Tag: GLP-1

Categories : Metabolic DisordersTags :

Pancreatic Alpha Cells also Secretly Produce Significant Amounts of GLP-1

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New study uncovers natural hormone shift that could transform type 2 diabetes treatment

A 3D map of the islet density routes throughout the healthy human pancreas. Source: Wikimedia CC0

A new study from Duke University School of Medicine is challenging long-standing views on blood sugar regulation — and pointing to a surprising new ally in the fight against type 2 diabetes. 

Published in Science Advances, the research reveals that pancreatic alpha cells, once thought to only produce glucagon – a hormone that raises blood sugar to maintain energy when fasting or exercising – also generate GLP-1, a powerful hormone that boosts insulin release from beta cells and helps regulate glucose. GLP-1 is the same hormone mimicked by blockbuster drugs like semaglutide. 

Using mass spectrometry, Duke researchers found that human alpha cells may naturally produce far more bioactive GLP-1 than previously believed. 

Led by Duke scientist Jonathan Campbell, PhD, the team of obesity and diabetes researchers analysed pancreatic tissue from mice and from humans across a range of ages, body weights, and diabetes statuses. They found that human pancreatic tissue produces much higher levels of bioactive GLP-1 and that this production is directly linked to insulin secretion. 

“Alpha cells are more flexible than we imagined,” said Campbell, an associate professor in the Division of Endocrinology in the Department of Medicine and a member of the Duke Molecular Physiology Institute. “They can adjust their hormone output to support beta cells and maintain blood sugar balance.” 

This flexibility could change the approach to treating type 2 diabetes, where beta cells in the pancreas can’t make enough insulin to keep blood sugar at a healthy level. By boosting the body’s own GLP-1 production, it may offer a more natural way to support insulin and manage blood sugar.  

Switching gears 

In mouse studies, when scientists blocked glucagon production, they expected insulin levels to drop. Instead, alpha cells switched gears – ramping up GLP-1 production, improving glucose control, and triggering stronger insulin release.  

“We thought that removing glucagon would impair insulin secretion by disrupting alpha-to-beta cell signaling,” Campbell said. “Instead, it improved it. GLP-1 took over, and it turns out, it’s an even better stimulator of insulin than glucagon.” 

To test this further, researchers manipulated two enzymes: PC2, which drives glucagon production, and PC1, which produces GLP-1. Blocking PC2 boosted PC1 activity and improved glucose control. But when both enzymes were removed, insulin secretion dropped and blood sugar spiked – confirming the critical role of GLP-1. 

Implications for diabetes treatment 

While GLP-1 is typically made in the gut, the study confirms that alpha cells in the pancreas can also release GLP-1 into the bloodstream after eating. This helps to lower blood sugar by increasing insulin and reducing glucagon levels. 

Common metabolic stressors, like a high-fat diet, can increase GLP-1 production in alpha cells – but only modestly. That opens the door to future research: If scientists can find ways to safely boost GLP-1 output from alpha cells they may be able to naturally enhance insulin secretion in people with diabetes.  

But measuring GLP-1 accurately hasn’t been easy. The team developed a high-specificity mass spectrometry assay that detects only the bioactive form of GLP-1 – the version that actually stimulates insulin — not the inactive fragments that often muddy results. 

“This discovery shows that the body has a built-in backup plan,” Campbell said. “GLP-1 is simply a much more powerful signal for beta cells than glucagon. The ability to switch from glucagon to GLP-1 in times of metabolic stress may be a critical way the body maintains blood sugar control.” 

Source: Duke University

Categories : Metabolic Disorders PaediatricsTags :

Dulaglutide Achieves Glycaemic Control in Diabetic Youths

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Photo by Towfiqu Barbhuiya on Unsplash

A trial testing dulaglutide in children and adolescents with diabetes found that it was effective in achieving glycaemic control. The findings, reported in the New England Journal of Medicine, suggest that dulaglutide may be a more convenient pharmacological treatment for youths.

The incidence of type 2 diabetes mellitus is increasing among youths, and metformin has shown high treatment failure against a backdrop of greater insulin resistance and deterioration in β-cell function than in adults. Daily liraglutide and weekly exenatide, glucagon-like peptide-1 receptor agonists, are available, but have complicated administration and exenatide is available only at a single dose level, making it harder to escalate glycaemic control. The researchers sought to determine whether once-weekly treatment with dulaglutide was effective with regard to glycaemic control in youths with type 2 diabetes.

In a double-blind, placebo-controlled, 26-week trial, 154 participants (aged 10–17; body-mass index [BMI], >85th percentile) being treated with lifestyle modifications alone or with metformin, with or without basal insulin, were randomised in a 1:1:1 ratio to receive once-weekly subcutaneous injections of placebo, dulaglutide at a dose of 0.75mg, or dulaglutide at a dose of 1.5 mg. Participants were then included in a 26-week open-label extension study in which those who had received placebo began receiving dulaglutide at a weekly dose of 0.75mg.

At 26 weeks, the mean glycated haemoglobin level had increased in the placebo group (0.6%) and had decreased in the dulaglutide groups compared to placebo (–0.6% in the 0.75mg group and −0.9% in the 1.5mg group). At 26 weeks, a significantly higher percentage of participants in the pooled dulaglutide groups than in the placebo group had a glycated haemoglobin level of less than 7.0% (51% vs 14%), which was a secondary endpoint. The fasting glucose concentration increased in the placebo group (17.1mg/dL) and decreased in the pooled dulaglutide groups (−18.9mg/dL), and BMI did not change between groups. More gastrointestinal adverse events were reported in dulaglutide therapy than with placebo, and dulaglutide’s safety profile was consistent with that reported in adults.

Overall, the researchers concluded that dulaglutide at a once-weekly dose of 0.75mg or 1.5mg was superior to placebo in improving glycaemic control through 26 weeks among youths with type 2 diabetes (with or without metformin or basal insulin), without an effect on BMI.

Categories : Cardiovascular Disease Metabolic DisordersTags :

GLP-1: The Missing Link of Diabetes and Hypertension

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Image by Nataliya Vaitkevich on Pexels

An international team of researchers has finally cracked the puzzle of why so many patients with hypertension also have diabetes. Their discovery has shown that glucagon-like peptide-1 (GLP-1) couples the body’s control of blood glucose and blood pressure.

Senior Author Professor Julian Paton at the University of Auckland, said: “We’ve known for a long time that hypertension and diabetes are inextricably linked and have finally discovered the reason, which will now inform new treatment strategies.”

The study is published online in Circulation Research.

It has long been known that GLP-1 is released from the wall of the gut after eating and acts to stimulate insulin from the pancreas to control blood sugar levels.  However, the researchers found that GLP-1 also stimulates the carotid body, a chemoreceptor located in the neck.

Researchers used RNA sequencing to read all the messages of the expressed genes in the carotid body in rats with and without high blood pressure. This led to the finding that the receptor that senses GLP-1 is located in the carotid body, but less so in hypertensive rats.

David Murphy, Professor of Experimental Medicine from Bristol Medical School: Translational Health Sciences (THS) and senior author, explained: “Locating the link required genetic profiling and multiple steps of validation.  We never expected to see GLP-1 come up on the radar, so this is very exciting and opens many new opportunities.”

Professor Paton added: “The carotid body is the convergent point where GLP-1 acts to control both blood sugar and blood pressure simultaneously; this is coordinated by the nervous system which is instructed by the carotid body.”

Even when on medication, many patients with hypertension and/or diabetes are at high risk of life-threatening cardiovascular disease. This is because most medications only treat symptoms and not causes of high blood pressure and high sugar.

Professor Rod Jackson, an epidemiologist from the University of Auckland, said: “We’ve known that blood pressure is notoriously difficult to control in patients with high blood sugar, so these findings are really important because by giving GLP-1 we might be able to reduce both sugar and pressure together, and these two factors are major contributors to cardiovascular risk.”

Lead author Audrys Pauža, PhD student in the Bristol Medical School, added: “The prevalence of diabetes and hypertension is increasing throughout the world, and there is an urgent need to address this.

“Drugs targeting the GLP-1 receptor are already approved for use in humans and widely used to treat diabetes. Besides helping to lower blood sugar these drugs also reduce blood pressure, however, the mechanism of this effect wasn’t well understood.

“This research revealed that these drugs may actually work on the carotid bodies to enact their anti-hypertensive effect. Leading from this work, we are already planning translational studies in humans to bring this discovery into practice so that patients most at risk can receive the best treatment available.”

The research has also revealed many novel targets for ongoing functional studies that the team hope will lead to studies in human hypertensive and diabetic patients.

Source: University of Bristol