Prediabetes is a serious and major global problem afflicting approximately 21% of the world's population. It is the intermediate stage between normal glucose levels and type 2 diabetes mellitus (T2DM). Prediabetes is associated with major complications including the development of T2DM and increased cardiovascular disease (CVD). It can be easily diagnosed with an inexpensive plasma glucose level and/or a hemoglobin A1c (HbA1c) measurement. The mainstay of treatment is intensive lifestyle (ILS) intervention, including reduction in calories, especially saturated fats, refined carbohydrates, etc., coupled with regular physical activity of 150 min per week since ILS changes, with at least a 5% weight loss, have been shown to reduce progression to T2DM in multiple studies globally. Also, metformin therapy has been shown to prevent the progression to T2DM. In conclusion, serious consideration by guideline committees to classify prediabetes as a disease is highly recommended based on its global burden, easy and cost-effective diagnosis, association with serious conditions of diabetes and CVD, and effective ILS intervention. Therapy targeting those at an especially high risk for T2DM, such as persons with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) with values ≥ 110 mg/dL (6.1 mmol/L), and/or HbA1c ≥ 6.0% (42 mmol/mol) coupled with overweightness or obesity.

This review focuses on the analysis of hemoglobin in the clinical laboratory with an emphasis on the structure–function relationships of hemoglobin and the various methodologies used for its measurement. In clinical laboratories, hemoglobin analysis may take on many forms. These include measuring the concentration of hemoglobin, as well as determining the percentage of oxyhemoglobin, deoxyhemoglobin and dyshemoglobins such as carboxyhemoglobin. There are also techniques available to estimate the oxygen affinity of hemoglobin. Hemoglobin separation techniques by means of electrophoresis or chromatography are essential in the diagnosis of hemoglobinopathies (such as sickle cell anemia) and thalassemias, where there is an imbalance in globin chain synthesis. Hemoglobin contains four globin subunits, which create a unique quaternary structure in which the oxygen affinity can be changed by allosteric modifiers, including oxygen itself. The heme iron-containing tetrapyrrole ring not only carries oxygen; it also controls the binding of oxygen to the other globin subunits. The organization and regulation of the globin genes are discussed to provide essential biological context for informed interpretation of clinical test results. Building on this foundation, selected hemoglobinopathies and thalassemias are highlighted to further illustrate structure–function relationships and their implications for diagnostic testing. However, an exhaustive analysis of hemoglobinopathies is beyond the intended scope of this review, which is not meant to be all-encompassing, as these subjects are extensively addressed in many textbooks and published articles and reviews.

Editorial Practical Diagnosis of Iron Deficiency Anemia William E. Winter 1 and Ishwarlal Jialal 2,*,† 1 Department of Pathology, University of Florida, Gainesville, FL 32611, USA 2 UC Davis School of Medicine, 2616 Hepworth Drive, Davis, CA 95618, USA * Correspondence: kjialal@gmail.com; Tel.: +1-530-902-0125 † Retired Distinguished Professor of Internal Medicine and Pathology. Received: 4 March 2025; Accepted: 12 March 025; Published: 8 April 2025

Prediabetes describes a state of dysglycemia that is the “watershed” between normoglycemia and type 2 diabetes. This review will examine the definitions of prediabetes, the adverse complications of prediabetes, the treatment of prediabetes, and diabetes prevention.

IntroductionThere are no established methods to identify children with atypical diabetes for further study. We aimed to develop strategies to systematically ascertain cases of atypical pediatric diabetes using electronic medical records (EMR).Research design and methodsWe tested two strategies in a large pediatric hospital in the USA. Strategy 1: we designed a questionnaire to rule out typical diabetes and applied it to the EMR of 100 youth with diabetes. Strategy 2: we built three electronic queries to generate reports of three atypical pediatric diabetes phenotypes: unknown type, type 2 diabetes (T2D) diagnosed <10 years old and autoantibody-negative type 1 diabetes (AbNegT1D).ResultsStrategy 1 identified six cases (6%) of atypical diabetes (mean diagnosis age=11±2.6 years, 16.6% men, 33% non-Hispanic white (NHW) and 66.6% Hispanic). Strategy 2: unknown diabetes type: n=68 (1%) out of 6676 patients with diabetes; mean diagnosis age=12.6±3.3 years, 32.8% men, 23.8% NHW, 47.6% Hispanic, 25.4% African American (AA), 3.2% other. T2D <10 years old: n=64 (6.6%) out of 1142 patients with T2D; mean diagnosis age=8.6±1.6 years, 20.3% men, 4.7% NHW, 65.6% Hispanic, 28.1% AA, 1.6% other. AbNegT1D: n=38 (5.6%) out of 680 patients with new onset T1D; mean diagnosis age=11.3±3.8 years; 57.9% men, 50% NHW, 19.4% Hispanic, 22.3% AA, 8.3% other.ConclusionsIn sum, we identified 1%–6.6% of atypical diabetes cases in a pediatric diabetes population with high racial and ethnic diversity using systematic review of the EMR. Better identification of these cases using unbiased approaches may advance precision diabetes.

Background. A−β+ ketosis-prone diabetes (KPD) in adults is characterized by presentation with diabetic ketoacidosis (DKA), negative islet autoantibodies, and preserved β-cell function in persons with a phenotype of obesity-associated type 2 diabetes (T2D). The prevalence of KPD has not been evaluated in children. We investigated children with DKA at “T2D” onset and determined the prevalence and characteristics of pediatric A−β+ KPD within this cohort. Methods. We reviewed the records of 716 children with T2D at a large academic hospital and compared clinical characteristics of those with and without DKA at onset. In the latter group, we identified patients with A−β+ KPD using criteria of the Rare and Atypical Diabetes Network (RADIANT) and defined its prevalence and characteristics. Results. Mean age at diagnosis was 13.7 ± 2.4 years: 63% female; 59% Hispanic, 29% African American, 9% non-Hispanic White, and 3% other. Fifty-six (7.8%) presented with DKA at diagnosis and lacked islet autoantibodies. Children presenting with DKA were older and had lower C-peptide and higher glucose concentrations than those without DKA. Twenty-five children with DKA (45%) met RADIANT A−β+ KPD criteria. They were predominantly male (64%), African American or Hispanic (96%), with substantial C-peptide (1.3 ± 0.7 ng/mL) at presentation with DKA and excellent long-term glycemic control (HbA1c 6.6% ± 1.9% at follow-up (median 1.3 years postdiagnosis)). Conclusions. In children with a clinical phenotype of T2D and DKA at diagnosis, approximately half meet criteria for A−β+ KPD. They manifest the key characteristics of obesity, preserved β-cell function, male predominance, and potential to discontinue insulin therapy, similar to adults with A−β+ KPD.

Background The most frequently ordered laboratory test worldwide is the complete blood count (CBC).Content In this primer, the red blood cell test components of the CBC are introduced, followed by a discussion of the laboratory evaluation of anemia and polycythemia.Summary As clinical chemists are increasingly tasked to direct laboratories outside of the traditional clinical chemistry sections such as hematology, expertise must be developed. This review article is a dedication to that effort.

Hemoglobin A1c (HbA1c) refers to non-enzymatically glycated hemoglobin and reflects the patient's glycemic status over approximately 3 months. An elevated HbA1c over 6.5% National Glycohemoglobin Standardization Program (NGSP) (48 mmol/mol the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)) can be used to diagnose diabetes mellitus. In our laboratory, HbA1c is determined by ion-exchange chromatography which has the advantage of detecting common Hb variants such as Hb S, C, E and D without adversely affecting the HbA1c determination. Certain homozygous or compound heterozygous hemoglobinopathies such as homozygous sickle disease and Hb SC disease can significantly lower the HbA1c by reducing red cell lifespan. Occasionally however, rare and mostly benign hemoglobinopathies can interfere with this technique resulting in an apparent elevation of HbA1c in an otherwise non-diabetic patient. In this report, we describe such a hemoglobinopathy termed Hb Wayne that resulted in a significant HbA1c elevation in a normoglycemic individual. HbA1c was determined by multiple methods including immunoassay, a modified capillary electrophoresis and an alternative ion-exchange system. These techniques yielded significantly lower A1c results, more in keeping with the patient's clinical background. The alternative ion-exchange system resulted in a low A1c that was qualified by warning flags on the chromatogram that indicated the result was not reportable. The hemoglobinopathy in question, Hb Wayne, is a frameshift mutation in the alpha globin gene that results in an extended alpha globin polypeptide that can form two variants Hb Wayne I and Wayne II. Hb Wayne is a clinically silent asymptomatic disorder with no hematologic consequences. The artifactual elevation of HbA1c is, in contrast, very significant because it may result in a misdiagnosis of diabetes mellitus leading to unnecessary treatment. In this report, we compare our findings with other descriptions of Hb Wayne in the literature and corroborate a number of previous observations and conclusions.

Background The most ordered laboratory test worldwide is the complete blood count (CBC).Content In this primer, an introduction to platelet testing in the context of the CBC is provided with a discussion of the laboratory evaluation of platelet abnormalities including thrombocytopenia and thrombocytosis.Summary As clinical chemists continue to be tasked to direct laboratories outside of the traditional clinical chemistry sections such as hematology, expertise must be developed. This primer is dedicated to that effort.