The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion-A Review.

The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion. Furthermore, GLP-1 inhibits glucagon secretion when plasma glucose concentrations are above normal fasting concentrations while GIP acts glucagonotropically at low glucose levels. A dual incretin receptor agonist designed to co-activate GLP-1 and GIP receptors was recently shown to elicit robust improvements of glycemic control (mean haemoglobin A1c reduction of 1.

Non-alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion.

Background & Aims: We recently showed that the functional capacity for ureagenesis is deficient in non-alcoholic fatty liver disease (NAFLD) patients. The aim of this study was to assess expression of urea cycle-related genes to elucidate a possible gene regulatory basis to the functional problem.

Methods: Liver mRNA expression analyses within the gene pathway governing hepatic nitrogen conversion were performed in 20 non-diabetic, biopsy-proven NAFLD patients (8 simple steatosis; 12 non-alcoholic steatohepatitis [NASH]) and 12 obese and 14 lean healthy individuals.

A role for exogenous GLP-1 in the management of postprandial hypoglycaemia after Roux-en-Y gastric bypass?

Roux-en-Y gastric bypass (RYGB) is one of the most common and successful bariatric surgeries. However, more than half of RYGB-operated individuals may suffer from post-bariatric hypoglycaemia (PBH) characterised by traditional hypoglycaemic symptoms occurring 1 to 4 hours after meal intake. The mechanisms underlying PBH most likely relate to accelerated delivery of nutrients to the small intestine resulting in unretarded nutrient absorption, large elevations in postprandial plasma glucose concentrations (constituting a potent insulin secretory stimulus), and grossly elevated postprandial plasma levels of the insulinotropic gut-derived hormone glucagon-like peptide 1 (GLP-1) potentiating glucose-stimulated insulin secretion.

Glucagon Receptor Signaling and Glucagon Resistance.

Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (glucagonomas). The suggested key role of glucagon in the development of diabetes has been termed the bihormonal hypothesis.

Investigating Intestinal Glucagon After Roux-en-Y Gastric Bypass Surgery.

Context: After Roux-en-Y gastric bypass (RYGB) surgery, postprandial plasma glucagon concentrations have been reported to increase. This occurs despite concomitant improved glucose tolerance and increased circulating plasma concentrations of insulin and the glucagon-inhibiting hormone glucagon-like peptide 1 (GLP-1).

Objective: To investigate whether RYGB-induced hyperglucagonemia may be derived from the gut.

Glucagon Receptor Signaling and Lipid Metabolism.

Glucagon is secreted from the pancreatic alpha cells upon hypoglycemia and stimulates hepatic glucose production. Type 2 diabetes is associated with dysregulated glucagon secretion, and increased glucagon concentrations contribute to the diabetic hyperglycemia. Antagonists of the glucagon receptor have been considered as glucose-lowering therapy in type 2 diabetes patients, but their clinical applicability has been questioned because of reports of therapy-induced increments in liver fat content and increased plasma concentrations of low-density lipoprotein.

Effect of liraglutide on body weight and pain in patients with overweight and knee osteoarthritis: protocol for a randomised, double-blind, placebo-controlled, parallel-group, single-centre trial.

Introduction: With an increasing prevalence of citizens of older age and with overweight, the health issues related to knee osteoarthritis (OA) will intensify. Weight loss is considered a primary management strategy in patients with concomitant overweight and knee OA. However, there are no widely available and feasible methods to sustain weight loss in patients with overweight and knee OA.

Liraglutide-Induced Weight Loss May be Affected by Autonomic Regulation in Type 1 Diabetes.

The role of the autonomic nervous system in the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients with type 1 diabetes is unknown. We assessed the association between autonomic function and weight loss induced by the GLP-1 RA liraglutide. Lira-1 was a randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of 1.

Metabolic profile in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives.

Objective: The prevalence of metabolic syndrome and insulin resistance is twice as high in patients with bipolar disorder compared with the general population, and possibly associated with a disabling illness trajectory of bipolar disorder, an increased risk of cardiovascular disease and premature death. Despite these detrimental effects, the prevalence of metabolic syndrome and insulin resistance in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives is largely unknown.

Methods: In a cross-sectional study of 206 patients with newly diagnosed bipolar disorder, 50 of their unaffected first-degree relatives and 109 healthy age- and sex-matched individuals, we compared the prevalence of metabolic syndrome and insulin resistance (HOMA-IR).

Association Between Topical Corticosteroid Use and Type 2 Diabetes in Two European Population-Based Adult Cohorts.

Objective: Topical corticosteroids (CSs) are commonly used to treat inflammatory skin conditions including eczema and psoriasis. Although topical CS package inserts describe hyperglycemia and glycosuria as adverse drug reactions, it is unclear whether topical CS use in real life is also associated with an increased risk of type 2 diabetes (T2D).

Research Design And Methods: Two matched case-control studies and one cohort study were conducted using routinely collected health care data from Denmark and the U.

[Glucagon-like peptide 1 receptor agonists for the treatment of Type 2 diabetes].

Supraphysiological levels of the incretin hormone glucagon-like peptide 1 (GLP-1) have demonstrated a marked glucose-lowering effect in patients with Type 2 diabetes. Six GLP-1 receptor agonists are currently available for the treatment of Type 2 diabetes and have all proven to render significant reductions in both glycated haemoglobin level and body weight. However, of the clinical available compounds only liraglutide, dulaglutide and semaglutide have demonstrated reductions in the risk of cardiovascular disease.

The Liver-α-Cell Axis and Type 2 Diabetes.

Both type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) strongly associate with increasing body mass index, and together these metabolic diseases affect millions of individuals. In patients with T2D, increased secretion of glucagon (hyperglucagonemia) contributes to diabetic hyperglycemia as proven by the significant lowering of fasting plasma glucose levels following glucagon receptor antagonist administration. Emerging data now indicate that the elevated plasma concentrations of glucagon may also be associated with hepatic steatosis and not necessarily with the presence or absence of T2D.

Continuous glucose monitoring in pregnant women with type 1 diabetes: an observational cohort study of 186 pregnancies.

Aims/hypothesis: The aim of this study was to analyse patterns of continuous glucose monitoring (CGM) data for associations with large for gestational age (LGA) infants and an adverse neonatal composite outcome (NCO) in pregnancies in women with type 1 diabetes.

Methods: This was an observational cohort study of 186 pregnant women with type 1 diabetes in Sweden. The interstitial glucose readings from 92 real-time (rt) CGM and 94 intermittently viewed (i) CGM devices were used to calculate mean glucose, SD, CV%, time spent in target range (3.

Clinical characteristics and glucose-lowering drug utilization among patients initiating liraglutide in Denmark: a routine clinical care prescription study.

Highlights This population-based real-world prescription study characterized all new users of liraglutide in northern Denmark from 2009 to 2015. More than half (57%) the patients had liraglutide prescribed as part of drug combinations outside the originally approved indications. Comorbidities or diabetes complications were present in most patients, with the highest prevalence observed among the 73% of initiators who would have been ineligible for the Liraglutide Effect and Action in Diabetes (LEAD) 1-5 trials that led to liraglutide registration, underscoring the need for further post-marketing studies.

Separate and Combined Effects of GIP and GLP-1 Infusions on Bone Metabolism in Overweight Men Without Diabetes.

Context: The gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have been suggested to play a role in bone metabolism. Exogenous administration of GIP inhibits bone resorption, but the effect of GLP-1 is less clear. Furthermore, the combined effect of exogenous GIP and GLP-1 on bone metabolism is unknown.

Plasma proteome profiling discovers novel proteins associated with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) affects 25% of the population and can progress to cirrhosis with limited treatment options. As the liver secretes most of the blood plasma proteins, liver disease may affect the plasma proteome. Plasma proteome profiling of 48 patients with and without cirrhosis or NAFLD revealed six statistically significantly changing proteins (ALDOB, APOM, LGALS3BP, PIGR, VTN, and AFM), two of which are already linked to liver disease.

[Biomarkers of cardiovascular disease in patients with Type 2 diabetes].

Patients with Type 2 diabetes have an increased risk of cardiovascular disease. However, there exists a considerable heterogeneity in cardiovascular risk in this patient population. A heterogeneity, which may escape the predictive capability of established clinical risk scores.

Bariatric surgery in patients with non-alcoholic fatty liver disease - from pathophysiology to clinical effects.

Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a significant liver disease, and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis (NASH) to fibrosis, subsequent cirrhosis, end-stage liver failure, and liver cancer with a potential need for liver transplantation. NAFLD and NASH are closely related to obesity, metabolic syndrome, and type 2 diabetes (T2D). The role of gut hormones, especially glucagon-like peptide 1 (GLP-1), is important in NAFLD.

Bone Status in Obese, Non-diabetic, Antipsychotic-Treated Patients, and Effects of the Glucagon-Like Peptide-1 Receptor Agonist Exenatide on Bone Turnover Markers and Bone Mineral Density.

Low bone mineral density (BMD) may constitute an underestimated comorbidity in schizophrenia patients undergoing long-term antipsychotic treatment. Glucagon-like peptide 1 (GLP-1) receptor agonists are antidiabetic drugs, which may also affect bone turnover. In planned secondary analyses of a 3 months, double-blind, randomized, placebo-controlled trial ( = 45), we explored effects of the GLP-1 receptor agonist exenatide 2 mg once-weekly ( = 23), or placebo ( = 22) on bone turnover markers (BTMs) and BMD in chronic, obese, antipsychotic-treated patients with schizophrenia spectrum disorder.

The efficacy and safety of exenatide once weekly in patients with type 2 diabetes.

Exenatide once weekly (QW) is a glucagon-like peptide 1 receptor agonist (GLP-1RA) that was approved in 2012 in Europe and the U.S.A.

Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study.

Aims/hypothesis: Glucagon-like peptide 1 (GLP-1) reduces appetite and energy intake in humans, whereas the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), seems to have no effect on eating behaviour. Interestingly, studies in rodents have shown that concomitant activation of GIP and GLP-1 receptors may potentiate the satiety-promoting effect of GLP-1, and a novel dual GLP-1/GIP receptor agonist was recently shown to trigger greater weight losses compared with a GLP-1 receptor agonist in individuals with type 2 diabetes. The aim of this study was to delineate the effects of combined GIP and GLP-1 receptor activation on energy intake, appetite and resting energy expenditure in humans.

Hepatic transcriptome signatures in patients with varying degrees of nonalcoholic fatty liver disease compared with healthy normal-weight individuals.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions ranging from simple steatosis (NAFL), over nonalcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis with end-stage disease. The hepatic molecular events underlying the development of NAFLD and transition to NASH are poorly understood. The present study aimed to determine hepatic transcriptome dynamics in patients with NAFL or NASH compared with healthy normal-weight and obese individuals.

Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are secreted postprandially and contribute importantly to postprandial glucose tolerance. In this study, we assessed the individual and combined contributions of endogenous GIP and GLP-1 to the postprandial changes in glucose and glucoregulatory hormones using the novel GIP receptor antagonist GIP(3-30)NH and the well-established GLP-1 receptor antagonist exendin(9-39)NH During 4-h oral glucose tolerance tests (75 g) combined with an ad libitum meal test, 18 healthy men received on four separate days in randomized, double-blinded order intravenous infusions of A) GIP(3-30)NH (800 pmol/kg/min) plus exendin(9-39)NH (0-20 min: 1,000 pmol/kg/min; 20-240 min: 450 pmol/kg/min), B) GIP(3-30)NH, C) exendin(9-39)NH, and D) saline, respectively. Glucose excursions were significantly higher during A than during B, C, and D, while glucose excursions during B were higher than during C and D.