Tag Archives: #insulin

Insulin is Necessary For Repairing Olfactory Neurons (Medicine)

Findings point to possible treatment for smell loss

Researchers have known for some time that insulin plays a vital role in regeneration and growth in some types of neurons that relay environmental sensory information to our brains, such as sight. However, they know relatively little about the role of insulin in the sense of smell. Now, investigators at the Monell Chemical Senses Center have shown that insulin plays a critical role in the maturation, after injury, of immature olfactory sensory neurons (OSNs). The team published their findings in eNeuro earlier this month.

“Our findings suggest that applying insulin into the nasal passage could be developed as a therapy for injury caused by a host of issues,” said first author Akihito Kuboki, MD, a postdoctoral fellow in the lab of Johannes Reisert, PhD.”

Knowing that insulin is part of the body’s repair pathway for visual neurons, Kuboki suspected that the hormone might also play a role in the maturation of OSNs after injury. He also notes there are many insulin receptors in the olfactory region of the brain. Taking these factors into account, Kuboki concluded that insulin may also be involved in the sense of smell.

“Although scientists don’t yet have a clear idea of how it works, we know that insulin plays a key role in preventing cell death,” said Kuboki. “If insulin levels are reduced, diabetes patients have a high susceptibility to cell death, which can cause smell loss.” He is pursuing this research path to shed light on why people with diabetes often suffer from smell loss, or anosmia.

The research team induced diabetes type 1 in mice to reduce levels of circulating insulin reaching the OSNs. The reduced insulin interfered with the regeneration of OSNs, resulting in an impaired sense of smell. They analyzed how the structure of the olfactory tissue in the nasal cavity and the olfactory bulb is impaired by comparing the number of mature OSNs and how well the axons of OSNs reached the olfactory bulb. The team also recorded odorant-induced responses in the OSNs in the nasal cavity. An odor-guided behavioral task, in which the mice needed to find a cookie reward depending on their ability to smell, measured olfactory function.

In addition, the team injured OSNs, which have a unique ability to regenerate in mammals. This approach allowed the investigators to ask whether OSNs required insulin to regenerate, which they found to be true. What’s more, they discovered that OSNs are highly susceptible to insulin deprivation-induced cell death eight to 13 days after an injury. This time window indicates that during a critical stage newly generated OSNs are dependent on insulin. They also found that insulin must be applied to regenerating OSNs at this critical time point in the neurons’ growth to be able to restore a mouse’s sense of smell.

Also of significance, the team found that insulin promotes regeneration of regenerating OSNs in both type 1 diabetic and nondiabetic mice. “Even in nondiabetic mice, we found that insulin can promote the regeneration of OSNs, which suggests that this could be a therapy for olfactory dysfunction in patients without diabetes,” said Kuboki. Specifically, the team only examined the OSN regeneration process after injury in type 1-diabetic mice and did not examine the effects of type 2 diabetes, but plan to in the future.

“Our findings suggest that insulin plays important roles when OSNs need to regenerate after severe injury that induces cell death in many OSNs,” said Kuboki. “From this, we hope that an insulin spray can be potentially applied to treat smell loss for various reasons, including head trauma and viral infection.”

Other members of the research team are Ichiro Matsumoto, PhD, from Monell; Nobuyoshi Otori, MD, PhD and Hiromi Kojima, MD, PhD, from Jikei University School of Medicine; and Shu Kikuta, MD, PhD and Tatsuya Yamasoba, MD, PhD, from the University of Tokyo.

Featured image: High dependency of new neurons on insulin signaling. © Monell Chemical Senses Center, eNeuro

Reference: Akihito Kuboki, Shu Kikuta, Nobuyoshi Otori, Hiromi Kojima, Ichiro Matsumoto, Johannes Reisert and Tatsuya Yamasoba, “Insulin-dependent maturation of newly generated olfactory sensory neurons after injury”, eNeuro 27 April 2021, ENEURO.0168-21.2021; DOI: https://doi.org/10.1523/ENEURO.0168-21.2021

Provided by Monell Chemical Senses Center

Once-a-week Insulin Treatment Could Be Game-changing For Patients With Diabetes (Medicine)

Treating people with Type 2 diabetes with a new once-a-week injectable insulin therapy proved to be safe and as effective as daily insulin injections, according to the results of two international clinical trials published online today in Diabetes Care. The studies suggest that the once-weekly treatment could provide a convenient alternative to the burden of daily insulin shots for diabetes patients.

Starting and maintaining insulin treatment remain a challenge for millions of patients worldwide with Type 2 diabetes. Fear of injections and the inconvenience and burden of injectable therapy contribute to the barriers against insulin therapy initiation and adherence. The effectiveness and safety of ongoing insulin treatment are also highly dependent on other factors, such as the accuracy of dosages, timing, and glycemic targets. Health care providers believe that reducing the frequency of treatment administration with advances, such as the once-weekly insulin used in these phase 2 trials, may decrease the reluctance to initiate insulin therapy while improving long-term adherence, glucose control, and ultimately, patient well-being.

Ildiko Lingvay, M.D., M.P.H., M.S.C.S. © UTSW

“Insulin, which has been the foundation of diabetes treatment for 100 years, is an effective glucose-lowering agent and is safe when used at the correct dose,” says Ildiko Lingvay, M.D., M.P.H., M.S.C.S., a professor of internal medicine and population and data sciences at UT Southwestern. “Insulin treatment is burdensome, requires frequent injections, and continues to carry a certain stigma. The development of an effective and safe insulin that can be administered once a week is a huge advance in the field.”

Lingvay, who is a consultant for Novo Nordisk, is the lead author of one of the studies, which involved 205 patients from seven countries (the U.S., Croatia, Germany, Hungary, Poland, Slovakia, and Spain). The clinical trial consisted of a two-week screening period, 16 weeks of treatment, and a five-week follow-up to evaluate three different ways to adjust and optimize the insulin dose and determine which one presented the best balance between effectively lowering glucose while minimizing low-glucose events.

She also is an author of the second study that included 154 patients from five countries (the U.S., Canada, the Czech Republic, Germany, and Italy). This trial followed the same 23-week time frame and evaluated practical aspects of insulin use as well as the best ways to transition from a daily regimen to the new weekly insulin injections. The researchers determined that starting with a higher first dose – called a loading dose – allowed patients to reach their optimal glucose target faster.

“These two studies served as the steppingstones for a large phase 3 clinical trial program that is currently ongoing at UT Southwestern and other sites, which is designed  to evaluate the efficacy of once-weekly insulin administration in patients with either Type 1 or Type 2 diabetes,” Lingvay says. “A weekly insulin is a game-changer that will decrease the treatment burden for patients while also improving compliance. This treatment will also decrease the burden on those who care for patients with diabetes requiring insulin. For example, for patients who need help injecting, those living in long-term care facilities, and those with memory problems, a once-weekly insulin will facilitate treatment and decrease the burden on the care providers.”

Novo Nordisk was the sponsor of both studies.

Reference: Harpreet S. Bajaj, Richard M. Bergenstal, Andreas Christoffersen, Melanie J. Davies, Amoolya Gowda, Joakim Isendahl, Ildiko Lingvay, Peter A. Senior, Robert J. Silver, Roberto Trevisan, Julio Rosenstock, “Switching to Once-Weekly Insulin Icodec Versus Once-Daily Insulin Glargine U100 in Type 2 Diabetes Inadequately Controlled on Daily Basal Insulin: A Phase 2 Randomized Controlled Trial”, Diabetes Care 2021 Apr; dc202877.https://doi.org/10.2337/dc20-2877

Provided by UT Southwestern Medical Center

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 23 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

Weekly Insulin Helps Patients With Type 2 Diabetes Achieve Similar Blood Sugar Control to Daily Insulin (Medicine)

Phase 2 clinical trial results show fewer episodes of low blood sugar and comparable safety

A new once-weekly basal insulin injection demonstrated similar efficacy and safety and a lower rate of low blood sugar episodes compared with a daily basal insulin, according to a phase 2 clinical trial. The study results, which will be presented at ENDO 2021, the Endocrine Society’s annual meeting, compared an investigational drug called basal insulin Fc (BIF) with insulin degludec, a commercially available long-lasting daily insulin, in patients with type 2 diabetes.

“These study results demonstrate that BIF has promise as a once-weekly basal insulin and could be an advancement in insulin therapy,” said Juan Frias, M.D., the study’s principal investigator and the medical director of the National Research Institute in Los Angeles, Calif.

The reduced number of injections with weekly insulin may improve adherence to insulin therapy, which could result in better patient outcomes than for daily basal insulins, Frias said. Once-weekly dosing also may increase the willingness of patients with type 2 diabetes to start insulin therapy when oral medication alone no longer gives adequate blood glucose control, he added.

The 32-week clinical trial was conducted in 399 patients and sponsored by Eli Lilly and Company. All patients had type 2 diabetes and were previous users of basal insulin combined with oral antidiabetic medications.

The patients received random assignments to one of three treatment groups: once-weekly injections of BIF at one of two different dosing algorithms (with different goals for fasting blood glucose levels) or the standard once-daily injections of insulin degludec. One fasting glucose target for patients receiving BIF was 140 milligrams per deciliter (mg/dL) or less, and the other was at or below 120 mg/dL. The fasting glucose target for insulin degludec was 100 mg/dL or less.

Compared with insulin degludec, patients taking BIF achieved similar long-term blood glucose control, as measured by hemoglobin A1c, the researchers reported. Study participants had an average A1c of 8.1 percent at the beginning of the study and at the end of the study had an average improvement in A1c of 0.6 percent for BIF and 0.7 percent for insulin degludec, the data showed.

Additionally, BIF use resulted in significantly lower rates of hypoglycemia, or low blood sugar (less than 70 mg/dL). Severe untreated hypoglycemia is a dangerous complication that can cause seizures, loss of consciousness and death. Frias said BIF has “the potential of a flatter and more predictable action than the current daily basal insulins, which may have contributed to the lower rates of hypoglycemia.”

Regarding safety, BIF had a generally comparable adverse event profile to that of insulin degludec, he said.

“Based on our promising data, further research with BIF has been initiated in patients with type 1 diabetes and other type 2 diabetes patient populations,” Frias said. 


Endocrinologists are at the core of solving the most pressing health problems of our time, from diabetes and obesity to infertility, bone health, and hormone-related cancers. The Endocrine Society is the world’s oldest and largest organization of scientists devoted to hormone research and physicians who care for people with hormone-related conditions.

The Society has more than 18,000 members, including scientists, physicians, educators, nurses and students in 122 countries. To learn more about the Society and the field of endocrinology, visit our site at www.endocrine.org. Follow us on Twitter at @TheEndoSociety and @EndoMedia.

Provided by Endocrine Society

Tubeless Automated Insulin Delivery System Improves Blood Glucose Outcomes (Medicine)

Study finds Omnipod® 5 simplifies diabetes management in type 1 diabetes

People with type 1 diabetes can improve their blood sugar control while reducing time with low blood sugar, or hypoglycemia, using Insulet Corporation’s Omnipod 5 Automated Insulin Delivery System compared to their standard insulin therapy. Results from an industry-sponsored study of the latest Omnipod, the first tubeless, wearable insulin pump, will be presented at ENDO 2021, the Endocrine Society’s annual meeting.

The Omnipod 5 System underwent three months of at-home testing in 128 adults and adolescents ages 14 to 70 years and 112 children ages 6 to less than 14 years. All study participants have type 1 diabetes and were first followed for two weeks using their standard therapy, either multiple daily insulin injections or an insulin pump. Using Omnipod 5, participants experienced significant average improvements in both hemoglobin A1c, a measure of blood glucose (sugar) control over the past several months, and the percentage of time the participants stayed within the recommended target glucose range (70 to 180 milligrams per deciliter), the researchers reported.

“These study results represent an advancement in diabetes therapies with a fully wearable device that enables continuous automated insulin modulation. This will expand the available treatment options for people with type 1 diabetes,” said the study’s senior investigator, Trang Ly, MBBS, FRACP, PhD, Senior Vice President and Medical Director of Insulet Corporation.

Insulet funded this study and manufactures Omnipod 5, which is under review by the U.S. Food and Drug Administration. It is an update to the Omnipod DASH and the original Omnipod System, which are sold in the U.S., Canada, Europe and the Middle East.

The Omnipod 5 System, according to Ly, is the first tubeless automated insulin delivery system integrated with the Dexcom G6 continuous glucose monitoring (CGM) system. She said this commonly used glucose monitor automatically measures glucose levels every five minutes and communicates directly with Omnipod 5. The Pod is now designed with an embedded algorithm that adjusts the pump’s insulin delivery automatically to a customizable glucose target, based on the CGM value and trend.

Users of Omnipod 5 inject insulin into a single-use Pod, which adheres to their skin for 72 hours of continuous infusion of insulin. At mealtimes, the user administers a bolus dose of insulin which is controlled by the Omnipod 5 app on the user’s personal smartphone or a separate wireless controller. Ly said the new system will have the ability to control the Pod from a compatible smartphone, making the wireless controller optional.

Ly reported that the adult/adolescent group’s A1c averaged 0.4 percent lower with Omnipod 5 than when they used their standard insulin therapy, an improvement from 7.2 percent to 6.8 percent.

With Omnipod 5, their average time in the glucose range recommended by the American Diabetes Association (70 to 180 milligrams per deciliter) was 2.2 hours a day longer, or 9.3 percent better, Ly stated. Overall, this group was in target range nearly 74 percent of the time when they used Omnipod 5, while the general population with type 1 diabetes is often in target glucose range 60 percent or less of the time.

“Even though many of the study participants had their diabetes well controlled before the study, they still experienced improved time in the target glucose range, regardless of their baseline control. This shows the potential of the technology in the broader population with diabetes,” Ly said.

One of their most important findings in the adult/adolescent group, according to Ly, was a reduction of time in hypoglycemia, measured on the sensor as glucose levels below 70 milligrams per deciliter, down to a median of 1.1 percent. Hypoglycemia is a dangerous drop in blood glucose levels. Only two episodes of severe hypoglycemia occurred, reportedly after user-initiated bolus doses.

Most study participants chose to continue using the Omnipod 5 during an extension of the original three-month study, which Ly said suggests a preference over their previous therapy.

Children participating in the study also had improved blood sugar control after using Omnipod 5.  The average A1c dropped by 0.7 percent, to 7 percent, and the time in range improved by nearly four hours per day. One event of diabetic ketoacidosis (excessive ketones in the blood due to insufficient insulin) occurred, which Ly attributed to infusion site failure. She said one severe hypoglycemia event occurred that was not attributable to device malfunction.

“Omnipod 5 protects you from both high and low glucose values,” Ly said. “It also is simple, intuitive, and easy to use.”

Sue Brown, M.D., of the University of Virginia in Charlottesville, Va., will present the data for adults and adolescents during an oral presentation at the meeting. Bruce Buckingham, M.D., of Stanford University, will present the pediatric data in a poster presentation.


Endocrinologists are at the core of solving the most pressing health problems of our time, from diabetes and obesity to infertility, bone health, and hormone-related cancers. The Endocrine Society is the world’s oldest and largest organization of scientists devoted to hormone research and physicians who care for people with hormone-related conditions.

The Society has more than 18,000 members, including scientists, physicians, educators, nurses and students in 122 countries. To learn more about the Society and the field of endocrinology, visit our site at www.endocrine.org. Follow us on Twitter at @TheEndoSociety and @EndoMedia.

Provided by Endocrine Society

Insulin Rises Before Cells Develop Resistance, New Diabetes Research Implies (Medicine)

Researchers at the University of Gothenburg have now presented results that may change our basic view of how type 2 diabetes occurs. Their study indicates that free fatty acids (FFAs) in the blood trigger insulin release even at a normal blood-sugar level, without an overt uncompensated insulin resistance in fat cells. What is more, the researchers demonstrate the connection with obesity: the amount of FFAs largely depends on how many extra kilos of adipose tissue a person carries, but also on how the body adapt to the increased adiposity.

Worldwide, extensive research is underway to clarify exactly what happens in the body as type 2 diabetes progresses, and why obesity is such a huge risk factor for the disease. For almost 50 years, diabetes researchers have been discussing their version of the chicken-or-egg question: Which comes first — insulin resistance or elevated insulin levels? The dominant hypothesis has long been that the pancreas steps up its insulin production because the cells have already become insulin-resistant, and blood sugar then rises. However, the results now published in the journal EBioMedicine support the opposing idea: that it is the insulin that increases first.

Detailed investigations

The study indicates that high FFA levels in the blood after the overnight fast raise insulin production in the morning. FFAs have long been part of the main research equation for type 2 diabetes, but it is now proposed that they also have another role: in progression of the disease.

For the study, researchers compared metabolism in adipose (fat-storing) tissue among 27 carefully selected research subjects (nine of normal weight, nine with obesity and normal blood sugar, and nine with both obesity and progressed type 2 diabetes). For several days, they underwent extensive examinations in which they had samples taken under varying conditions. The researchers analyzed metabolism and gene expression in the participants’ subcutaneous fat, and the levels of blood sugar, insulin, and FFAs in their blood.

FFAs seem to trigger insulin production

The people with obesity but not diabetes proved to have the same, normal blood-sugar levels as the healthy individuals of normal weight.

Emanuel Fryk. Photo: Johan Wingborg

“Interestingly, the nondiabetics with obesity had elevated levels of both free fatty acids and insulin in their blood, and those levels were similar to or higher than the levels we were able to measure in blood from the participants with both obesity and type 2 diabetes,” says Emanuel Fryk, resident doctor specializing in general medicine and doctoral student at Sahlgrenska Academy, University of Gothenburg, who is one of the study’s first authors.

In collaboration with researchers at Uppsala University, he observed the same pattern in a population study based on blood samples taken from 500 people after an overnight fast.

“The fact that we saw a link between free fatty acids and insulin there too suggests that the fatty acids are connected with the insulin release, and contribute to increased insulin production on an empty stomach, when blood sugar hasn’t risen,” says Fryk, who nevertheless points out that the finding needs to be confirmed with more research.

Ongoing research

Free fatty acids are found naturally in the bloodstream and, like glycerol, are a product of the body’s fat metabolism. In the subjects, the amount of glycerol released proved to be broadly the same per kilo of body fat, regardless of whether they were of normal weight, had obesity alone, or also had type 2 diabetes.

“Our hypothesis is that the free fatty acids increase in the blood because the adipose tissue can’t store the excess energy anymore. We believe, in that case, it could be an early sign of incipient type 2 diabetes. If our findings are confirmed when other research methods are used, there may be a chance that some specific fatty acids could be developed into biomarkers. But that’s a long way off,” Fryk says.

Lifestyle crucial

Diabetes is one of the most common diseases, with an estimated 500,000 people affected in Sweden. There are also a large number of undetected cases, since many with type 2 diabetes are not yet aware they are ill. Diabetics are at an increased risk for a number of serious conditions, such as cardiovascular disease (which may result in heart attacks and strokes).

“There are many factors that contribute to the progression of type 2 diabetes, but it’s our lifestyle that has, in absolute terms, the largest impact for most people. Our study provides another argument that the most important thing you can do to slow diabetes progression is to change your life style early in the progression of the disease, before blood glucose is elevated,  Fryk says.

Featured image credit: Bildbyrån iStock

TitleHyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids

Provided by University of Gothenburg

Scientists Find Static Magnetic Field Helpful to Prevent Development of Type 2 Diabetes in Mice (Medicine)

Recently, Prof. ZHANG Xin and her research team from the Hefei Institutes of Physical Science (HFIPS) reported a specific static magnetic field (SMF) setting could prevent the development of type 2 diabetes (T2D) in mice by improving iron metabolism.

Diabetes is one of the biggest health challenges worldwide. Among the different types of diabetes, T2D is the predominant type that accounts for 90% of all diabetic patients.  

In this study, the group compared four different SMF settings with various magnetic field intensity, direction and distribution, for their effects on the development of T2D in mice.

By exposing the C57BL/6J mice to different SMF conditions and feeding them with high food diet (HFD) for six weeks, followed by intraperitoneal injection of 45 mg kg-1 streptozotocin (STZ) for three consecutive days at 11-week old to induce T2D, the researchers found that one of the magnetic field settings could decrease the blood glucose level by approximately 23.2%.

In addition, this SMF setting ameliorated T2D related symptoms, including weight gain, fatty liver and tissues injury. Besides, iron metabolism, pancreatic β cell function and gut microbiota were all improved.

This study shows that a device made of permanent magnets could significantly lower blood sugar level in T2D mice, providing a low-cost and non-invasive potential physical method to prevent and/or treat T2D.

“The effects of magnetic fields can be directly influenced by magnetic field intensity, direction and distributions,” said Prof. ZHANG Xin from the High Magnetic Field Laboratory of HFIPS, who led the study, “so more clinical trials are needed to explore their potential applications on humans in the future.”

This work was supported by the National Key R&D Program of China, the National Natural Science Foundation of China, and the HFIPS Director’s Fund et al.

Featured image: A static magnetic field with specific parameters improves iron metabolism and prevents HFD/STZ-induced diabetes. (Image by YU Biao)

Reference: Biao Yu, Juanjuan Liu, Jing Cheng, Lei Zhang, Chao Song, Xiaofei Tian, Yixiang Fan, Yue Lv, Xin Zhang,
A Static Magnetic Field Improves Iron Metabolism and Prevents High-Fat-Diet/Streptozocin-Induced Diabetes, The Innovation, Volume 2, Issue 1, 2021, 100077, ISSN 2666-6758,

Provided by Chinese Academy of Sciences

‘Weak’ and ‘Strong’ Cells Bonding Boosts Body’s Diabetes Fight (Medicine)

Scientists have broadened our understanding of how ‘weak’ cells bond with their more mature cellular counterparts to boost the body’s production of insulin – improving our knowledge of the processes leading to type 2 diabetes – a significant global health problem.

Type 2 diabetes mellitus occurs when β-cells cannot release enough insulin – a tightly controlled process requiring hundreds of such cells clustered together to co-ordinate their response to signals from food, such as sugar, fat and gut hormones.

An international research team – led by scientists at the University of Birmingham – have discovered that immature β-cells (PDX1LOW/MAFALOW) are able to overcome their relative deficiencies by partnering with ‘stronger’ counterparts to drive insulin release.

Publishing their findings today in Nature Communications, the researchers reveal that subtle differences in the levels of PDX1 and MAFA proteins (found only in β-cells) , and more broadly, differences in β-cell maturity, contribute to how clusters of insulin-producing cells, known as islets, function.

The corresponding author David Hodson, Professor of Cellular Metabolism, at the University of Birmingham, commented: “Our research shows that differences in β-cell maturity, defined using PDX1 and MAFA levels, are needed across the islet for proper insulin release. Unexpectedly, increases in the proportion of mature β-cells, is associated with islet failure. It seems that, rather like society, the islet needs cells with all ages to be properly functional.

“Redressing the balance between immature and mature β-cells restores islet function under conditions of metabolic stress – an excess of sugar and fat in the diet – providing evidence that both ’weak’ and ‘strong’ β-cells could contribute to proper islet function and insulin release.”

“This is the first glimpse that immature cells might contribute to the regulation of insulin release across the islet. Our study indicates a promising line of investigation that could be leveraged to make islets more resilient during type 2 diabetes or when generating new islets in a ‘dish’ for the purpose of transplantation.”

Normally, mature and immature β-cells co-exist within the adult islet and can be grouped into subpopulations according to differences in their levels of specific genes and proteins. Immature β-cells are generally considered to be poorly functional when viewed alone, as single cells.

Researchers found that islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells showed defects in cell function (metabolism, ionic fluxes and insulin secretion). The team believes maintaining a mix of ‘strong’ and ‘weak’ β-cells is important for effective insulin production.

Reference: Nasteska, D., Fine, N.H.F., Ashford, F.B. et al. PDX1LOW MAFALOW β-cells contribute to islet function and insulin release. Nat Commun 12, 674 (2021). https://www.nature.com/articles/s41467-020-20632-z https://doi.org/10.1038/s41467-020-20632-z

Provided by University of Birmingham

Scientists Discover a New Promising Target for Diabetes Treatment (Medicine)

Researchers have discovered a novel and druggable insulin inhibitory receptor, named inceptor. The latest study from Helmholtz Zentrum Muenchen, the Technical University of Munich and the German Center for Diabetes Research is a significant milestone for diabetes research as the scientific community celebrates 100 years of insulin and 50 years of insulin receptor discovery. The blocking of inceptor function leads to an increased sensitisation of the insulin signaling pathway in pancreatic beta cells. This might allow protection and regeneration of beta cells for diabetes remission.

Diabetes mellitus is a complex disease characterized by the loss or dysfunction of insulin-producing beta cells in the islets of Langerhans, a specialist “micro-organ” in the pancreas that controls systemic blood sugar levels. Diabetes complications, such as chronic high blood sugar, systemic metabolic failure and, in the long-term, multi-organ damage, create enormous medical and social burdens and leads to premature death. Currently no pharmacological treatment can stop or reverse disease progression. Previous studies have demonstrated that intensive insulin therapy has the potential for improved blood sugar control and diabetes remission but also leads to unintended weight gain and even more severe side effects, such as an increased risk of deep drop in blood sugar causing unawareness.

Heiko Lickert’s* research focuses on the development of regenerative approaches to treat diabetes complementary and alternative to the classical immunological and metabolic therapies. “Insulin resistance in pancreatic beta cells causes diabetes. Therapies that sensitize those cells to insulin may protect patients with diabetes against beta cell loss and failure”, says Lickert. With the discovery of the insulin inhibitory receptor, his research group has found a promising molecular target for beta cell protection and regeneration therapy that does not carry the unintended side effects of intensive insulin therapy.

Heiko Lickert © Helmholtz Zentrum Muenchen

In experiments with mice, the researchers showed that the function of inceptor is to shield the insulin-producing beta cells from constitutive insulin pathway activation. Remarkably, inceptor is upregulated in diabetes and by blocking insulin signaling it might contribute to insulin resistance.

What happens if the function of inceptor is inhibited genetically or pharmacologically? The group explored this question by knocking out inceptor in beta cells and by blocking its function using monoclonal antibodies. “The result was exactly what we were hoping for: Insulin signaling and the functional beta cell mass was increased. This makes inceptor a very promising target to treat the root cause of diabetes, the loss and dysfunction of beta cells,” says Ansarullah, one of the first-authors of the study published in Nature and diabetes researcher at Helmholtz Zentrum München.

“Frederick Banting noted already in his Nobel Prize lecture for the discovery of the life-saving drug insulin a hundred years ago that ‘Insulin is not a cure for diabetes, but a treatment of the symptoms’. This has not changed in the last century. Our goal for future research is to leverage on the discovery of inceptor and develop drugs for beta cell regeneration. This could be beneficial for patients with type 1 and 2 diabetes and ultimately lead to diabetes remission”, states Lickert.

“A hundred years ago, the discovery of insulin has transformed a deadly illness into a manageable disease. Our discovery of the insulin inhibitory receptor now is another important step to finally get rid of the disease,” says Matthias Tschöp, CEO at Helmholtz Zentrum München. “While the COVID-19 pandemic represents an immediate threat we will overcome, we must not forget that diabetes remains one of the biggest and fastest growing killers on our planet. With a series of recent breakthroughs, now including the discovery of inceptor, our Helmholtz Diabetes Center is doubling down on its mission that is a world without diabetes.”

Featured image credit: Model of insulin inhibitory receptor ‘inceptor’ (in black) desensetizing the insulin receptor (in color) on a pancreatic beta cell. Insulin in blue. © Helmholtz Zentrum München

Reference: Ansarullah et al., 2021: Inceptor counteracts insulin signalling in β-cells to control glycaemia. Nature, DOI: 10.1038/s41586-021-03225-8

Provided by Helmholtz Zentrum Muenchen

About Helmholtz Zentrum Muenchen

Helmholtz Zentrum Muenchen is a research center with the mission to discover personalized medical solutions for the prevention and therapy of environmentally-induced diseases and promote a healthier society in a rapidly changing world. It investigates important common diseases which develop from the interaction of lifestyle, environmental factors and personal genetic background, focusing particularly on diabetes mellitus, allergies and chronic lung diseases. Helmholtz Zentrum Muenchen is headquartered in Neuherberg in the north of Munich and has about 2,500 staff members. It is a member of the Helmholtz Association, the largest scientific organization in Germany with more than 40,000 employees at 19 research centers.

Diabetes Powerfully Associated with Premature Coronary Heart Disease in Women (Medicine)

A new biomarker of insulin resistance was tied to a 600 percent increase in risk of premature coronary heart disease.

While deaths related to heart disease have declined among older people, studies suggest that death rates among younger patients have remained stagnant or increased slightly. To understand what factors put younger individuals at higher risk of premature coronary heart disease (CHD), researchers from Brigham and Women’s Hospital and the Mayo Clinic analyzed more than 50 risk factors in 28,024 women who participated in the decades-long Women’s Health Study. Notably, women under 55 with type-2 diabetes had a tenfold greater risk of having CHD over the next two decades, with lipoprotein insulin resistance (LPIR) proving to be a strong, predictive biomarker as well. Findings are published in JAMA Cardiology.

“We’re going to see, unfortunately, younger and younger people having heart attacks,” said corresponding author Samia Mora, MD, MHS, of the Brigham’s Center for Lipid Metabolomics in the Division of Preventive Medicine and an associate professor at Harvard Medical School. “When a younger individual has a cardiovascular event, it will affect their quality of life going forward, their productivity, and their contribution to society.”

“Prevention is better than cure, and many risk factors for heart disease are preventable. This study shows the impact that lifestyle has on heart health in women of all ages, and younger women in particular,” said Sagar Dugani, MD, PhD, a hospital internal medicine practitioner at Mayo Clinic in Rochester, MN. Dr. Dugani is a co-first author of the study.

The researchers analyzed approximately 50 biomarkers associated with cardiovascular health. Commonly used metrics like low-density lipoprotein (LDL) cholesterol (or “bad” cholesterol) and hemoglobin A1C (a measure of blood sugar levels) had much weaker associations with CHD onset in women younger than 55 years than LPIR, a newer metric for insulin resistance. LPIR uses a weighted combination of six lipoprotein measures and is analyzed through specialized laboratory testing. Whereas LDL cholesterol was only associated with a 40 percent increase in risk of CHD onset in women under 55, LPIR demonstrated a sixfold (600 percent) increase.

“In otherwise healthy women, insulin resistance, type-2 diabetes, and its sister diagnosis, metabolic syndrome, were major contributors to premature coronary events,” said Mora. “Women under 55 who have obesity had about a fourfold-increased risk for coronary events, as did women in that age group who smoked or had hypertension. Physical inactivity and family history are all part of the picture as well.”

The researchers acknowledged the study is limited in its generalizability — beyond its focus on women, who have been shown to have worse outcomes after premature cardiac events than men, its participants were over 95 percent white. According to Mora, findings could be even more dramatic in ethnic and racial groups that have a greater prevalence of metabolic syndrome, insulin resistance and diabetes, among other risk factors.

“Diabetes is mostly preventable, but it’s a systems-wide problem, and we urgently need further research into new strategies to address it,” Mora said. “These could be innovative lifestyle-based strategies, like community efforts, greater public health efforts, ways to medically target metabolic pathways, or new surgical approaches.”

With the prevalence of diabetes and its associated risk factors increasing dramatically, and affecting more women than men, the researchers emphasize the urgency of developing effective interventions.

We need new strategies to improve outcomes in these younger individuals and address the risk of diabetes, because we’re only seeing the beginning of this epidemic now,” said Mora.

This work was supported by grants from the National Institutes of Health (CA-047988, HL-043851, HL-080467, HL-099355, and UM1CA182913 to Women’s Health Study), R01 HL134811, HL 117861, R01 DK112940, and K24 HL136852, with additional grant funding from the Molino Family Trust; grant K01 HL135342 and United Arab Emirates-Harvard Medical School Cooperative Research Award, Dubai, UAE.

Reference: Dugani, SB, et al. “Association of Lipid, Inflammatory, and Metabolic Biomarkers With Age at Onset for Incident Coronary Heart Disease in Women” JAMA Cardiology DOI: 10.1001/jamacardio.2020.7073

Provided by Brigham and Women’s Hospital