Despite clinicians recommending that many patients with diabetes take statins, nearly one in five opt to delay treatment. In a new study, researchers from Mass General Brigham found that patients who started statin therapy right away reduced the rate of heart attack and stroke by one third compared to those who chose to delay taking the medication. The results, which can help guide decision-making conversations between clinicians and their patients, are published in the Journal of the American Heart Association.
“I see patients with diabetes on a regular basis, and I recommend statin therapy to everyone who is eligible,” said senior author Alexander Turchin, MD, MS, of the Division of Endocrinology at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system. “Some people refuse because they want to first try lifestyle interventions or other drugs. But other interventions are not as effective at lowering cholesterol as starting statin therapy as soon as possible. Time is of the essence for your heart and brain health.”
Heart attacks and strokes remain the leading cause of complications and mortality for patients with diabetes. Statin therapy reduces risk of these cardiovascular events by preventing plaque buildup in the blood vessels.
The researchers used an artificial intelligence method called Natural Language Processing to gather data from the electronic health records of 7239 patients at Mass General Brigham who ultimately started statin therapy during the nearly 20-year study period. The median patient age was 55, with 51% being women, 57% white, and a median HbA1c of 6.9.
Nearly one-fifth (17.7%) of the patients in the study declined statin therapy when it was first recommended by their clinicians, then later accepted the therapy (after a median of 1.5 years) upon repeated recommendation by their clinician. Of those who delayed, 8.5% had a heart attack or stroke. But for patients who started statins immediately, the rate of those cardiovascular events was just 6.4%.
“Clinicians should recognize the increased cardiovascular risk associated with delaying statin therapy for patients with diabetes and use this information to guide shared decision-making conversations with their patients,” said Turchin.
In many countries, males are more likely than females to get sick and die from three common conditions, and less likely to get medical care, according to a new study by Angela Chang of the University of Southern Denmark, and colleagues, published May 1st in the open-access journal PLOS Medicine.
Many health policies are the same for males and females, even though there is strong evidence that sex and gender can substantially influence a person’s health outcomes. In the new study, researchers gathered global health data for people of different sexes and ages for three conditions, hypertension, diabetes, and HIV and AIDS. By comparing rates of diseases between males and females and differences in diagnosis and treatment, the researchers sought to illuminate and reduce health inequities between the sexes.
The analysis identified significant differences between the sexes at each step in the “health pathway,” which includes exposure to a risk factor, development of the condition, diagnosis, treatment and death. Males and females received different care for hypertension, diabetes and HIV and AIDS in 200, 39, and 76 countries, respectively. Males had higher rates of disease and higher rates of death compared to females, and in some countries, were less likely to seek out health care and adhere to treatment. In most countries, males were also more likely to smoke, while females were more like to be obese and engage in unsafe sex.
Overall, the study suggests that public health professionals need to develop strategies to encourage males to participate in preventive and health care services. The researchers also highlight the importance of examining health data by sex to understand health inequities and guide appropriate interventions at multiple points along the health pathway. They conclude that we need more comprehensive datasets for these and other conditions so that we can monitor for sex differences and implement equitable health care policies.
Professors Kent Buse and Sarah Hawkes, co-founders and co-CEOs of Global 50/50 say, “We have long advocated the benefits of publishing sex disaggregated data. As our Gendered Health Pathways demonstrates, such data can reveal where the health journeys of men and women diverge be it in relation to the risk factors they are exposed to, their health care seeking behaviors or their experiences in health care systems. That is an important first step towards health equity. Most of these differences are not explained by sex (biology) alone, but by socially-constructed gender – highlighting the importance of taking a gender justice approach to reducing health inequities. A gender analysis can help to shape systems of health for all.”
Angela Chang, senior author, adds, “The evidence is clear: sex differences persist at nearly every point along the health pathway, from higher smoking rates in men to higher obesity prevalence in women, yet interventions rarely reflect this. Without sex-disaggregated cascade data, we’re flying blind – unable to detect who is falling through the cracks in prevention, diagnosis, and care.”
SCP -Using modern CT technology, radiologists can search for narrowed arteries in various parts of the body, including the neck and brain. This process is called CT angiography.
Radiology provides crucial insights into the complications caused by diabetes, allowing for timely diagnosis, effective management and monitoring of disease progression. Early detection of these complications can significantly improve patient outcome and quality of life.
What is diabetes?
Diabetes is known as a ‘silent killer’ because it is quite often asymptomatic at the onset. Diabetes, a major lifestyle disorder, has become one of the most dangerous and common diseases in the world. It is a chronic disease that causes high blood sugar levels and occurs when the body doesn’t produce enough insulin or use insulin properly.
Types of diabetes
Type 1 diabetes: The body’s immune system destroys the cells that produce insulin
Type 2 diabetes: The body doesn’t produce enough insulin or the body’s cells don’t react to insulin as they should
Gestational diabetes: Sometimes occurs during pregnancy when the placenta releases hormones that cause insulin resistance. This tampers with the expectant mom’s blood sugar level, changing the amount of glucose in the blood
Around 4.2 million people in South Africa have diabetes – 90% of whom have type 2 diabetes, a lifestyle disease exacerbated by dietary factors, coupled with too little physical activity and high levels of obesity.
Dr Jean de Villiers, senior partner and radiologist at SCP Radiology, discusses the imaging techniques used to identify and manage complications of diabetes.
Cardiovascular Disease: People with diabetes are at higher risk of developing heart disease and other cardiovascular problems. Imaging techniques such as CT angiography can be used to assess the heart’s blood vessels and detect issues such as atherosclerosis, coronary artery narrowing or blockage of the arteries. CT angiography is also used for the neck, arm and leg arteries, as well as the arteries to the gut.
Stroke: Diabetes increases the risk of stroke by damaging blood vessels through high blood sugar levels, leading to the formation of fatty deposits and clots within the arteries. This can increase the chance of clot formation and block blood flow to the brain and cause a stroke. Imaging techniques such as MRI, CT scans, and ultrasound may be able to detect these fatty deposits in the arteries. The deposits are generally seen as areas of narrowing in the involved arteries or calcification of the walls of the arteries.
Blood vessel damage: Chronic high blood sugar levels can directly damage the lining of blood vessels, making them more susceptible to inflammation and clot formation. Essentially, the excess glucose in the blood weakens and stiffens the blood vessel walls, making them more prone to blockages. CT or MRI scans can be critical in identifying and assessing strokes, transient ischemic attacks (TIAs) or other cerebrovascular issues in diabetic patients.
High blood pressure association: People with diabetes often also have high blood pressure, which can exacerbate the damage to blood vessels and increases stroke risk. A CT of the coronary arteries is used to visualise blockages in the coronary blood vessels and assess the severity of atherosclerosis in diabetic patients. This helps in planning for interventions like stent placement or bypass surgery.
Kidney disease: Diabetes affects your kidneys by potentially damaging the blood vessels within the kidneys due to high blood sugar levels. This can lead to impaired kidney function, causing the kidneys to leak protein into the urine and eventually progressing to chronic kidney disease if left uncontrolled. This condition is often referred to as ‘diabetic nephropathy.’
Diabetic nephropathy can lead to kidney damage and radiology plays a role in assessing kidney size, structure and function. Renal ultrasound can help assess kidney size and detect signs of chronic kidney disease (CKD). In advanced cases, a CT scan or MRI can be used to further evaluate the kidneys for the presence of complications such as renal artery stenosis or renal scarring.
Diabetic neuropathy: Diabetic neuropathy is a complication of diabetes where high blood sugar levels damage nerves throughout the body. Most commonly affected are the nerves in the legs and feet, leading to symptoms like numbness, tingling, pain and sometimes muscle weakness. It can also impact internal organs, depending on which nerves are affected and is considered a serious diabetes complication that can affect up to 50% of diabetics.
While radiology is not typically used for direct diagnosis of diabetic neuropathy, it can help rule out other causes of neuropathy. MRI and CT scans can assess for structural issues, such as spinal problems or other nerve impingements that may be contributing to symptoms.
Infections: Diabetic patients have a higher susceptibility to infections due to impaired immune response.
Diabetic foot ulcers and infections: Over time, high blood sugar levels damage nerves, blood vessels and skin in the feet. Damaged nerves can cause loss of feeling in the feet, while damaged blood vessels slow blood flow to the feet, preventing the healing of injuries.
Imaging techniques like CT, MRI and ultrasound are useful for detecting and monitoring bone and soft tissue infections. These can be critical for determining the appropriate course of antibiotic treatment or surgical intervention. X-rays, CT and MRI can be used to assess for infection in diabetic foot, such as ulcers, osteomyelitis or abscesses that may progress to amputation if left untreated.
Liver disease: Non-alcoholic fatty liver disease (NAFLD) is commonly seen in diabetic patients. Ultrasound is the primary tool for detecting fatty liver, while CT and MRI may offer further details on liver fat content or cirrhosis. Regular monitoring through imaging can help prevent more severe liver damage.
Osteoporosis: Long-term diabetes, especially type 1, can increase the risk of osteoporosis due to lower bone density. A DEXA scan helps assess bone mineral density (BMD), aiding in the early detection of osteoporosis and providing information on fracture risk.
‘As with any lifestyle disease, prevention is best. However, second to this is early detection and timely diagnosis, effective management and monitoring of the disease,’ says Dr de Villiers. ‘In the case of diabetes, we work with physicians and patients to detect possible complications early enough to help improve medical care, monitor treatment response and ultimately, improve quality of life.’
Staphylococcus aureus is a leading cause of antibiotic resistance associated infections and deaths. It is also the most prevalent bacterial infection among those with diabetes mellitus, a chronic condition that affects blood sugar control and reduces the body’s ability to fight infections.
Microbiologists at the UNC School of Medicine have just shown that people with diabetes are more likely to develop antibiotic-resistant strains of Staph, too. Their results, which were published in Science Advances, show how the diabetic microbial environment produces resistant mutations, while hinting at ways antibiotic resistance can be combatted in this patient population.
“We found that antibiotic resistance emerges much more rapidly in diabetic models than in non-diabetic models of disease,” said Brian Conlon, PhD, associate professor of immunology. “This interplay between bacteria and diabetes could be a major driver of the rapid evolution and spread of antibiotic resistance that we are seeing.”
Staph feeds off the high levels of blood glucose in diabetes, allowing it to reproduce more rapidly. The bacterium can also grow without consequence, as diabetes also impairs the immune system’s ability to destroy cells and control infection.
As the numbers of bacteria increase in a diabetic infection, so does the likelihood of resistance. Random mutations appear and some build up resistance to external stressors, like antibiotics. Once a resistant mutant is present in a diabetic infection, it rapidly takes over the population, using the excess glucose to drive its rapid growth.
“Staphylococcus aureus is uniquely suited to take advantage of this diabetic environment,” said Lance Thurlow, PhD, assistant professor of microbiology and immunology. “Once that resistant mutation happens, you have excess glucose and you don’t have the immune system to clear the mutant and it takes over the entire bacterial population in a matter of days.”
Conlon, an expert on antibiotic treatment failure, and Thurlow, an expert on Staph pathogenesis in diabetes, have long been interested in comparing the effectiveness of antibiotics in a model with and without diabetes. Using their connections within the Department of Microbiology and Immunology, the researchers brought their labs together to perform a study with antibiotics in a diabetic mouse model of S. aureus infection.
First, the team prepared a mouse model with bacterial infection in the skin and soft tissue. The mouse models were divided into two groups: one half was given a compound that selectively kills cells in the pancreas, rendering them diabetic, and the other half was not given the compound. Researchers then infected both diabetic and non-diabetic models with S. aureus and treated them with rifampicin, an antibiotic where resistance evolves at a high rate.
After five days of infection, it was time to observe the results.
Conlon and Thurlow were quick to notice that the rifampicin had practically no effect in diabetic models. So, they took some samples to investigate. Researchers were shocked to find that the bacteria had evolved to become resistant to rifampicin, with the infection harboring over a hundred million rifampicin resistant bacteria. There were no rifampicin resistant bacteria in the non-diabetic models.
Their new findings have left Conlon and Thurlow with many questions; however, they are certain that the evolution of antibiotic resistance in people with diabetes could spell trouble for the population at large.
And, even more surprisingly, the mutation had taken over the entire infection in just four days. They next inoculated diabetic and non-diabetic models with Staphylococcus aureus as before, but this time supplemented with a known number of rifampicin resistant bacteria. Again, these bacteria rapidly took over the diabetic infection, but remained as only a sub-population in non-diabetic models after 4 days rifampicin treatment.
Their new findings have left Conlon and Thurlow with many questions; however, they are certain that the evolution of antibiotic resistance in people with diabetes could spell trouble for the population at large. Antibiotic-resistant strains of bacteria spread from person to person in the same ways as other bacteria and viruses do – in the air, on doorknobs, and the food that we eat – which makes preventing these types of infections a major priority.
So, what can be done to prevent it? Well, the Conlon and Thurlow labs showed that reducing blood sugar levels in diabetic models (through administration of insulin) deprived bacteria of their fuel, keeping their numbers at bay, and reducing the chances of antibiotic-resistant mutations from occurring. Their findings suggest that controlling blood sugar through insulin use could be key in preventing antibiotic resistance.
“Resistance and its spread are not only associated with the prescription of drugs, but also the health status of those that are taking antibiotics,” said Conlon. “Controlling blood glucose then becomes really important. When we gave our mice insulin, we were able to bring their blood sugar back to normal and we didn’t get this rapid proliferation of resistant bacteria.”
Now, Conlon and Thurlow are expanding their efforts to study the evolution of resistance in humans (with and without diabetes) and other antibiotic-resistant bacteria of interest, including Enterococcus faecalis, Pseudomonas aeruginosa, and Streptococcus pyogenes. Recognizing how large a role the host plays a role in the evolution of antibiotic resistance, the researchers plan to perform similar studies in patients undergoing chemotherapy and recent transplant recipients to see if those populations are also prone to antibiotic resistant infections.
Myocardial infarction, stroke, neuropathy: when a person has any of these chronic diabetes complications, they are more likely to have a mental health disorder, and vice versa, according to a University of Michigan-led study.
“We wanted to see if chronic diabetes complications led to mental health disorders or if mental health disorders led to those diabetes complications – but we found that both relationships are true,” said Brian Callaghan, MD, MS, senior author of the study published in Diabetes Care.
“The findings highlight a need for clinicians to actively screen for mental health disorders in patients with diabetes in addition to screening for chronic complications, which is the recommended standard of care in diabetes.”
Three-times greater risk
The research team, led by Michigan Medicine and the Department of Biostatistics at the U-M School of Public Health, examined insurance claims data from over 500 000 individuals with type 1 or type 2 diabetes and 350 000 people without diabetes.
The results reveal that people with chronic diabetes complications had up to a three-times greater risk of having a mental health condition, such as anxiety or depression. This effect increased as adults got older.
Those with mental health disorders were up to 2.5 times more likely to experience sustained diabetes complications.
In adults younger than 60 years old, having type 1 diabetes was more associated with chronic complications. People with the more common type 2 diabetes were more likely to experience mental health difficulties.
A possible reason for this bi-directional relationship, researchers say, may be that having a diabetes complication or mental health condition has direct effects on developing the other complication.
“For instance, a stroke causes detrimental effects on the brain, which may directly lead to depression,” Callaghan said.
“And having a mental health condition and diabetes may affect a person’s self-management of their condition – like poor glycaemic control or not taking medications – which, in turn, may increase their risk of diabetes complications.”
Common risk factors
The relationship may also be less direct. Diabetes complications and mental health conditions share common risk factors; obesity, issues with glycaemic control and social determinants of health can all increase the likelihood of developing both comorbidities.
“Most likely, a combination of direct and indirect effects and shared risk factors drive the association we are seeing,” said first author Maya Watanabe, MS, a biostatistician at the Harvard T.H. Chan School of Public Health and former graduate student research assistant at U-M.
“Diabetes care providers may be able to simultaneously prevent the risk of multiple complications by providing interventions to treat these shared risk factors.”
Depiction of multiple myeloma. Credit: Scientific Animations
People who use metformin are less likely to develop a myeloproliferative neoplasm (MPN) over time, indicating that the treatment may help prevent the development of certain types of cancers, according to a study published in Blood Advances.
Metformin is a therapy used to treat high blood sugar in people with type 2 diabetes that increases the effect of insulin, reduces how much glucose is released from the liver and helps the body absorb glucose. A meta-analysis of previous studies connected the therapy with a reduction in the risk of gastrointestinal, breast, and urologic cancers, while a retrospective study of US veterans found that metformin users have a reduced risk for solid and haematological cancers.
Metformin’s anti-inflammatory properties in focus
“Our team was interested in understanding what other effects we see with commonly prescribed treatments like metformin,” said Anne Stidsholt Roug, MD, PhD, chief physician at Aarhus University Hospital and clinical associate professor at Aalborg University Hospital in Denmark. “The anti-inflammatory effect of metformin interested us, as MPNs are very inflammatory diseases. This is the first study to investigate the association between metformin use and risk of MPN.”
MPNs are a group of diseases that affect how bone marrow produces blood cells, resulting in an overproduction of red blood cells, white blood cells, or platelets that can lead to bleeding problems, a greater risk of stroke or heart attack, and organ damage.
Surprisingly strong association
The researchers compared metformin use among patients diagnosed with MPNs and a matched population from the Danish general population between 2010 and 2018. Of the 3816 MPN cases identified from the sample, a total of 268 (7.0%) individuals with MPN had taken metformin as compared to 8.2% (1573 out of 19 080) of the control group of people who had taken metformin but were not diagnosed with MPN. Just 1.1% of MPN cases had taken metformin for more than five years, as compared to 2.0% of controls. The protective effect of metformin was seen in all subtypes of MPN when adjusting for potential confounders.
“We were surprised by the magnitude of the association we saw in the data,” said Daniel Tuyet Kristensen, MD, PhD student, at Aalborg University Hospital and lead author of the study. “We saw the strongest effect in people who had taken metformin for more than five years as compared to those who had taken the treatment for less than a year.” Dr Kristensen added that this makes clinical sense, as MPNs are diseases that develop over a long period of time, like other types of cancer.
The researchers noted that while the protective effect of long-term metformin use was seen in all subtypes of MPN, the study was limited by its registry-based retrospective design. Further, they could not account for risk-modifying lifestyle factors, such as smoking, obesity, and dietary habits.
Dr Roug noted that while the study team were unable to assess exactly why metformin seems to protect against the development of MPN, they hope additional research will be conducted to better understand why this may be. Moving forward, the researchers aim to identify any similar trends with myelodysplastic syndromes and acute myeloid leukaemia in population-level data for future study.
South Africa has seen the quickest and most alarming rise of diabetes on the continent; from an estimated 1.9 million people living with the condition in 2011 to 4.2 million by 2021 – with 7.5 million predicted to be afflicted by 20451. South Africa also has the fastest rising prevalence on the continent with an estimated 20% of the adult population either diabetic or pre-diabetic1. Globally, diabetes prevalence is predicted to rise by 46% between 2019 and 20452. It currently stands at some 537 million people worldwide1.
This emerged at the recently held annual Sanofi medical meeting, the Cardio-Metabolic Axis Forum from April 19th–21st in Cape Town. This was a meeting of leading endocrinologists, specialist physicians, nephrologists, diabetes-treating doctors, academics and Patient Advocacy Groups (PAGs).
Speaking at the conference, specialist physician and endocrinologist, Dr Landi Lombard – former editor of the South Africa Journal of Diabetes and Vascular Disease – told delegates that the risk of death associated with diabetes in cardiovascular conditions is more than twice that of people with non-diabetes, while in all-cause mortality, it’s just under twice that of a person living without diabetes. Of the estimated 537 million people living with diabetes globally, only about half are diagnosed, of whom 25% receive care, 12.5% achieve treatment targets, and 6% live a life free of diabetes-related complications1.
Dr Lombard said that the pandemic is being driven by poor lifestyle choices and diet, lack of exercise and widespread obesity in the population, so better healthcare worker communication and education of patients is vital to stem the tide of diabetes.
Professor Robert Ritzel of the Department of Endocrinology, Diabetology and Angiology at Schwabing Hospital in Munich, said the Pacific Islands and the Middle East led the world with diabetes prevalence at between 25 % and 40 %. He said what precipitated a surge in diabetes was the speed at which a nation changed from a traditional to a modern lifestyle. When this happened within a few years, diabetes prevalence was likely to range between 20% and 40%. However, when change occurred over many generations, it gave epidemiologists and clinicians time to adapt.
Lombard said one of the biggest challenges was what diabetologists called ‘therapeutic inertia’ which contributes to a patient living with sub-optimal blood sugar control for many years. This term embraced physician, patient and healthcare system factors, patient injection related factors, time and resource constraints among physicians and the lack of a proper healthcare system plan. He said that in people with Type 2 diabetes, the median time it takes for the disease to intensify while taking one or more anti-diabetic drugs is 2.9 years. However, the use of an injectable slowed intensification down to 7.2 years or more.
Reasons for failure to intensify treatment or progress to injectable therapies varied between specialist and primary care physicians but were mainly because of a patient fear of injection, too many injections, perceptions of this being a ‘last resort’ treatment, fear of weight gain, fear of low blood sugar, and poor communication with patients.
Lombard said even 1 year of poor blood sugar control in people with Type 2 diabetes could result in an increase in the cumulative incidence of kidney disease of 18%, neuropathy of 8%, retinopathy of 7% and a significantly increased risk of heart attack (67%), heart failure (64%), stroke (51%) and composite cardiovascular events (62%).
Professor Naomi ‘Dinky’ Levitt, former Head of Endocrinology and Diabetic Medicine at the University of Cape Town and Groote Schuur Hospital and Director of the Chronic Disease Initiative for Africa, highlighted gestational diabetes as one of the greatest challenges.
Described as the “doyenne” of endocrinology in South Africa (SA), Levitt said one third of women who have gestational diabetes go on to develop diabetes within 6 years of giving birth, so post-partum intervention is crucial.
According to Levitt, lifestyle interventions had about a 20% positive effect, mainly because new mothers were pulled in all directions by family, the baby, husband, and domestic and work needs.
She said that with 31.4% of SA women estimated to have developed gestational diabetes, it would be ideal to screen all pregnant women at 24 and 28 weeks. However, this would collapse the healthcare system because of the healthcare staffing demands, so the alternative was to focus on risk factors such as being over 30 years old or being overweight.
She said that focusing on women with gestational diabetes would have the greatest impact on the pandemic, as treatment can help avoid pre-eclampsia and improve foetal development, resulting in fewer admissions to the neonatal ICU.
Speaking on behalf of Sanofi the conference sponsor, Dr Asafika Mbangata said: “Sanofi puts patients first and the aim of the conference was to empower stakeholders with the right information to help make critical care decisions for patients by sharing the latest data on advancements in treatments and technologies, along with insights into global and local policy changes impacting diabetes care.”
“As we chase the miracles of science to improve people’s lives, we know we cannot shape the future of diabetes management without partnerships with healthcare professionals and other stakeholders. Collaboration across all medical disciplines is essential if we are to overcome this pandemic, and we’re hopeful the conference opened the door to future robust collaborative actions that improve patient outcomes,” concluded Dr Mbangata.
References
Adapted from IDF Diabetes Atlas (10th edition). International Diabetes Federation. 2022. http://www.diabetesatlas.org/. Accessed 23 April, 2024.
Conditions such as diabetes, heart attack and vascular diseases commonly diagnosed in people with spinal cord injuries can be traced to abnormal post-injury neuronal activity that causes abdominal fat tissue compounds to leak and pool in the liver and other organs, a new animal study published in Cell Reports Medicine has found.
After discovering the connection between dysregulated neuron function and the breakdown of triglycerides in fat tissue in mice, researchers found that a short course of the drug gabapentin, commonly prescribed for nerve pain, prevented the damaging metabolic effects of the spinal cord injury – though not without side effects.
Gabapentin inhibits a neural protein that, after the nervous system is damaged, becomes overactive and causes communication problems – in this case, affecting sensory neurons and the abdominal fat tissue to which they’re sending signals.
“We believe there is maladaptive reorganisation of the sensory system that causes the fat to undergo changes, initiating a chain of reactions – triglycerides start breaking down into glycerol and free fatty acids that are released in circulation and taken up by the liver, the heart, the muscles, and accumulating, setting up conditions for insulin resistance,” said senior author Andrea Tedeschi, assistant professor of neuroscience in The Ohio State University College of Medicine.
“Through administration of gabapentin, we were able to normalise metabolic function.”
Previous research has found that cardiometabolic diseases are among the leading causes of death in people who have experienced a spinal cord injury. These often chronic disorders can be related to dysfunction in visceral white fat (or adipose tissue), which has a complex metabolic role of storing energy and releasing fatty acids as needed for fuel, but also helping keep blood sugar levels at an even keel.
Earlier investigations of these diseases in people with neuronal damage have focused on adipose tissue function and the role of the sympathetic nervous system, but also a regulator of adipose tissue that surrounds the abdominal organs.
Instead, Debasish Roy, a postdoctoral researcher in the Tedeschi lab and first author on the paper, decided to focus on sensory neurons in this context. Tedeschi and colleagues have previously shown that a neuronal receptor protein called alpha2delta1 is overexpressed after spinal cord injury, and its increased activation interferes with post-injury function of axons, the long, slender extensions of nerve cell bodies that transmit messages.
In this new work, researchers first observed how sensory neurons connect to adipose tissue under healthy conditions, and created a spinal cord injury mouse model that affected only those neurons – without interrupting the sympathetic nervous system.
Experiments revealed a cascade of abnormal activity within seven days after the injury in neurons – though only in their communication function, not their regrowth or structure – and in visceral fat tissue. Expression of the alpha2delta1 receptor in sensory neurons increased as they over-secreted a neuropeptide called CGRP, all while communicating through synaptic transmission to the fat tissue – which, in a state of dysregulation, drove up levels of a receptor protein that engaged with the CGRP.
“These are quite rapid changes. As soon as we disrupt sensory processing as a result of spinal cord injury, we see changes in the fat,” Tedeschi said. “A vicious cycle is established – it’s almost like you’re pressing the gas pedal so your car can run out of gas but someone else continues to refill the tank, so it never runs out.”
The result is the spillover of free fatty acids and glycerol from fat tissue, a process called lipolysis, that has gone out of control. Results also showed an increase in blood flow in fat tissue and recruitment of immune cells to the environment.
“The fat is responding to the presence of CGRP, and it’s activating lipolysis,” Tedeschi said. “CGRP is also a potent vasodilator, and we saw increased vascularisation of the fat – new blood vessels forming as a result of the spinal cord injury. And the recruitment of monocytes can help set up a chronic pro-inflammatory state.”
Silencing the genes that encode the alpha2delta1 receptor restored the fat tissue to normal function, indicating that gabapentin – which targets alpha2delta1 and its partner, alpha2delta2 – was a good treatment candidate. Tedeschi’s lab has previously shown in animal studies that gabapentin helped restore limb function after spinal cord injury and boosted functional recovery after stroke.
But in these experiments, Roy discovered something tricky about gabapentin: the drug prevented changes in abdominal fat tissue and lowered CGRP in the blood, in turn preventing spillover of fatty acids into the liver a month later, establishing normal metabolic conditions. But paradoxically, the mice developed insulin resistance, a known side effect of gabapentin.
The team instead tried starting with a high dose, tapering off and stopping after four weeks.
“This way, we were able to normalise metabolism to a condition much more similar to control mice,” Roy said. “This suggests that as we discontinue administration of the drug, we retain beneficial action and prevent spillover of lipids in the liver. That was really exciting.”
Finally, researchers examined how genes known to regulate white fat tissue were affected by targeting alpha2delta1 genetically or with gabapentin, and found both of these interventions after spinal cord injury suppress genes responsible for disrupting metabolic functions.
Tedeschi said the combined findings suggest starting gabapentin treatment early after a spinal cord injury may protect against detrimental conditions involving fat tissue that lead to cardiometabolic disease – and could enable discontinuing the drug while retaining its benefits and lowering the risk for side effects.
A new study finds that the modest weight loss from taking metformin is attributable to an appetite-suppressing molecule that is abundant after exercise
Photo by I Yunmai on Unsplash
An “anti-hunger” molecule produced after vigorous exercise is responsible for the moderate weight loss caused by the diabetes medication metformin, according to a new study in mice and humans. The anti-hunger molecule, lac-phe, was discovered by Stanford Medicine researchers in 2022.
The finding, made jointly by researchers at Stanford Medicine and at Harvard Medical School and published in Nature Metabolism, further cements the critical role the molecule, called lac-phe, plays in metabolism, exercise and appetite. It may pave the way to a new class of weight loss drugs.
“Until now, the way metformin, which is prescribed to control blood sugar levels, also brings about weight loss has been unclear,” said Jonathan Long, PhD, an assistant professor of pathology. “Now we know that it is acting through the same pathway as vigorous exercise to reduce hunger. Understanding how these pathways are controlled may lead to viable strategies to lower body mass and improve health in millions of people.”
Many people with diabetes who are prescribed metformin lose around 2% to 3% of their body weight within the first year of starting the drug. Although this amount of weight loss is modest when compared with the 15% or more often seen by people taking semaglutide, the discoveries that led to those drugs also grew from observations of relatively minor, but reproducible, weight loss in people taking first-generation versions of the medications.
Post-workout appetite loss
When Long and colleagues at Baylor University discovered lac-phe in 2022, they were on the hunt for small molecules responsible for curtailing hunger after vigorous exercise. What they found was a mishmash of lactate and an amino acid called phenylalanine. They dubbed the hybrid molecule lac-phe and went on to show that it’s not only more abundant after exercise but it also causes people (as well as mice and even racehorses) to feel less hungry immediately after a hard workout.
“There is an intimate connection between lac-phe production and lactate generation,” Long said. “Once we understood this relationship, we started to think about other aspects of lactate metabolism.”
Metformin was an obvious candidate because as it stimulates the breakdown of glucose (thus reducing blood sugar levels) it can trigger the generation of lactate.
The researchers found that obese laboratory mice given metformin had increased levels of lac-phe in their blood. They ate less than their peers and lost about 2 grams of body weight during the nine-day experiment.
Long and his colleagues also analysed stored blood plasma samples from people with Type 2 diabetes before and 12 weeks after they had begun taking metformin to control their blood sugar. They saw significant increases in the levels of lac-phe in people after metformin compared with their levels before treatment. Finally, 79 participants in a large, multi-ethnic study of atherosclerosis who were also taking metformin had significantly higher levels of lac-phe circulating in their blood than those who were not taking the drug.
“It was nice to confirm our hunch experimentally,” Long said. “The magnitude of effect of metformin on lac-phe production in mice was as great as or greater than what we previously observed with exercise. If you give a mouse metformin at levels comparable to what we prescribe for humans, their lac-phe levels go through the roof and stay high for many hours.”
Further research revealed that lac-phe is produced by intestinal epithelial cells in the animals; blocking the ability of mice to make lac-phe erased the appetite suppression and weight loss previously observed.
Finally, a statistical analysis of the people in the atherosclerosis study who lost weight during the several-year study and follow-up period found a meaningful association between metformin use, lac-phe production and weight loss.
“The fact that metformin and sprint exercise affect your body weight through the same pathway is both weird and interesting,” Long said. “And the involvement of the intestinal epithelial cells suggests a layer of gut-to-brain communication that deserves further exploration. Are there other signals involved?”
Long noted that, while semaglutide drugs are injected into the bloodstream, metformin is an oral drug that is already prescribed to millions of people. “These findings suggest there may be a way to optimize oral medications to affect these hunger and energy balance pathways to control body weight, cholesterol and blood pressure. I think what we’re seeing now is just the beginning of new types of weight loss drugs.”
An unassuming brown bovine from the south of Brazil has made history as the first transgenic cow capable of producing human insulin in her milk. The advancement, led by researchers from the University of Illinois Urbana-Champaign and the Universidade de São Paulo, could herald a new era in insulin production, one day eliminating drug scarcity and high costs for people living with diabetes.
“Mother Nature designed the mammary gland as a factory to make protein really, really efficiently. We can take advantage of that system to produce a protein that can help hundreds of millions of people worldwide,” said Matt Wheeler, professor in the Department of Animal Sciences, part of the College of Agricultural, Consumer and Environmental Sciences (ACES) at U. of I.
Wheeler is lead author on a new Biotechnology Journal study describing the development of the insulin-producing cow, a proof-of-concept achievement that could be scaled up after additional testing and FDA approval.
Precise insertion of DNA
Wheeler’s colleagues in Brazil inserted a segment of human DNA coding for proinsulin – the protein precursor of the active form of insulin – into cell nuclei of 10 cow embryos. These were implanted in the uteruses of normal cows in Brazil, and one transgenic calf was born. Thanks to updated genetic engineering technology, the human DNA was targeted for expression – the process whereby gene sequences are read and translated into protein products – in mammary tissue only.
“In the old days, we used to just slam DNA in and hope it got expressed where you wanted it to,” Wheeler said. “We can be much more strategic and targeted these days. Using a DNA construct specific to mammary tissue means there’s no human insulin circulating in the cow’s blood or other tissues. It also takes advantage of the mammary gland’s capabilities for producing large quantities of protein.”
When the cow reached maturity, the team unsuccessfully attempted to impregnate her using standard artificial insemination techniques. Instead, they stimulated her first lactation using hormones. The lactation yielded milk, but a smaller quantity than would occur after a successful pregnancy. Still, human proinsulin and, surprisingly, insulin were detectable in the milk.
“Our goal was to make proinsulin, purify it out to insulin, and go from there. But the cow basically processed it herself. She makes about three to one biologically active insulin to proinsulin,” Wheeler said. “The mammary gland is a magical thing.”
The insulin and proinsulin, which would need to be extracted and purified for use, were expressed at a few grams per liter in the milk. But because the lactation was induced hormonally and the milk volume was smaller than expected, the team can’t say exactly how much insulin would be made in a typical lactation.
Conservatively, Wheeler says if a cow could make 1 gram of insulin per liter and a typical Holstein makes 40 to 50 litres per day, that’s a lot of insulin. Especially since the typical unit of insulin equals 0.0347 milligrams.
“That means each gram is equivalent to 28,818 units of insulin,” Wheeler said. “And that’s just one liter; Holsteins can produce 50 liters per day. You can do the math.”
The team plans to re-clone the cow, and is optimistic they’ll achieve greater success with pregnancy and full lactation cycles in the next generation. Eventually, they hope to create transgenic bulls to mate with the females, creating transgenic offspring that can be used to establish a purpose-built herd. Wheeler says even a small herd could quickly outcompete existing methods – transgenic yeast and bacteria – for producing insulin, and could do so without having to create highly technical facilities or infrastructure.
“With regard to mass-producing insulin in milk, you’d need specialized, high-health-status facilities for the cattle, but it’s nothing too out of the ordinary for our well-established dairy industry,” Wheeler said. “We know what we’re doing with cows.”
An efficient system to collect and purify insulin products would be needed, as well as FDA approval, before transgenic cows could supply insulin for the world’s diabetics. But Wheeler is confident that day is coming.
“I could see a future where a 100-head herd, equivalent to a small Illinois or Wisconsin dairy, could produce all the insulin needed for the country,” he said. “And a larger herd? You could make the whole world’s supply in a year.
