Fulminant type 1 diabetes mellitus (FT1DM) develops as a result of very rapid and almost complete destruction of pancreatic β cell. The most common form of type 1 diabetes mellitus with onset during pregnancy has been shown to be FT1DM at least in Japan. We previously reported that the ratio of glycated albumin (GA) to HbA1c (GA/HbA1c ratio) is elevated in FT1DM patients at the diagnosis. In the present study, we investigated whether the GA/HbA1c ratio is also elevated in FT1DM with onset during pregnancy (P-FT1DM). The study subjects consisted of 7 patients with P-FT1DM. Ten patients with untreated type 2 diabetes mellitus (T2DM) discovered during pregnancy (P-T2DM) and 9 non-pregnant women with untreated T2DM (NP-T2DM) were used as controls. All study patients satisfied HbA1c<8.7%, the diagnostic criteria for FT1DM. The GA/HbA1c ratio in the P-FT1DM patients at the diagnosis was significantly higher than that in the P-T2DM patients and the NP-T2DM patients. The GA/HbA1c ratio was ≥3.0 in all P-FT1DM patients, whereas it was <3.0 in 8 of 10 P-T2DM patients and all NP-T2DM patients. The GA/HbA1c ratio was also elevated in P-FT1DM patients at the diagnosis compared with T2DM with or without pregnancy

Hanafusa, Toshiaki

Imagawa, Akihisa

Kasayama, Soji

Kobayashi, Tetsuro

Koga, Masafumi

Murai, Jun

Saito, Hiroshi

Shimizu, Ikki

the Members of the Japan Diabetes Society’s Committee of Research on Type 1 Diabetes Mellitus,

Tokushima University Institutional Repository

INTRODUCTIONFulminant type 1 diabetes mellitus (FT1DM) isa new subtype of type 1 diabetes mellitus (T1DM)reported by Imagawa et al. in 2000 (1). FT1DM ischaracterized by a very rapid onset and developsdue to nearly complete destruction of pancreatic βcells (1, 2). FT1DM accounts for about 20% of T1DM in Japanese patients (2). Moreover, in a nation-wide survey in Japan, the most common form ofT1DM with onset during pregnancy has been shownto be FT1DM (3). FT1DM that develops duringORIGINALThe glycated albumin to HbA1c ratio is elevated inpatients with fulminant type 1 diabetes mellitus withonset during pregnancyMasafumi Koga1, Ikki Shimizu2, Jun Murai3, Hiroshi Saito3, Soji Kasayama4,Tetsuro Kobayashi5, Akihisa Imagawa6, Toshiaki Hanafusa7, and the Members ofthe Japan Diabetes Society’s Committee of Research on Type 1 Diabetes Mellitus1Department of Internal Medicine, Kawanishi City Hospital, Hyogo, Japan, 2Department of Diabetes,The Sakakibara Heart Institute of Okayama, Okayama, Japan, 3Department of Internal Medicine,Kinki Central Hospital, Hyogo, Japan, 4Department of Medicine, Nissay Hospital, Osaka, Japan, 5TheThird Department of Internal Medicine, University of Yamanashi School of Medicine, Yamanashi,Japan, 6Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka,Japan, 7Department of Internal Medicine (I), Osaka Medical College, Osaka, JapanAbstract : Fulminant type 1 diabetes mellitus (FT1DM) develops as a result of very rapidand almost complete destruction of pancreatic β cell. The most common form of type 1diabetes mellitus with onset during pregnancy has been shown to be FT1DM at least inJapan. We previously reported that the ratio of glycated albumin (GA) to HbA1c (GA/HbA1c ratio) is elevated in FT1DM patients at the diagnosis. In the present study, we in-vestigated whether the GA/HbA1c ratio is also elevated in FT1DM with onset during preg-nancy (P-FT1DM). The study subjects consisted of 7 patients with P-FT1DM. Ten patientswith untreated type 2 diabetes mellitus (T2DM) discovered during pregnancy (P-T2DM)and 9 non-pregnant women with untreated T2DM (NP-T2DM) were used as controls. Allstudy patients satisfied HbA1c 8.7%, the diagnostic criteria for FT1DM. The GA/HbA1cratio in the P-FT1DM patients at the diagnosis was significantly higher than that in theP-T2DM patients and the NP-T2DM patients. The GA/HbA1c ratio was 3.0 in all P-FT1DM patients, whereas it was 3.0 in 8 of 10 P-T2DM patients and all NP-T2DM pa-tients. The GA/HbA1c ratio was also elevated in P-FT1DM patients at the diagnosis com-pared with T2DMwith or without pregnancy. J. Med. Invest. 60 : 41-45, February, 2013Keywords : glycated albumin, HbA1c, fulminant type I diabetes mellitus, pregnancyReceived for publication August 27, 2012 ; accepted October 12,2012.Address correspondence and reprint requests to Masafumi KogaMD, PhD, Department of Internal Medicine, Kawanishi CityHospital, 5 -21-1 Higashi -Uneno, Kawanishi, Hyogo 666-0195,Japan and Fax : +81-72-794-6321.The Journal of Medical Investigation Vol. 60 201341pregnancy affects not only the mother, but also thefetus, and is associated with a high rate of still-births (4). Therefore, FT1DM developing duringpregnancy should be diagnosed and be treated im-mediately.In diabetic patients, glycation of various proteinsis known to be increased, and some of these gly-cated proteins are thought to be involved in the on-set and progression of chronic diabetic complica-tions (5). Of these proteins, HbA1c is widely usedclinically as a marker of glycemic control (6). Asthe half-life of serum albumin is shorter than thatof erythrocytes, glycated albumin (GA) is used asa marker of plasma glucose levels over a shorterperiod (about 2 weeks) (7-9). Thus, GA reflectsshorter term control of plasma glucose than HbA1c.We previously reported that HbA1c is only mildlyelevated in FT1DM patients because of the abruptrise in plasma glucose, whereas GA is clearly ele-vated (10). Therefore, the ratio of GA to HbA1c(GA/HbA1c ratio) is elevated in FT1DM patientsat the diagnosis, being 3.2 in most FT1DM pa-tients [using the HbA1c-Japan Diabetes Society(JDS) value ;3.0 using the HbA1c-National Gly-cohemoglobin Standardization Program (NGSP)value]. However, in most patients with type 2 dia-betes mellitus (T2DM), the GA/HbA1c ratio is3.2(using the HbA1c-JDS value ;3.0 using the HbA1c-NGSP value) (10).From mid through late pregnancy, HbA1c lev-els are increased (11, 12), whereas GA levels arenot changed (13, 14). This has been shown to bedue to iron deficiency (13, 14), which occurs inmost women in late pregnancy. Because HbA1c,but not GA, is increased under the influence ofiron deficient conditions (15, 16), the GA/HbA1cratio is decreased from mid through late pregnancy(13, 14).In this study, we investigated whether the GA/HbA1c ratio is also elevated in FT1DM patients withonset during pregnancy compared with T2DM pa-tients under these situations.PATIENTS AND METHODSPatientsThis study included 7 patients with FT1DM withonset during pregnancy (P-FT1DM), all cases byJDS’s Comittee on Research of T1DM or reportedcases, in whom HbA1c and GA were simultaneouslymeasured at initial evaluation (Table 1). As con-trols, we included 10 patients with untreated T2DMdiscovered during pregnancy (P-T2DM) and 9non-pregnant women with untreated T2DM (NP-T2DM) evaluated at Kinki Central Hospital, inwhom HbA1c and GA were simultaneously meas-ured before treatment. T2DM was diagnosed basedon JDS criteria (17). In pregnancy, oral glucosetolerance test (OGTT) was performed for diagno-sis of diabetes mellitus. All study patients satis-fied HbA1c8.3% (using the JDS value ;8.7% us-ing NGSP value), one of the diagnostic criteria forFT1DM (18). Patients with liver, renal or thyroiddisease and those taking glucocorticoid therapywere excluded. For the P-T2DM patients, patientswith gestational diabetes mellitus (19) were ex-cluded. The institutional review board approved thisTable 1 Clinical characteristics of study patients in this studyFulminant type 1 diabeteswith onset in pregnancyType 2 diabetes withonset in pregnancyType 2 diabetes innon-pregnant women(P-FT1DM) (P-T2DM) (NP-T2DM)Total number 7 10 9Age (years) 29.63.0 35.25.0# 49.418.1#Body mass index (kg/m2) 19.31.8 27.76.4## 23.64.4#Duration of pregnancy (weeks) 20.312.6 (5-36) 18.08.8 (6-36) -Disease duration (days) 2.62.9 - -Plasma glucose (mg/dl) 764213* (505-983) 13562**, ### (81-227) 13524** (113-181)HbA1c (%) 6.00.4 (5.6 -6.5) 6.50.7 (5.5 -7.9) 7.20.7## (6.4 -8.3)GA (%) 20.51.9 (17.1-22.9) 17.53.4 (13.2-23.1) 19.11.7 (17.6-23.0)# : p0.05, ## : p0.01, ### : p0.001 vs. P-FT1DM, * : randomly measured plasma glucose,** : fasting plasma glucose, parentheses denote rangeM. Koga, et al. High GA/HbA1c in FT1DMwith pregnancy42study, and all T2DM patients as control group pro-vided written informed consent.Laboratory analysisHbA1c was measured by high performance liq-uid chromatography. The value for HbA1c (%) wasestimated as an NGSP equivalent value (%) calcu-lated by the formula HbA1c (%)=HbA1c (JDS) (%)+0.4%, considering the relational expression of HbA1c(JDS) (%), as measured by the previous Japanesestandard substance and measurement methods andHbA1c (NGSP) (17). Serum GA was determined byan enzymatic method using albumin-specific pro-teinase, ketoamine oxidase and albumin assay re-agent (Lucica GA-L ; Asahi Kasei Pharma Co.,Tokyo, Japan) (20).Statistical analysisAll data are presented as meansSD. For statis-tical analyses, the Mann-Whitney U test was usedto compare two groups. Simple regression analyseswere employed in order to assess the associationbetween continuous variables. A p value of0.05was considered to be statistically significant.RESULTSThe P-FT1DM patients were significantly youngerthan the P-T2DM patients and the NP-T2DM pa-tients (Table 1). Body mass index (BMI) in the P-FT1DM patients was significantly lower than that inthe P-T2DM patients and the NP-T2DM patients.Randomly measured plasma glucose levels in theP-FT1DM patients were markedly higher than thatin the P-T2DM patients and in the NP-T2DM pa-tients. HbA1c levels in the P-FT1DM patients andthat in the P-T2DM patients did not significantlydiffer. It was significantly lower in the P-FT1DMpatients than in the NP-T2DM patients. On theother hand, GA did not significantly differ among the3 groups (Table 1).In each group, HbA1c was significantly correlatedwith GA, but the regression line for HbA1c andGA in the P-FT1DM patients showed an upwardshift in comparison with that in the P-T2DM pa-tients and that in the NP-T2DM patients (Fig. 1).The GA/HbA1c ratio in the P-FT1DM patients wassignificantly higher compared with the P-T2DMpatients and the NP-T2DM patients (P-FT1DM :3.40.2 vs. P -T2DM : 2.70.4 ; p0.01, vs. NP -T2DM : 2.70.2 ; p0.01) (Fig. 2). The GA/HbA1cratio was3.0 in all P-FT1DM patients, whereasthat was3.0 in 8 of 10 P-T2DM patients and in allNP-T2DM patients.DISCUSSIONIn T2DM patients, the GA/HbA1c ratio is re-ported to be about 3.0, with a range of 2.0 to 4.0 (9,21). In diabetic patients with poor glycemic control,Figure 1 Correlation between HbA1c and GA in each group.Relationship between HbA1c and GA in the patients with fulmi-nant type 1 diabetes mellitus with onset during pregnancy (P-FT1DM) (closed circles), the patients with type 2 diabetes mel-litus with onset during pregnancy (P-T2DM) (open circles), andthe patients with type 2 diabetes mellitus in non-pregnant women(NP-T2DM) (open squares). Regression line is shown for eachgroup.Figure 2 The GA/HbA1c ratio in each group.The GA/HbA1c ratio in the patients with fulminant type 1 dia-betes mellitus with onset during pregnancy (P-FT1DM) (closedcircles), the patients with type 2 diabetes mellitus with onsetduring pregnancy (P-T2DM) (open circles), and the patients withtype 2 diabetes mellitus in non-pregnant women (NP-T2DM)(open squares). MeanSD values and individual values of theGA/HbA1c ratio in each group are shown. Dotted line indicatesthe GA/HbA1c ratio of 3.0.The Journal of Medical Investigation Vol. 60 February 2013 43when plasma glucose rapidly improves, the GA/HbA1c ratio is decreased because the degree ofdecrease in GA is larger than that in HbA1c (8, 9).Conversely, when glycemic control rapidly worsens,the degree of increase in GA is also expected to belarger compared with HbA1c. In this study, basedon a higher GA/HbA1c ratio in the FT1DM patientswith onset during pregnancy, a high GA/HbA1cratio at the time of acute plasma glucose elevationcould be confirmed.FT1DM with onset during pregnancy must bediagnosed and be treated immediately. In most pa-tients with FT1DM, its diagnosis is relatively easydue to the presence of marked hyperglycemia andketoacidosis in addition to hyperglycemic symp-toms. However, only mildly elevated plasma glucosehas been reported at the time of onset in somepatients with FT1DM (22). Based on the findingsin this study, if HbA1c is8.9% and the GA/HbA1cratio is 3.0 in diabetic patients with onset duringpregnancy, FT1DM is strongly suspected.Because HbA1c is increased under the influenceof iron deficiency, which occurs in most women inlate pregnancy, the GA/HbA1c ratio is decreasedfrom mid through late pregnancy (13, 14). Althoughthe GA/HbA1c ratio (3.40.2) in the P-FT1DM pa-tients was slightly lower than that (3.70.5) in theFT1DM patients without pregnancy described pre-viously (10), there was no significant difference be-tween both groups. Thus, the influence of iron de-ficiency in pregnancy on the GA/HbA1c ratio is neg-ligible compared with the influence of FT1DM.BMI in the P-FT1DM patients was significantlylower than that in the P-T2DM patients and the NP-T2DM patients. We reported that BMI negativelyinfluences GA, but not HbA1c, in non-diabetic sub-jects and diabetic patients (21, 23). The differencesof BMI might influence the GA/HbA1c ratio in eachgroup. However, similar results were obtained whenthe GA/HbA1c ratio was adjusted by BMI (data notshown).Because P-FT1DM is a relatively rare condition,the number of P-FT1DM patients was small in thisstudy. In the future, the GA/HbA1c ratio in P-FT1DM patients should be examined using a large num-ber of patients.CONFLICT OF INTERESTThe authors declared no conflict of interest rele-vant to this manuscriptREFERENCES1. Imagawa A, Hanafusa T, Miyagawa J,Matsuzawa Y : A novel subtype of type 1 dia-betes mellitus characterized by a rapid onsetand an absence of diabetes-related antibodies.N Engl J Med 342 : 301-317, 20002. Imagawa A, Hanafusa T, Uchigata Y, KanatsukaA, Kawasaki E, Kobayashi T, Shimada A,Shimizu I, Toyoda T, Maruyama T, Makino H :Fulminant type 1 diabetes : a nationwide surveyin Japan. Diabetes Care 26 : 2345-2352, 20033. Shimizu I, Makino H, Osawa H, Kounoue E,Imagawa A, Hanafusa T, Kawasaki E : Associa-tion of fulminant type 1 diabetes with preg-nancy. 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The glycated albumin to HbA1c ratio is elevated in patients with fulminant type 1 diabetes mellitus with onset during pregnancy

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The glycated albumin to HbA1c ratio is elevated in patients with fulminant type 1 diabetes mellitus with onset during pregnancy

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