Category: Metabolic Disorders

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Varenicline Effective in Helping Smokers with Diabetes to Quit

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A new study published in JAMA Network has found that varenicline helps patients with type 2 diabetes to quit smoking.

Not only is cigarette smoking a major risk factor for cardiovascular disease, it is highly prevalent among patients with type 2 diabetes. Smoking worsens the effects of hyperglycaemia and other risk factors, accelerating vascular damage in patients with diabetes.

Compared with nonsmokers with diabetes, smokers have greater risks of mortality, coronary heart disease, stroke, and peripheral arterial disease. Quitting smoking has been associated with reduced mortality risk in patients with type 2 diabetes, as welling achieving better glycaemic control and lower cardiometabolic risk factors.

Smokers with type 2 diabetes are more reluctant quit than smokers without diabetes in part due to fear of weight gain. Weight gain needs to be controlled as part of any cessation intervention. The smoking cessation drug varenicline has been shown to help people without diabetes to quit, but considering the special behavioural and metabolic conditions of smokers with type 2 diabetes, its use and efficacy warranted investigation,

To this end, Cristina Russo, MD, and colleagues conducted a multicentre, double-blind, placebo-controlled randomised clinical trial with 300 participants. Patients with type 2 diabetes, average age 57.4 years who were smoking at least 10 cigarettes a day, and who intended to quit were randomised to either twice-daily varenicline 1mg or placebo treatment. Both groups received smoking cessation counselling. The trial consisted of a 12-week treatment phase followed by a 40-week follow-up, nontreatment phase. Intention-to-treat data analysis was performed from December 2020 to April 2021.

At weeks 9 to 24, continuous smoking abstinence was significantly higher for the varenicline than placebo group (24.0% vs 6.0%). At weeks 9 to 12 (31.3% vs 7.3%) and weeks 9 to 52 (18.7% vs 5.3%) were significantly higher for the varenicline vs placebo group. Adverse events in the varenicline group compared with the placebo group were nausea, insomnia, abnormal dreams, anxiety, and irritability. Serious adverse events were infrequent in both groups and not treatment-related.

The researchers concluded that using varenicline in a smoking cessation programme for people with type 2 diabetes is effective in achieving long-term abstinence without serious adverse events.

Categories : Cardiovascular Disease Metabolic DisordersTags :

In Diabetes, Oestrogen Protects Against Cardiomyopathy

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Oestrogen may protect diabetes patients from cardiomyopathy, according to research published in Circulation: Heart Failure. The study showed that severe insulin resistance in the heart causes cardiomyopathy and death in male mice, but also showed that oestrogen protected female mice.

“Cardiovascular disease is the major cause of morbidity and mortality for diabetic patients,” explained Shaodong Guo, PhD, primary investigator for the study at Texas A&M.

“Previous studies have shown that while there’s a lower instance of both cardiovascular disease and Type 2 diabetes in premenopausal women than in their age-matched male counterparts, these incidences rise sharply after female menopause,” Prof Guo said.

This indicates that the ovaries and ovarian hormones, such as oestrogen, may protect from Type 2 diabetes and cardiovascular diseases, he said.

The study investigated the role of ovaries and oestrogen in cardiac function and energy metabolism with mice who had the the cardiac insulin receptor substrate, IRS, modified or suppressed to mimic cardiac insulin resistance.

“Our previous studies reported that impaired cardiac insulin signalling with loss of insulin receptor substrate IRS1 and IRS2 genes leads to death of male mice,” he said. “In this study, we wanted to know how the removal of the ovaries might affect cardiomyopathy in female mice and also what other impacts the loss of insulin receptors might have on energy metabolism and mitochondrial function.” 

Insulin resistance and signaling

About 90–95% of patients with Type 2 diabetes suffer from insulin resistance, a risk factor for heart failure. In healthy tissue, insulin binds to insulin receptors, activating a network of intracellular signalling pathways. Disruptions in these signalling pathways have been linked to mitochondrial dysfunction, cardiomyopathy, and impaired glucose and fatty acid metabolism, among other health issues.

In this study, mice lacking IRS developed dilated cardiomyopathy, and analysis showed lowered activity of genes important for mitochondrial function and energy metabolism.

“Type 2 diabetes patients and insulin-resistant patients exhibit mitochondrial dysfunction,” Prof Guo explained.

The study fills in some blanks in understanding the role of insulin and estrogen signaling in mitochondrial function.

Study findings

Guo said there were four important findings from the study:

  • All female mice that lacked insulin receptor substrates survived for more than a year.
  • Female mice without insulin receptor substrates were less likely to experience severe cardiac dysfunction and death if they had ovaries. If the mice also lacked ovaries but received oestrogen, it prolonged their lifespans. Doses of oestrogen also protected IRS-altered male mice from heart dysfunction. 

Guo said oestrogen also prevents cardiomyopathy induced by loss of cardiac insulin receptor substrates.

“And removal of the ovaries leads to the death of female cardiac IRS1 and IRS2 double genes knockout mice if there is no reintroduction of oestrogen,” he said.

Loss of IRS1 and IRS2 genes in heart tissue disrupts cardiac energy metabolism, gene activity involved in mitochondrial function, and whole-body energy metabolism. However, oestrogen partially reverses these effects.

Oestrogen is important for healthy cellular signalling pathways and promotes mitochondrial function.

Prof Guo said the study shows that oestrogen enhances cardiac function, promotes energy metabolism, prevents cardiomyopathy and prolongs survival in both male and ovariectomy female mice lacking the insulin receptor substrates.  

“This study provides evidence for the gender difference for the incidence of cardiovascular disease and implies that oestrogen replacement therapy is feasible for the treatment of diabetic cardiomyopathy through enhancement of mitochondrial function and energy metabolism,” he said. “It also reveals some of the signalling pathways that may be potential therapeutic targets for the prevention or treatment of cardiovascular diseases in patients with Type 2 diabetes.” 

Guo also noted that diet could also play a role with oestrogens in foods.

“The study implies that food-derived oestrogens or phytoestrogens may play similar roles to oestrogen, as observed in mice,” he said. “This may help us reshape our knowledge of nutrient and food sciences related to plant hormones that can modulate chronic metabolic diseases such as Type 2 diabetes and associated cardiovascular complications.”

Source: Texas A&M University

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Researchers Successfully Restore Pancreatic Beta Cells in Type 1 Diabetes

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Scientists have successfully treated type 1 diabetes in mice using pancreatic beta-cell, target-specific, chimeric antigen-receptor (CAR) regulatory T cells (Tregs), showing the feasibility of replicating this in humans according to data presented at ENDO 2022, the Endocrine Society’s annual meeting.

The study was led by Professor Juan Carlos Jaume, MD, at the University of Toledo.

Adoptive cell transfer therapies with CAR cytotoxic T cells have proven effective for the treatment of haematologic malignancies. Prof Jaume and colleagues attempted to replicate an equally effective experimental treatment for type 1 diabetes using instead non-cytotoxic, anti-inflammatory Tregs.

“The purpose of this study was to determine if pancreatic beta-cell, target-specific, human CAR Tregs could also identify human pancreatic beta cells and home to human pancreatic islets in culture as they do in mice undergoing CAR Treg treatment for T1D,” Prof Jaume said.

The researchers drew blood one to two weeks prior to pancreas surgery, followed by a collection of a a 5cc wedge of the pancreas after the pancreas was removed for a clinically indicated reason, either cancer or pancreatitis.

The researchers isolated Tregs from the blood samples and expanded them in vitro. Those cells were genetically modified to express a beta-cell, target-specific CAR combined with a green fluorescence protein (GFP) marker.

The next step was to process the pancreas tissue for islet separation. Following this, they co-cultured the human pancreatic islets combined with the beta-cell, target-specific CAR Tregs.

Within 24 hours, confocal microscopy demonstrated the successful migration of the GFP positive, CAR Tregs onto the pancreatic islets. What’s more, the CAR Tregs significantly proliferated while in physical contact with the pancreatic islets in the subsequent 72 hours.

“Ours is the first successful, pancreatic beta-cell, target-specific CAR-Treg treatment of T1D in a humanized mouse model that closely resembles the human disease. Based on our mice and human in-vitro data, we believe treatment with pancreatic beta-cell, target-specific, CAR-Tregs will allow for recovery and reconstitution of beta cells in human T1D patients as well,” Prof Jaume said.

Source: EurekAlert!

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Why Only Some Obese Patients Develop Diabetes

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A 3D map of the islets in the human pancreas. Source: Wikimedia

Oregon State University researchers have used a new analytical method to shed light on an enduring mystery in type 2 diabetes: why some obese patients develop diabetes and others don’t. The reason is down to a genetic pathway linking diet and gut microbiota to macrophages and white adipose tissue. Their findings appear in the Journal of Experimental Medicine.

Type 2 diabetes is frequently associated with obesity. Ins some patients, that means insulin resistance. Later stages of the disease sees the pancreas producing insufficient insulin to maintain normal glucose levels.

In either case, hyperglycaemia is the result, which, if left untreated, impairs many major organs, sometimes to disabling or life-threatening degrees. Overweight status is a key risk factor for type 2 diabetes, often a result of eating too much fat and sugar in combination with low physical activity.

Associate Professors Andrey Morgun and Natalia Shulzhenko of OSU and Giorgio Trinchieri of the National Cancer Institute developed a novel analytical technique, multi-organ network analysis, to explore the mechanisms behind early-stage systemic insulin resistance.

The scientists sought to learn which organs, biological pathways and genes are playing roles.

The findings showed that a particular type of gut microbe leads to white adipose tissue containing macrophage cells associated with insulin resistance.

“Our experiments and analysis predict that a high-fat/high-sugar diet primarily acts in white adipose tissue by driving microbiota-related damage to the energy synthesis process, leading to systemic insulin resistance,” said Morgun. “Treatments that modify a patient’s microbiota in ways that target insulin resistance in adipose tissue macrophage cells could be a new therapeutic strategy for type 2 diabetes.”

The human gut microbiome is incredibly complex, comprising more than 10 trillion microbial cells from about 1000 different bacterial species.

Associate Profs Morgun and Shulzhenko, in earlier research developed a computational method, transkingdom network analysis, that predicts specific types of bacteria controlling the expression of mammalian genes connected to specific medical conditions such as diabetes.

“Type 2 diabetes is a global pandemic, and the number of diagnoses is expected to keep increasing over the next 10 years,” Associate Prof Shulzhenko said. “The so-called ‘western diet’ – high in saturated fats and refined sugars – is one of the primary factors. But gut bacteria have an important role to play in mediating the effects of diet.”

In the new study, the scientists made use of transkingdom network analysis and multi-organ network analysis. Mouse experiments examined the intestine, liver, muscle and white adipose tissue, and the molecular signature (gene expression) of white adipose tissue macrophages in obese human patients.

“Diabetes induced by the western diet is characterised by microbiota-dependent mitochondrial damage,” Associate Prof Morgun said. “Adipose tissue has a predominant role in systemic insulin resistance, and we characterised the gene expression program and the key master regulator of adipose tissue macrophage that are associated with insulin resistance. We discovered that the Oscillibacter microbe, enriched by a western diet, causes an increase of the insulin-resistant adipose tissue macrophage.”

The researchers add, however, that Oscillibacter is likely not the only microbial regulator for expression for the genetic pathway they discovered, while clearly instrumental, is probably not the only important pathway, depending on which gut microbes are present.

“We previously showed that Romboutsia ilealis worsens glucose tolerance by inhibiting insulin levels, which may be relevant to more advanced stages of type 2 diabetes,” Shulzhenko said.

Source: Oregon State University

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New SGLT-2 Inhibitors Could Reduce Heart Failure Risk in Diabetes

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A study published in Annals of Internal Medicine has suggested that the new SGLT-2 inhibitors may be viable as a first-line treatment in patients with type 2 diabetes, with reduced odds of hospitalisation for heart failure compared to those receiving metformin.

In cardiovascular outcome trials among adults with type 2 diabetes (T2D), sodium-glucose co-transporter 2 inhibitors (SGLT-2i) have shown therapeutic promise, including reduced risk of hospitalisation for heart failure compared to placebo. However, SGLT-2i have mainly been evaluated as a second-line treatment – metformin is generally given as a first-line, antidiabetic treatment.

In this new study, researchers from the Brigham and Women’s Hospital compared cardiovascular outcomes among adults with T2D who initiated first-line treatment with either metformin or SGLT-2i. For the study, 8613 patients receiving SGLT-2i were matched to 17 226 patients receiving metformin.

The researchers reported that that patients receiving SGLT-2i showed a similar risk for myocardial infarction, stroke, and all-cause mortality, and a lower risk for hospitalisation for heart failure compared with patients who received metformin. The risk for adverse events was similar except for an increased risk for genital infections compared with those receiving metformin.

“Our results suggest that SGLT-2i may be considered as first-line treatment for patients with T2D and cardiovascular disease or who are at increased risk for cardiovascular events,” said lead author HoJin Shin, BPharm, PhD, of the Division of Pharmacoepidemiology and Pharmacoeconomics. “However, more evidence from randomised clinical trials or observational studies will help us to identify patients who would benefit most from using SGLT-2i as first-line type 2 diabetes treatment.”

Source: EurekAlert!

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Diabetes may Weaken Teeth, Promoting Tooth Decay

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People with both Type 1 and Type 2 diabetes are prone to tooth decay, and a new study published in Archives of Oral Biology may explain why: reduced strength and durability of enamel and dentin, the hard substance under enamel that gives structure to teeth.

Researchers induced Type 1 diabetes in 35 mice and used a Vickers microhardness tester to compare their teeth with those of 35 healthy controls over 28 weeks. Although the two groups started with comparable teeth, enamel grew significantly softer in the diabetic mice after 12 weeks, and the gap continued to widen throughout the study. Significant differences in dentin microhardness arose by week 28.

“We’ve long seen elevated rates of cavity formation and tooth loss in patients with diabetes, and we’ve long known that treatments such as fillings do not last as long in such patients, but we did not know exactly why,” said Mohammad Ali Saghiri, an assistant professor of restorative dentistry at the Rutgers School of Dental Medicine.

The study advances a multiyear effort by Assistant Prof Saghiri and other researchers to understand how diabetes affects dental health and to develop treatments that counter its negative impact. Previous studies have established that people with both types of diabetes have significantly elevated rates of most oral health issues, both in the teeth and the soft tissues that surround them. Assistant Prof Saghiri and other researchers also have demonstrated that diabetes can interfere with the ongoing process of adding minerals to teeth as they wear away from normal usage.

“This is a particular focus of mine because the population of people with diabetes continues to grow rapidly,” Assistant Prof Saghiri said. “There is a great need for treatments that will allow patients to keep their teeth healthy, but it has not been a major area for research.”

Source: EurekAlert!

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How Breast Cancer Cells Sabotage Insulin Production to Fuel Themselves

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Scanning Electron Micrograph of a breast cancer cell. Credit: NIH

Breast cancer and diabetes have long been suspected to have some kind of relationship, but now new research in Nature Cell Biology reveals how breast cancer cells sabotage insulin production to fuel their own cravings for glucose.

Diabetes risk begins to increase two years after a breast cancer diagnosis, and by 10 years post-diagnosis, the risk is 20% higher in breast cancer survivors than in age-matched women without breast cancer.

But these epidemiological linkages are not clear-cut or definitive, and some studies have found no associations at all. In the paper, a research team describe a possible biological mechanism connecting the two diseases, in which breast cancer suppresses the production of insulin, resulting in diabetes, and the impairment of blood sugar control promotes tumour growth.

“No disease is an island because no cell lives alone,” said corresponding study author Shizhen Emily Wang, PhD, professor of pathology at UC San Diego School of Medicine. “In this study, we describe how breast cancer cells impair the function of pancreatic islets to make them produce less insulin than needed, leading to higher blood glucose levels in breast cancer patients compared to females without cancer.”

The researchers name the culprit as extracellular vesicles (EV), which carry DNA, RNA, proteins, fats and other materials between cells, a sort of cargo communication system.

The cancer cells were found to be secreting microRNA-122 into the vesicles. When vesicles reach the pancreas, Prof Wang said, they can enter the islet cells, offload their miR-122 cargo and damage the islets’ critical function in maintaining a normal blood glucose level.

“Cancer cells have a sweet tooth,” Prof Wang said. “They use more glucose than healthy cells in order to fuel tumor growth, and this has been the basis for PET scans in cancer detection. By increasing blood glucose that can be easily used by cancer cells, breast tumors make their own favorite food and, meanwhile, deprive this essential nutrient from normal cells.”

Feeding mice slow-releasing insulin pellets or an SGLT2 inhibitor restored normal control of glucose in the presence of a breast tumour, in turn suppressed the tumour’s growth.

“These findings support a greater need for diabetes screening and prevention among breast cancer patients and survivors,” remarked Prof Wang, noting that a miR-122 inhibitor is currently in clinical trial as a potential treatment for chronic hepatitis C. It has been found to be effective in restoring normal insulin production and suppressing tumour growth in mouse models of breast cancer.

“These miR-122 inhibitors, which happen to be the first miRNA-based drugs to enter clinical trials, might have a new use in breast cancer therapy,” Prof Wang posited.

Source: University of California – San Diego

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Vitamin D Doesn’t Prevent the Development of Type 2 Diabetes

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Daily vitamin D supplements do not seem to prevent the development of type 2 diabetes in people already at high risk of the condition, according to a Japanese trial published by The BMJ.

While no clinically meaningful effect was seen in high risk adults, the results hinted that there may be a benefit for people with insufficient insulin secretion.

Type 2 diabetes affects around 480 million people worldwide, and is predicted to increase to 700 million by 2045. Another half a billion people have impaired glucose tolerance or pre-diabetes (higher than normal blood sugar levels that, if left untreated, can develop into type 2 diabetes).

Weight loss and exercise can lower the risk of progression to type 2 diabetes, but are difficult to sustain, so new strategies are needed to tackle the problem.

An association between vitamin D deficiency and an increased risk of future diabetes has been shown in some studies, but trials of vitamin D supplements for preventing type 2 diabetes show inconsistent results.

To address this knowledge gap, researchers therefore set out to assess whether eldecalcitol (an active form of vitamin D used to treat osteoporosis in Japan) could reduce the risk of developing type 2 diabetes among people with impaired glucose tolerance.

The study involved 1256 Japanese adults with impaired glucose tolerance with an average age of 61 years; 46% were women, and 59% had a family history of type 2 diabetes.

Participants were randomly assigned to receive either a standard daily dose of eldecalcitol (630 participants) or placebo (626 participants) and were assessed for diabetes every three months over a three-year follow-up period.

During this period, the researchers found no meaningful differences between groups in those who developed diabetes (12.5% in the eldecalcitol group and 14% in the placebo group) or whose blood sugar levels returned to normal (23% in the eldecalcitol group and 20% in the placebo group).

However, after adjusting for 11 potentially influential factors, including age, sex, blood pressure, body mass index, and family history of diabetes, the results suggested that eldecalcitol might prevent type 2 diabetes in pre-diabetic patients with insufficient insulin secretion. But this finding remains unclear and the researchers say further work is needed before any firm conclusions can be made.

They did, however, find a significant increase in both lower back and hip bone mineral densities among those taking eldecalcitol compared with placebo.

No significant difference in serious adverse events was seen between the two groups.

The researchers acknowledge some uncertainties, such as whether the dose of eldecalcitol used was appropriate for preventing diabetes, and whether the results apply to all ethnicities. Nevertheless, this was a large trial with regular follow-up and high adherence to treatment, suggesting that the findings are robust.

As such, they say: “Although treatment with eldecalcitol did not significantly reduce the incidence of diabetes among people with pre-diabetes, the results suggested the potential for a beneficial effect of eldecalcitol on people with insufficient insulin secretion.” And they call for further research to determine whether vitamin D is beneficial to people with pre-diabetes.

This new trial was well conducted and results are consistent with two other recent trials, said Tatiana Christides at Queen Mary University of London in a linked editorial.

However, several questions remain, she writes, including whether vitamin D supplementation may be more effective for particular populations, and whether longer duration of treatment or younger age at initiation might be more beneficial.

Until further data are available from high quality randomized trials, she suggests healthcare professionals “should continue to discuss with patients the musculoskeletal health benefits of vitamin D and support them to achieve and maintain lifestyle changes that, although challenging to sustain, are known to decrease development of type 2 diabetes.”

Source: News-Medical.Net

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Reduce Blood Sugar ASAP After Diabetes Diagnosis, Study Suggests

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Findings from new research published in Diabetes, Obesity and Metablism suggest that people with type 2 diabetes may need to reduce their blood sugar levels sooner after diagnosis than previously thought, to prevent major cardiovascular events such as heart attacks.

The University of Surrey study Surrey suggests that achieving glycaemic control within the first year of diagnosis reduces the incidence of major cardiovascular events. Additionally, the team found that the greater the variation in blood levels 12-months after diagnosis, the more likely a patient was to experience dangerous cardiovascular events.

Dr Martin Whyte, co-author of the study and Reader in Metabolic Medicine at the University of Surrey, said: “The conventional wisdom has been to slowly and steadily treat type 2 diabetes with diet and medicine dose-escalation over years – the period over which it took people to reduce their sugar levels after diagnosis was thought less important for major vascular protection. However, our observational study suggests that getting blood levels under control quickly — within the first 12 months after diagnosis — will significantly help reduce cardiovascular events.”

Type 2 diabetes is a common condition that results in the level of sugar in the blood becoming too high. The condition is linked to obesity or a family history of type 2 diabetes and can increase a person’s risk of getting serious health conditions.

The University of Surrey’s study used Royal College of General Practitioners’ Research and Surveillance Centre database to perform a comprehensive examination of glycaemic control achieved within the first year of diagnosis and subsequent blood sugar level variability with cardiovascular disease incidents.

Source: University of Surrey

Categories : COVID Metabolic DisordersTags :

Diabetes Almost Doubles COVID Mortality Risk

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Compared to those without diabetes, the COVID mortality risk for people with diabetes is almost double, with almost three times the risk of being critically or severely ill, according to a review of research by researchers from the University of Aberdeen.

Fortunately, the review study, which is published in Endocrinology, Diabetes and Metabolism, also found that good management of the condition can mitigate against the risks.

Specifically, it was found that while diabetes presents a significant risk of severe illness and death with COVID, good glycaemic control in these patients can mitigate this risk.

The researchers reviewed findings from 158 studies, encompassing more than 270 000 participants from around the world to determine COVID’s impact on people with diabetes.

The pooled results showed that people with diabetes were 1.87 times more likely to die with COVID, 1.59 times more likely to be admitted to ICU, 1.44 times more likely to require ventilation, and 2.88 times more likely to be classed as severe or critical, when compared to patients without diabetes.

This is the first time a study has looked at the risks of COVID in patients with diabetes while factoring in the patients’ location and thereby highlighting potential healthcare resources available as well as possible ethnic differences and other societal factors.

Patients in China, Korea and the Middle East were found to be at higher risk of death than those from EU countries or the US. This, they suggested, may be the result of differences in healthcare systems and affordability of healthcare which may explain the finding that maintaining optimal glycaemic control, significantly reduces adverse outcomes in patients with diabetes and COVID.

Stavroula Kastora, who worked on the study explained: “We found that following a COVID infection, the risk of death for patients with diabetes was significantly increased in comparison to patients without diabetes.

“Equally, collective data from studies around the globe suggested that patients with diabetes had a significantly higher risk of requiring an intensive care admission and supplementary oxygen or being admitted in a critical condition in comparison to patients without diabetes.

“However, we found that the studies that reported patient data from the EU or US displayed less extreme differences between the patient groups. Ultimately, we have identified a disparity in COVID outcomes between the eastern and western world. We also show that good glycaemic control may be a protective factor in view of COVID-related deaths.

“In light of the ongoing pandemic, strengthening outpatient diabetes clinics, ensuring consistent follow up of patients with diabetes and optimising their glycaemic control could significantly increase the chances of survival following a COVID infection.”

Source: University of Aberdeen