Total adiponectin in indigenous Melanesians on Kitava.

Objectives: Experimental and small human studies have indicated that high total adiponectin levels have beneficial cardiometabolic effects. In contrast, however, high total adiponectin levels are also associated with higher all-cause and cardiovascular mortality in thoroughly adjusted epidemiological studies. To gain further insight into these seemingly contradictory results, we report results on total adiponectin from the indigenous Melanesian population of Kitava, Trobriand Islands, Papua New Guinea, where an apparent absence of cardiometabolic disease has been previously reported.

The dual incretin co-agonist tirzepatide increases both insulin secretion and glucose effectiveness in model experiments in mice.

Tirzepatide is a dual GIP and GLP-1 receptor co-agonist which is approved for glucose-lowering therapy in type 2 diabetes. Here, we explored its effects on beta cell function, insulin sensitivity and insulin-independent glucose elimination (glucose effectiveness) in normal mice. Anesthetized female C57/BL/6 J mice were injected intravenously with saline or glucose (0.

Paradigm Shift in the Management of Metabolic Diseases-Next-Generation Incretin Therapy.

Recently impressive weight loss has been reported for novel incretin therapies based on dual-and triple-hormone receptor coagonists. These agents have potential as being positioned as early therapeutics for metabolic diseases for which weight loss is preferred, such as type 2 diabetes, obesity, cardiovascular diseases, and nonalcoholic liver disease. This development will change the landscape of future therapy and also place weight reduction at the centerpiece for therapy of metabolic diseases.

Proportion of participants with type 2 diabetes achieving a metabolic composite endpoint with once-weekly semaglutide treatment versus comparators: Post hoc pooled analysis from SUSTAIN 1-5, 7-10 and SUSTAIN China.

Aim: To compare the proportion of participants with type 2 diabetes (T2D) treated with once-weekly (OW) subcutaneous (SC) semaglutide versus comparators who achieved a composite metabolic endpoint.

Materials And Methods: SUSTAIN 1-5, 7-10 and SUSTAIN China trial data were pooled. Participants with T2D (aged ≥18 years) and glycated haemoglobin ≥7.

Gut hormone-based pharmacology: novel formulations and future possibilities for metabolic disease therapy.

Glucagon-like peptide-1 (GLP-1) receptor agonists are established pharmaceutical therapies for the treatment of type 2 diabetes and obesity. They mimic the action of GLP-1 to reduce glucose levels through stimulation of insulin secretion and inhibition of glucagon secretion. They also reduce body weight by inducing satiety through central actions.

Contribution of GIP and GLP-1 to the Insulin Response to Oral Administration of Glucose in Female Mice.

It has previously been shown that the incretin effect accounts for ≈50% of the insulin response to oral glucose in normal mice. Now, I have proceeded and studied the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) to the insulin response to oral glucose in female mice by using receptor antagonists. A specific GIP receptor antagonist (mGIP(3-30); 50 or 500 nmol/kg), a specific GLP-1 receptor antagonist (exendin(9-39); 3 or 30 nmol/kg), the combination of mGIP (500 nmol/kg) and exendin(9-39) (30 nmol/kg), or saline was given intravenously four minutes after administration of glucose (50 mg) through a gastric tube in anesthetized C57/BL6J mice ( = 95) with samples obtained before glucose administration and after 15, 30 and 60 min.

Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 secretion in humans: Characteristics and regulation.

Aims/introduction: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important incretin hormones. They are released from the gut after meal ingestion and potentiate glucose-stimulated insulin secretion. Their release after meal ingestion and oral glucose are well established and have been characterized previously.

The Glucose Sensitivity of Insulin Secretion-Lessons from In Vivo and In Vitro Studies in Mice.

This study explored the relationship between the glucose dose and insulin response from beta cells in vivo and in vitro in mice. Glucose was administered intravenously at different dose levels (from 0 to 0.75 g/kg) in anesthetized C57BL/6J mice, and the glucose and insulin concentrations were determined in samples taken after 50 min.

Assessing the Effect of Incretin Hormones and Other Insulin Secretagogues on Pancreatic Beta-Cell Function: Review on Mathematical Modelling Approaches.

Mathematical modelling in glucose metabolism has proven very useful for different reasons. Several models have allowed deeper understanding of the relevant physiological and pathophysiological aspects and promoted new experimental activity to reach increased knowledge of the biological and physiological systems of interest. Glucose metabolism modelling has also proven useful to identify the parameters with specific physiological meaning in single individuals, this being relevant for clinical applications in terms of precision diagnostics or therapy.

Glucose-dependent insulinotropic polypeptide secretion after oral macronutrient ingestion: The human literature revisited and a systematic study in model experiments in mice.

Aims/introduction: The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is secreted after meal ingestion. This study explored the relative influence of classes of macronutrients on GIP secretion.

Materials And Methods: The human literature was revisited by identifying articles from PubMed using key words GIP, macronutrients, carbohydrates, fat, protein, healthy subjects.

Temporal Patterns of Glucagon and Its Relationships with Glucose and Insulin following Ingestion of Different Classes of Macronutrients.

Background: glucagon secretion and inhibition should be mainly determined by glucose and insulin levels, but the relative relevance of each factor is not clarified, especially following ingestion of different macronutrients. We aimed to investigate the associations between plasma glucagon, glucose, and insulin after ingestion of single macronutrients or mixed-meal.

Methods: thirty-six participants underwent four metabolic tests, based on administration of glucose, protein, fat, or mixed-meal.

Glucagon-like peptide-1 and beta cell glucose sensitivity - a glucose ramp study in mice.

The incretin glucagon-like peptide-1 (GLP-1) is a gut hormone but also locally produced in pancreatic islets. We evaluated effects of GLP-1 on the insulin response to a gradual increase in glucose in mice within physiological levels. We initially developed a glucose ramp technique in mice.

Hepatic and Extrahepatic Insulin Clearance in Mice with Double Deletion of Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide Receptors.

The aim of this study was to investigate whether incretins, at physiological levels, affect hepatic and/or extrahepatic insulin clearance. Hepatic and extrahepatic insulin clearance was studied in 31 double incretin receptor knockout (DIRKO) and 45 wild-type (WT) mice, which underwent an Intravenous Glucose Tolerance Test (IVGTT). A novel methodology based on mathematical modeling was designed to provide two sets of values (FE, CL; FE, CL) accounting for hepatic and extrahepatic clearance in the IVGTT first and second phases, respectively, plus the respective total clearances, CL and CL.

Impact of Incretin Hormone Receptors on Insulin-Independent Glucose Disposal in Model Experiments in Mice.

A large contribution to glucose elimination from the circulation is achieved by insulin-independent processes. We have previously shown that the two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) increase this process and, therefore, seem to contribute to glucose disposal both through this effect and through the classical incretin effect resulting in enhanced insulin levels. We have now explored in more detail the potential contribution by incretin hormone receptors to insulin-independent processes for glucose elimination.

The Insulin Response to Oral Glucose in GIP and GLP-1 Receptor Knockout Mice: Review of the Literature and Stepwise Glucose Dose Response Studies in Female Mice.

A key factor for the insulin response to oral glucose is the pro-glucagon derived incretin hormone glucagon-like peptide-1 (GLP-1), together with the companion incretin hormone, glucose-dependent insulinotropic polypeptide (GIP). Studies in GIP and GLP-1 receptor knockout (KO) mice have been undertaken in several studies to examine this role of the incretin hormones. In the present study, we reviewed the literature on glucose and insulin responses to oral glucose in these mice.

Glucose-lowering action through targeting islet dysfunction in type 2 diabetes: Focus on dipeptidyl peptidase-4 inhibition.

Dipeptidyl peptidase-4 (DPP-4) inhibition is a glucose-lowering medication for type 2 diabetes. It works through stimulation of insulin secretion and inhibition of glucagon secretion in a glucose-dependent manner, resulting in lowered fasting and postprandial glycemia with low risk of hypoglycemia. As impaired insulin secretion and augmented glucagon secretion are key factors underlying hyperglycemia in type 2 diabetes, DPP-4 inhibition represents a therapy that targets the underlying mechanisms of the disease.

Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test.

Glucagon is secreted from the pancreatic alpha cells and plays an important role in the maintenance of glucose homeostasis, by interacting with insulin. The plasma glucose levels determine whether glucagon secretion or insulin secretion is activated or inhibited. Despite its relevance, some aspects of glucagon secretion and kinetics remain unclear.

The mediation by GLP-1 receptors of glucagon-induced insulin secretion revisited in GLP-1 receptor knockout mice.

To study whether activation of GLP-1 receptors importantly contributes to the insulinotropic action of exogenously administered glucagon, we have performed whole animal experiments in normal mice and in mice with GLP-1 receptor knockout. Glucagon (1, 3 or 10 μg/kg), the GLP-1 receptor antagonist exendin 9-39 (30 nmol/kg), glucose (0.35 g/kg) or the incretin hormone glucose-dependent insulinotropic polypeptide (GIP; 3 nmol/kg) was injected intravenously or glucose (75 mg) was given orally through gavage.

Glucose effectiveness: Lessons from studies on insulin-independent glucose clearance in mice.

Besides insulin-mediated transport of glucose into the cells, an important role is also played by the non-insulin-mediated transport. This latter process is called glucose effectiveness (acronym S ), which is estimated by modeling of glucose and insulin data after an intravenous glucose administration, and accounts for ≈70% of glucose disposal. This review summarizes studies on S , mainly in humans and rodents with focus on results achieved in model experiments in mice.

Consequences on islet and incretin hormone responses to dinner by omission of lunch in healthy men.

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.

The Incretin Effect in Female Mice With Double Deletion of GLP-1 and GIP Receptors.

To establish the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) for the incretin effect after oral glucose, studies were undertaken in female mice with genetic deletion of receptors for GIP and GLP-1 (double incretin receptor knockout [DIRKO] mice) and their wild-type (WT) counterparts. Insulin secretion was explored after oral glucose (doses ranging from 0 to 100 mg), after intravenous glucose (doses ranging from 0 to 0.75 g/kg), and after oral and intravenous glucose at matching circulating glucose.

Persistent whole day meal effects of three dipeptidyl peptidase-4 inhibitors on glycaemia and hormonal responses in metformin-treated type 2 diabetes.

Aim: Dipeptidyl peptidase-4 (DPP-4) inhibition has effects on both fasting and postprandial glucose. However, the extent of this effect over the whole day and whether different DPP-4 inhibitors have the same effects have not been established. We therefore explored the whole day effects of three different DPP-4 inhibitors versus placebo on glucose, islet and incretin hormones after ingestion of breakfast, lunch and dinner in subjects with metformin-treated and well-controlled type 2 diabetes.

Effect of Liraglutide on Times in Glycaemic Ranges as Assessed by CGM for Type 2 Diabetes Patients Treated With Multiple Daily Insulin Injections.

Introduction: The effects of the GLP-1 analogue liraglutide on time in hypoglycaemia, time in hyperglycaemia, and time in range for type 2 diabetes patients initially treated with multiple daily insulin injections (MDI) were investigated. Variables associated with hypoglycaemia in the current population were also identified.

Methods: Analyses were based on data from a previously performed double-blind, placebo-controlled trial in which 124 MDI-treated patients with type 2 diabetes were randomized to liraglutide or placebo.

Reduction in Glycated Hemoglobin and Daily Insulin Dose Alongside Circadian Clock Upregulation in Patients With Type 2 Diabetes Consuming a Three-Meal Diet: A Randomized Clinical Trial.

Objective: In type 2 diabetes, insulin resistance and progressive β-cell failure require treatment with high insulin doses, leading to weight gain. Our aim was to study whether a three-meal diet (3Mdiet) with a carbohydrate-rich breakfast may upregulate clock gene expression and, as a result, allow dose reduction of insulin, leading to weight loss and better glycemic control compared with an isocaloric six-meal diet (6Mdiet).

Research Design And Methods: Twenty-eight volunteers with diabetes (BMI 32.

Islet adaptation in GIP receptor knockout mice.

Glucose-dependent insulinotropic polypeptide (GIP) receptor knockout (KO) mice are tools for studying GIP physiology. Previous results have demonstrated that these mice have impaired insulin response to oral glucose. In this study, we examined the insulin response to intravenous glucose by measuring glucose, insulin and C-peptide after intravenous glucose (0.