The effect of small increases in blood glucose on insulin secretion and endogenous glucose production in humans.

Small glycemic increments (≤0.5 mmol/L) can exert suppressive actions on endogenous glucose production (EGP) however it is unclear if this is an insulin dependent or independent process. Here, we performed a low-rate glucose infusion in control participants without diabetes and in people with type 1 diabetes (T1D) to better understand this phenomenon.

Bile acids mediate fructose-associated liver tumour growth in mice.

High fructose diets are associated with an increased risk of liver cancer. Previous studies in mice suggest increased lipogenesis is a key mechanism linking high fructose diets to liver tumour growth. However, these studies administered fructose to mice at supraphysiological levels.

Class IIa HDACs inhibit cell death pathways and protect muscle integrity in response to lipotoxicity.

Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism.

The impact of a single dose of whey protein on glucose flux and metabolite profiles in normoglycemic males: insights into glucagon and insulin biology.

Protein ingestion concurrently stimulates euglycemic glucagon and insulin secretion, a response that is particularly robust with rapidly absorbing proteins. Previously, we have shown that ingestion of repeated doses of rapidly absorbing whey protein equally stimulated endogenous glucose production (EGP) and glucose disposal (Rd), thus explaining the preservation of euglycemia. Here, we aimed to determine if a smaller single dose of whey could elicit a large enough glucagon and insulin response to stimulate glucose flux.

Translating glucose tolerance data from mice to humans: Insights from stable isotope labelled glucose tolerance tests.

Objective: The glucose tolerance test (GTT) is widely used in human and animal biomedical and pharmaceutical research. Despite its prevalent use, particularly in mouse metabolic phenotyping, to the best of our knowledge we are not aware of any studies that have attempted to qualitatively compare the metabolic events during a GTT in mice with those performed in humans.

Methods: Stable isotope labelled oral glucose tolerance tests (siOGTTs; [6,6-H]glucose) were performed in both human and mouse cohorts to provide greater resolution into postprandial glucose kinetics.

Insulin resistance in type 1 diabetes managed with metformin (INTIMET): Study protocol of a double-blind placebo-controlled, randomised trial.

Background: Insulin resistance is an under-recognised metabolic defect and cardiovascular risk factor in Type 1 diabetes. Whether metformin improves hepatic, muscle or adipose tissue insulin sensitivity has not been studied in adults with Type 1 diabetes. We initiated the INTIMET study (INsulin resistance in Type 1 diabetes managed with METformin), a double-blind randomised, placebo-controlled trial to measure the effect of metformin on tissue-specific insulin resistance in adults with Type 1 diabetes.

Loss of protein kinase D activity demonstrates redundancy in cardiac glucose metabolism and preserves cardiac function in obesity.

Objective: Protein kinase D (PKD) signaling has been implicated in stress-induced cardiac remodeling and function as well as metabolic processes including contraction-mediated cardiac glucose uptake. PKD has recently emerged as a nutrient-sensing kinase that is activated in high-lipid environments, such as in obesity. However, the role of PKD signaling in cardiac glucose metabolism and cardiac function in both normal and obese conditions remains unknown.

Mapping the Associations of the Plasma Lipidome With Insulin Resistance and Response to an Oral Glucose Tolerance Test.

Context: Insulin resistance (IR) remains a global health challenge. Lipidomics offers an opportunity to identify biomarkers and better understand mechanisms of IR associated with abnormal lipid metabolism.

Objective: The objective of this article is to determine plasma lipid species associated with indices of IR and evaluate the lipidome response to an oral glucose tolerance test (OGTT).

The Effects of Early-Onset Pre-Eclampsia on Placental Creatine Metabolism in the Third Trimester.

Creatine is a metabolite important for cellular energy homeostasis as it provides spatio-temporal adenosine triphosphate (ATP) buffering for cells with fluctuating energy demands. Here, we examined whether placental creatine metabolism was altered in cases of early-onset pre-eclampsia (PE), a condition known to cause placental metabolic dysfunction. We studied third trimester human placentae collected between 27-40 weeks' gestation from women with early-onset PE ( = 20) and gestation-matched normotensive control pregnancies ( = 20).

Treatment of type 2 diabetes with the designer cytokine IC7Fc.

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice.

Mechanisms of hyperinsulinaemia in apparently healthy non-obese young adults: role of insulin secretion, clearance and action and associations with plasma amino acids.

Aims/hypothesis: This study aimed to examine the metabolic health of young apparently healthy non-obese adults to better understand mechanisms of hyperinsulinaemia.

Methods: Non-obese (BMI < 30 kg/m) adults aged 18-35 years (N = 254) underwent a stable isotope-labelled OGTT. Insulin sensitivity, glucose effectiveness and beta cell function were determined using oral minimal models.

Placental creatine metabolism in cases of placental insufficiency and reduced fetal growth.

Creatine is a metabolite involved in cellular energy homeostasis. In this study, we examined placental creatine content, and expression of the enzymes required for creatine synthesis, transport and the creatine kinase reaction, in pregnancies complicated by low birthweight. We studied first trimester chorionic villus biopsies (CVBs) of small for gestational age (SGA) and appropriately grown infants (AGA), along with third trimester placental samples from fetal growth restricted (FGR) and healthy gestation-matched controls.

Phosphatidylserine decarboxylase is critical for the maintenance of skeletal muscle mitochondrial integrity and muscle mass.

Objective: Phosphatidylethanolamine (PtdEtn) is a major phospholipid in mammals. It is synthesized via two pathways, the CDP-ethanolamine pathway in the endoplasmic reticulum and the phosphatidylserine (PtdSer) decarboxylase (PSD) pathway in the mitochondria. While the CDP-ethanolamine pathway is considered the major route for PtdEtn synthesis in most mammalian tissues, little is known about the importance of the PSD pathway in vivo, especially in tissues enriched with mitochondria such as skeletal muscle.

Reduced insulin action in muscle of high fat diet rats over the diurnal cycle is not associated with defective insulin signaling.

Objective: Energy metabolism and insulin action follow a diurnal rhythm. It is therefore important that investigations into dysregulation of these pathways are relevant to the physiology of this diurnal rhythm.

Methods: We examined glucose uptake, markers of insulin action, and the phosphorylation of insulin signaling intermediates in muscle of chow and high fat, high sucrose (HFHS) diet-fed rats over the normal diurnal cycle.

Modest changes to glycemic regulation are sufficient to maintain glucose fluxes in healthy young men following overfeeding with a habitual macronutrient composition.

Currently, it is unclear whether short-term overfeeding in healthy people significantly affects postprandial glucose regulation, as most human overfeeding studies have utilized induced experimental conditions such as the euglycemic-hyperinsulinemic clamp technique to assess glucoregulation. The aim of this study was to quantify glucose fluxes [rates of meal glucose appearance (R), disposal (R), and endogenous glucose production (EGP)] in response to 5 and 28 days of overfeeding (+45% energy) while maintaining habitual macronutrient composition (31.0 ± 1.

UNICORN Babies: Understanding Circulating and Cerebral Creatine Levels of the Preterm Infant. An Observational Study Protocol.

Creatine is an essential metabolite for brain function, with a fundamental role in cellular (ATP) energy homeostasis. It is hypothesized that preterm infants will become creatine deplete in the early postnatal period, due to premature delivery from a maternal source of creatine and a limited supply of creatine in newborn nutrition. This potential alteration to brain metabolism may contribute to, or compound, poor neurological outcomes in this high-risk population.

Postprandial Aminogenic Insulin and Glucagon Secretion Can Stimulate Glucose Flux in Humans.

Insulin and glucagon exert opposing actions on glucose metabolism, and their secretion is classically viewed as being inversely regulated. This is, however, context specific as protein ingestion concomitantly stimulates euglycemic insulin and glucagon secretion. It remains enigmatic how euglycemia is preserved under these conditions.

Urinary sodium is positively associated with urinary free cortisol and total cortisol metabolites in a cross-sectional sample of Australian schoolchildren aged 5-12 years and their mothers.

High Na intake and chronically elevated cortisol levels are independently associated with the development of chronic diseases. In adults, high Na intake is associated with high levels of urinary cortisol. We aimed to determine the association between urinary Na and K and urinary cortisol in a cross-sectional sample of Australian schoolchildren and their mothers.

A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism.

Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans.

Endogenous glucose production after sequential meals in humans: evidence for more prolonged suppression after ingestion of a second meal.

Single-meal studies have shown that carbohydrate ingestion causes rapid and persistent suppression of endogenous glucose production (EGP). However, little is known about the regulation of EGP under real-life eating patterns in which multiple carbohydrate-containing meals are consumed throughout the day. Therefore, we aimed to characterize the regulation of EGP in response to sequential meals, specifically during the breakfast-lunch transition.

Skeletal muscle-specific overexpression of heat shock protein 72 improves skeletal muscle insulin-stimulated glucose uptake but does not alter whole body metabolism.

Aims: The induction of heat shock protein 72 (Hsp72) via heating, genetic manipulation or pharmacological activation is metabolically protective in the setting of obesity-induced insulin resistance across mammalian species. In this study, we set out to determine whether the overexpression of Hsp72, specifically in skeletal muscle, can protect against high-fat diet (HFD)-induced obesity and insulin resistance.

Materials And Methods: An Adeno-Associated Viral vector (AAV), designed to overexpress Hsp72 in skeletal muscle only, was used to study the effects of increasing Hsp72 levels on various metabolic parameters.

AgRP Neurons Require Carnitine Acetyltransferase to Regulate Metabolic Flexibility and Peripheral Nutrient Partitioning.

AgRP neurons control peripheral substrate utilization and nutrient partitioning during conditions of energy deficit and nutrient replenishment, although the molecular mechanism is unknown. We examined whether carnitine acetyltransferase (Crat) in AgRP neurons affects peripheral nutrient partitioning. Crat deletion in AgRP neurons reduced food intake and feeding behavior and increased glycerol supply to the liver during fasting, as a gluconeogenic substrate, which was mediated by changes to sympathetic output and peripheral fatty acid metabolism in the liver.

Perilipin 5 Deletion Unmasks an Endoplasmic Reticulum Stress-Fibroblast Growth Factor 21 Axis in Skeletal Muscle.

Lipid droplets (LDs) are critical for the regulation of lipid metabolism, and dysregulated lipid metabolism contributes to the pathogenesis of several diseases, including type 2 diabetes. We generated mice with muscle-specific deletion of the LD-associated protein perilipin 5 (PLIN5, ) and investigated PLIN5's role in regulating skeletal muscle lipid metabolism, intracellular signaling, and whole-body metabolic homeostasis. High-fat feeding induced changes in muscle lipid metabolism of mice, which included increased fatty acid oxidation and oxidative stress but, surprisingly, a reduction in inflammation and endoplasmic reticulum (ER) stress.