Category: Metabolic Disorders

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Sanofi Commits to Affordable Insulin Pens for Diabetic Patients

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Novolog insulin pen. Photo by Dennis Klicker on Unsplash

Over the past few years, there has been a notable shift towards the use of insulin pens in the public sector, replacing traditional vials. This transition has been driven by the advantages insulin pens offer, including improved dosing accuracy, ease of use for patients, greater convenience, and better adherence to treatment.1

The move to basal insulin is in line with the National Strategic Plan for the Prevention and Control of Non-Communicable Diseases 2022-2027, which outlines specific targets for managing diabetes. This plan aims to improve early detection and treatment of diabetes by ensuring that 90% of people over 18 know their blood pressure and blood sugar levels. It also aims for 60% of those with high levels to receive treatment, and 50% of those treated to have their levels under control. These measures are designed to improve the management and outcomes of diabetes in the population.2

Since May 2023, the Department of Health has faced insulin pen rationing as the previous sole supplier opted not to tender. Nearly 50% of the insulin required for patients was expected to come in pen sets. To mitigate the impact, the health department has sourced a limited supply of insulin pens and analogues for vulnerable groups like the elderly, young children, and visually impaired individuals, despite the higher cost of insulin analogues, which offer more convenient and effective blood sugar management.3

In 2021, long-acting analogue insulins were added to the WHO Model List of Essential Medicines (EML) and have significantly reduced aligning with those of human insulin.3 Recognising this need, Sanofi has adjusted the price of its basal insulin to the cost of human insulin in South Africa.

Sanofi has been engaging with the National Department of Health to meet the needs of vulnerable patient groups,” says Dr Asafika Mbangata, Medical Advisor for Diabetes and Established Products, Sanofi. “A circular has been released by the department, identifying patient groups that would benefit from analogue insulins. This includes vulnerable groups like the elderly, young children, and visually impaired individuals. Sanofi is committed to ensuring that patients have access to treatment which will help control the disease by achieving adequate glycaemic control and eventually, prevention of complications in South Africa.”

Long-acting insulin analogues offer significant clinical benefits over human insulin, including prolonged duration of action,4 more stable glucose control with less hypoglycaemia, and reduced need for multiple daily doses.5 These benefits are particularly crucial for patients experiencing dangerously low blood glucose levels with human insulin.5 In addition, reductions in HbA1c (a key blood sugar indicator) are greater with all basal insulin analogues compared to human basal insulins.6

Diabetes Type 1

It’s estimated that more than 31 000 people in South Africa live with Type 1 diabetes and require full insulin replacement therapy, with multiple daily injections. Among them, 5000 are children.7

“Insulin pens, which are more accurate, user-friendly, and associated with less pain when used with short and fine needles, significantly enhance their quality of life,” says Dr. Mbangata. “This is particularly important for children, who are more likely to adhere to their treatment schedules with the easier-to-use and less painful pens.”

Diabetes Type 2

According to the International Diabetes Federation (IDF), 4.2 million South African adults are living with diabetes, primarily type 2.7 Of these, 84% access diabetes care in the public sector. Diabetes is the second leading cause of death in South Africa, following tuberculosis, and the leading cause of death among females.8

More than 9% of the South African population is 60 or older.9 Around 600 000 elderly individuals are living with diabetes, with approximately 500 000 of them accessing public sector healthcare.10

Treating diabetes in the elderly often requires a multidrug regimen, including insulin therapy. However, due to comorbidities such as dementia, vision loss, neuropathies, poor mobility, and manual dexterity issues, elderly patients are at increased risk of hypoglycaemia and dosing errors associated with insulin administration. Insulin pen devices have been shown to provide more reliable, accurate, and simplified dosing, making them a safer and more acceptable method of insulin delivery for the elderly population.11

Impaired vision

Diabetic retinopathy (impaired vision) is the third most common cause of blindness in South Africa, following cataracts and glaucoma​​.12 A pilot project screening for diabetic retinopathy in primary care at three Cape Town community healthcare centres assessed 400 patients living with diabetes. Over 80% had significantly reduced visual acuity, and 63% had retinopathy.12 These visually impaired patients would greatly benefit from using insulin pens, which make a clicking sound when the dial is turned, indicating the dose.

“Against the backdrop of these statistics, Sanofi continues in its efforts to make insulin pens more affordable and accessible, and our aim is to improve the quality of life and healthcare outcomes for South Africa’s diabetic population,” says Prudence Selani, External Affairs Head, Sanofi.

References

  1. Diabetes Spectr 2012;25(2):117–122
  2. Health Policy Watch. New WHO Essential Medicines List Includes Controversial Insulin Analogues. Available from: https://healthpolicy-watch.news/who-essential-medicines-insulin-analogues/
  3. Brunetti VC et al. Diabetes ObesMetab. 2022;1–13
  4. Sims EK et al. Nat Med. 2021;27:1154-64
  5. MannucciE et al. Endocrine. 2021;74:508-17
  6. IDF Diabetes Atlas 10th edition 2021
  7. Report-03-08-012018 (www.statssa.gov.za)
  8. StatsSA report: Marginalised Groups Series VI: The Social Profile of Older Persons, 2017–2021
  9. Werfalli M, Kassanjee R, Kalula S, Kowal P, Phaswana-Mafuya N, Levitt NS. Diabetes in South African older adults: prevalence and impact on quality of life and functional disability – as assessed using SAGE Wave 1 data. Glob Health Action. 2018;11(1):1449924. doi: 10.1080/16549716.2018.1449924. PMID: 29699475; PMCID: PMC5933282.
  10. Wright BM, Bellone JM, McCoy EK. A review of insulin pen devices and use in the elderly diabetic population. Clin Med Insights Endocrinol Diabetes. 2010;3:53-63. doi: 10.4137/CMED.S5534. Epub 2010 Nov 22. PMID: 22879787; PMCID: PMC3411523.
  11. Bertram MY, Jaswal AV, Van Wyk VP, Levitt NS, Hofman KJ. The non-fatal disease burden caused by type 2 diabetes in South Africa, 2009. Glob Health Action 2013;6:12944. [http://dx.doi.org/10.3402/gha.v6i0.19244]
  12. Cairncross JP, Steinberg WJ, Labuschagne MJ. Prevalence of eye pathology in a group of diabetic patients at National District Hospital Outpatient Department in Bloemfontein, South Africa. Afr J Prim Health Care Fam Med. 2017 Sep 27;9(1):e1-e7. doi: 10.4102/phcfm.v9i1.1440. PMID: 29041796; PMCID: PMC5645559.
Categories : Metabolic DisordersTags :

Strong Link Between Haem Iron in Red Meat and Type 2 Diabetes Risk

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Photo by Jose Ignacio Pompe on Unsplash

Higher intake of haem iron, the type found in red meat and other animal products – as opposed to non-haem iron, found mostly in plant-based foods – was associated with a higher risk of developing type 2 diabetes (T2D) in a new study published in Nature Metabolism. While the link between haem iron and T2D has been reported previously, the findings from this study, which was led by Harvard T.H. Chan School of Public Health, more clearly establish and explain the link.

“Compared to prior studies that relied solely on epidemiological data, we integrated multiple layers of information, including epidemiological data, conventional metabolic biomarkers, and cutting-edge metabolomics,” said lead author Fenglei Wang, research associate in the Department of Nutrition. “This allowed us to achieve a more comprehensive understanding of the association between iron intake and T2D risk, as well as potential metabolic pathways underlying this association.”

The researchers assessed the link between iron and T2D using 36 years of dietary reports from 206 615 adults (79% female) enrolled in the Nurses’ Health Studies I and II and the Health Professionals Follow-up Study. They examined participants’ intake of various forms of iron – total, haem, non-haem, dietary (from foods), and supplemental (from supplements) – and their T2D status, controlling for other health and lifestyle factors.

The researchers also analysed the biological mechanisms underpinning haem iron’s relationship to T2D among smaller subsets of the participants. They looked at 37 544 participants’ plasma metabolic biomarkers, including those related to insulin levels, blood sugar, blood lipids, inflammation, and two biomarkers of iron metabolism. They then looked at 9024 participants’ metabolomic profiles – plasma levels of small-molecule metabolites.

The study found a significant association between higher haem iron intake and T2D risk. Participants in the highest intake group had a 26% higher risk of developing T2D than those in the lowest intake group. In addition, the researchers found that haem iron accounted for more than half of the T2D risk associated with unprocessed red meat and a moderate proportion of the risk for several T2D-related dietary patterns. In line with previous studies, the researchers found no significant associations between intakes of non-haem iron from diet or supplements and risk of T2D.

The study also found that higher haem iron intake was associated with blood metabolic biomarkers associated with T2D. A higher haem iron intake was associated with higher levels of biomarkers such as C-peptide, triglycerides, C-reactive protein, leptin, and markers of iron overload, as well as lower levels of beneficial biomarkers like HDL cholesterol and adiponectin.

The researchers also identified a dozen blood metabolites – including L-valine, L-lysine, uric acid, and several lipid metabolites – that may play a role in the link between haem iron intake and TD2 risk. These metabolites have been previously associated with risk of T2D.

On a population level, the study findings carry important implications for dietary guidelines and public health strategies to reduce rates of diabetes, according to the researchers. In particular, the findings raise concerns about the addition of heme to plant-based meat alternatives to enhance their meaty flavor and appearance. These products are gaining in popularity, but health effects warrant further investigation.

“This study underscores the importance of healthy dietary choices in diabetes prevention,” said corresponding author Frank Hu, Fredrick J. Stare Professor of Nutrition and Epidemiology. “Reducing haem iron intake, particularly from red meat, and adopting a more plant-based diet can be effective strategies in lowering diabetes risk.”

The researchers noted that the study had several limitations, including the potential for incomplete accounting for confounders and measurement errors in the epidemiological data. In addition, the findings – based on a study population that was mostly white – need to be replicated in other racial and ethnic groups.

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

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Do Dietitians have Weight Bases Towards Themselves and Others?

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In a survey-based study, UK dietitians exhibited significant weight stigma, both towards themselves and towards others.

The study in the Journal of Human Nutrition and Dietetics involved an online survey completed in 2022 by 402 registered dietitians aged 20–70 years old. Most respondents reported personally experiencing weight stigma prior to (51%) and after becoming (59.7%) registered dieticians, and nearly a quarter (21.1%) felt that their weight influenced their own ability to perform as a dietitian.

Weight stigma was experienced across the weight spectrum. Participants reported explicit (or conscious) weight bias attitudes, moderate beliefs that obesity is controllable, and implicit (or unconscious) anti-fat bias.

“The study highlights the need to address weight stigma and its implications within the dietetic profession,” the authors wrote.

Source: Wiley

Categories : Metabolic Disorders New Compounds and TreatmentsTags :

Controlling Lipid Levels with Less Side Effects Possible with New Drug

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Image Credit: Institute of Transformative Bio-Molecules (ITbM), Nagoya University

Researchers at Nagoya University in Japan have developed a new compound, ZTA-261, that binds to thyroid hormone receptor beta (THRβ). THRβ plays an important role in the regulation of lipid metabolism, which affects lipid levels in the blood. Mice administered the drug showed decreased lipid levels in the liver and blood, with fewer side effects in the liver, heart, and bones compared to existing compounds.  These findings, published in Communications Medicine, suggest that ZTA-261 is an effective treatment for lipid disorders such as dyslipidaemia.

Approximately one in ten people is classified as obese or overweight, often due to abnormalities in lipid metabolism. Abnormal levels of lipids in the blood, known as dyslipidaemia, lead to an increased risk of chest pain, heart attack, and stroke.

There is growing interest in developing treatments for dyslipidaemia that leverage the properties of thyroid hormones. Thyroid hormones increase overall metabolism through binding to two types of receptors: alpha (THRα) and beta (THRβ). The brain, heart, and muscle contain the α-subtype, whereas the liver and pituitary gland primarily express the β-subtype.

Treatments that rely on THR activation face challenges due to the side effects of thyroid hormones. Although THRα regulates cardiovascular functions, excess levels of thyroid hormone lead to adverse effects in nearby organs such as heart enlargement and muscle and bone wasting. On the other hand, activation of THRβ influences lipid metabolism without these severe side effects.

As a result, THRβ has become a desirable target for treating metabolic disorders such as dyslipidaemia. However, common treatments, such as the natural thyroid hormone T3, show almost no selectivity between the α and β receptors, making it difficult to avoid the severe side effects caused by binding to THRα.

To address this problem, a research team, including Masakazu Nambo, Taeko Ohkawa, Ayato Sato, Cathleen Crudden, and Takashi Yoshimura from Nagoya University’s WPI-ITbM, developed ZTA-261, a thyroid hormone derivative drug with a similar structure. To test its efficacy, they compared it with GC-1, another thyroid hormone derivative, and the natural thyroid hormone T3 in a mouse model.

They found that ZTA-261 had almost 100 times higher selectivity for THRβ than THRα. In comparison, GC-1 showed only a 20-fold difference in affinity, showing ZTA-261’s superior selectivity. This was confirmed by the significant increase in heart weight and bone damage indicators in T3-treated mice but not in those treated with ZTA-261.

“Our findings suggest that ZTA-261 is much less toxic than T3 and even less toxic than GC-1, which is known as a THRβ-selective compound,” Ohkawa said. “I find it amazing that the difference in THR beta-selectivity between ZTA-261 and GC-1 – 100 times selectivity versus 20 times selectivity – truly has this big an impact on heart and bone toxicity.”

As many drugs have been discontinued in preclinical trials because of their toxicity in the liver, the researchers checked for potential liver toxicity by measuring alanine aminotransferase (ALT) levels in the blood. Their findings confirmed the safety of the drug, finding no significant differences in ALT levels between mice treated with ZTA-261 and those treated with saline. Although these results are promising, more studies, including human trials, will be necessary before considering ZTA-261 for clinical use. However, this breakthrough represents a significant step forward in the development of safer treatments for lipid disorders.

“ZTA-261 has extremely high affinity and selectivity for THRβ among the thyroid hormone derivatives developed to date,” Nambo explained. “In the process of synthesising a variety of derivatives, we have found that precise molecular design is crucial for both selectivity and affinity. We believe that this study will provide new and important insights into drug discovery.”

Source: Institute of Transformative Bio-Molecules (ITbM), Nagoya Universityy

Categories : Metabolic DisordersTags :

Body Appreciation Varies Across Cultures

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Body appreciation levels are associated with internalisation of thin ideals and with sociocultural pressure, which vary by culture and age

Photo by I Yunmai on Unsplash

People from different cultures show both similarities and differences in how body appreciation, sociocultural pressure, and internalisation of thin ideals vary, according to a study published July 31, 2024 in the open-access journal PLOS ONE by Louise Hanson from Durham University, UK, and colleagues.

Body image is a multifaceted and complex phenomenon encapsulating how we think, behave, and feel about our body. To date, most body image research has focused on young, White, Western women, and has focused on negative rather than positive body image.

By contrast, Hanson and colleagues examined body appreciation, encapsulating positive thoughts and feelings regarding one’s own body. They also included participants not only from Western countries (ie, Australia, Canada, United Kingdom, United States of America), but also China and Nigeria. A final sample of 1186 women completed the questionnaires and were included in the analysis.

The results did not reveal significant difference in body satisfaction between women of different ages, but there was significant variation between cultures. Black Nigerian women had the highest body appreciation, followed by Eastern Asian Chinese women, with White Western women reporting lowest body appreciation. The findings suggest that ethnicity and culture are important influences on body appreciation and might act as protective factors that promote positive body image.

High internalisation of the thin ideal, and high perceived pressure about appearance from family, peers, and the media, were associated with lower body appreciation. Internalisation varied by age in some cultures: older White Western and Black Nigerian women reported lower thin-ideal internalisation than younger women, but Chinese women experienced the same thin-ideal internalisation across the lifespan.

For women from all cultures, older women reported lower perceived sociocultural pressure than younger women. White Western women experienced more perceived pressure from the media than Black Nigerian and Chinese women, but Chinese women reported the most pressure from peers. The results also showed that Black Nigerian women reported the lowest sociocultural pressure overall, and that Chinese women reported the most pressure.

The authors suggest that future studies should include more women in older age groups to obtain a fully representative picture of women’s body appreciation across the lifespan. In addition, further development of measurement tools is necessary for future research in cross-cultural contexts. According to the authors, the results of the current study could be used to target positive body image interventions to each culture. Further research may be required to develop effective interventions for each group.

The authors add: “We found that body appreciation was relatively stable across all ages and sociocultural pressure was evident in all cultures. However, the extent to which this pressure was experienced and where it came from differed across cultures.”

Provided by PLOS

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Recent Steps in Treatment and Management Show Promise in Stemming the Rise of Diabetes

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A new paper surveying advances in diabetes pathogenesis and treatment explores the complex factors contributing to the onset and progression of the disease, suggesting that an understanding of these dynamics is key to developing targeted interventions to reduce the risk of developing diabetes and managing its complications.

In a paper in a special 50th anniversary issue of the peer-reviewed journal Cell, the authors surveyed hundreds of studies that have emerged over the years looking at the causes underpinning types 1 (T1D) and 2 (T2D) diabetes and new treatments for the disease. They examine the role that genes, environmental factors, and social determinants of health play and diabetes’ effect on cardiovascular and kidney disease.

What they found shows there are many advances in treatments that could stem the tide of a disease that has struck millions of people around the globe and continues to grow. In addition, some of these advances could be used to treat other disorders. But there are still challenges ahead.

“As the prevalence of diabetes continues to grow around the world, it is important to understand the latest advancements in research so that clinicians can provide the best care to their patients, and patients can make informed choices that support improved health outcomes,” said lead author Dr E. Dale Abel, chair of the UCLA Department of Medicine. “This is an educational resource that integrates the latest research and trends in diabetes management, which may have implications for clinical practice as the diabetic patient population continues to grow.

“This review will be the go-to reference for physicians and researchers, providing a state-of-the-art update of where the field is currently, and where it is headed,” Abel added.

Most people are affected by type 2 diabetes, for which inadequate diet and obesity are important underlying causes. Type 1 diabetes accounts for fewer than 5% of all cases. As of 2021 about 529 million people around the world were diagnosed with diabetes, representing about 6.1% of the global population, or about one in 16 people. Prevalence in some regions is as high as 12.3%. Type 2 diabetes comprises about 96% of cases, with more than half due to obesity. Some 1.31 billion people are projected to have the disease by 2050, with prevalence rising as high as 16.8% in North Africa and the Middle East and 11.3% in Latin America and the Caribbean, the researchers write.

Genetics, the central nervous system, and the interplay between various organs as well as social and environmental factors such as food insecurity and air pollution play a role in development of diabetes.

But some recent discoveries represent significant strides toward managing and perhaps even reversing the disease. For instance, a 2019 study found that a 14-day course of the antibody teplizumab delayed the progression of type 1 diabetes from stage 1 to stage 3 by 24 months. A follow-up analysis in 2021 showed that the delay could be up to 32.5 months.

Based on these results, the U.S. Food and Drug Administration approved teplizumab as the first disease-modifying therapy for type 1 diabetes, the researchers write.

Advances in insulins with optimised pharmacokinetics, algorithm-driven subcutaneous insulin pumps, continuous glucose monitoring, and improved tools for self-management have significantly improved the quality of life and outcomes for people with stage 3 type 1 diabetes.

In addition, stem cells could replace insulin-producing cells that are lost in type 1 diabetes, Abel said.

For type 2 diabetes, three classes of glucose-lowering medicines that were introduced in the last 20 years – GLP1RAs (glucagon like peptide-1 receptor agonists), DPP-4 inhibitors, and SGLT-2 inhibitors – have enabled people to control their glucose levels without gaining weight and with a low risk of developing hypoglycaemia. Personalised and precision medicine approaches are being explored to target the molecular mechanisms behind diabetes. However, they must demonstrate that benefits are clinically superior to standard care and are cost-effective. Also, it remains to be seen if precision approaches can be implemented in all settings worldwide, including those with few resources.

Combinations of GLP1Ras and with molecules that target other receptors such as GIP have shown even greater efficacy in treating diabetes. Recent trials have also shown that they are very effective in treating obesity, certain types of heart failure and even sleep apnoea, in part because of their potency to induce weight loss and reduce inflammation. Clinical trials are now underway to test their efficacy in treating other disorders such as Alzheimer’s disease, Abel said.

“Advances in therapy now raise the hope of preventing or curing T1D and treating T2D in ways that not only improve metabolic homeostasis, but also concretely reduce the risk and progression of cardio-renal disease,” the researchers write. “Finally, as we understand and develop tools for discerning the underlying heterogeneity leading to diabetes and its complications, the stage will be set for targeting therapies and prevention strategies to optimize their impact, in ways that will be broadly applicable across diverse populations and availability of health care resources.”

Source: UCLA Health

Categories : Gastrointestinal Metabolic DisordersTags :

Targeting Inflammation may Not Help Reduce Liver Fibrosis in MAFLD

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Source: CC0

Researchers at UCLA Health uncovered new information about the role inflammation plays in mitigating liver fibrosis, which is associated with metabolic-associated fatty liver disease (MAFLD).  While inflammation in the liver has long been considered a prerequisite to developing liver fibrosis, the scarring and thickening of tissue that can impair the liver’s ability to function, this new research, published in the Journal of Clinical Investigation, suggests that reducing inflammation may not influence the extent of fibrosis. 

“Liver fibrosis is the critical feature that creates chronic liver disease and liver cancer. If we can keep fibrosis in check then we can meaningfully impact liver disease,” said Tamer Sallam, MD, corresponding author of the study and vice chair and associate professor in the department of medicine at the David Geffen School of Medicine at UCLA. 

“For decades we have believed that targeting inflammation is one of the most important ways to reduce MAFLD. But this new research indicates that inflammation, while still important, may not be the main driver of fibrosis.”

The study looked specifically at a protein called lipopolysaccharide binding protein (LBP), which is involved in the body’s immune response, and how LBP functions in mice. Findings showed that mice without LBP in their liver cells had lower levels of liver inflammation and better liver function but no change in fibrosis. 

In addition to mouse models, the researchers also studied genetic analyses from large human datasets and human tissue samples from MAFLD patients at different stages in the disease, to examine the consequence of loss of LBP function. The evidence combined showed that the LBP does not alter scar tissue markers. 

Sallam indicated a need to further explore how LBP influences inflammation and whether other factors can offer a more potent reduction in inflammation and have an impact on reducing fibrosis. 

“Reducing scar burden is one of the holy grails in the treatment of advanced liver diseases,” Sallam said. “These results suggest that certain ways of targeting inflammation may not be a viable option and that more directed therapies against other pathways could help us better target fibrosis and improve outcomes for patients.”

Source: UCLA Health

Categories : Diet and Nutrition Metabolic DisordersTags :

Caution Advised in Following High-protein ‘Paleo’ Diets

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Photo by Jose Ignacio Pompe on Unsplash

High-protein diets, known as ‘‘Paleolithic diets’’, are popular. Using mouse models, scientists at the University of Geneva (UNIGE) have studied their impact. While effective in regulating weight and stabilizing diabetes, these diets are not without risks. Excess protein greatly increases ammonium production, overwhelming the liver. Excess ammonium can cause neurological disorders and, in severe cases, lead to coma. These results, published in the Journal of Biological Chemistry, suggest caution when following these diets.

While current treatments help control the progression of the type 2 diabetes, they do not cure it. Losing weight is often an essential part of the treatment.

‘‘Diets rich in animal and/or plant proteins, known as Paleolithic diets, can be used to stabilise type 2 diabetes and regulate weight,’’ explains Pierre Maechler, full professor at the Department of Cell Physiology and Metabolism at the UNIGE Faculty of Medicine, who led this research. These diets are inspired by the meat-based diets of pre-agricultural time. ‘‘But what impact do they have on the body? Are they harmless? That’s what we set out to find out.’’

Liver under Pressure

Ammonium is a normal waste product of protein breakdown, essentially eliminated in the liver by the enzyme glutamate dehydrogenase (GDH). In the event of protein overload, the GDH enzyme comes under pressure. To study the impact of high-protein diets, Pierre Maechler’s team fed healthy mice and mice lacking the GDH enzyme in their liver a diet with a protein content mimicking the so-called Paleolithic diet.

Scientists observed that in healthy mice, although excess protein increased ammonium production, the liver managed this excess due to the action of the GDH enzyme, which detoxifies ammonium before it can cause damage. ‘‘In contrast, in mice lacking the GDH enzyme, the liver is unable to eliminate the excess of toxic ammonium derived from proteins. No need to wait for weeks or months; a change of diet lasting a few days is enough to observe major consequences,’’ explains Karolina Luczkowska, a former PhD student at the Department of Cell Physiology and Metabolism at the UNIGE Faculty of Medicine, and the study’s first author.

Caution is Advised

These results suggest that in case of dysfunctional GDH enzyme, high-protein diets may cause a harmful excess of ammonium. Ammonium not eliminated by the liver can cause severe disorders, particularly neurological ones. A blood test could assess GDH activity to avoid overloading the metabolism with proteins in people whose GDH enzyme is deficient. ‘‘It is therefore important to be well informed before following a high-protein diet,’’ concludes Pierre Maechler.

Source: Université de Genève

Categories : Metabolic DisordersTags :

New Method Could Boost GLP-1 Agonists While Reducing Side Effects

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By modulating a network of proteins found in the central nervous system, the effectiveness and reduce the side effects of glucagon-like peptide (GLP)-1 agonists.

The study, published in the Journal of Clinical Investigation, focused on two proteins called melanocortin 3 and melanocortin 4 found primarily on the surface of neurons in the brain that play a central role in regulating feeding behaviour and maintaining the body’s energy balance.

Melanocortin 3 and melanocortin 4 impact everything from sensing long-term energy stores to processing signals from the gut regarding short-term fullness, or satiety, said U-M physiologist Roger Cone, who led the study.

The GLP-1 agonist class, which includes semaglutides and tirzepatides, has received substantial attention recently for their effectiveness in treating not only type 2 diabetes, but also obesity, heart disease and potentially addiction. They work by mimicking a natural satiation hormone, triggering the brain to reduce feeding behaviour.

“So the obvious question for us was: How do these GLP-1 drugs, which work by manipulating satiety signals, function when we prime the melanocortin system?” said Cone, professor of molecular and integrative physiology at the U-M Medical School and director of the U-M Life Sciences Institute where his lab is located.

Working in mouse models, Cone and his colleagues tested the effects of several hormones that reduce food intake. They compared the results in normal mice with mice that genetically lacked the MC3R protein, in mice that were given chemicals to block the activity of MC3R, and in mice that were given a drug to increase the activity of MC4R. (Because MC3R is a natural negative regulator of MC4R, meaning it decreases the activity of MC4R, blocking MC3R and increasing MC4R activity has similar effects.)

In all cases, Naima Dahir, first author of the study and a postdoctoral research fellow in Cone’s lab, and colleagues found that adjusting the melanocortin system – either by inhibiting MC3R or increasing MC4R activity – made the mice more sensitive to GLP-1 drugs and other hormones that affect feeding behaviour. The mice that were given a GLP-1 drug in combination with an MC4R agonist or MC3R antagonist showed up to five times more weight loss and reduced feeding than mice receiving only the GLP-1 drugs.

“We found that activating the central melanocortin system hypersensitises animals to the effects of not just GLP-1s, but to every anti-feeding hormone we tested,” Cone said.

The researchers also measured activity in parts of the brain thought to trigger nausea in response to GLP-1 drugs and observed no increased activation when GLP-1 drugs were combined with alterations to the melanocortin system. In contrast, priming of the melanocortin neurons significantly increased GLP-1 drug activation of neurons in hypothalamic feeding centres in the brain.

The findings indicate that pairing the existing GLP-1 drugs with an MC4R agonist could increase sensitivity to the desired effects of the drugs by up to fivefold, without increasing unwanted side effects. Ultimately, this approach could enable patients who are sensitive to the side effects to take a lower dose, or could improve the results in patients who have not responded to the existing drug dosages. Further drug development and clinical testing are needed before this can occur.

While this research has been conducted only in mouse models, Cone is optimistic that the results will translate well to humans.

“The melanocortin system is highly conserved in humans,” he said. “Everything we’ve observed in the mouse over the past decades studying these proteins has also been found in humans, so I suspect that these results would also be translatable to patients.”

Source: University of Michigan

Categories : Metabolic Disorders OphthalmologyTags :

Study Reveals Association Between Semaglutide Use and Optic Neuropathy

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Photoreceptor cells in the retina. Credit: Scientific Animations

Researchers from Mass Eye and Ear have discovered an association between semaglutide use and an increased risk of nonarteritic anterior ischaemic optic neuropathy (NAION) in patients with type 2 diabetes, overweight or obesity. The findings, which appear in JAMA Ophthalmology, only show an association and cannot establish causation.

Though NAION is relatively rare, occurring in in about 10 in 100 000, it is the second most common cause of optic nerve blindness, behind glaucoma, and it is the most common cause of sudden optic nerve blindness. Caused by decreased blood flow to the optic disc, it usually affects only one eye but in 15% of cases both eyes are involved. There are no treatments for this disease and little prospect for improvement, although it is painless.

The study was led by Joseph Rizzo, MD, director of the Neuro-Ophthalmology Service at Mass Eye and Ear and the Simmons Lessell Professor of Ophthalmology at Harvard Medical School.

In mid-2023 Rizzo, a resident (study co-author Seyedeh Maryam Zekavat, MD, PhD) and other Mass Eye and Ear neuro-ophthalmologists noticed a disturbing trend – three patients in their practice had been diagnosed with vision loss from this relatively uncommon optic nerve disease in just one week. They did notice however that all three were taking semaglutide.

“The use of these drugs has exploded throughout industrialised countries and they have provided very significant benefits in many ways, but future discussions between a patient and their physician should include NAION as a potential risk,” said Rizzo, corresponding author of the study. “It is important to appreciate, however, that the increased risk relates to a disorder that is relatively uncommon.” 

This prompted the Mass Eye and Ear research team to run a retrospective analysis of their patient population to see if they could identify a link between this disease and these drugs.

They performed matched cohort study of 16 827 patients revealed higher risk of NAION in patients prescribed semaglutide compared with patients prescribed non–GLP-1 receptor agonist medications for diabetes or obesity.

The researchers found that patients with diabetes who were prescribed and took semaglutide were four times (hazard ratio [HR], 4.28) more likely to be receive a NAION diagnosis. The odds increased to more than seven times (HR, 7.64) when the prescription was for weight control in obesity.

The researchers analysed the records of more than 17 000 Mass Eye and Ear patients treated over the six years since Ozempic was released and divided the patients in those who were diagnosed with either diabetes or overweight/ obesity. The researchers compared patients who had received prescriptions for semaglutide compared to those taking other diabetes or weight loss drugs. Then, they analysed the rate of NAION diagnoses in the groups, which revealed the significant risk increases.

Study limitations include the fact that Mass Eye and Ear sees an unusually high number of people with rare eye diseases, and the number of NAION cases seen over the six-year study period is relatively small. With small case numbers, statistics can change quickly, Rizzo noted. Medication adherence could also not be assessed.

Only correlation can be shown by the study, not causality. How or why this association exists remains unknown. Likewise, the reason for the reported difference between diabetic and overweight groups – but this does not appear to result from a difference in baseline characteristics. The optic nerve is known to host GLP-1 receptors, but the study did not adequately address all the confounding factors. They also caution against generalising the results (from a majority white population) since Black individuals have a lower risk of NAION.

“Our findings should be viewed as being significant but tentative, as future studies are needed to examine these questions in a much larger and more diverse population,” Rizzo said. “This is information we did not have before and it should be included in discussions between patients and their doctors, especially if patients have other known optic nerve problems like glaucoma or if there is pre-existing significant visual loss from other causes.”