More Accurate Conversion of Average Blood Glucose to Hemoglobin A1c

Dr. Norris

What is Hemoglobin A1c? Hemoglobin A1c (HbA1c) is a blood test that measures the amount of glucose that is attached to a persons hemoglobin — the oxygen carrying protein found in red blood cells. The higher a person’s blood sugar, the more glucose that becomes attached. Because red blood cells last about 90 days, the HbA1c value reflects a person’s average blood glucose over the past 3 months. A HbA1c value over 6.4% indicates that a person has diabetes. For persons with diabetes, higher blood glucoses increase the risk of long term complications. Higher HbA1c levels are associated with increased rates of complications including diabetic eye disease, kidney disease, and neuropathy. For this reason, the American Diabetes Association recommends that most persons with diabetes have a goal of maintaining their HbA1c at less than 7%.

What is average blood glucose? In the past, HbA1c was the only widely available method to assess a person’s recent average blood glucose levels. Fortunately, technological advances over the past decades have enabled frequent testing of blood glucose using portable meters and even more powerfully using continuous glucose monitors (CGMs). CGMs are wearable devices that measure a persons approximate blood glucose every few minutes. Modern glucose meters and CGMs can report a user’s recent average blood glucoses.

Converting between average blood glucose and HbA1c A common question asked by persons with diabetes is what HbA1c is predicted by their recent average blood glucose. There are multiple online conversion calculators that address this question, allowing the user to enter an average glucose for which a predicted HbA1c is returned. However, two scientists at the University of Iowa recently identified and reported a small mathematical error in the equations commonly used by online calculators to predict HbA1c from recent average blood glucose. As a result, the erroneous online calculators do not provide optimal predictions. The two scientists were Dr. Joseph Lang from the Department of Statistics and Actuarial Science and Dr. Andrew Norris from our Division. The two then derived new equations that correct the error. Their findings and new equations have been peer reviewed and now are published as a letter in the prominent journal Diabetes Care (link to article).  Dr Norris would like to thank Dr Lang for uncovering the error and devising the approach for its correction. The hope is that the improved equations will be adopted by online calculators. In the meantime, on a positive note, many continuous glucose monitors report an estimated HbA1c that is termed “GMI” (“glucose management indicator”) and the equations used for GMI are typically correct. Drs. Norris and Lang’s letter also comments on a recently published perspective that highlights ongoing issues in the interconversion of recent average blood glucose to HbA1c. It is important to understand that neither HbA1c nor meter/monitor derived average blood glucose are perfectly accurate. Unsurprisingly, interconversions between these two measurements often do not agree. The revised equations of Dr Lang and Dr Norris will help the situation to some degree but perfect agreement is not possible in real life. Additional data and understanding of the variances that impact the relationship between these two measurements are needed.

A Newly Identified Mechanism of Obesity-Induced Pituitary Dysfunction Contributes to Metabolic Dysfunction Associated Fatty Liver Disease

Dr. Norris

Obesity impairs various aspects of pituitary function. Perturbations in the thyroid, growth hormone, gonadal, and adrenal axes are well documented. However, the mechanisms involved are not well understood. Furthermore, it is possible that the pituitary dysfunction induced by obesity might contribute to the medical complications of obesity. Dr. Norris, from our division, recently assisted with new research that begins to address these knowledge gaps. The investigators found that obesity in mice impaired the ability of pituitary cells to activate their cellular unfolded protein response (UPR). The UPR is a mechanism that helps protect cells against various stressors. Importantly, when the UPR was disrupted in pituitary cells by genetic manipulation, pituitary dysfunction similar to that in obesity resulted, especially in the thyroid axis. Furthermore, primary genetic UPR disruption in the pituitary resulted in UPR disruption in the liver in a manner that could contribute to fatty liver disease. The work will be published in Cell Metabolism and its abstract is available on PubMed (link). The work was conducted in the lab of Dr. Ling Yang in the F.O.E. Diabetes Research Center at the University of Iowa.

Screening for Diabetes in Persons with Turner Syndrome

Persons with Turner syndrome are at higher risk than normal to develop diabetes. It would be ideal to screen for diabetes to allow treatment early in the disease process. The natural history of diabetes in persons with Turner syndrome is not well understood. Likewise, the optimal screening approach is not known. To help address this knowledge gap, Dr. Pinnaro from our division led a team that compared results between multiple types of screening tests for diabetes assessed concurrently in persons with Turner syndrome. The screening tests compared were fasting plasma glucose, oral glucose tolerance test, and hemoglobin A1c. The results showed only partial concordance between the different tests. Interpreted conservatively, the data suggest that various hemoglobin A1c thresholds could be used to indicate need for closer evaluation for diabetes. The results are published in the journal Hormone Research in Paediatrics as an article entitled “Screening for Turner syndrome-associated hyperglycemia: Evaluating hemoglobin A1c and fasting blood glucose”. Study authors from our division were Drs. Pinnaro, Parra Villasmil, and Norris. The article’s Pubmed abstract can be found at this link.

Opposing Impacts of Sirtuin1 on Muscle Insulin Sensitivity

Dr. Norris

Sirtuin1 is a protein that is essential for health. Insulin resistance results when sirtuin1 is lost from skeletal muscle. A team at the University of Iowa led by Drs. Kaiko Irani and Qiuxia Li investigated the impact of sirtuin1 in the vasculature. To accomplish this they knocked out sirtuin1 from the cells that line the inside of blood vessels. As expected, the resulting blood vessels were dysfunctional. Typically, skeletal muscle will become insulin resistant when blood vessels are dysfunctional . However, in this case, the skeletal muscles of the mice lacking blood vessel sirtuin1 were unexpectedly more sensitive to insulin. Importantly, to understand this surprising finding the investigative team identified the mechanism that increases muscle insulin sensitivity. Specifically, the loss of sirtuin1 caused the blood vessel cells to secrete thymosin beta-4, an enhancer of insulin sensitivity in skeletal muscle. These findings highlight the complex actions of sirtuin1 on insulin sensitivity. The publication resulting from the work is entitled “Deficiency of endothelial sirtuin1 in mice stimulates skeletal muscle insulin sensitivity by modifying the secretome”, is published in the journal Nature Communications, and can be found at this link. Dr. Norris from our division is a co-author on the manuscript and contributed to the work by helping direct the studies measuring muscle insulin sensitivity.

Normal SARS-CoV-2 Immunity in Children with Type 1 Diabetes, Including after Vaccination

Persons with diabetes can have weakened immune systems that are unable to fight off infections. Vaccination response depends on the immune system creating protective immunity after exposure to an antigen. Indeed, under some circumstances persons with diabetes fail to develop immunity after vaccination. Most data to date however have focused on adults. In particular, no studies have examined the response of children with diabetes to COVID vaccination. In a collaboration between the Microbiology Department, our Division set out to address this knowledge gap. Both antibody levels and cellular immunity against the COVID virus were compared between children with and without type 1 diabetes. The levels were also compared between the children that had versus had-not received COVID booster vaccination. Importantly, the children with diabetes exhibited normal levels of immunity that matched those of children without diabetes. This result shows that children with diabetes have normal immune responses, at least as regards protection against COVID, including before and after booster vaccination. Surprisingly, COVID booster vaccination did not statistically raise immunity against the Omicron COVID variant in either group of children. One possible reason for this may have been that the children groups appeared to already have a degree of immunity against Omicron even without booster vaccination, though the study was not designed to properly address this possibility. By contrast, adults were also studied and experienced a robust enhancement of immunity in response to booster vaccination. Members of our Division who helped create and conduct the study were Drs. Pinnaro, Tansey, and Norris, as well as research manager Shannon Christensen. The publication can be found at this Pubmed link. The authors wish to thank the children and families who volunteered for the study.

New Supplement to Diabetes Research Training Grant

Dr. Norris

Since 2017, the F.O.E. Diabetes Research Center has maintained a NIH supported Diabetes Research Training Program for postdoctoral scholars. The purpose of this Program is mentor and train the next generation of investigators who will devise better approaches to prevent, treat, and ultimately reverse diabetes. The Training Program is led by Dr. Norris from our Division. The Program supports up to 6 concurrent postdoctoral trainees. This spring, the Program had an unprecedented number of outstanding applicants. To better support training under these circumstances, Dr. Norris partnered with Dr. Bertha Martín, one of the applicants, and her mentor Dr. Jon Resch to create a grant supplement application. This application has now been funded, as NIH grant 3T32DK112751-07S1. We look forward to Dr. Martín’s research development.

Setting Research Priorities to Better Understand, Treat, and Prevent Cystic Fibrosis Related Diabetes

Potent medications have recently been developed to treat cystic fibrosis. These new therapies dramatically improve lung disease for those with cystic fibrosis. Persons with cystic fibrosis often develop a unique form of diabetes termed cystic fibrosis related diabetes (CFRD). It is not yet clear how the new therapies will impact the propensity of persons with cystic fibrosis to develop CFRD. A group of researchers, clinical experts, and patients/families were assembled by the NIH and the Cystic Fibrosis Foundation to discuss research priorities to better understand treat and prevent CFRD. This group convened in June of 2021 at a workshop open to the public. This group has now written and published a summary describing their collective thoughts on research priorities priorities CFRD, Their writings appear this month in the two journals Diabetes and Diabetes Care. Contributing to the article were two physicians from our division: Dr. Norris and Dr. Larson Ode, with Dr. Norris serving as one of the lead authors of the work. The publication can be found at the following Pubmed link.

New Clues in the Pursuit to Understand the Fatty Acid Imbalance of Cystic Fibrosis

Dr. Norris

Persons with cystic fibrosis typically have an imbalance in their fatty acid levels. A prominent aspect of this imbalance is a deficiency of linoleic acid, which is one of the so-called essential fatty acids. Despite decades of research, the mechanisms of the imbalance are not fully understood. To better understand this fatty acid imbalance, a group of researchers at the University of Iowa, Kansas State University, and the Karolinska Institutet in Stockholm Sweden worked together to study pigs and ferret with cystic fibrosis. The results showed that the imbalance exists at birth even before first feeding. This result argues strongly against one of the leading prior hypotheses which was that the imbalance might stem from the nutrient malabsorption that occurs in cystic fibrosis. Instead, the results suggest that several molecular mechanisms might be responsible for the imbalance, including excess metabolism of arachidonic acid, oxidative isomerization of unsaturated fatty acids, and/or biliary loss of phospholipids containing unsaturated fatty acids. The senior author of the resulting manuscript describing the findings was Dr. Norris from our Division. The work can be found published in the journal Clinical Science (link).

Highly Effective Modulator Therapy for Cystic Fibrosis Impacts Body Mass Index and Insulin Sensitivity

Cystic fibrosis is a genetic disease that causes dysfunction in multiple systems, but especially in the lungs which progressively deteriorate. The past few years have seen massive progress in the medical treatment of cystic fibrosis. Drugs have come to market that correct the basic molecular defects that cause cystic fibrosis. These drugs are classified as “highly effective modulator therapies”. These therapies must be tailored to each person, by matching to the different mutations that cause cystic fibrosis. In 2019, a blend of three modulators was approved for treatment of the most common form of cystic fibrosis involving the “F508del” mutation. This therapy combines elexacaftor, tezacaftor, and ivacaftor (“ETI”). This therapy dramatically improves lung dysfunction in persons with cystic fibrosis due to F508del mutation. Persons with cystic fibrosis are at very high risk to develop diabetes. For example, those who have only have F508del mutation have an over 80% chance of developing diabetes by middle age. It is currently not known if ETI-therapy for cystic fibrosis will impact diabetes risk. To address this knowledge gap, investigators from 5 institutions conducted a study of twenty persons with cystic fibrosis. Each person underwent an oral glucose tolerance test before and roughly 10 months after starting ETI-therapy. Interestingly, there was not a significant change in glucose levels after starting ETI. However, C-peptide levels increased with ETI therapy, consistent increased insulin secretion. Accordingly, an insulin resistance index significantly increased as did body mass index. Taken together, these results suggest that ETI therapy produces a degree of insulin resistance, likely related to an increase in body mass index. The longer term impact of ETI and related therapies on diabetes risk and body weight will need careful ongoing study. The faculty investigators involved in the study from our division were Dr. Larson Ode and Dr. Norris. The publication describing the study and results can be found at this Pubmed link.

Diabetes Research Training Program Receives Renewed Grant Support

Fraternal Order of Eagles Diabetes Research Center

There is a drastic need to devise better approaches to prevent, treat, and ultimately reverse diabetes. Essential to any progress is the constant training of skilled cohorts of research investigators. To this end, since 2017, the University of Iowa has nurtured a Diabetes Research Training Program. The Program supports mentored postdoctoral training focused on various diabetes research topics. Six postdoctoral trainees are supported at any given time, typically for two years each. To date, 19 postdoctoral trainees have been support by this Program, including pediatric endocrine faculty Dr. Pinnaro while she was a fellow. The Program was conceived by adult endocrinologist Dr. Dale Abel and pediatric endocrinologist Dr. Norris. Based on a proposal detailing their vision, they received a 5-year “T32” grant from the NIH to fund the program 2017-2022. During this time, the Program has been a resounding success, with most trainees having progressed onward in their research careers in academia or related private industry. Based on the strengths of the initial trainees, their research, and career progress, last year Drs. Norris and Abel wrote a renewed 5-year proposal for ongoing training. Today, we are pleased to announce that the proposal was viewed very favorably and that an additional 5 years of grant support will be provided by the NIH (you can view a summary of the grant at this link). Future or existing pediatric endocrine fellows who are interested a career focused on diabetes research can benefit from this program and are encouraged to contact Dr. Norris to discuss the application process.