Category: Metabolic Disorders

Categories : Diet and Nutrition Metabolic DisordersTags :

Red Meat Consumption Linked to Increased Type 2 Diabetes Risk

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“Meat’s back off the menu, boys”

Photo by Jose Ignacio Pompe on Unsplash

People who eat just two servings of red meat per week may have an increased risk of developing type 2 diabetes compared to people who eat fewer servings, and the risk increases with greater consumption, according to a new study in The American Journal of Clinical Nutrition. However, substituting plant or diary protein for red meat was associated with reduced risk of type 2 diabetes.

“Our findings strongly support dietary guidelines that recommend limiting the consumption of red meat, and this applies to both processed and unprocessed red meat,” said first author Xiao Gu, postdoctoral research fellow in the Department of Nutrition at Harvard T.H. Chan School of Public Health.

While previous studies have found a link between red meat consumption and type 2 diabetes risk, this study, which analysed a large number of type 2 diabetes cases among participants being followed for an extended period of years, adds a greater level of certainty about the association.

Type 2 diabetes rates are increasing rapidly in the US and worldwide. This is concerning not only because the disease is a serious burden, but it also is a major risk factor for cardiovascular and kidney disease, cancer, and dementia.

For this study, the researchers analysed health data from 216 695 participants from the Nurses’ Health Study (NHS), NHS II, and Health Professionals Follow-up Study (HPFS). Diet was assessed with food frequency questionnaires every two to four years, for up to 36 years. During this time, more than 22 000 participants developed type 2 diabetes.

The researchers found that consumption of red meat, including processed and unprocessed red meat, was strongly associated with increased risk of type 2 diabetes. Participants who ate the most red meat had a 62% higher risk of developing type 2 diabetes compared to those who ate the least. Every additional daily serving of processed red meat was associated with a 46% greater risk of developing type 2 diabetes and every additional daily serving of unprocessed red meat was associated with a 24% greater risk.

The researchers also estimated the potential effects of substituting one daily serving of red meat for another protein source. They found that substituting a serving of nuts and legumes was associated with a 30% lower risk of type 2 diabetes, and substituting a serving of dairy products was associated with a 22% lower risk.

“Given our findings and previous work by others, a limit of about one serving per week of red meat would be reasonable for people wishing to optimise their health and wellbeing,” said senior author Walter Willett, professor of epidemiology and nutrition.

In addition to health benefits, swapping red meat for healthy plant protein sources would help reduce greenhouse gas emissions and climate change, and provide other environmental benefits, according to the researchers.

Source: Harvard T.H. Chan School of Public Health

Categories : Metabolic DisordersTags :

Brain Changes from Shift Work Increase Appetite

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Photo by Ernest Brillo on Unsplash

Scientists have uncovered why night shift work is associated with changes in appetite in a new University of Bristol-led study. The study shows that circadian disruption can disrupt the brain’s regulation of appetite hormones. The findings, published in Communications Biology, could help the millions of people that work through the night and struggle with weight gain.

Scientists from Bristol and the University of Occupational and Environmental Health in Japan, sought to understand how ‘circadian misalignment’ – a phenomenon commonly associated with ‘jet-lag’ whereby the body’s biological clock is disrupted – affects the hormones responsible for regulating appetite.

Prevalent in night shift workers, in this new study, the international team reveal how circadian misalignment can profoundly alter the brain’s regulation of hormones controlling hunger to the detriment of metabolic health.

The team focused on glucocorticoid hormones in the adrenal gland which regulate many physiological functions including metabolism and appetite. Glucocorticoids are known to directly regulate a group of brain peptides controlling appetitive behaviour, with some increasing appetite (orexigenic) and some decreasing appetite (anorexigenic).

In an experiment using animal models, comprising a control group and a out-of-phase ‘jet-lagged’ group, the team found misalignment between light and dark cues led the out-of-phase group’s orexigenic hypothalamic neuropeptides (NPY) to become dysregulated, driving an increased desire to eat significantly more during the inactive phase of the day.

Strikingly, the team discovered that rats in the control group ate 88.4% of their daily intake during their active phase, and only 11.6% during their inactive phase. In contrast, the ‘jet-lagged’ group consumed 53.8% of their daily calories during their inactive phase (without an increase in activity during this time). This equated to nearly five-times more (460% more) than what the control group consumed during the inactive phase. These results show that it is timing of consumption that has been affected.

This new discovery revealed how completely, and significantly, disordered the neuropeptides become when daily glucocorticoid levels are out of synch with light and dark cues. However, the authors suggest the neuropeptides identified in this study may be promising targets for pharmacological treatments for eating disorders and obesity.

Research Fellow Dr Becky Conway-Campbell, the study’s senior author, said: “For people working throughout the night, a reversed body clock can play havoc with their health.

“For those who are working night shifts long-term, we recommend they try to maintain daylight exposure, cardiovascular exercise and mealtimes at regulated hours. However, internal brain messages to drive increased appetite are difficult to override with ‘discipline’ or ‘routine’ so we are currently designing studies to assess rescue strategies and pharmacological intervention drugs. We hope our findings also provide new insight into how chronic stress and sleep disruption leads to caloric overconsumption.”

Professor Stafford Lightman, co-senior author on the study, added: “The adrenal hormone corticosterone, which is normally secreted in a circadian manner, is a major factor in the daily control of brain peptides that regulate appetite. Furthermore when we disturb the normal relationship of corticosterone with the day to night light cycle it results in abnormal gene regulation and appetite during the period of time that the animals normally sleep.

“Our study shows that when we disturb our normal bodily rhythms this in turn disrupts normal appetite regulation in a way that is at least in part a result of desynchrony between adrenal steroid hormone production and the timing of the light and dark cycle.”

Dr Benjamin Flynn, one of the study’s co-authors who conducted the study while at Bristol but is now based at the University of Bath, added: “This is further evidence of how phase shift ‘jet-lag’ affects feeding behaviours and neuronal gene expression – data important for shift work co-morbidity research.”

Source: University of Bristol

Categories : Gastrointestinal Metabolic DisordersTags :

For Weight Loss, the Side Effects of GLP-1 Agonists can be Hard to Stomach

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Photo by Andres Ayrton on Pexels

GLP-1 agonists are being lauded as game-changers in the fight against obesity, but GLP-1 agonist drugs like semaglutide may come with a heightened risk of severe gastrointestinal problems, according to new research published in JAMA.

Designing their study for the side effects rather than the efficacy of the drugs, the researchers found that GLP-1 agonists are associated with an increased risk of serious medical conditions including gastroparesis (stomach paralysis), pancreatitis and bowel obstruction.

While previous studies highlighted some of these risks in patients with diabetes, this study from the University of British Columbia is the first large, population-level study to examine adverse gastrointestinal events in non-diabetic patients using the drugs specifically for weight loss.

“Given the wide use of these drugs, these adverse events, although rare, must be considered by patients thinking about using them for weight loss,” said first author Mohit Sodhi, a graduate of UBC’s experimental medicine program and fourth year UBC medical student studying the adverse events of commonly prescribed medications. “The risk calculus will differ depending on whether a patient is using these drugs for diabetes, obesity or just general weight loss. People who are otherwise healthy may be less willing to accept these potentially serious adverse events.”

GLP-1 agonists have exploded in popularity over the past decade as an off-label weight-loss tool, reaching approximately 40 million prescriptions in the US in 2022.

It was only in 2021 that some forms of the medications were approved as a treatment for obesity. However, randomised clinical trials examining the efficacy of the medications for weight loss were not designed to capture rare gastrointestinal events due to their small sample sizes and short follow-up periods.

“There have been anecdotal reports of some patients using these drugs for weight loss and then presenting with repeated episodes of nausea and vomiting secondary to a condition referred to as gastroparesis,” said senior author Dr Mahyar Etminan, an epidemiologist and associate professor in the department of ophthalmology and visual sciences at the UBC faculty of medicine. “But until now, there hasn’t been any data from large epidemiologic studies.”

To help fill this knowledge gap, UBC researchers examined health insurance claim records for approximately 16 million US patients and looked at people prescribed either semaglutide or liraglutide, two main GLP-1 agonists, between 2006 and 2020. They included patients with a recent history of obesity, and excluded those with diabetes or who had been prescribed another antidiabetic drug.

The researchers analysed the records to see how many patients developed one of four gastrointestinal conditions, and compared that rate to patients using another weight-loss drug, bupropion-naltrexone. Compared to bupropion-naltrexone, GLP-1 agonists were associated with a:

  • 9.09 times higher risk of pancreatitis, which can cause severe abdominal pain and, in some cases, require hospitalisation and surgery.
  • 4.22 times higher risk of bowel obstruction, resulting in symptoms like cramping, bloating, nausea and vomiting. Depending on the severity, surgery may be required.
  • 3.67 times higher risk of gastroparesis, limiting the passage of food from the stomach to the small intestine and results in symptoms like vomiting, nausea and abdominal pain.

Additionally, the study found a non-significant higher incidence of biliary disease.

The researchers say that although the events are rare, with millions around the world using the drugs, it could still lead to hundreds of thousands of people experiencing these conditions.

“These drugs are becoming increasingly accessible, and it is concerning that, in some cases, people can simply go online and order these kinds of medications when they may not have a full understanding of what could potentially happen. This goes directly against the mantra of informed consent,” said Sodhi.

In the meantime, the researchers hope that regulatory agencies and drug makers will consider updating the warning labels for their products, which currently don’t include the risk of gastroparesis.

“This is critical information for patients to know so they can seek timely medical attention and avoid serious consequences,” said Sodhi.

Source: University of British Columbia

Categories : Metabolic Disorders Obstetrics & GynaecologyTags :

Metformin Trial Offers Hope for Women with Gestational Diabetes

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A significant step forward has been taken in the management of gestational diabetes mellitus after a clinical trial involving pregnant women provided new hope for expectant mothers suffering the condition. The findings from the trial are published in the Journal of American Medical Association.

Gestational diabetes affects almost 3 million pregnant women worldwide every year. It is a condition characterised by elevated blood sugar levels during pregnancy, posing increased health risks for both mothers and their babies.

The EMERGE, randomised, placebo-controlled trial, was conducted by the University of Galway and involved more than 500 pregnant women.

The trial results showed that:

  • Women assigned to metformin were 25% less likely to need insulin, and when insulin was necessary, it was started later in the pregnancy.
  • Fasting and post-meal glycaemic values in the mother were significantly lower in the metformin exposed group at weeks 32 and 38.
  • Women receiving metformin gained less weight throughout the trial and maintained this weight difference at the 12-week post-delivery visit.
  • Importantly, delivery occurred at the same mean gestational age (39.1 weeks) in both groups. There was no evidence of any increase in preterm birth (defined as birth before 37 weeks) among those who received metformin.
  • Infants born to mothers who received metformin weighed, on average, 113g less at birth, with significantly fewer infants classified as large at birth, or weighing over 4kg.
  • While there was a slight reduction in infant length (0.7cm), there were no other significant differences in baby measurements.
  • There were slightly more babies who were small at birth but this did not reach statistical significance.

The study also revealed no differences in adverse neonatal outcomes, including the need for intensive care treatment for new-borns, respiratory support, jaundice, congenital anomalies, birth injuries or low sugar levels.

Additionally there were no variations in rates of labour induction, caesarean delivery, maternal haemorrhage, infection or blood pressure issues during or after birth.

Professor Fidelma Dunne managed the trial, and presented the results at the 59th Annual Meeting of the European Association for the Study of Diabetes in Hamburg, Germany.

Professor Dunne said, “While there is convincing evidence that improved sugar control is associated with improved pregnancy outcomes, there was uncertainty about the optimal management approach following a diagnosis of gestational diabetes.

“In our pursuit of a safe and effective treatment option we explored an alternative approach – administering the drug metformin. A previous trial compared metformin to insulin and found it to be effective, yet concerns remained, especially regarding preterm birth and infant size.”

To address concerns comprehensively, the team at University of Galway conducted a ground-breaking placebo-controlled-trial, filling a critical gap in the gestational diabetes treatment landscape.

  • 535 pregnant women took part, with 268 receiving metformin and 267 a placebo.
  • 98% of women remained in the trial until delivery, with 88% completing the 12-week post-delivery follow up assessment.
  • Only 4.9% of women discontinued medication due to side effects, highlighting the safety of the interventions.

Professor Dunne said, “Traditionally, gestational diabetes has been managed initially through dietary advice and exercise, with insulin introduced if sugar levels remain sub optimal. While effective in reducing poor pregnancy outcomes, insulin use is associated with challenges, including low sugars in both the mother and infant which may require neonatal intensive care, excess weight gain for mothers, and higher caesarean birth rates.” Professor Dunne added: “The results from the EMERGE study are a significant step forward for women with gestational diabetes. Metformin has emerged as an effective alternative for managing gestational diabetes, offering new hope for expectant mothers and healthcare providers worldwide.”

Source: University of Galway

Categories : Gender Metabolic DisordersTags :

Study Suggests Lowering Type 2 Diabetes Diagnosis Threshold in Women under 50

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Photo by National Cancer Institute on Unsplash

New research published in the journal Diabetes Therapy suggests that the diagnosis threshold for type 2 diabetes (T2D) should be lowered in women aged under 50 years, since natural blood loss through menstruation could be affecting their blood sugar management.

Analysis of the national diabetes audit results has shown that women of younger age with type 2 diabetes mellitus (T2D) seem to have a higher mortality rate than men. The underlying mechanisms remain unclear. However, it is known that women are on average diagnosed with T2D at a later age than men. In this new study, the authors investigated whether a contributing factor to this late diagnosis may be a sex difference in the levels of glycated haemoglobin (HbA1c) due to haemoglobin replacement linked to menstrual blood loss.

This mechanism behind this could be shorter erythrocyte (red blood cell) survival which results in shorter exposure of haemoglobin to glucose compared with individuals who do not menstruate. Given that the diagnosis of T2D is also based on HbA1c, the use of the same reference range irrespective of age and sex, when a slightly lower point for T2D for premenopausal women may be appropriate, could potentially lead to under diagnosis of T2D in women and missed opportunities for intervention.

The study, by Dr Adrian Heald, Salford Royal Hospital, UK, and colleagues, examined HbA1c testing across seven UK laboratory sites (representing 5% of UK population). They conducted an exploratory analysis in two cohorts: cohort 1 was from one laboratory tested between 2012 and 2019 (146 907 participants). They assessed the sex and age differences of HbA1c in individuals who underwent single testing only, that had not been diagnosed with diabetes and had an HbA1c result of equal to or less than 48mmol/mol (the cutoff for diagnosing diabetes). The process was replicated in cohort 2 results from six laboratories with individuals tested between 2019 and 2021 (total people included 938 678). The possible national impact was estimated by extrapolating findings based on the Office of National Statistics (ONS) England population data and National Diabetes Audit published T2D prevalence and related excess mortality.

At age 50 years, average HbA1c levels in women lag by approximately five years compared to men. The data also show women aged under 50 years old had an HbA1c distribution that was lower than that of men by an average of 1.6mmol/mol (4.7% of the overall mean) while the difference in the distribution of HbA1c for individuals aged 50 years and over was less pronounced.  Further analysis showed that, at HbA1c of 48mmol/mol, 50% fewer women could be diagnosed with T2D than men under the age of 50, whilst only 20% fewer women could be diagnosed with T2D than men over or equal to the age of 50. These findings were consistent with those in cohort 2.

Based on these observations, the authors estimated the effects of lowering the threshold for diagnosis of diabetes from HbA1c (48mmol/mol) by 4.2% to 46mmol/mol for women under the age of 50. This analysis showed that an additional 35 345 currently undiagnosed women in England would be reclassified as being diagnosed with T2D (17% more than the current 208 000 recorded women with T2D aged under 50 years). Lifestyle changes and treatment for diabetes would then be initiated for these women enabling improvement in health outcomes over both the short and longer term.

The authors also highlight that sex and gender difference in adverse cardiovascular risk factors are known to be present prior to the development of T2D. Once diagnosed, the prevalence of atherosclerotic cardiovascular disease is twice as high in patients with diabetes mellitus compared to those without diabetes mellitus. For women, diabetes mellitus is a stronger risk factor for cardiovascular disease than for men: women with diabetes aged 35–59 years have the highest relative cardiovascular death risk across all age and sex groups.

Furthermore, there is disparity in cardiovascular risk factor management between men and women, including in high-risk groups such as women with T2D.  Women are less likely than men to receive treatment and cardiovascular risk reduction interventions that are recommended by international guidelines on diabetes. In addition, concordance with medication or prescription treating cardiovascular risk factors is lower in women than men with T2D, with less use of statins, aspirin and beta blockers. The authors say taken together, these factors mean “timely diagnosis of type 2 diabetes and initiation of preventative treatment has the potential to improve cardiovascular risk profile over lifetime and facilitate longer life quality and expectancy in women. Our findings provide evidence that the HbA1c threshold for this group should be re-evaluated.”

Source: EurekAlert!

Categories : Metabolic DisordersTags :

Researchers Find a Mechanistic Link between Zinc Levels and Risk of Diabetes

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Researchers have identified a mechanistic link between zinc levels in humans and the risk of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). The research, published today as a Reviewed Preprint in eLife, is described by editors as a fundamental study that substantially advances our understanding of the role of zinc in metabolism. The evidence comes from genetic analysis of a large population of human participants and comprehensive lab studies of a potential therapeutic target for NAFLD and type 2 diabetes.

Converging lines of evidence have shown that zinc plays a crucial role in insulin production and glucose metabolism. “We know that increasing zinc intake improves blood glucose control in people with prediabetes or type 2 diabetes, and people with a mutation in a key zinc transporter protein have reduced risk of diabetes.” says first author Shek Man Chim, Principal Scientist at Regeneron Pharmaceuticals, Inc, New York, US. “However, the mechanism for how zinc influences systemic blood glucose levels and diabetes risk remains unclear.”

To explore the diabetes-protective role of zinc, Chim and colleagues tested loss-of-function mutations from genetic sequence data collected from a large population of participants of European ancestry who took part in the Regeneron Genetics Center-Geisinger Health System DiscovEHR study. This identified a rare mutation that causes loss of function in a zinc transporter protein called SLC39A5, associated with increased circulating zinc levels.

To confirm this, they looked at how loss-of-function mutations in SLC39A5 were associated with type 2 diabetes in a meta-analysis of four multi-ethnic European and US studies totalling >62 000 cases of diabetes and > 518 000 healthy controls. This confirmed that circulating zinc levels in carriers of the SLC39A5 loss-of-function mutation were elevated and associated with a reduced risk of diabetes.

Having identified SLC39A5 as an important clinical link between zinc and diabetes, the team explored its function by genetically deleting the zinc transporter protein in mice. As anticipated, these mice had elevated blood and tissue levels of zinc. When the team fed mice a high-fat, high-fructose diet to induce obesity, there was a significant reduction in fasting glucose compared to the control mice fed the same diet. Similar results were observed in a congenital (leptin receptor-deficiency) model of obesity. Loss of SLC39A5 also resulted in reduced insulin resistance.

As diabetes often coincides with NAFLD, the team explored whether loss of SLC39A5 protects the liver, too. As hoped, mice lacking SLC39A5 had less build-up of fat in the liver and in blood markers of liver damage. Moreover, mice lacking SLC39A5 but fed a high-fat, high-fructose diet also had less fat accumulation in the liver and improved insulin sensitivity compared to control mice.

The improvements seen in the livers of mice lacking SLC39A5 prompted the researchers to see whether loss of SLC39A5 protects against progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis (NASH), a more severe liver inflammation that leads to fibrosis. They used a high-fat, high-cholesterol diet to induce NASH in mice and found increased markers of liver damage, body weight, fasting blood glucose and liver fibrosis. By contrast, the mice lacking SLC39A5 had reduced liver damage markers, fasting blood glucose and improvements in liver inflammation and fibrosis.

One concern highlighted by public reviewers was that observed differences in the metabolic consequences of SLC39A5 inactivation between male and female mice remained unclear. Further work will need to explore this further, as well as characterise the role of SLC39A5 in pancreatic cell function and glucose tolerance more fully.

“Our study provides for the first-time genetic evidence demonstrating the protective role of zinc against high blood sugar and unravels the mechanistic basis underlying this effect,” concludes senior author Harikiran Nistala, currently Head of functional Genomics at Alkermes Inc, Waltham, US. “Our observations suggest that blocking SLC39A5 could be a potential therapeutic avenue for type 2 diabetes and other indications where zinc supplementation alone is inadequate.”

Source: eLife

Categories : Diet and Nutrition Metabolic DisordersTags :

Almonds Help Weight Loss and Improve Cardiometabolic Health

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Diets often recommend avoiding nuts as they contain a large amount of fat even though they are high in protein and fibre. Now, a large study published in the journal Obesity demonstrated that including almonds in an energy restricted diet not only helped participants to lose weight, but also improved their cardiometabolic health.

Examining the effects of energy restricted diets supplemented with Californian almonds or with carbohydrate- rich snacks, researchers found that both diets successfully reduced body weight by about 7kg.

Globally, more than 1.9 billion adults are overweight (650 million with obesity). Two in three people (approximately 12.5 million adults) are overweight or have obesity, as do one in every two South Africans.

UniSA researcher Dr Sharayah Carter says the study demonstrates how nuts can support a healthy diet for weight management and cardiometabolic health.

“Nuts, like almonds, are a great snack. They’re high in protein, fibre, and packed with vitamins and minerals, but they also have a high fat content which people can associate with increased body weight,” Dr Carter says.

“Nuts contain unsaturated fats – or healthy fats – which can improve blood cholesterol levels, ease inflammation, and contribute to a healthy heart.

“In this study we examined the effects of an almond-supplemented diet with a nut-free diet to identify any influence on weight and cardiometabolic outcomes.

“Both the nut and nut free diets resulted in approximately 9.3% reduction in body weight over the trial.

“Yet the almond-supplemented diets also demonstrated statistically significant changes in some highly atherogenic lipoprotein subfractions, which may lead to improved cardiometabolic health in the longer term.

“Additionally, nuts have the added benefit of making you feel fuller for longer, which is always a pro when you’re trying to manage your weight.”

The study, funded by the Almond Board of California, had 106 participants complete a 9-month eating program (a three-month energy-restricted diet for weight loss in Phase 1, followed by Phase 2, a six-month energy-controlled diet for weight maintenance). In both phases, 15% of participants’ energy intake comprised unsalted whole almonds with skins (for the nut diet) or 15% carbohydrate-rich snacks – such as rice crackers or baked cereal bars (for the nut-free diet).

Reductions occurred in fasting glucose (−0.2mmol/L), insulin (−8.1pmol/L), blood pressure (−4.9 mmHg systolic, −5.0mmHg diastolic), total cholesterol (−0.3 mmol/L), low-density lipoprotein (LDL) (−0.2mmol/L), very low-density lipoprotein (−0.1mmol/L), and triglycerides (−0.3mmol/L), and high-density lipoprotein increased (0.1mmol/L) by the end of Phase 2 in both groups.

Source: University of South Australia

Categories : Cardiovascular Disease Metabolic DisordersTags :

New Research Points to Clot Lysis Protein for Cholesterol Control

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Source: Wikimedia CC0

While high levels of low-density lipoprotein (LDL) can be reduced by drugs such as statins, reducing the risk of myocardial infarction and stroke, risk still remains in the form of other cholesterols. New research published in the journal Science describes how manipulating a protein involved in blood clot lysis could help bring cholesterol levels even more under control.

Heart disease remains a leading cause of death worldwide, despite advances in cholesterol-lowering medication such as proprotein convertase subtilisin-kexin type 9 inhibitors, which were approved by the FDA in 2015. One clinical trial following patients taking proprotein convertase subtilisin-kexin type 9 inhibitors demonstrated a benefit while also revealing an opportunity for improvement as the absolute risk reduction was considered modest at 1.5%.

“It is clear that there is more going on than just what statins and these newer inhibitor drugs can control,” says Ze Zheng, MBBS, PhD, MCW assistant professor of medicine. “More therapies are needed, and to get them we need to know more about other sources of risk for heart disease, especially heart attacks and strokes.”

So-called “bad cholesterol” is carried by apolipoprotein B (apoB) which forms well-structured particles with lipids and proteins. These particles serve as stable vehicles for transporting lipids such as cholesterol in the bloodstream. These lipid-rich particles mostly include very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). Current cholesterol-lowering reduce mainly LDL levels, which though important to control, is not the only risk factor for heart disease. In fact, the other lipoproteins in the same group as LDL are not reduced by much with available treatments. Dr Zheng and her team are investigating how to reduce levels of other members of this family of lipoproteins, especially VLDL.

“With my background in lipid metabolism, I found myself consistently checking lipid levels even during studies regarding blood clot lysis and how an impairment in the body’s ability to remove blood clots affects the risk of blood vessel blockages,” Dr Zheng adds. “I was just naturally curious about it, and I noticed that a protein I was studying may have an effect on the amount of circulating cholesterol.”

In prior research, Dr Zheng has helped define a new cellular source of this protein, tissue-type plasminogen activator (tPA), and its role in breaking down blood clots and preventing blood vessel blockages. To understand its potential influence on cholesterol levels, her team used a gene-editing technique to stop liver cells from producing tPA in mice prone to blood vessel plaque formation. The scientists found that the mice developed increased lipoprotein-cholesterol in this experiment, and then validated the findings in follow-up studies using human liver cells and a type of rat liver cell known to produce VLDL in a way similar to human liver cells. With these and other experimental results, Dr Zheng and her team have demonstrated a new, important role that liver tPA influences blood cholesterol levels while underscoring a meaningful connection between the liver, heart and blood vessels.

“After defining this new role for tPA, we turned our attention to the question of how it changes blood cholesterol levels,” notes Wen Dai, MD, research scientist, Versiti Blood Research Institute.

The liver contributes to the majority of the “bad” apoB-lipoproteins by making VLDL. The team focused on whether and how tPA impacts the process of VLDL assembly in the liver. Microsomal triglyceride transfer protein (MTP) is required for the assembly of VLDL due to its role carrying lipids to the apoB. The scientists determined that tPA binds with the apoB protein in the same place as MTP. The more tPA is present, the fewer opportunities MTP has to connect with apoB and catalyse the creation of new VLDL. Essentially, MTP tries to pass a cholesterol to apoB, but tPA interferes with this pocess.

“Based on our prior research, we knew it also was critical to look at tPA’s primary inhibitor,” Dr. Zheng says.

Plasminogen activator inhibitor-1 (PAI-1) is known to block the activity of tPA. Scientists also have found a correlation between PAI-1 levels in blood and the development of disease due to plaque formation and blockages in blood vessels. The team found that higher levels of PAI-1 reduced the ability of tPA to bind with apoB proteins, rendering tPA less effective at competing with MTP to prevent VLDL production. Returning to the biological gridiron, PAI-1 might be a decoy receiver that distracts tPA until MTP connects with apoB for a big gain. The team studied this interaction in human subjects with a naturally occurring mutation in the gene carrying the code for PAI-1. The researchers found that these individuals, as predicted, had higher tPA levels and lower LDL and VLDL levels than individuals from the same community who did not have the same mutation.

“We are investigating therapeutic strategies based on these findings regarding tPA, MTP and PAI-1,” Dr Zheng notes. “I think we may be able to reduce the residual cardiovascular risk that has persisted even as treatment has advanced.”

Source: Medical College of Wisconsin

Categories : Metabolic DisordersTags :

Semaglutide Eliminates Insulin Injections in Some Newly-diagnosed Type 1 Diabetes Patients

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Novolog insulin pen. Photo by Dennis Klicker on Unsplash

Treating newly diagnosed Type 1 diabetes patients with semaglutide may drastically reduce or even eliminate their need for injected insulin, according to the remarkable findings of a small University at Buffalo study reported in the New England Journal of Medicine.

“Our findings from this admittedly small study are, nevertheless, so promising for newly diagnosed Type 1 diabetes patients that we are now absolutely focused on pursuing a larger study for a longer period of time,” says Paresh Dandona, MD, PhD, professor and senior author on the paper.

A total of 10 patients at UB’s Clinical Research Center in the Division of Endocrinology were studied from 2020 to 2022, all of whom had been diagnosed in the past three to six months with Type 1 diabetes. The mean HbA1c level over 90 days at diagnosis was 11.7, far above the American Diabetes Association’s HbA1c recommendation of 7 or below.

The patients were treated first with a low dose of semaglutide while also taking meal-time (bolus) insulin and basal (background) insulin. As the study continued, semaglutide dosing was increased while mealtime insulin was reduced in order to avoid hypoglycaemia.

“Within three months, we were able to eliminate all of the mealtime insulin doses for all of the patients,” says Dandona, “and within six months we were able to eliminate basal insulin in 7 of the 10 patients. This was maintained until the end of the 12-month follow-up period.”

During that time, the patients’ mean HbA1c fell to 5.9 at six months and 5.7 at 12 months.

Applying Type 2 diabetes drugs to treat Type 1 diabetes

For more than a decade, Dandona has been interested in how drugs developed for Type 2 diabetes might be utilized in treating Type 1 diabetes as well.

He and his colleagues were the first to study how liraglutide, another drug for Type 2 diabetes, might work in patients with Type 1 diabetes in a study he published in 2011.

“As we extended this work, we found that a significant proportion of such diabetics still have some insulin reserve in the beta cells of their pancreas,” Dandona explains. “This reserve is most impressive at the time of diagnosis, when 50% of the capacity is still present. This allowed us to hypothesise that semaglutide, which works through stimulation of insulin secretion from the beta cell, could potentially replace mealtime insulin administration.”

From the outset, the goal of the current study was to see if semaglutide treatment could be used to replace mealtime insulin, thereby reducing the insulin dosage, improving glycaemic control, reducing the HbA1c and eliminating potentially dangerous swings in blood sugar and hypoglycaemia.

The most common side effects for patients were nausea and vomiting as well as appetite suppression, which led a number of patients to experience weight loss, an outcome that Dandona says is generally an advantage since 50% of patients with Type 1 diabetes in the US are overweight or obese.

“As we proceeded with the study, we found that even the dose of basal insulin could be reduced or eliminated altogether in a majority of these patients,” he says. “We were definitely surprised by our findings and also quite excited. If these findings are borne out in larger studies over extended follow-up periods, it could possibly be the most dramatic change in treating Type 1 diabetes since the discovery of insulin in 1921.”

Source: University at Buffalo

Categories : Metabolic Disorders Regenerative MedicineTags :

Microvascular Implants may Enable Faster Healing of Chronic Wounds

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Researchers in South Korea have achieved a ground-breaking milestone in tissue regeneration with a technology that utilises autologous blood to produce three-dimensional microvascular implants. These implants hold immense potential for various applications requiring vascular regeneration, including the treatment of chronic wounds in conditions such as diabetes, as well as the potential for scarless healing.

Led by Professor Joo H. Kang from the Department of Biomedical Engineering at UNIST, the team successfully developed a microfluidic system capable of processing blood into an artificial tissue scaffold. Unlike previous methods based on cell-laden hydrogel patches using fat tissues or platelet-rich plasma, this innovative approach enables the creation of robust microcapillary vessel networks within skin wounds. The utilisation of autologous whole blood ensures compatibility and promotes effective wound healing.

Creating optimal stiffness

The technology, described in Advanced Materials, leverages microfluidic shear stresses to align bundled fibrin fibres along the direction of blood flow streamlines while activating platelets. This alignment and activation process results in moderate stiffness within the microenvironment – optimal conditions for facilitating endothelial cell maturation and vascularisation. When applied as patches to rodent dorsal skin wounds, these implantable vascularided engineered thrombi (IVETs) demonstrated superior wound closure rates (96.08 ± 1.58%), increased epidermis thickness, enhanced collagen deposition, hair follicle regeneration, reduced neutrophil infiltration, and accelerated wound healing through improved microvascular circulation.

Chronic wounds pose significant challenges as they often fail to heal properly over time and can lead to complications associated with diabetes and vascular diseases. In severe cases, they may result in sepsis due to insufficient oxygen supply and nutrients caused by loss of blood vessels.

By harnessing the power of microfluidic technology, Professor Kang’s team transformed autologous blood into IVETs suitable for transplantation. These IVETs were implanted into full-thickness skin wounds in experimental mice, resulting in rapid and scarless recovery of the entire damaged area. The study demonstrated successful regeneration of blood vessels within the wound site, facilitated movement of immune cells crucial for wound healing, and accelerated overall recovery.

Furthermore, the team evaluated the efficacy of IVET transplantation by infecting the skin damage area with methicillin-resistant Staphylococcus aureus (MRSA). When artificial blood clots made from autologous blood were implanted into infected mice, quick vascular recovery was observed alongside enhanced migration of proteins and immune cells to combat bacterial infection. Additionally, collagen formation and hair follicle regeneration occurred without scarring.

These ground-breaking findings pave the way for advanced techniques in tissue engineering and wound healing using autologous blood-based implants. With further development and refinement, this technology holds tremendous potential to revolutionise treatment strategies for chronic wounds while contributing to advancements in regenerative medicine.

Source: Ulsan National Institute of Science and Technology (UNIST)