Reflecting on Hemoglobin A1C, 1,5-Anhydroglucitol, and the Glycated Proteins Fructosamine and Glycated Albumin

In Brief This article reviews the advantages and limitations of the current glycemic From R esearch to Practice/Glycemic M arkers: A R eview o f the T ools W e ll L ove, Perha p s oo Dearly? biomarkers, including A1C, 1,5-anhydroglucitol, and the glycated proteins fructosamine and glycated albumin. It provides patient encounter case studies and related discussion to guide health care professionals on the appropriate use of the various glycemic biomarkers in clinical practice.

The Challenge of the Use of Glycemic Biomarkers in Diabetes: Reflecting on Hemoglobin A1C, 1,5-Anhydroglucitol, and the Glycated Proteins Fructosamine and Glycated Albumin

Frequent evaluation, as well as pre- nique to assess glycemic control.5 It cise measurement, of glycemic control provides information about the degree Lorena Alarcon-Casas Wright, MD, is a crucial part of optimal care for of glucose control during the previ- and Irl B. Hirsch, MD patients with diabetes. Glycemic bio- ous 8–12 weeks in the nonpregnant markers are important tools used to population.6 A1C has been used as a determine whether a patient’s meta- primary treatment target for diabetes bolic control has been maintained because of the large intervention stud- within the target range, but most ies in both type 1 and type 2 diabetes importantly, theyare used as surro- associating improved glycemic control gates to estimate and reduce the risk with a decreased risk of microvascular of chronic diabetes complications. disease.7,8 Below, we review clinical instances in It should be noted that early use which A1C should not be used and of A1C in these two landmark stud- reflect on the use of other glycemic ies could not be extrapolated to biomarkers that can be used in sub- others because of the lack of assay stitution, as well as their individual standardization of A1C. Currently, limitations. the National Glycohemoglobin Standardization Program (NGSP) Hemoglobin A1C has decreased potential technical In 1969, an increase in an “unusual” errors, and standardization is close to hemoglobin was first observed in universal.7 patients with diabetes.1 It was later However, in addition to the impor- learned that, in red blood cells (RBCs), tance of standardization, it is also glucose binds to the α-amino position important to be aware of other clini- of hemoglobin β-chains (valine) in an cal situations in which A1C may not aldimine or Schiff base linkage, and be an accurate reflection of glycemic this process could partially re​arrange control in diabetes. in a reversible manner to form a ketoamine linkage, resulting in a “gly- Average Glycemia Versus Glycemic cated” hemoglobin, or hemoglobin Variability A1C. 2,3 In 1976, it was reported that Exposure to dysglycemia in diabe- A1C reflects the mean blood glucose tes can be simplified as a function concentration over previous weeks to of several components, including months and that its periodic moni- the duration and severity of chronic toring could provide a useful way of hyperglycemia and the acute fluctua- documenting glycemic control.4 tions of glucose over a time period. Currently, A1C is a widely used A1C in a patient with a normal hema- glycemic marker and is considered by tological profile is the reflection of the American Diabetes Association, that patient’s average glucose control along with self-monitoring of blood during the previous 2–3 months; as glucose (SMBG), as the primary tech- such, A1C is mainly a reflection of the Diabetes Spectrum Volume 25, Number 3, 2012 141 first component of dysglycemia, with targeted more aggressively. But, as of associated with hemoglobin concen- contributions from postprandial and now, there is no definitive proof that trations and negatively associated with fasting hyperglycemia.8,9 improving glycemic variability can erythropoietin dose.20 In addition to Recent studies in vitro10–12 and in change the natural history of diabetic erythropoietin, medications that affect humans13,14 strongly suggest a second vascular disease. One problem is that RBC mass, such as dapsone,21 will component, namely, the acute excur- there is not a perfect serum biomarker affect A1C results. sions of glucose around a mean value of glycemic variability. The falsely lowered A1C may lead (i.e., hyperglycemic glucose fluctua- to the wrong assumption of adequate tions but also hypoglycemic exposure A1C: Sources of Misinterpretation glycemic control. Table 1 summarizes around mean glucose) described as sources of misinterpretation for A1C 1. RBC lifespan “glycemic variability.” Glycemic vari- and other glycemic biomarkers. RBCs are freely permeable to glucose. ability may be a significant risk factor As a result, glucose enters the cells 2. Presence of hemoglobinopathies for microvascular complications, and attaches to hemoglobin at a rate along with A1C and genetics, and it Hemoglobinopathies such as sickle dependent on the serum blood glucose. cell traits (hemoglobin S) and other may help to explain why some patients Hence, A1C glycation is dynamic and develop microvascular complications abnormal hemoglobin variants such as depends not only on average glycemia hemoglobin C and E can lead to falsely and others having the same A1C do but also in the rate of production (and high or low A1C readings depend- not. In a study involving patients destruction) of RBCs. Conditions that ing on the laboratory methodology with either type 1 or type 2 diabetes affect RBC lifespan will invariably used.22–24 Comprehensive information using continuous glucose monitoring have an impact on A1C results. regarding A1C assay interferences in (CGM), the standard deviation (SD; a RBCs that have a short lifespan patients with hemoglobinopathies is measure of variability) had no impact secondary to destruction (i.e., hemo- found at the NGSP Web site.7 on A1C in type 2 diabetic patients but lytic anemia,17 destruction through the did influence A1C in type 1 diabetic passage of abnormal heart valves,18 3. Iron status patients.15 or splenomegaly) will result in a low Previous studies suggest that iron defi- It is therefore important to be A1C independent of the mean serum ciency with25 and without25,26 anemia aware that A1C in general is a crude glucose. This situation is also pres- affect the level of A1C independent of marker of dysglycemia. It is also ent in circumstances in which the glycemia. Iron is important for hemo- important to note that postprandial bone marrow increases the produc- globin synthesis and RBC production. hyperglycemia does not necessarily tion of young RBCs (reticulocytes), In negative iron balance status, the equate to glycemic variability; instead, as seen in patients with chronic iron and hemoglobin deficiencies are postprandial hyperglycemia should be kidney disease (CKD) who receive followed by deficient RBC production, regarded as a component of glycemic erythropoietin treatment for anemia; translating to a slow turnover of RBCs variability.16 post-hemorrhage, as the healthy bone and mostly “mature” cells circulat- As a result of the development of marrow is stimulated by hypoxia; or ing in the bloodstream, allowing more outpatient CGM capabilities, glyce- after a blood transfusion.19 A1C val- time for glycation and falsely increas- mic variability is being studied and ues have been found to be positively ing the values of A1C. Table 1. The Most Common Sources of Error in the Interpretation of Glycemic Biomarkers Sources of Error A1C Glycated Proteins 1,5-AG Mechanism Conditions or treatments that Conditions or treatments that Conditions or treatments that alter RBC half-life alter protein metabolism alter renal function or thresh- old for glucose Falsely High • Iron deficiency • Hypothyroidism • CKD stage 4–5 Values • Anemia • Cirrhosis of the liver • Hemoglobinopathies • Race: African American, Hispanic, Asian

Falsely Low • Hemolysis • Hypoalbuminemia: • Pregnancy Values • Reticulocytosis protein-losing enteropathy, • Chronic liver disease • Hemoglobinopathies nephrotic syndrome, liver • Glucokinase–maturity- • Post-hemorrhage or failure onset diabetes of the young post-transfusion • Hyperthyroidism • Drugs: iron, erythropoietin, • Hyperuricemia dapsone • Hypertriglyceridemia • Uremia • Nonalcoholic fatty liver • Splenomegaly disease

142 Diabetes Spectrum Volume 25, Number 3, 2012 Data from the National Health and production of A1C),33 and differences uninterpretable A1C, patients with 34 Nutrition Examination Survey 1999– in RBC transmembrane gradients. CKD frequently receive erythro- From R esearch to Practice/Glycemic M arkers: A R eview o f the T ools W e ll L ove, Perha p s oo Dearly? 200627 found that iron deficiency Recently, a cross-sectional study poietin, with the expectation of an was, not surprisingly, more common in African-American and white increase in the production of RBCs in women than in men and that this people with and without diabe- as part of treatment, and, as a result, iron deficiency was not necessar- tes was conducted to investigate such increase in proportion of young ily accompanied by anemia. Among such racial disparities in A1C and RBCs will result in an erroneous low women, 13.7% had iron deficiency, included glycemic biomarkers that A1C value. and 30% of iron-deficient women would be unaffected by hemoglobin In advanced CKD, alternative had anemia. Iron deficiency is much glycation and erythrocyte turnover markers of glycemia such as fructos- less common in men; 1.6% had iron (fructosamine and 1,5-anhydroglu- amine and glycated albumin (GA) may deficiency, and 33% of iron-deficient citol [1,5-AG]). 35 The results were in be preferable.39 men had anemia. In this representative agreement with previous studies that healthy, adult, American population A1C is higher in African-American Glycated Proteins sample, it was found that iron defi- people; however, they also had sig- In addition to hemoglobin, other ciency shifted A1C slightly upward at nificantly higher values of other proteins in the plasma can become gly- the lower end of the A1C spectrum glycated proteins compared to white cated. Glucose can attach to proteins independent of fasting glucose level.27 people before and after adjustment and form ketoamines or fructos- These observations were also reported for covariates and fasting glucose. amines. The concentration of such in other studies involving people with Serum 1,5-AG was lower in African proteins can be measured and used as iron deficiency anemia presenting with Americans compared to white peo- an estimation of glucose control. The higher A1C values relative to plasma ple, although this was statistically index of glycemia will be dependent glucose levels. significant only in the nondiabetic on the half-life of the proteins mea- Conversely, correction of iron adult cohort. The results of this study sured (just as the lifespan of RBCs is deficiency with oral iron results in suggest that such discrepancies may important when interpreting A1C; see a decrease of pretreatment levels of actually not be completely indepen- Table 1). A1C. 26,28 In one of the studies in peo- dent of glycemia.35 Nonetheless, the The advantage of the glycated ple without diabetes, A1C decreased etiology of such differences remains proteins fructosamine and GA is that significantly after iron treatment from poorly understood. their glycation is unaffected by RBC a mean of 7.4 ± 0.8 to 6.2 ± 0.6% lifespan. Both of these proteins, used (P < 0.001).26 A1C in Patients With CKD commercially as glycemic biomarkers, Recently, a study in India29 of 116 A common clinical challenge in assess- are extracellular, as opposed to A1C. young adults with different degrees of ing glycemic control is encountered in Therefore, factors such as RBC per- glucose tolerance, as characterized by patients with diabetes and CKD. Not meability to glucose or differences in an oral glucose tolerance test (OGTT), infrequently and depending on the 2,3-diphosphoglycerate would not be showed that the sole use of A1C to degree of renal impairment, patients expected to affect their glycation rate. diagnose diabetes or pre-diabetes with CKD present with anemia of may spuriously elevate its prevalence, multifactorial etiology; erythropoietin 1. Fructosamine independent of glycemic tolerance, as deficiency, decrease in RBC survival, Fructosamine refers to the measure- significantly influenced by iron sta- decreased response of marrow pre- ment of total serum proteins that have tus. Based on these observations, iron cursor cells to erythropoiesis signals, become stable irreversible ketoamines, deficiency with and without anemia and iron deficiency are among the with GA accounting for ~ 90%. Serum must be ruled out or corrected before causes.36,37 proteins have a shorter half-life (15–20 any diagnostic or therapeutic decision Uremia has been proposed as a key days) than A1C, providing an index of is made based solely on A1C. Table 2 factor in the short lifespan of RBCs glucose control over a period of 2–3 summarizes the effect of iron treat- of patients undergoing hemodialysis, weeks. ment on A1C values in people with possibly secondary to an increase in There are clinical situations in and without diabetes. osmotic and mechanical fragility of which fructosamine should not be RBCs; however, the mechanisms are used. Abnormal protein turnover 4. Racial differences still unclear.37 The uremic state also influences fructosamine values, as Several epidemiological studies have affects the accuracy of the A1C assay in thyroid disease (i.e., in thyrotoxic found higher A1C values in minority through direct interactions with gly- and hypothyroid patients, in whom groups, mainly African Americans, cated hemoglobin analyses and by protein turnover is increased and across different degrees of glucose tol- induction of hemoglobin modification, decreased, respectively).40 Values are erance status30,31 and independent of forming carbamylated hemoglobin, also influenced by low concentrations glycemic control.32 When adjusted for which interferes with the laboratory of albumin and plasma proteins, as in variables such as age, sex, duration of analysis. Current high-performance cases of protein-losing enteropathy, diabetes, and glucose tolerance sta- liquid chromatography, standardized nephrotic syndrome, or liver failure41 tus among many others, A1C values and aligned to the Diabetes Control and by low-molecular-weight sub- remained higher. Several hypotheses and Complications Trial assay, stances such as urea, uric acid, and have been proposed, including dif- should minimize or eliminate this bilirubin.42 ferences in the RBC permeability to interference.7,38 Clinicians must exercise cau- glucose, differences in 2,3-diphospho- In addition to the above abnor- tion when interpreting fructosamine glycerate (responsible for the rate of malities that can clearly result in an results in patients with an abnormal Diabetes Spectrum Volume 25, Number 3, 2012 143 Table 2. Studies in Iron-Deficient Participants With and Without Diabetes Comparing A1C Before and After Treatment With Iron Supplements A1C Before Treatment With A1C After Treatment With P Iron (%) Iron (%) El-Agouza et al.25 6.15 ± 0.62 5.25 ± 0.45 < 0.001 Coban et al.26 7.4 ± 0.8 6.2 ± 0.6 < 0.001 Tarim et al.28 • Patients with diabetes 10.1 ± 2.7 8.2 ± 3.1 < 0.05 • Patients without diabetes 7.6 2.6 6.2 1.4 0.05 ± ± < rate of serum protein turnover. Van Although GA is not influenced measures of glycemia are secondary to Dieijen-Visser et al.43 were the first to by disorders of hemoglobin metabo- physiological processes independent of confirm that the fructosamine concen- lism or RBC survival, it is affected plasma glucose that could affect the tration depends on the concentration by disorders of albumin metabolism. frequency of micro- and macrovascu- of serum albumin and suggested The same clinical situations in which lar complications. that the values be corrected by sub- fructosamine should not be used, as The GG is an index of the variance tracting 0.023 mmol fructosamine described above, also apply for GA in A1C determined by processes in for every gram of albumin per liter. because fructosamine is primarily the both the intra- and extracellular com- Subsequently, a study that considered quantification of glycation of serum partments compared to those unique estimated average analytical vari- proteins, ~90% of which are albu- to the extracellular space.50 It has been ance and intra-individual variance44 min.47 GA also shows lower values in proposed as a clinical research tool proposed the following formula: relation to glycemia in patients with to further explore the hypothesis that corrected fructosamine (mmol/l) = nephrotic syndrome, thyroid disease, factors beyond A1C glycosylation may [measured fructosamine + 0.03 (40 – and glucocorticoid administration, contribute to the risk of microvascular serum albumin g/l)], mmol/l. in which albumin metabolism is complications. The GG is negative if Because it is uncertain which cor- increased; and higher values relative to measured A1C is less than A1C pre- rection or formula is best for use in plasma glucose levels in patients with dicted from fructosamine and positive clinical practice, we recommend liver cirrhosis and hypothyroidism, in if measured A1C is greater than pre- ensuring that the patient has a normal which albumin metabolism decreases. dicted A1C. GG is zero when A1C and albumin level when deciding to use It has also been shown that GA is set fructosamine are concordant. fructosamine as a marker of glycemic lower in relation to plasma glucose lev- Previous studies50,51 have reported els in smokers, hyperuricemic patients, control. The need to correct or adjust that in type 1 and type 2 diabetic sub- patients with hypertriglyceridemia, to albumin levels is clearly a limitation jects in whom A1C and fructosamine and men with nonalcoholic fatty liver to the use of this glycemic biomarker. were available to calculate the GG and disease with high alanine amino- Given the glomerular lesion of dia- followed over time, a high positive transferase levels, in whom chronic betic kidney disease, fructosamine correlation was found between GG inflammation is evoked.47 levels may have limitations in this Table 3. Approximate population. Glycation Gap Hypothesis Comparison of Glucose, A1C, The glycation gap (GG) refers to the 48,49 2. Glycated albumin difference between A1C and the A1C and Fructosamine GA has been studied mainly in the predicted by the serum fructosamine. nephrology field. Several studies Glucose Fructosamine A1C Table 3 shows a rough estimate of (mg/dl) (µmol) (%) have shown its superiority compared fructosamine values and their com- to A1C in patients with CKD stage parison with mean glucose and A1C 90 212.5 5.0 4–5 who are undergoing hemodialy- values.48,49 39,45,46 120 250 6.0 sis. In patients with advanced Glycation of A1C happens intra- CKD, CGM for 48 hours was used cellularly (within the RBCs) where 150 287.5 7.0 to assess glycemic control; a seven- hemoglobin is located, whereas 180 325 8.0 point glucose profile was also used to glycation of serum proteins (i.e., fruc- determine the SMBG average for each tosamine) reflects a process outside 210 362.5 9.0 patient and to compare to the mean the RBCs, in the extracellular com- 240 400 10.0 glucose concentration obtained with partment. We have reviewed how CGM.45 No association was found A1C can vary with hemoglobinopa- 270 437.5 11.0 between A1C and mean glucose by thies, anemia, renal dysfunction, and 300 475 12.0 CGM. Fructosamine performed better other conditions. Such influencing than A1C as an indicator of glycemic factors are independent of glucose 330 512.5 13.0 control. However, GA was reported control. However, an important 360 550 14.0 as the best indicator among the three question remains, and that is whether biomarkers in this study.45 differences between A1C and other 390 587.5 15.0 144 Diabetes Spectrum Volume 25, Number 3, 2012 and the risk of progressing nephropa- tion, males were also found to have diabetic women.5,65,66 In this specific thy. Conversely, a negative GG was higher 1,5-AG levels than females, and population, A1C reflects the previous From R esearch to Practice/Glycemic M arkers: A R eview o f the T ools W e ll L ove, Perha p s oo Dearly? described in the group of subjects with this included patients (4.5 ± 2.3 vs. 6–8 weeks of average glycemia (versus no nephropathy50 or with a lower risk 3.4 ± 1.6 µg/ml, P = 0.003) and con- 8–12 weeks in the nonpregnant popu- of progression.51 Furthermore, in trols (26.0 ± 6.6 vs. 23.5 ± 6.0 µg/ml, lation) because of the mean age of the subjects with type 2 diabetes, the GG P = 0.02).55 RBCs and increased erythropoiesis predicted the progression of nephropa- When serum glucose is high in during pregnancy.67 thy, even after adjustment for A1C.51 diabetic patients, glucose prevents In a study68 that included 24 The GG has also been associated 1,5-AG reabsorption in the renal women with diabetes first diagnosed with the risk of developing retinopa- tubules, leading to its excretion in the during pregnancy, with a mean base- thy in a study that included 84 type urine and thus decreasing levels in line A1C of 8.8 ± 1.8%, followed 1 diabetic patients followed for com- serum.54 It has also been shown that, during the first 1–4 weeks of treatment plications over 4–14 years.52 A1C, after achieving better glycemic control to achieve normoglycemia, a decrease fructosamine, and random glucose in previously hyperglycemic patients, in A1C at a rate of 0.5% per week was measured at the 4-year exam were levels of 1,5-AG increase,56 indicat- demonstrated. It is unknown whether significantly higher in those who sub- ing that decreased levels are reversible iron supplementation played a role sequently developed retinopathy than once glucose control is improved.57 in such rapid A1C decline; nonethe- in those who did not. Fifty percent of 1,5-AG is a reflection of glycemic less, in this population, in which close the patients developed retinopathy at control over the previous 48 hours follow-up is important, adequate 9 years, and a significant difference in to 2 weeks and may provide unique treatment to achieve normoglycemia, the GG was found between those with information beyond that provided by guided by frequent point-of-care A1C and without subsequent retinopathy, A1C, particularly in patients in whom monitoring throughout pregnancy, is being positive in those with retinopa- A1C is < 8%. In such patients with a reasonable recommendation. thy and negative in those without. close-to-goal or optimal A1C, 1,5-AG Other glycemic markers such as Further studies are needed to is a powerful predictor of postprandial GA and fructosamine have not been investigate the physiology behind the hyperglycemia because it measures studied as extensively as A1C. One differences in glycation processes in glucose excursions. As such, a lower study69 in a Japanese cohort of preg- the different compartments and their level of 1,5-AG may be helpful as a nant patients with diabetes reported influence and correlation with diabe- complementary tool in the fine-tuning that A1C levels were elevated in late tes complications. The identification of glucose control.55,58 pregnancy because of iron deficiency, of such processes affecting glycation Clinicians should be cautious when but that GA was not affected, under- not only may have bearing on the use evaluating levels in patients whose scoring the importance of iron status of glycemic markers, but also may renal function or renal threshold on the correct interpretation of A1C, help determine, alleviate, or prevent to glucose are different from nor- particularly in this population at risk the rate of development of diabetes- mal (i.e., individuals with CKD59or for iron deficiency. related complications. tubular defects60) during pregnancy The literature on 1,5-AG during complicated by diabetes,61 in gluco- pregnancy is limited.70,71 Levels of 1,5-AG kinase–maturity-onset diabetes of 1,5-AG decrease during normal ges- 1,5-AG was first discovered in the the young,62, and in chronic liver dis- tation in the presence of detectable plant family Polygala senega in 1888. ease.63 A recent study in 269 patients glycosuria, secondary to changes in The structure was identified in 1943, with type 2 diabetes and different the renal threshold to glucose dur- and the presence of the compound stages of renal dysfunction found ing pregnancy,61 confirming that in human blood was established in that 1,5-AG may be useful as a glyce- 1,5-AG levels in pregnant women are 1973. 1,5-AG has been clinically used mic marker in individuals with mild low independently of serum glucose. in Japan for more than a decade to to moderate kidney dysfunction, SMBG continues to be the cornerstone monitor short-term glycemic control. with stage 1–2 corresponding to an of hyperglycemia management during It originates mostly from foods, with estimated glomerular filtration rate pregnancy, and it should be consid- the dietary intake closely matched (eGFR) ≥ 60 ml/min/1.73 m2; poten- ered an empowering tool for patients by the daily excretion rate and a tially in stage 3 CKD, with eGFR and their doctors to decrease fetal and small percentage originating from de < 60 ml/min/1.73 m2; but not in maternal complications. novo biosynthesis.53 1,5-AG is well individuals with advanced renal fail- absorbed in the intestine and distrib- ure stage 4–5, with eGFR < 30 ml/ Case Presentations utes to all organs and tissues. Dietary min/1.73 m2. Finally, 1,5-AG has not variation of this compound was not been adequately studied in patients Case study 1 found to affect the efficacy of 1,5- with significant hyperglycemia and A 52-year-old white woman with type AG as a marker of glycemic control. marked glycosuria (A1C > 10%). 64 2 diabetes receiving insulin glargine However, this has only been assessed and three oral agents has A1C levels in Japanese patients and not in other Pregnancy Complicated by Diabetes consistently in the range of 7.4–7.8%. populations with different dietary A1C is widely used in the manage- Her glucose meter average (on the habits.53 ment of pregnant diabetic patients, meter itself) with three tests/day is In a healthy cohort, 1,5-AG varied and, in combination with SMBG, it usually in the range of 220–240 mg/dl. widely (12–40 mg/ml), with mean val- is considered the main tool to guide She has no anemia; iron studies and ues in males significantly higher than treatment, with the goal of decreasing reticulocyte count are normal; and she in females.54 In the pediatric popula- the risk of complications in infants of has normal renal and liver function. Diabetes Spectrum Volume 25, Number 3, 2012 145 Because of the discrepancy between continue frequent SMBG, particularly a combination of them that can best her SMBG average and her A1C, a when on an intensive insulin regimen. translate accurate glycemic control. fructosamine level was measured. Similarly, clinicians should be able to Several days later, results showed her Case study 2 identify situations in which glycemic fructosamine was 399 µmol (normal With increasing comorbidities more markers are unreliable, by taking into < 285 µmol). What does this mean and often seen in aging patients, traditional consideration the period examined, how should this patient be managed biomarkers will not reflect glycemic comorbidities, and medications used and monitored? control accurately. In this case: by the patient. • A1C is not accurate because of When using A1C as a diagnostic Case study 2 AVR and CKD. tool for diabetes and pre-diabetes A 64-year-old man with type 2 dia- • Fructosamine is not accurate and before any diagnostic or thera- betes comes in for his first visit after because of proteinuria and subse- peutic decision is made based solely an aortic valve replacement (AVR) 3 quent hypoalbuminuria. on A1C, we recommend ensuring months earlier. His A1C levels have • 1,5-AG is not accurate because of a normal hematological profile and usually been in the 7.5–8% range, and CKD stage 4–5. normal iron status. We advocate for his A1C is now 6.2%. His SMBG aver- Solution: Monitoring glycemic con- SMBG values and averages to be age, checking 3–4 times daily, is 177 trol in this case will be dependent on routinely compared to the elected gly- mg/dl, with an SD of 62 mg/dl. It is SMBG results. cemic biomarker(s). The frequency of decided to measure fructosamine and SMBG will depend on the need for 1,5-AG levels, which are 235 µmol Case study 3 insulin therapy, presence of complica- (normal < 285 µmol) and 11.5 µg/ml The patient had three of three abnor- tions and comorbidities, and treatment (normal > 10 µg/ml), respectively. He mal glucose values during a 75-g regimen (insulin, oral hypoglycemic has nephrotic-range proteinuria, with OGTT. (Only one is needed for the agents, or diet/exercise) to corrobo- a serum creatinine of 2.9 mg/dl (eGFR diagnosis of GDM.) There are no rate concordance to results of serum 26 ml/min). How should this patient clear guidelines for the frequency of glycemic marker(s). If a glycation gap be monitored? A1C testing during pregnancy. In this is discovered, fructosamine should be situation and at this point in time, no preferred over A1C. Case study 3 conclusions can be made based solely SMBG becomes more crucial as A 24-year-old Hispanic woman is on the A1C results or trend because: we learn more about the different referred to the clinic for manage- • A1C is lower during pregnancy glycemic biomarkers and how they ment of gestational diabetes mellitus than in the nonpregnant state. can complement each other. Finally, (GDM). She was initially seen by her • It is a standard of care to initiate further research is needed to correlate obstetrician the previous week at ges- prenatal vitamins with iron during the different glycemic biomarkers with tational week 12, and a screening 75-g pregnancy. Correction of iron defi- diabetes-related complications. OGTT showed the following results: ciency will concomitantly result in fasting glucose: 100 mg/dl, 1- and lower A1C values. This possibility References 2-hour glucose levels: 184 and 159 cannot be ruled out in this patient, 1 mg/dl, respectively. An initial A1C and we should not assume the Rahbar S, Blumenfeld O, Ranney HM: trend of her A1C was solely sec- Studies of an unusual hemoglobin in patients at that time was 5.6%. She was pre- with diabetes mellitus. Biochem Biophys Res scribed prenatal vitamins. ondary to lifestyle modifications. Commun 36:838–843, 1969 Today at the clinic, she is asymp- 2 Solution: Intensive SMBG is the Bunn HF, Haney DN, Gabbay KH, Gallop tomatic and tells you that, secondary cornerstone of glycemic control in PM: Further identification of the nature and linkage of the carbohydrate in hemoglo- to her new diagnosis of GDM, she pregnancy complicated by diabetes. has started walking daily and avoid- bin A1c. Biochem Biophys Res Commun Once iron stores have been repleted, 67:103–109, 1975 ing carbohydrates. A fasting glucose A1C can be used as a glucose-control 3 measurement by point-of-care meter is Trivelli LA, Ranney HM, Lai HT: biomarker when the result is com- Hemoglobin components in patients with dia- 94 mg/dl, and her A1C is 5.2%. What pared to the woman’s previous value, betes mellitus. N Engl J Med 284:353–357, are your recommendations? but only in conjunction with SMBG. 1971 Then, the rate of change of A1C 4Koenig RJ, Peterson CM, Jones RL, Saudek Cases Recommendations (increase or decrease) may be of clini- C, Lehrman M, Cerami A: Correlation of cal utility. glucose regulation and hemoglobin A1c in Case study 1 diabetes mellitus. N Engl J Med 295:417– This patient has a negative GG, Conclusions 420, 1976 meaning that her measured A1C All currently available glycemic 5American Diabetes Association: Executive is lower than predicted by fructos- biomarkers have advantages and lim- summary: standards of medical care in amine and also discordant with diabetes—2012. Diabetes Care 35 (Suppl. itations. It is unclear which marker 1):S4–S10, 2012 results of her average SMBG. To pre- or combination of markers may have 6 vent diabetes-related complications, the best relationship to complications Goldstein DE: Is glycosylated hemoglobin clinically useful? N Engl J Med 310:384–385, her hyperglycemia should be treated for different populations of patients. 1984 aggressively with the addition of pran- Clinicians taking care of patients 7National Glycohemoglobin Standardization dial insulin. Glycemic control should with diabetes should become famil- Program: Background [article online]. be monitored using fructosamine iar with the individual nuances of Available from http://www.ngsp.org/ rather than A1C. She should also such biomarkers and identify one or bground.asp. Accesed 9 March 2012 146 Diabetes Spectrum Volume 25, Number 3, 2012 8Monnier L, Lapinski H, Colette C: tion on hemoglobin A(1c). 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