total PMG AUC0‐2h, and FPG were −42.5 mg/dL, −67.0 mg·h/dL and −11.2 mg/dL, respectively (all P <0.001). The incidence of adverse events (AEs) overall and incidence of predefined AEs of clinical interest (symptomatic hypoglycaemia, urinary tract infection, genital infection, hypovolaemia and polyuria/pollakiuria) were similar in the two groups. Conclusions: In Japanese patients with T2D, sitagliptin 50 mg once daily added to ipragliflozin 50 mg once daily monotherapy provided significant improvement in glycaemic control and was generally well tolerated. ClinicalTrials.gov: NCT02577016. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of adding the once‐weekly oral dipeptidyl peptidase‐4 inhibitor omarigliptin to treatment of Japanese patients with type 2 diabetes and inadequate glycaemic control on insulin monotherapy. Materials and Methods: In a 52‐week clinical trial, Japanese patients on insulin monotherapy were randomized to once‐weekly omarigliptin 25 mg (N = 123) or placebo (N = 61) for a 16‐week, double‐blind, placebo‐controlled period. After Week 16, patients continued or switched to omarigliptin for a 36‐week open‐label period. Results: From a mean baseline of approximately 8.8%, the Week 16 least squares mean changes in HbA1c were −0.61% (omarigliptin) and 0.29% (placebo); the between‐group difference was −0.90% (p <.001). At Week 52, the mean change from baseline in HbA1c was −0.57% in both the group on omarigliptin for 52 weeks and the group on omarigliptin for 36 weeks (switched from placebo at Week 16). During the first 16 weeks of treatment, the incidences of adverse events (AEs), serious AEs, drug‐related AEs and discontinuation from trial medication because of an AE were similar in both groups. A slight increase in incidence of symptomatic hypoglycaemia was observed in the omarigliptin group (n = 13 [10.6%]) compared with placebo (n = 4 [6.6%]). No severe hypoglycaemia was reported during the study. No new safety signals emerged with treatment beyond Week 16 through Week 52. Conclusion: The addition of once‐weekly omarigliptin to insulin therapy for up to 52 weeks was generally well tolerated and provided clinically meaningful improvement in glycaemic control throughout the trial period. ClinicalTrials.gov: NCT02906709 [ABSTRACT FROM AUTHOR]

Background: Studies evaluating endocrine and exocrine functions in fibrocalculous pancreatic diabetes (FCPD) are scarce. Methods: Insulin, C‐peptide, glucagon, incretin hormones (glucagon‐like peptide 1 [GLP‐1] and gastric inhibitory peptide [GIP]), and dipeptidyl peptidase IV (DPP‐IV) were estimated in patients with FCPD (n = 20), type 2 diabetes mellitus (T2DM) (n = 20), and controls (n = 20) in fasting and 60 minutes after 75 g glucose. Results: Fasting and post‐glucose C‐peptide and insulin in FCPD were lower than that of T2DM and controls. Plasma glucagon decreased after glucose load in controls (3.72, 2.29), but increased in T2DM (4.01, 5.73), and remained unchanged in FCPD (3.44, 3.44). Active GLP‐1 (pmol/L) after glucose load increased in FCPD (6.14 to 9.72, P = <.001), in T2DM (2.87 to 4.62, P <.001), and in controls (3.91 to 6.13, P <.001). Median active GLP‐1 in FCPD, both in fasting and post‐glucose state (6.14, 9.72), was twice that of T2DM (2.87, 4.62) and 1.5 times that of controls (3.91, 6.13) (P <.001 for all). Post‐glucose GIP (pmol/L) increased in all: FCPD (15.83 to 94.14), T2DM (21.85 to 88.29), and control (13.00 to 74.65) (P <.001 for all). GIP was not different between groups. DPP‐IV concentration (ng/mL) increased in controls (1578.54, 3012.00) and FCPD (1609.95, 1995.42), but not in T2DM (1204.50, 1939.50) (P =.131). DPP‐IV between the three groups was not different. Fecal elastase was low in FCPD compared with T2DM controls. Conclusions: In FCPD, basal C‐peptide and glucagon are low, and glucagon does not increase after glucose load. GLP‐1, but not GIP, in FCPD increases 1.5 to 2 times as compared with T2DM and controls (fasting and post glucose) without differences in DPP‐IV. [ABSTRACT FROM AUTHOR]

Although the brain was once considered an insulin‐independent organ, insulin signalling is now recognised as being central to neuronal health and to the function of synapses and brain circuits. Defective brain insulin signalling, as well as related signalling by insulin‐like growth factor 1 (IGF‐1), is associated with neurological disorders, including Alzheimer's disease, suggesting that cognitive impairment could be related to a state of brain insulin resistance. Here, I briefly review key epidemiological/clinical evidence of the association between diabetes, cognitive decline and AD, as well as findings of reduced components of insulin signalling in AD brains, which led to the initial suggestion that AD could be a type of brain diabetes. Particular attention is given to recent studies illuminating mechanisms leading to neuronal insulin resistance as a key driver of cognitive impairment in AD. Evidence of impaired IGF‐1 signalling in AD is also examined. Finally, we discuss potentials and possible limitations of recent and on‐going therapeutic approaches based on our increased understanding of the roles of brain signalling by insulin, IGF‐1 and glucagon‐like peptide 1 in AD. Brain signalling by insulin is known to be important for synapse, circuits and memory, and is deregulated in Alzheimer's disease (AD). The current article reviews evidence indicating how brain insulin signalling becomes deregulated in AD, and explores potential therapeutic implications of brain singling by insulin, insulin‐like growth factor‐1 and glucagon‐like peptide‐1 receptor agonists. [ABSTRACT FROM AUTHOR]

Aims: Unimolecular peptides targeting the receptors for glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) (GLP‐1/GIP co‐agonist) have been shown to outperform each single peptide in the treatment of obesity and cardiometabolic disease in preclinical and clinical trials. By combining physiological treatment endpoints with plasma proteomic profiling (PPP), we aimed to identify biomarkers to advance non‐invasive metabolic monitoring of compound treatment success and exploration of ulterior treatment effects on an individual basis. Materials and methods: We performed metabolic phenotyping along with PPP in body weight‐matched male and female diet‐induced obese (DIO) mice treated for 21 days with phosphate‐buffered saline, single GIP and GLP‐1 mono‐agonists, or a GLP‐1/GIP co‐agonist. Results: GLP‐1R/GIPR co‐agonism improved obesity, glucose intolerance, non‐alcoholic fatty liver disease (NAFLD) and dyslipidaemia with superior efficacy in both male and female mice compared with mono‐agonist treatments. PPP revealed broader changes of plasma proteins after GLP‐1/GIP co‐agonist compared with mono‐agonist treatments in both sexes, including established and potential novel biomarkers for systemic inflammation, NAFLD and atherosclerosis. Subtle sex‐specific differences have been observed in metabolic phenotyping and PPP. Conclusions: We herein show that a recently developed unimolecular GLP‐1/GIP co‐agonist is more efficient in improving metabolic disease than either mono‐agonist in both sexes. PPP led to the identification of a sex‐independent protein panel with the potential to monitor non‐invasively the treatment efficacies on metabolic function of this clinically advancing GLP‐1/GIP co‐agonist. [ABSTRACT FROM AUTHOR]

Aims: To gain insight in the uptake and practice variation in the prescription of 2 new medicine groups for common conditions in primary care (direct-acting oral anticoagulants [DOACs] and incretin-based therapies) from introduction, around 2007, to 2019 and the correlation between the adoption of those medicines in primary care., Methods: Prescription data from general practices in the Dutch Nivel Primary Care Database from 2007 to 2019 were used. The percentage of patients with prescriptions for DOACs of all patients with prescriptions for DOACs and vitamin K antagonists was calculated per practice per year, as was the percentage of patients prescribed incretin-based therapies as a proportion of all patients with diabetes medication. Multilevel models were used to estimate practice variation for DOACs and incretin-based therapies, expressed as intraclass correlation coefficients. Linear regression analysis was used to study the association between the prescription of DOACs and incretin-based therapies., Results: Per year, 46-424 general practices and 179 933-1 654 376 patients were included. In 2019, the mean percentage of patients per practice using DOACs or incretin-based therapies was 54.9 and 9.7%, respectively. The intraclass correlation coefficient decreased from 0.75 to 0.024 for DOACs and from 0.33 to 0.074 for incretin-based medicines during the study period. No clear correlation was found between the prescription of DOACs and incretin-based therapies., Conclusion: DOACs and incretin-based therapies have different adoption profiles and practice variation is large, especially in the years before these medicines were introduced in guidelines. Early adopters of both medicine classes differ., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aim: The aim of this observational study was to investigate relationships between physiological levels of glucometabolic biomarkers and cognitive test results in a population‐based setting. Methods: Cross‐sectional data were obtained from the Swedish population‐based Malmö Diet and Cancer Study Re‐examination 2007–2012 comprising 3001 older people (mean age 72 years). Through oral glucose tolerance testing (OGTT), fasting and post‐load levels of serum insulin, plasma glucagon, serum glucose‐dependent insulinotropic peptide (GIP) and plasma glucagon‐like peptide‐1 (GLP‐1) were measured. Insulin resistance and insulin sensitivity levels were calculated. In 454 participants, advanced glycation end products (AGEs) were estimated through skin autofluorescence. Associations between biomarkers and two cognitive tests, the Mini‐Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT) respectively, were explored in multiple regression analyses. Results: Positive associations following adjustments for known prognostic factors were found between MMSE scores and insulin sensitivity (B = 0.822, P = 0.004), 2‐h plasma glucagon (B = 0.596, P = 0.026), 2‐h serum GIP (B = 0.581, P = 0.040) and 2‐h plasma GLP‐1 (B = 0.585, P = 0.038), whereas negative associations were found between MMSE scores and insulin resistance (B = −0.734, P = 0.006), fasting plasma GLP‐1 (B = −0.544, P = 0.033) and AGEs (B = −1.459, P = 0.030) were found. Conclusions: Higher levels of insulin sensitivity, GIP and GLP‐1 were associated with better cognitive outcomes, but AGEs were associated with worse outcomes, supporting evidence from preclinical studies. Glucagon was linked to better outcomes, which could possibly reflect neuroprotective properties similar to the related biomarker GLP‐1 which has similar intracellular properties. Longitudinal and interventional studies are needed to further evaluate neuromodulating effects of these biomarkers. Abstract presented at the European Association for the Study of Diabetes (EASD) 2019, Barcelona, Spain What's new?: Preclinical studies suggest that insulin and incretin hormones exert neuroprotective effects in the brain and that advanced glycation end products (AGEs) are linked to Alzheimer's disease. Glucagon has not been studied in relation to cognition, but has similar intracellular properties to the incretin hormone glucagon‐like peptide‐1.This cross‐sectional population‐based study supports previous evidence that insulin and incretin hormones may be neuroprotective and that AGEs may have negative effects on cognition. Furthermore, glucagon was positively associated with cognitive test results, which is a novel finding.These results contribute with new information to the important research field of diabetes‐related cognitive impairment. [ABSTRACT FROM AUTHOR]

Summary: Background: Omission of breakfast results in higher glucose and lower insulin and incretin hormone levels after both lunch and dinner. Whether omission of lunch has a similar impact on the following meal is not known. Aim: This study therefore explored whether omission of lunch ingestion affects glucose, islet and incretin hormones after dinner ingestion in healthy subjects. Materials & Methods: Twelve male volunteers (mean age 22 years, BMI 22.5 kg/m2) underwent two test days in random order with standard breakfast and dinner on both days with provision or omission of standard lunch in between. Results: The results showed that throughout the 300 minutes study period, glucose, insulin, glucagon and GIP levels after dinner ingestion did not differ between the two tests. In contrast, C‐peptide, and GLP‐1 levels were 26%‐35% higher at later time points after dinner ingestion when lunch had been omitted (P <.05). Conclusion: We conclude that omission of lunch increases GLP‐1 and insulin secretion and possibly also insulin clearance resulting in unchanged glucose and insulin levels after dinner ingestion. [ABSTRACT FROM AUTHOR]

Aims/Introduction: To explore the factors associated with the glucose‐lowering efficacy of sitagliptin treatment in Japanese patients with type 2 diabetes mellitus. Materials and Methods: This was a post‐hoc analysis of pooled data from seven sitagliptin phase II and III clinical studies carried out in Japan. All studies were double‐blind, randomized, placebo‐controlled, parallel‐group and of 12‐week duration. The analysis population consisted of 1,075 type 2 diabetes mellitus patients. In two of the trials, sitagliptin 50 mg and/or 100 mg daily were used as monotherapy; in five others, sitagliptin 50 mg daily was used as add‐on treatment to ongoing pioglitazone, glimepiride, metformin, voglibose or glinides. Efficacy (reduction in hemoglobin A1c [HbA1c]) was evaluated in 12 sets of subgroups defined by demographic, glycemic, pancreatic β‐cell function and insulin resistance parameters. An analysis of covariance model was used to evaluate the interaction between each parameter and efficacy. Results: Sitagliptin consistently provided a clinically meaningful reduction in HbA1c relative to placebo across all subgroups. Within subgroups, a greater absolute HbA1c reduction was associated with higher baseline HbA1c, fasting plasma glucose and 2‐h post‐meal glucose. Lower β‐cell function, represented by homeostatic model assessment of β‐cell function and insulinogenic index, was also associated with greater HbA1c reduction. In contrast, age, sex, body mass index, duration of type 2 diabetes mellitus and insulin resistance‐related parameters did not interact with HbA1c changes. Conclusions: Sitagliptin treatment was associated with clinically meaningful improvement in glycemic control in all subgroups of Japanese patients with type 2 diabetes mellitus that were evaluated. Higher baseline glycemic status and lower baseline β‐cell function were identified as factors associated with greater HbA1c reduction after sitagliptin treatment. [ABSTRACT FROM AUTHOR]

Aim: To assess whether dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor agonists are associated with an increased lung cancer risk among individuals with type 2 diabetes. Methods: We conducted a population‐based cohort study using the UK Clinical Practice Research Datalink. We identified 130 340 individuals newly treated with antidiabetes drugs between January 2007 and March 2017, with follow‐up until March 2018. We used a time‐varying approach to model use of dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor agonists compared with use of other second‐ or third‐line antidiabetes drugs. We used Cox proportional hazards models to estimate the adjusted hazard ratios, with 95% CIs, of incident lung cancer associated with use of dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor agonists, separately, by cumulative duration of use, and by time since initiation. Results: A total of 790 individuals were newly diagnosed with lung cancer (median follow‐up 4.6 years, incidence rate 1.5/1000 person‐years, 95% CI 1.4–1.6). Compared with use of second‐/third‐line drugs, use of dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor agonists was not associated with an increased lung cancer risk (hazard ratio 1.07, 95% CI 0.87–1.32, and hazard ratio 1.02, 95% CI 0.68–1.54, respectively). There was no evidence of duration–response relationships. Conclusions: In individuals with type 2 diabetes, use of incretin‐based drugs was not associated with increased lung cancer risk. What's new?: Although incretin‐based drugs improve glycaemic levels among individuals with type 2 diabetes, the role of these drugs in cancer incidence is currently debated, particularly in lung cancer where the limited evidence to date warrants further investigation.Compared with use of other second‐/third‐line drugs, incretin‐based drugs were not associated with increased lung cancer risk. The association remained nonsignificant in subgroups of individual drug classes and molecules, and in subgroups of individuals with long‐term use and smoking history.This study suggests that incretin‐based drugs do not increase lung cancer risk in individuals with type 2 diabetes in the first decade of use. [ABSTRACT FROM AUTHOR]

Incretins are hormones secreted from enteroendocrine cells after nutrient intake that stimulate insulin secretion from β cells in a glucose‐dependent manner. Glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the only two known incretins. Dysregulation of incretin secretion and actions are noted in diseases such as obesity and diabetes. In this review, we first summarize our traditional understanding of the physiology of GIP and GLP‐1, and our current knowledge of the relationships between GIP and GLP‐1 and obesity and diabetes. Next, we present the results from major randomized controlled trials on the use of GLP‐1 receptor agonists for managing type 2 diabetes, and emerging data on treating obesity and prediabetes. We conclude with a glimpse of the future with possible complex interactions between nutrients, gut microbiota, the endocannabinoid system, and enteroendocrine cells. [ABSTRACT FROM AUTHOR]

Background: An increasing number of studies have investigated associations of antidiabetes medications with cancer risk. Antidiabetes medications are classified by their mechanisms of action on tissues and organs. They potentially act as both causative and confounding factors in the temporal association of diabetes and cancer. Aim: To present the current evidence regarding both the carcinogenic and anti‐carcinogenic effects of antidiabetes medications on cancer in humans. Methods: A review of the scientific literature. Results: The most conclusive evidence shown of an association of antidiabetes medication with a specific cancer was for that of the thiazolidinedione pioglitazone with bladder cancer. Currently, there is inconclusive evidence regarding a possible association of incretin therapies, drugs of the dipeptidyl peptidase‐4 inhibitor class, with the risk of pancreatic cancer. Insulin, sulfonylureas, metformin and sodium‐glucose co‐transporter‐2 inhibitors appear not to be associated with increased risk of any cancer. Sparse evidence suggests possible protective effects against cancer incidence of metformin, sulfonylureas, thiazolidinediones, incretin‐based drugs and sodium‐glucose co‐transporter‐2 inhibitors. Conclusion: The conflicting evidence regarding associations of antidiabetes medications with cancer risk is apparently attributable to both methodological issues and to the complexity of the subject. More recent and better‐designed studies have weakened the evidence for links between antidiabetes medications and cancer risk. What's new?: As diabetes is recognized for its association with cancer risk, the study of associations of antidiabetes medications and cancer risk has become a clinical and research focus in recent years.Conflicting observational evidence has associated some antidiabetes medications with increased cancer risk and other antidiabetes medications with decreased cancer risk.Secondary analyses of randomized controlled trials and most observational studies that have addressed time‐related biases do not support associations of exposure to antidiabetes medications with cancer risk.Still lacking are well‐designed observational studies with appropriate definitions of exposure and inclusion criteria that control for sample selection so as to account for bias, confounding factors and missing data, and with suitable censoring methods and outcomes, to establish the associations of antidiabetes medications and site‐specific cancer risk. [ABSTRACT FROM AUTHOR]

Background: The determinants of type 2 diabetes (T2D) remission and/or relapse after gastric bypass (RYGB) remain fully unknown. This study characterized β‐ and α‐cell function, in cretin hormone release and insulin sensitivity in individuals with (remitters) or without (non‐remitters) diabetes remission after RYGB. Methods: This is a cross‐sectional study of two distinct cohorts of individuals with or without diabetes remission at least 2 years after RYGB. Each individual underwent‐either an oral glucose (remitters) or a mixed meal (non‐remitters) test; glucose, proinsulin, insulin, C‐peptide, glucagon, incretins and leptin were measured. Results: Compared to remitters (n = 23), non‐remitters (n = 31) were older (mean [±SD] age 56.1 ± 8.2 vs. 46.0 ± 8.9 years, P < 0.001), had longer diabetes duration (13.1 ± 10.1 vs. 2.2 ± 2.4 years, P < 0.001), were further out from the surgery (5.6 ± 3.3 vs. 3.5 ± 1.7 years, P < 0.01), were more insulin resistant (HOMA‐IR 4.01 ± 3.65 vs. 2.08 ± 1.22, P < 0.001), but did not differ for body weight. As predicted, remitters had higher β‐cell glucose sensitivity (1.95 ± 1.23 vs. 0.86 ± 0.55 pmol/kg/min/mmol, P < 0.001) and disposition index (1.55 ± 1.75 vs 0.33 ± 0.27, P = 0.003), compared to non‐remitters, who showed non‐suppressibility of glucagon during the oral challenge (time × group P = 0.001). Higher proinsulin (16.55 ± 10.45 vs. 6.62 ± 3.50 PM, P < 0.0001), and proinsulin: C‐peptide (40.83 ± 29.43 vs. 17.13 ± 7.16, P < 0.001) were strongly associated with non‐remission status, while differences in incretins between remitters and non‐remitters were minimal. Conclusions: Individual without diabetes remission after gastric bypass have poorer β‐cell response and lesser suppression of glucagon to an oral challenge; body weight and incretins differ minimally according to remission status. [ABSTRACT FROM AUTHOR]

Aim: To investigate the incretin axis in people with cystic fibrosis. Methods: Adults with cystic fibrosis‐related diabetes, cystic fibrosis without diabetes, and controls (adults without cystic fibrosis and without diabetes) underwent an oral glucose tolerance test and then a closely matched isoglycaemic i.v. glucose infusion. On each occasion, glucose, insulin, C‐peptide, total and active glucagon‐like peptide‐1 and gastric inhibitory polypeptide responses were recorded and incremental areas under curves were calculated for 60 and 240 min. Results: Five adults with cystic fibrosis‐related diabetes, six with cystic fibrosis without diabetes and six controls, matched for age and BMI, completed the study. Glucose during oral glucose tolerance test closely matched those during isoglycaemic i.v. glucose infusion. The calculated incretin effect was similar in the control group and the cystic fibrosis without diabetes group (28% and 29%, respectively), but was lost in the cystic fibrosis‐related diabetes group (cystic fibrosis‐related diabetes vs control group: –6% vs 28%; p=0.03). No hyposecretion of glucagon‐like peptide‐1 or gastric inhibitory polypeptide was observed; conversely, 60‐min incremental area under the curve for total glucagon‐like peptide‐1 was significantly higher in the cystic fibrosis‐related diabetes group than in the control group [1070.4 (254.7) vs 694.97 (308.1); p=0.03] Conclusions: The incretin effect was lost in cystic fibrosis‐related diabetes despite adequate secretion of the incretin hormones. These data support the concept that reduced incretin hormone insulinotropic activity contributes significantly to postprandial hyperglycaemia in cystic fibrosis‐related diabetes. What's new?: This study is the first to measure the incretin effect in people with cystic fibrosis (CF).The incretin effect is lost in people with cystic fibrosis‐related diabetes (CFRD) despite adequate secretion of glucagon‐like peptide‐1 and gastric inhibitory polypeptide.In people with CF but not diabetes, the incretin effect is similar to that in people without CF.These data suggest the lack of incretin effect contributes to postprandial hyperglycaemia, a hallmark of CFRD, most likely as a consequence of reduced β‐cell mass. [ABSTRACT FROM AUTHOR]

Patients who have undergone gastric bypass surgery (GB) have enhanced postprandial hyperinsulinaemia and a greater incretin effect is apparent. In the present study, we sought to determine the effect of vagal activation, a neural component of the enteroinsular axis, on postprandial glucose metabolism in patients with and without hypoglycaemia after GB. Seven patients with documented post‐GB hypoglycaemia, seven asymptomatic patients without hypoglycaemia post‐GB, and 10 weight‐matched non‐surgical controls with normal glucose tolerance were recruited. Blood glucose, and islet hormone and incretin secretion were compared during mixed meal tolerance tests (MMTs) with and without prior sham‐feeding on two separate days. Sham feeding preceding the MMT caused a more rapid increase in prandial blood glucose levels but lowered overall glycaemia in all three groups (P < 0.05). Sham feeding had a similar effect to increase early (P < 0.05), but not overall, meal‐induced insulin secretion in the three groups. Prandial glucagon concentrations were significantly greater in the GB groups, and sham feeding accentuated this response (P < 0.05). The effect of vagal activation on prandial glucose and islet‐cell function is preserved in patients who have undergone GB, in those both with and without hypoglycaemia. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is an unmet need for a safer and more effective treatment for obesity. This study assessed the effects of licogliflozin, a dual inhibitor of sodium‐glucose co‐transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity. METHODS: Patients with obesity (BMI, 35‐50 kg/m2) were enrolled into a 12‐week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two‐part study, comprising a single‐dose cross‐over study (N = 12; 2.5 − 300 mg) and a 14‐day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE24) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP‐1, PYY3‐36, and GIP), insulin and glucagon. RESULTS: Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% (P < 0.001; incremental AUC0‐4h) and suppressed insulin by 90% (P < 0.01; incremental AUC0‐4h). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24‐hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE24 to 100 g (P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP‐1 by 54% (P < 0.001) and PYY3‐36 by 67% (P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% (P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12‐week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%‐43% with licogliflozin vs 9%‐11% with placebo in the 12‐week study) were among the other gastrointestinal events reported. CONCLUSION: Licogliflozin treatment (1‐84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes. [ABSTRACT FROM AUTHOR]

Aims: In people with metformin‐treated diabetes, to evaluate the risk of acute pancreatitis, pancreatic cancer and other diseases of the pancreas post second‐line anti‐hyperglycaemic agent initiation. Methods: People with Type 2 diabetes diagnosed after 2004 who received metformin plus a dipeptidyl peptidase‐4 inhibitor (DPP‐4i, n = 50 095), glucagon‐like peptide‐1 receptor agonist (GLP‐1RA, n = 12 654), sulfonylurea (n = 110 747), thiazolidinedione (n = 17 597) or insulin (n = 34 805) for at least 3 months were identified in the US Centricity Electronic Medical Records. Time to developing acute pancreatitis, other diseases of the pancreas and pancreatic cancer was estimated, balancing and adjusting anti‐hyperglycaemic drug groups for appropriate confounders. Results: In the DPP‐4i group, the adjusted mean time to acute pancreatitis was 2.63 [95% confidence intervals (CI) 2.38, 2.88] years; time to pancreatic cancer was 2.70 (2.19, 3.21) years; and time to other diseases of the pancreas was 2.73 (2.33, 3.12) years. Compared with DPP‐4i, the insulin group developed acute pancreatitis 0.48 years (P < 0.01) earlier and the GLP‐1RA group developed pancreatic cancer 3 years later (P < 0.01). However, with the constraint of no event within 6 months of insulin initiation, the risk of acute pancreatitis in the insulin group was insignificant. No other significant differences were observed between groups. Conclusions: No significant differences in the risk of developing pancreatic diseases in those treated with various anti‐hyperglycaemic drug classes were found. What's new?: Association of treatment with incretin‐based therapies and the risk of pancreatic diseases remains controversial. However, no study explored the comparative safety of different anti‐hyperglycaemic drugs in this context.This study provides a holistic population‐level comparative outcome evaluation of the risk of pancreatic diseases from the time of receiving different second‐line anti‐hyperglycaemic drugs post metformin.Although treatment with incretin‐based therapies was not found be to be associated with an increased risk of pancreatic diseases, people treated with insulin experienced higher risk of such diseases. [ABSTRACT FROM AUTHOR]

Purpose Incretin‐based medications are a novel class of agents for the treatment of type‐2 diabetes mellitus (DM2). The safety profile of these medications is not firmly established, and concerns have been raised about their potential carcinogenicity. The objective of our study was to produce new evidence on the effect of incretin‐based medications on cancer risk in patients with DM2. Methods: We conducted a "retrospective cohort" study with data from the Clinical Practice Research Datalink and the Hospital Episodes Statistics in the UK. New users of either an incretin‐based medication (n = 18 885) or a sulfonylurea medication (n = 36 929) between 2007 and 2013 were identified and followed for up to 8 years. Cox proportional‐hazards models were used to estimate the quasi‐intention‐to‐treat and quasi‐per‐protocol hazard‐ratios for the association between incretin‐based medications with cancer while adjusting for potential confounders. Results: The adjusted hazard ratio (95% confidence interval) for use of incretin‐based medications versus use of sulfonylurea medications for the overall‐cancer outcome was 0.97 (0.90, 1.05) in the quasi‐intention‐to‐treat analysis and 0.90 (0.81, 1.00) in the quasi‐per‐protocol analysis. In both analyses, the hazard‐ratio functions over the 8‐year follow‐up seemed fairly constant, and the 8‐year cumulative‐risk functions in the two subcohorts were similar. Conclusions: Our study suggests that the use of incretin‐based medications in patients with DM2 does not increase the risk of cancer relative to the use of sulfonylurea medications, at least in the first several years of the use. Further research is needed to assess long‐term effects of the use of incretin‐based medications on cancer risk. [ABSTRACT FROM AUTHOR]

Background: Supraphysiological insulin and incretin responses to a cereal‐based diet have been described in horses and ponies with insulin dysregulation (ID). However, the hormonal responses to grazing have not yet been described. Objectives: To determine if there is a difference in the insulin and incretin responses to grazing pasture between insulin‐dysregulated and healthy ponies. Animals A cohort of 16 ponies comprising 5 with normal insulin regulation (NIR), 6 with moderate ID (MID), and 5 with severe ID (SID). Methods: In this case‐control study, an oral glucose test (OGT) was used to determine the insulin responsiveness of each pony to PO carbohydrate before grazing pasture (4 hours) for 3 consecutive days. Serial blood samples collected during grazing were analyzed for glucose, insulin, glucose‐dependent insulinotropic peptide (GIP) and active glucagon‐like peptide‐1 (aGLP‐1), and compared among pony groups and day of pasture access. Results: The area under the insulin curve when grazing increased with ID severity (P < .03). The median (range) maximal insulin concentration was greater in the MID (72.5 [129] μIU/mL) and SID (255 [338.5] μIU/mL) groups, compared to the NIR (11.7 [24.9] μIU/mL) group (P < .03) and occurred within 2‐4 hours of grazing. Postprandial OGT insulin concentration was positively correlated with 2 hours post‐grazing insulin across all 3 grazing days (P ≤ .03). The aGLP‐1 and GIP concentrations increased in response to grazing but did not differ among groups. Conclusions and Clinical Importance: Grazing pasture provoked an increased insulin and incretin response in insulin‐dysregulated ponies within 4 hours of grazing. The pasture and OGT insulin concentrations were correlated. [ABSTRACT FROM AUTHOR]

Prolonged exposure to high levels of glucose and fatty acid (FFA) can induce tissue damage commonly referred to as glucolipotoxicity and is particularly harmful to pancreatic β‐cells. Glucolipotoxicity‐mediated β‐cell failure is a critical causal factor in the late stages of diabetes, which suggests that mechanisms that prevent or reverse β‐cell death may play a critical role in the treatment of the disease. Transcription factor PDX1 was recently reported to play a key role in maintaining β‐cell function and survival, and glucolipotoxicity can activate mammalian sterile 20‐like kinase 1 (Mst1), which, in turn, stimulates PDX1 degradation and causes dysfunction and apoptosis of β‐cells. Interestingly, previous research has demonstrated that increased glucagon‐like peptide‐1 (GLP‐1) signalling effectively protects β cells from glucolipotoxicity‐induced apoptosis. Unfortunately, few studies have examined the related mechanism in detail, especially the role in Mst1 and PDX1 regulation. In the present study, we investigate the toxic effect of high glucose and FFA levels on rat pancreatic RINm5F β‐cells and demonstrate that the GLP‐1 analogue liraglutide restores the expression of PDX1 by inactivating Mst1, thus ameliorating β‐cell impairments. In addition, liraglutide also upregulates mitophagy, which may help restore mitochondrial function and protect β‐cells from oxidative stress damage. Our study suggests that liraglutide may serve as a potential agent for developing new therapies to reduce glucolipotoxicity. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effect of kisspeptin on glucose‐stimulated insulin secretion and appetite in humans. Materials and methods: In 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose‐stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose‐stimulated insulin secretion in vitro in human pancreatic islets and a human β‐cell line (EndoC‐βH1 cells). Results: Kisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose‐stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men. Conclusions: Collectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin‐based therapies for reproductive and potentially metabolic conditions. [ABSTRACT FROM AUTHOR]

Carbohydrate includes both fibers and sugars. In Kir6.2-deficient (Kir6.2KO) mice, glucose-induced insulin secretion and response to incretins are severely impaired, whereas insulin secretion induced through the vagal nerve is maintained. The excessive secretion of insulin observed in ST-fed Kir6.2KO mice; that is, cephalic phase-mediated insulin secretion, plays a more important role in ST-fed mice than it does in NC-fed mice. [Extracted from the article]

Aim: To evaluate the effect of gastric distension, induced using a gastric 'barostat', on the secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the presence and absence of small intestinal nutrients in healthy individuals., Materials and Methods: Eight healthy participants (two females, six males, mean age 69.3 ± 1.2 years, body mass index 23.5 ± 0.8 kg/m 2 ) were each studied on four occasions when they received an intraduodenal infusion of either (i) 0.9% saline or (ii) glucose delivered at a rate of 3 kcal/min both with, and without, an intragastric balloon with the pressure set to 8 mmHg above the intragastric minimum distending pressure., Results: Following intraduodenal saline or glucose infusion, there was no difference in plasma GLP-1 with or without gastric distension (P = 1.00 for both saline and glucose infusions). There was also no difference in plasma GIP with or without gastric distension (P = 1.00 for saline infusion and P = .99 for glucose infusion)., Conclusions: Gastric distension, either alone or during small intestinal glucose exposure, does not stimulate incretin hormone secretion significantly in healthy humans., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Abstract: The inhibition of dipeptidyl peptidase‐IV (DPP‐IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP‐IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP‐IV and drug‐like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP‐IV noncovalent inhibition according to the binding site structure of DPP‐IV, (b) explain the most important selectivity cliffs for DPP‐IV noncovalent inhibition in comparison with other related enzymes (i.e., DPP8 and DPP9), and (c) use the information deriving from this activity/selectivity cliff analysis to suggest how virtual screening protocols might be improved to favor the early identification of potent and selective DPP‐IV inhibitors in molecular databases (because they have not succeeded in identifying selective DPP‐IV inhibitors with IC50 ≤ 100 nM). All these goals are achieved with the help of available homology models for DPP8 and DPP9 and an analysis of the structure–activity studies used to develop the noncovalent inhibitors that form part of some of the complexes with human DPP‐IV available at the PDB. [ABSTRACT FROM AUTHOR]

Semaglutide is a human glucagon‐like peptide‐1 (GLP‐1) analogue that is in development for the treatment of type 2 diabetes. In the pre‐approval cardiovascular outcomes trial SUSTAIN 6, semaglutide was associated with a significant increase in the risk of diabetic retinopathy (DR) complications vs placebo. GLP‐1 receptor (GLP‐1R) expression has previously been demonstrated in the retina in animals and humans; however, antibodies used to detect expression have been documented to be non‐specific and fail to detect the GLP‐1R using immunohistochemistry (IHC), a problem common for many G‐protein coupled receptors. Using a validated GLP‐1R antibody for IHC and in situ hybridization for GLP‐1R mRNA in normal human eyes, GLP‐1Rs were detected in a small fraction of neurons in the ganglion cell layer. In advanced stages of DR, GLP‐1R expression was not detected at the protein or mRNA level. Specifically, no GLP‐1R expression was found in the eyes of people with long‐standing proliferative DR (PDR). In conclusion, GLP‐1R expression is low in normal human eyes and was not detected in eyes exhibiting advanced stages of PDR. [ABSTRACT FROM AUTHOR]

Low‐calorie sweeteners (LCSs) are widely used for weight control despite limited evidence of their effectiveness and studies linking LCS consumption with incident obesity. We tested the hypothesis that regular LCS consumption is associated with higher postprandial glucose‐dependent insulinotropic polypeptide (GIP) secretion, which has been linked to obesity. We used data from participants in the Baltimore Longitudinal Study of Aging who had completed a diet diary, had at least one visit during which they underwent an oral glucose tolerance test (OGTT), and had no diabetes. Of 232 participants, 166 contributed 1, 39 contributed 2, and 27 contributed 3 visits, and 96 (41%) reported using LCS. Plasma OGTT samples were analysed for glucose, insulin and GIP. Fasting glucose, insulin and GIP levels were no different between LCS users and non‐users. The association of LCS use with 2‐hour OGTT responses after adjustment for covariates was non‐significant for glucose (P = .98) and insulin (P = .18), but significant for greater increase in GIP in LCS users (P = .037). Regular consumption of LCSs was associated with greater increases in GIP secretion after food intake, which may potentially lead to weight gain through the lipogenic properties of GIP. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study? Glucagon‐like peptide‐1 (GLP‐1) is an important obesity/diabetes target, with effects dependent on circulating GLP‐1 concentrations. Peripheral tissues extract GLP‐1; therefore, sampling venous versus arterialized blood might provide different GLP‐1 concentrations. This study examined whether arterialization alters GLP‐1 concentrations during fasting and feeding. What is the main finding and its importance? This study demonstrates that venous blood provides lower postprandial but not fasting GLP‐1 concentrations versus arterialized blood. Therefore, when accurate assessment of postprandial peripheral availability of GLP‐1 is required, blood sampling methods should be considered carefully, reported clearly, and arterialization is recommended. Abstract: Glucagon‐like peptide‐1 (GLP‐1) displays concentration‐dependent effects on metabolism, appetite and angiogenesis; therefore, accurate determination of circulating GLP‐1 concentrations is important. In this study, we compared GLP‐1 concentrations in venous versus arterialized blood in both fasted and fed conditions. Venous and arterialized blood samples were obtained simultaneously from 10 young, healthy men before and 30, 60 and 120 min after ingestion of 75 g glucose. Plasma GLP‐1 concentrations increased in response to glucose ingestion (time effect, P < 0.01) and to a lesser extent in venous versus arterialized plasma (time × arterialization interaction, P < 0.01). Accordingly, the plasma incremental area under the curve was lower in venous versus arterialized plasma (974 ± 88 versus 1214 ± 115 pmol l (120 min)−1, respectively, P = 0.049). In the postprandial state, there was a positive relationship between arterialized GLP‐1 concentrations and the venous–arterialized difference in GLP‐1 concentrations (r2 = 0.51; P < 0.01). Both arterialized and venous peak GLP‐1 concentrations showed positive relationships with peak arterialized insulin concentrations (both r2 > 0.6, P < 0.01). Venous sampling results in lower concentrations of GLP‐1 in the postprandial but not the fasted state compared with arterialized blood. This absolute difference is biologically meaningful and is magnified when GLP‐1 availability is high. Therefore, sampling from arterialized blood may provide a better chance of detecting small differences in postprandial GLP‐1 availability with interventions. If absolute GLP‐1 concentrations are of interest, the blood sampling method should be considered carefully and reported clearly. [ABSTRACT FROM AUTHOR]

This study aimed to quantify the effect of the immediate release (IR) of exenatide, a short‐acting glucagon‐like peptide‐1 (GLP‐1) receptor agonist (GLP‐1RA), on gastric emptying rate (GER) and the glucose rate of appearance (GluRA), and evaluate the influence of drug characteristics and food‐related factors on postprandial plasma glucose (PPG) stabilization under GLP‐1RA treatment. A quantitative systems pharmacology (QSP) approach was used, and the proposed model was based on data from published sources including: (1) GLP‐1 and exenatide plasma concentration‐time profiles; (2) GER estimates under placebo, GLP‐1 or exenatide IR dosing; and (3) GluRA measurements upon food intake. According to the model's predictions, the recommended twice‐daily 5‐ and 10‐μg exenatide IR treatment is associated with GluRA flattening after morning and evening meals (48%‐49%), whereas the midday GluRA peak is affected to a lesser degree (5%‐30%) due to lower plasma drug concentrations. This effect was dose‐dependent and influenced by food carbohydrate content, but not by the lag time between exenatide injection and meal ingestion. Hence, GER inhibition by exenatide IR represents an important additional mechanism of its effect on PPG. [ABSTRACT FROM AUTHOR]

Aims: To inform patients and their carers about both the probability of reducing glycated haemoglobin (HbA1c) to clinically desirable levels and the sustainability of such control over 2 years with major second‐line antidiabetic therapies, in individual risk scenarios, with and without third‐line intensification. Materials and Methods: From US Centricity Electronic Medical Records, 163 081 patients with type 2 diabetes aged 18 to 80 years, who had initiated metformin, intensified their treatment with dipeptidyl peptidase‐4 (DPP‐4) inhibitors, glucagon‐like peptide‐1 (GLP‐1) receptor agonists (GLP‐1RAs), sulphonylureas (SUs), insulin or thiazolidinediones (TZDs), and continued second‐line treatment for ≥6 months, were selected. Treatment groups were balanced with regard to baseline characteristics, and glycaemic achievements were estimated using logistic regression analysis. Results: With HbA1c concentrations of 58–63.9 mmol/mol (7.5–7.9%) at second‐line treatment initiation, the adjusted probabilities of achieving HbA1c <53 mmol/mol (<7%) at 6 months were 32%, 38%, 39%, 26% and 38% in the SU, DPP‐4 inhibitor, GLP‐1RA, insulin and TZD groups, respectively, while with baseline HbA1c concentrations of 64–75 mmol/mol (8–9%), the corresponding probabilities of reducing HbA1c to <58 mmol/mol (<7.5%) were 38%, 44%, 40%, 34% and 42%, respectively. In these baseline HbA1c categories, the adjusted probabilities of sustaining HbA1c achievements over 2 years were higher in the GLP‐1RA and TZD groups, compared with the SU and insulin groups (P < .01). With baseline HbA1c concentrations of 75.1–108 mmol/mol (9.1–12%) 38% of patients achieved an HbA1c concentration <58 mmol/mol (<7.5%) at 6 months. The adjusted probability of sustaining this control over 2 years was higher in the incretin and TZD groups (range 62%‐75%), while insulin and SUs offered lower chances of sustainable control (range 54%‐56%). Conclusions: Patients treated with second‐line incretins and TZDs had a significantly higher probability of achieving and sustaining glycaemic control over 2 years without further intensification, compared with those treated with SUs or insulin. [ABSTRACT FROM AUTHOR]

Abstract: Over the past decade, several new medications have been developed to treat type 2 diabetes mellitus. Large‐scale outcome trials have been performed with patients at high cardiovascular risk to assess the cardiovascular safety of these agents. These trials are changing the landscape of diabetes therapy with evidence beyond safety to cardiovascular benefits of sodium‐glucose cotransporter 2 (SGLT‐2) inhibitors and some glucagon‐like peptide‐1 receptor agonists. This review provides an overview of incretin‐based therapies and SGLT‐2 inhibitors with a particular focus on the results of published cardiovascular outcome trials, which have also provided unique opportunities to evaluate uncommon but potentially serious adverse events of these newer agents. The cardiovascular benefits of SGLT‐2 inhibitors and some glucagon‐like peptide‐1 receptor agonists suggest that they may be the preferred choice, usually as an add‐on to metformin, for patients with type 2 diabetes mellitus at high cardiovascular risk. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the safety and efficacy of once‐weekly subcutaneous semaglutide as monotherapy or combined with an oral antidiabetic drug (OAD) vs an additional OAD added to background therapy in Japanese people with type 2 diabetes (T2D) inadequately controlled on diet/exercise or OAD monotherapy. Methods: In this phase III, open‐label trial, adults with T2D were randomized 2:2:1 to semaglutide 0.5 mg or 1.0 mg, or one additional OAD (a dipeptidyl peptidase‐4 inhibitor, biguanide, sulphonylurea, glinide, α‐glucosidase inhibitor or thiazolidinedione) with a different mode of action from that of background therapy. The primary endpoint was number of adverse events (AEs) after 56 weeks. Results: Baseline characteristics were balanced between treatment arms (601 randomized). More AEs were reported in the semaglutide 0.5 mg (86.2%) and 1.0 mg (88.0%) groups than in the additional OAD group (71.7%). These were typically mild/moderate. Gastrointestinal AEs were most frequent with semaglutide, which diminished over time. The mean glycated haemoglobin (HbA1c) concentration (baseline 8.1%) was significantly reduced with semaglutide 0.5 mg and 1.0 mg vs additional OAD (1.7% and 2.0% vs 0.7%, respectively; estimated treatment difference [ETD] vs additional OAD −1.08% and −1.37%, both P < .0001). Body weight (baseline 71.5 kg) was reduced by 1.4 kg and 3.2 kg with semaglutide 0.5 mg and 1.0 mg, vs a 0.4‐kg increase with additional OAD (ETD −1.84 kg and −3.59 kg; both P < .0001). For semaglutide‐treated participants, >80% achieved an HbA1c concentration <7.0% (Japanese Diabetes Society target). Conclusions: Semaglutide was well tolerated, with no new safety issues identified. Semaglutide treatment significantly reduced HbA1c and body weight vs additional OAD treatment in Japanese people with T2D. [ABSTRACT FROM AUTHOR]

Postprandial glycaemia makes a substantial contribution to overall glycaemic control in diabetes, particularly in patients whose preprandial glycaemia is relatively well controlled and glycated haemoglobin (HbA1c) only modestly elevated. Our review addresses the determinants of postprandial glycaemia and how it may be targeted therapeutically in children with diabetes. Postprandial glycaemia is influenced by preprandial glycaemia, macronutrients and their absorption, insulin delivery and sensitivity, the action of the enteroendocrine system, and the rate of gastric emptying. Contemporary continuous glucose monitoring systems reveal patterns of post prandial glycaemia and allow management to be guided more precisely. Delays in blood glucose determination, insulin delivery and its absorption remain challenges in the rapidly evolving closed loop continuous subcutaneous insulin and glucagon delivery systems developed for children with type 1 diabetes. Augmentation of the incretin system through nutritional preloads or incretin mimetics targets postprandial glycaemia by slowing gastric emptying as well as insulinotropic and glucagonostatic effects. These treatments are of particular relevance to children with type 2 diabetes. Following the development of targeted therapies in adults, postprandial blood glucose control will now be increasingly targeted in the treatment of diabetes in children. [ABSTRACT FROM AUTHOR]