There remains much to learn about endocrinology, and most of the conditions we treat do not have definitive cures. To help advance the field, the faculty in our Division direct endocrinology-focused research ranging from laboratory biomedical science to clinical studies. Here we report some of our noteworthy progress.
Persons who have experienced pancreatitis sometimes will develop diabetes. Diabetes that occurs as a result of pancreatitis is not the same as type 1 or type 2 diabetes, and sometimes it is called “type 3c diabetes”. While a fellow in our program, Dr. Parra Villasmil set out to compile knowledge on this subject, especially as relates to pediatric aged patients. Her review on this subject has now been published in the journal Gastroenterology Clinics of North America (permanent link to the article). In the review, Dr. Parra Villasmil summarizes data that 6-8% of children who experience pancreatitis will develop diabetes. The risk can occur after even one episode of pancreatitis but increases after multiple bouts of pancreatitis. The risk of developing diabetes is even higher for persons that have inherited forms of pancreatitis. Dr. Parra Villasmil stress the importance of continued screening for diabetes in persons who have experienced diabetes. The possible pathophysiology of pancreatitis-induced diabetes and treatment options are also discussed. This is an important review, in part because strategies to prevent diabetes in persons who have experienced pancreatitis do not yet exist. The article was written with Dr. Melena Bellin, a Pediatric Endocrinologist at the University of Minnesota. We thank these authors for their contributions to knowledge dissemination.
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.
Turner syndrome is a genetic condition cause by complete or partial loss of an X chromosome in a person who otherwise would have an XX karyotype. There are multiple ways in which the X chromosome can be missing or partially lost. Sometimes, a person with Turner syndrome will have a mixture of cells in their body. An uncommon form of Turner syndrome occurs when some cells are have only one X chromosome (45,X karyotype) and other cells have three X chromosomes – termed 45,X/47,XXX mosaicism. The health implications of this form of Turner syndrome have not been well studied until now. A group of Turner syndrome experts across the United States, including our own Dr. Pinnaro, have cooperated to combine their experiences. Their findings are now published in the American Journal of Medical Genetics (PubMed link). They found that features of this form of Turner syndrome could be more subtle than more common forms. Because Turner syndrome can cause a wide variety of rare but serious health concerns, it is important for persons with Turner syndrome to receive medical care in a specialized clinic, such as the one staffed at our center by Dr. Pinnaro and Dr. Alexandrou.
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.
Dr. Eirene AlexandrouDr. PalmerDr. Catherina PinnaroDr. Akhila Ramakrishna
Each year, pediatric endocrinologists from around the world attend the “PES Annual Meeting”, hosted by the Pediatric Endocrine Society (PES). The mission of the PES is primarily to “advance and promote the endocrine health and well being of children and adolescents“. This year, several Division members submitted abstracts describing new research and advances for review by the PES. The following were selected for presentation at this years PES meeting, which was just held May 2-5 in Chicago.
Dr. Eirene Alexandrou: “Gonadotropin-Releasing Hormone Agonist Therapy in Patients Undergoing Dialysis – A Cautionary Tale!” – selected for a poster presentation. Co-author from our division on this work is Dr. Akhila Ramakrishna.
Dr. Ben Palmer: “Adolescent-driven Retrospective Glucose Data Self-Review is Associated with Improved Glycemic Control in Type 1 Diabetes Mellitus.” – selected for a poster presentation. Co-authors from our division on this work are Dr. Catherina Pinnaro, Dr, Andrew Norris, and Dr. Michael Tansey.
Dr. Catherina Pinnaro: “Influence of X Chromosome Parent-of-origin on Glycemia in Individuals with Turner syndrome” – selected for an prestigious oral presentation. Co-author from our division on this work is Dr. Andrew Norris.
Dr. Akhila Ramakrishna: “A rare case of a female with 47 XXY ovo-testicular DSD.” – selected for an prestigious oral presentation.
Congratulations to all for helping advance the field of Pediatric Endocrinology.
The 2024 Pediatric Research Day was held on the afternoon of April 12th, highlighting seven speakers , a data blitz, and a poster session. Our Division of Endocrinology and Diabetes was well represented. Dr. Parra Villasmil was selected as one of the three top abstract authors, and asked to present to her research work as a talk entitled “Dysglycemia in children with acute recurrent or chronic pancreatitis”. There were four posters that included authors from our Division as well.
Almost 10 years ago, investigators from our Division determined that young kids with cystic fibrosis (CF), less than 5 years of age, often have high blood sugars in response to a standardized sugary drink. However, the long term importance of these findings is unknown. Furthermore, we don’t know if this issue occurs when young kids are eating their usual foods and drink. To address this shortcoming, Dr. Katie Larson Ode of our Division, has partnered with other researchers across the country to create a study using wearable continuous glucose monitors. In one part of the study, they are using these monitors to determine what blood sugars do in young kids with CF in their usual environment (home, school, etc). However, so little is known about what blood sugars do in healthy young kids that it is difficult to know exactly what is normal. To address this, Dr. Larson Ode and her research partners will also study young, healthy kids. Dr. Larson Ode has just received grant funding to conduct the study, entitled “BEGIN Substudy: Continuous Glucose Monitoring in Healthy Children“. We thank Dr. Larson Ode and her research volunteers for their work to help advance knowledge.
Dr. Pinnaro is part of the leadership team that has created a new national registry to track the health of persons with Turner syndrome. The initiative has been named the “Inspiring New Science to Guide Healthcare in Turner Syndrome (InsighTS)” Registry. The leadership group of the InsighTS Registry has now published their study’s design and goals. The publication’s abstract can be found on PubMed at the following link. Persons with Turner syndrome have unique health risks, and ideally should be seen regularly in a clinic with Turner syndrome expertise, such as the one at the University of Iowa Stead Family Children’s Hospital (2023 link to the Turner syndrome clinic) headed by Dr. Alexandrou and Dr. Pinnaro.
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.
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.
