Preparing for the pandemic impact on diabetes testing

During the peak of the COVID-19 pandemic, the Centers for Disease Control and Prevention (CDC) reported in September 2020 that concerns about the virus impacted an estimated 41% of adults who delayed or avoided medical care, including urgent and emergency care (12%), as well as routine care (32%).¹

This avoidance was reported most prevalently amongst unpaid caregivers for adults, people with underlying medical conditions, Black adults, Hispanic adults, young adults and the disabled.

People with chronic disease, such as diabetes, were at higher risk than others for COVID-19, resulting in hospitalizations. According to a study by Matthew C. Wagner, PhD, and Thomas Lohmann, MD, which appeared in the November 2020 issue of Medical Laboratory Observer,² 28.3% of COVID-19 deaths had diabetes mellitus as a comorbidity. Patients with poorly controlled or uncontrolled diabetes had a higher rate of morbidity, and the rate of people hospitalized with COVID and diabetes rose as high as 85.9%.

In MLO’s State of the Industry (SOI) survey on disease management (page 38 of this issue), MLO editors asked laboratory professionals about the types of tests they are conducting to diagnose and monitor diabetes. The most popular response was HbA1c at 78.5%; fasting plasma glucose test, 75.8%; random plasma glucose test, 67.8%; oral glucose tolerance test, 55.7%; and 17.4% of labs replied diabetes testing was not applicable to them.

The MLO editors also asked labs about the method of testing that they used for HbA1c, and the most popular answer, at 40.3%, was immunoassay. With nearly a quarter of labs (24.8%) responding that this test was not applicable at their location, the remaining responders revealed enzymatic HbA1c testing was the next most popular, 17.4%; followed by cation exchange HPLC, 14.1%; capillary separation, 4.7%; and boronate affinity chromatography, 4%.

The SOI explores additional areas where laboratorians conquered complications, potentially due to lack of screening and other issues of disease management during the pandemic.

COVID-19 impacted diabetes control

University of Michigan³ recently reported about the vast undertreatment of diabetes in a global study, citing only one in ten people in certain low- and middle-income countries were getting the comprehensive care they needed.

For further insight on whether people with diabetes were getting the medical services they need, MLO asked a Promedica lab in Michigan about its local diabetes testing during the pandemic.

“People who do have health issues were not put by the wayside,” assured Wendy Magoon, Registar Phlebotomist at Promedica Laboratory in Newport, MI. “People with diabetes continued to get testing during the pandemic, but they did not see the doctor in person as often. There were much more telehealth visits, but the coverage did continue.”

However, when it came to a new diagnosis, the same could not be said. “Patients who did not have the diagnosis of the illness, or thought they could wait until the pandemic was over, waited longer than people who were already diagnosed to be tested. People who were already diagnosed with diabetes were much more pro-active during the pandemic.”

Monitoring delays lead to diabetic complications

Lack of monitoring can result in dire consequences for diabetics. Delaying proper foot care for diabetics can result in nails growing into the skin, known as onychogryphosis, or which may require a fungal test.

Ulcers, which may require a blood test to screen for infection, and neuropathy can impact mobility and blossom into necrosis, possibly resulting in limb amputation if not treated in time, as nerve and blood vessels are damaged by hyperglycemia, reducing blood flow, and causing tissue death.⁴

Consequences of unmonitored diabetes can be compounded by risk factors like smoking, which doubles the risk of heart disease for diabetics.⁴ Additional complications include high blood pressure, which contributes to kidney diseases and eye complications, such as diabetic retinopathy, which may involve fluorescein angiography, an optical coherence tomography test, and regular injections into the eye, potentially leading to complications like developing glaucoma and/or cataracts, which may require surgical intervention.

The National Institutes of Health (NIH)5 reported diabetics have a greater LV cardiac mass, which may be related to an increased adipocyte release of cytokines, notably Leptin and Resistin, which have hypertrophic effects on cardiomyocytes. Diabetics have been noted to have a slightly diminished diastolic function, which may be due to increased triglyceride synthesis, leading to increased myocardial triglycerides. This increased accumulation has been noted with lipotoxicity and altered calcium hemostasis in myocardium, which both negatively impact diastolic function.

A slight systolic function impact could be from impaired contractile reserve and myocardial sympathetic innervation. Interstitial fibrosis with increased collagen deposits observed in diabetics could contribute to diminished cardiac function.⁵ With an increased risk of cardiovascular disease and a higher incidence of myocardial infarction, the one-year mortality rate of diabetics after myocardial infarction is nearly 50%.

When having open heart surgery, being diabetic is a risk factor for sternal nonunion,⁶ which occurs when the sternum does not heal back together properly after a sternotomy or blunt chest trauma, resulting in clicking, pain, a gap that can sometimes be felt, and range of motion issues. Computed tomography (CT) scans help identify the location of fractures, fragments and wires, and bone density may be tested to determine optimum wire tension to prevent loss of fixation.

Beyond diabetes, other risk factors include obesity, chronic obstructive pulmonary disease, osteoporosis, malnutrition, radiation to the chest wall, and steroid use, as they inhibit healing. This can also be caused by technical errors when closing the sternum, paramedian (off-midline) sternotomy, being on prolonged ventilatory support, having a decreased cardiac function, fracture pattern, fracture gap, and the harvest of bilateral internal mammary arteries for grafting, which results in bone deterioration and mechanical failure. Sternal nonunion is associated with significant morbidity and is a precursor to osteomyelitis, mediastinitis and deep sternal space infections.⁶

Diabetic Ketoacidosis

“Diabetic Ketoacidosis is a serious complication of Type 1 Diabetes Mellitus; however, it can also affect individuals with Type 2 Diabetes, and is a danger zone for diabetics,“ said Jenna Coen, Reagents Marketing Manager at Randox Laboratories Ltd.

“There are known limitations with testing procedures for Diabetic Ketoacidosis when using nitroprusside-based methods, as they lack sensitivity and present greater risk of false negatives. The nitroprusside method used in semi-quantitative dipstick tests, for example, only detects acetone and acetoacetate, when D-3-hydroxybutyrate is the most abundant ketone produced during ketosis, and as such, the measurement of this analyte is much more sensitive and specific. This is something that healthcare and laboratory professionals need to be fully aware of when treating or diagnosing patients.”

Precision and quantitative detection of D-3-Hydoxybutyrate is also used for diagnosing serious clinical conditions, such as sepsis, childhood epilepsy, or gestational diabetes.

“Raising awareness of the advancements in diagnostic methodologies and understanding what is already available in the market is so important for healthcare and laboratory professionals, to help overcome the growing challenges in ketone testing amidst what has been deemed as a ‘Silent Diabetes Pandemic,’” said Coen.

Gestational diabetes (GDM)

The National Institute for Health Care Excellence recommends5 screening for gestational diabetes if patients have risk factors such as obesity, a large weight gain, previous gestational diabetes, or a family history of diabetes.

Gestational diabetes can be treated several ways, depending on the severity of the gestational diabetes. The first mode of treatment is diet, and that’s usually set up through a dietitian with experience with pregnancy. If that is not successful, pills are the next option, such as Metformin.

The length a patient may stay on medication depends. While there is an increased risk of miscarriage in patients with Type 2 diabetes, for patients with polycystic ovarian syndrome (PCOS) and insulin dependence, some obstetricians may prefer to maintain the Metformin through the first trimester to decrease the risk of miscarriage. If management with pills is not successful, then injectable exogenous insulin may be initiated.

If a patient has PCOS and is insulin resistant, there is a higher risk of miscarriage. The theory is that by decreasing the insulin resistance with the Metformin, it decreases the risk of miscarriage.

Around 24-28 weeks of pregnancy, a screening should be done,⁷ which may consist of the fasting plasma glucose (FPG), HbA1c or 75 g oral glucose tolerance test (OGTT), with the FPG and HbA1c ideally repeated twice to confirm overt diabetes. Note that HbA1c can be used for diabetes screening, but it should not be used for screening GDM, due to the very low sensitivity.

During the COVID-19 pandemic, OGTT’s were not performed as often, due to high exposure risks, resulting in some different guidelines for using HbA1c, FPG, or RPG as an alternative during the pandemic.⁷ Currently, the threshold for overt diabetes is an HbA1c greater than or equal to 6.5%; however, recent studies revealed this should potentially be lowered to greater than or equal to 5.9%.⁷

Patients with gestational diabetes should get a glucose tolerance test at six weeks post-partum to make sure the diabetes has resolved, and they are not Type 2 diabetic. If they have Type 2 diabetes, then standard diabetes care should be followed.

Additionally, gestational diabetics are at risk of polyhydramnios, increased amounts of amniotic fluid surrounding the baby, which can cause uterine irritability and is associated with an increased risk of umbilical cord prolapse.

Mothers that develop gestational diabetes tend to have larger babies, especially if they’re blood sugars are out of control. The babies are exposed to elevated glucose levels from their mothers; thus, the baby secretes more insulin to keep its sugar levels normal. With the increased insulin secretion, babies gain more weight.

Macrosomia⁸ is the term for a larger than normal baby, which is commonly defined as a baby larger than 4000 grams or 8.8 pounds (some sources note 4500 grams, 9.9 pounds, for babies of gestational diabetics). This increases risk of additional birth complications, such as shoulder dystocia, when the baby’s shoulders get stuck inside the mother; clavicle fractures; damage to the nerve that sends signals to the arm, known as brachial plexus injury; uterine rupture; and vaginal tearing.

The babies can develop hypoglycemia after birth,⁸ as they continue to create excess insulin. Since they are not exposed to their mother’s high sugar levels anymore, their sugars crash. Needing additional glucose, which may be simply sugar water in a bottle, some get so weak, they cannot even suckle and may reqire an IV with glucose supplementation to raise their glucose levels to normal.

Babies with fetal macrosomia have a risk of childhood obesity and metabolic syndrome.⁸

How labs are testing for diabetes

In a paper by H. David McIntyre,⁹ et al., “Testing for gestational diabetes during the COVID-19 pandemic,” that appeared in Diabetes Research and Clinical Practice, in November 2020, the authors showed how testing for gestational diabetes shifted during the COVID-19 pandemic in different countries across the globe.

For example, the United Kingdom did risk factor based testing, going from 75 g OGTT to no OGTT during the pandemic, and post pandemic, they have transitioned to universal screening for fasting glucose and HbA1c. Pre-pandemic, GDM was if fasting venous puncture glucose (FVPG) was greater than or equal to 5.6 mmol/L and/or 2 h VPG greater than or equal to 7.8 mmol/L. During the pandemic, that changed to being GDM if the HbA1c is greater than or equal to 5.7% (39 mmol/mol), and/or FVPG is greater than or equal to 5.6 mmol/L, and/or Random VPG (not preferred) is greater than or equal to 9 mmol/L.

To reduce the risk of diabetes, the World Health Organization (WHO)¹⁰ launched the Global Diabetes Compact initiative, coinciding with the 100th anniversary of the discovery of insulin, helping efforts to scale up diabetes care globally.

Advances in diabetes

With diabetes testing becoming more commonplace, labs have access to new technology that helps automate diabetes diagnostics.

Vendors of chemistry platforms have advanced the level of automation in diabetes diagnostics, and though the HbA1c and glucose tests are popular, more in-depth diagnostics are available, such as a Fructosamine liquid assay, which monitors the degree of glycemia over 1-3 week timeframes. The American Diabetes Association advises that this may be a better choice when the A1C cannot be measured reliably.¹¹

Additional automated assays include the Access C-Peptide, which distinguishes exogenous vs. endogenous insulin excess, helping to differentiate between Type 1 and Type 2 diabetes in human serum, plasma, and urine. CSF Albumin is another urine test to detect low or rising albumin levels, which could reflect kidney complications in diabetics.¹¹

Automation of the quality control process for diabetes testing also has improved. For example, “the new InteliQ Diabetes quality control helps clinical labs automate their diabetes QC workflow through the load-and-go efficiency of the barcoded, patient-like QC tubes,” said Mary Buchanan, Associate Director of Marketing, Quality Systems, Clinical Diagnostic Group at Bio-Rad Laboratories.

“These barcoded tubes eliminate the need for tedious pour-off steps and manual data entry, which are steps typically performed in most diabetes QC workflows today. Eliminating these manual steps reduces turnaround time, minimizes human error, and increases the labs overall efficiency. As an added benefit, the InteliQ Diabetes control is compatible with major instrument platforms, including Siemens Atellica, Roche cobas, and Abbott Alinity among others, providing a flexible solution for every QC lab.”

Diabetic advances on the horizon are even more exciting. The Washington University School of Medicine in St. Louis (WUSTL) has teamed up with other organizations to focus on stem cell research and diabetes. In 2016,¹² researchers from WUSTL and Harvard University produced insulin-secreting pancreatic beta cells from skin stem cells of Type 1 diabetes patients. This led to the university publishing an article in the journal Science Translational Medicine¹³ with Cornell University demonstrating a nanofiber implant, about the width of a few strands of hair, with cells that secrete insulin in response to sugar in the blood, reversing diabetes without drugs.

They are still perfecting the micro-porous implant, as a challenge is protecting the cells without starving them of needed nutrients while they are inside the device. However, this offers a potential future treatment for diabetes that would not require immune suppressing drugs.¹³

As the labs come back to full volume, pre-pandemic testing levels, the ease of automated diagnostics for diabetes will only lead to more promising discoveries on the horizon for diabetes.

References

Delay or avoidance of medical care because of COVID-19–related concerns - United States, June 2020. Centers for Disease Control and Prevention. https://www.cdc.gov/mmwr/volumes/69/wr/mm6936a4.htm. Published September 10, 2020. Accessed June 4, 2021.
Wagner A, Lohmann T. Hyperglycemia associated with hospitalization for severe COVID-19 infection. Medical Laboratory Observer. https://www.mlo-online.com/continuing-education/article/21158867/hyperglycemia-associated-with-hospitalization-for-severe-covid19-infection. Accessed June 1, 2021.
Vast undertreatment of diabetes seen in global study. University of Michigan News. https://news.umich.edu/vast-undertreatment-of-diabetes-seen-in-global-study/. Published May 24, 2021. Accessed June 1, 2021.
Put the brakes on diabetes complications. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/library/features/prevent-complications.html. Published October 21, 2019. Accessed June 4, 2021.
Raets L, Beunen K, Benhalima K. Screening for gestational diabetes mellitus in early pregnancy: what is the evidence? J. Clin. Med. 2021;10(6):1257. doi:10.3390/jcm10061257.
Chepla KJ, Salgado CJ, Tang CJ, Mardini S, Evans KK. Late complications of chest wall reconstruction: management of painful sternal nonunion. Semin Plast Surg. 2011;25(1):98-106. doi:10.1055/s-0031-1275176.
Leon BM. Diabetes and cardiovascular disease: epidemiology, biological mechanisms, treatment recommendations and future research. WJD. 2015;6(13):1246. doi:10.4239/wjd.v6.i13.1246.
Fetal macrosomia. Mayo Clinic. May 29, 2020. https://www.mayoclinic.org/diseases-conditions/fetal-macrosomia/symptoms-causes/syc-20372579. Accessed June 4, 2021.
McIntyre HD, Gibbons KS, Ma RCW, et al. Testing for gestational diabetes during the COVID-19 pandemic. An evaluation of proposed protocols for the United Kingdom, Canada and Australia. Diabetes Res. Clin. Pract. 2020;167. doi:10.1016/j.diabres.2020.108353.
The WHO Global Diabetes Compact. World Health Organization. https://www.who.int/initiatives/the-who-global-diabetes-compact. Accessed June 9, 2021.
Diabetes diagnostic solutions. Beckman Coulter. https://www.beckmancoulter.com/en/solutions/diabetes-diagnostics. Accessed June 8, 2021.
Millman JR, Xie C, Van Dervort A, Gürtler M, Pagliuca FW, Melton DA. Generation of stem cell-derived β-cells from patients with type 1 diabetes. Nat. Commun. 2016;7(1). doi:10.1038/ncomms11463.
Wang X, Maxwell KG, Wang K, et al. A nanofibrous encapsulation device for safe delivery of insulin-producing cells to treat type 1 diabetes. Sci. Transl. Med. 2021;13(596). doi:10.1126/scitranslmed.abb4601.