1)
Fineberg SE, Kawabata TT, Finco-Kent D, Fountaine RJ, Finch GL, Krasner AS. Immunological
responses to exogenous insulin. Endocr Rev. 2007; 28: 625-52.
2)
Kahn CR, Rosenthal AS. Immunologic reactions to insulin: insulin allergy, insulin resistance, and the
autoimmune insulin syndrome. Diabetes Care. 1979; 2: 283-95.
3)
Eguchi Y. Scatchard analysis of insulin autoantibodies in the insulin autoimmune syndrome. Tokyo
Joshi Ikadaigaku Zasshi 1989; 59: 1296–1305 (Japanese).
4)
Baxter RC, Yue DK, Turtle JR. Equilibrium binding studies of insulin antibodies in diabetic subjects.
Clin Chem. 1976; 22: 1089-94.
5)
Hu X, Chen F. Exogenous insulin antibody syndrome (EIAS): a clinical syndrome associated with
insulin antibodies induced by exogenous insulin in diabetic patients. Endocr Connect. 2018; 7: R4755.
6)
Hirota Y, Ogawa W, Murawaki A, Nishiumi T, Komada H, Miyake K, Sakaguchi K, Kasuga M.
Deterioration of glycaemic control associated with anti-insulin antibodies likely induced by health
supplements. Diabet Med. 2009; 26: 948-51.
7)
Yoshida M, Murakami M, Ogawa K, Asai M, Miyata M, Maeda H, Oiso Y. Repeated hypoglycemia
caused by the overproduction of anti-insulin antibodies and isolated ACTH deficiency in a type 2
diabetic patient receiving insulin therapy. Diabetes Care. 2013; 36: e22.
8)
Uchigata Y, Kuwata S, Tsushima T, Tokunaga K, Miyamoto M, Tsutchikawa K, Hirata Y, Juji T,
Omori Y. Patients with Graves’ disease who developed in- sulin sutoimmune syndrome (Hirata’
disease), possess HLA-Bw62/Cw4/DR4 carrying CRB1*0406. J Clin Endocrinol Metab. 1993;
77: 249-54
9)
Ishida Y, Ohara T, Okuno Y, Ito T, Hirota Y, Furukawa K, Sakaguchi K, Ogawa W, Kasuga M.
Alpha-lipoic acid and insulin autoimmune syndrome. Diabetes Care. 2007; 30: 2240-1.
10) Tahara Y, Shima K. Kinetics of HbA1c, glycated albumin, and fructosamine and analysis of their
weight functions against preceding plasma glucose level. Diabetes Care. 1995; 18: 440-7.
11) Suwa T, Ohta A, Matsui T, Koganei R, Kato H, Kawata T, Sada Y, Ishii S, Kondo A, Murakami K,
Katabami T, Tanaka Y. Relationship between clinical markers of glycemia and glucose excursion
evaluated by continuous glucose monitoring (CGM). Endocr J. 2010; 57: 135-40.
12) Tsutsumi C, Imagawa A, Onishi M, Sano H, Nakagawa S, Murase-Mishiba Y, Terasaki J Hanafusa T.
Glycated albumin as a useful clinical biomarker for glycemic variability in type 1 diabetes assessed
10
by continuous glucose monitoring. Diabetol Int. 2013; 4: 156-9.
13) Koga M, Murai J, Saito H, Kasayama S. Glycated albumin and glycated hemoglobin are influenced
differently by endogenous insulin secretion in patients with type 2 diabetes. Diabetes Care. 2010; 33:
270-2.
14) Ogawa A, Hayashi A, Kishihara E, Yoshino S, Takeuchi A, Shichiri M. New indices for predicting
glycaemic variability. PLoS One. 2012; 7: e46517.
15) Yoshiuchi K, Matsuhisa M, Katakami N, Nakatani Y, Sakamoto K, Matsuoka T, Umayahara Y,
Kosugi K, Kaneto H, Yamasaki Y, Hori M. Glycated albumin is a better indicator for glucose
excursion than glycated hemoglobin in type 1 and type 2 diabetes. Endocr J. 2008; 55: 503-7.
16) Hirata Y. Methimazole and insulin autoimmune syndrome with hypoglycemia. Lancet. 1983; 2: 10378.
17) Koga M, Inada S, Taniguchi J, Nakatani Y, Yoshino H, Yoshino G, Okauchi Y, Mineo I. High
glycated albumin (GA) levels and the GA/HbA1c ratio in patients with insulin autoimmune
syndrome. Diabetol Int. 2016; 8: 199-204.
18) Kashiwagi A.,Kasuga M, Araki E, et al. International clinical harmonization of glycated hemoglobin
in Japan: From Japan Diabetes Society to National Glycohemoglobin Standardization Program
values. Diabetol Int. 2012; 3: 8-10.
19) Kouzuma T, Usami T, Yamakoshi M, Takahashi M, Imamura S. An enzymatic method for the
measurement of glycated albumin in biological samples. Clin Chim Acta. 2002; 324: 61-71.
20) Greenfield JR, Tuthill A, Soos MA, Semple RK, Halsall DJ, Chaudhry A, O'Rahilly S. Severe insulin
resistance due to anti-insulin antibodies: response to plasma exchange and immunosuppressive
therapy. Diabet Med. 2009; 26: 79-82.
21) Su CT, Lin YC. Hyper insulinemic hypoglycemia associated with insulin antibodies caused by
exogenous insulin analog. Endocrinol Diabetes Metab Case Rep. 2016; 2016: 16-0079.
22) Matsuyoshi A, Shimoda S, Tsuruzoe K, Taketa K, Chirioka T, Sakamoto F, Sakakida M, Miyamura
11
N, Araki E. A case of slowly progressive type 1 diabetes with unstable glycemic control caused by
unusual insulin antibody and successfully treated with steroid therapy. Diabetes Res Clin Pract.
2006; 72: 238-43.
23) Honda M, Kawashima Y, Kawamura H, Fujikawa H, Kikuchi K, Ohashi H, Mori Y, Miyakawa H,
Ishibashi M. Acute liver dysfunction complicated with uncontrollable glycemia due to insulin
antibody: successful treatment with glucocorticoid and lispro insulin. Intern Med. 2006; 45: 1225-9.
24) Taya N, Kato K, Oida T, Mitsui E, Taki H. A Case of Diabetes Mellitus With Fasting Hyperglycemia
Due to Changes in the Characteristics of Insulin Antibodies After the Administration of an Insulin
Analogue (Glargine). J. Japan Diab. Soc. 2019; 62: 170-177.
25) Segal T, Webb E, Viner R, Pusey C, Wild G, Allgrove J. Severe insulin resistance secondary to
insulin antibodies: successful treatment with the immunosuppressant MMF. Pediatr Diabetes. 2008;
9: 250-4.
26) Murakami A, Nomiyama T, Takahashi H, Kita S, Yamao Y, Hamanoue N, Motonaga R, Tanabe M,
Yanase T, Kawanami D. The Effect of GLP-1 Receptor Agonist Dulaglutide on Aggravated
Glycemic Control Due to Anti-insulin Antibody in a Patient With Type 2 Diabetes Mellitus:A Case
Report. J. Japan Diab. Soc. 2020; 63: 139~145
27) Hayashi A, Takano K, Kawai S, Shichiri M. SGLT2 inhibitors provide an effective therapeutic option
for diabetes complicated with insulin antibodies. Endocrine Journal. 2016; 63, 187-191.
28) Lahtela JT, Knip M, Paul R, Antonen J, Salmi J. Severe antibody-mediated human insulin resistance:
successful treatment with the insulin analog lispro. A case report. Diabetes Care. 1997; 20: 71-3.
29) Itoh A, Saisho Y, Mitsuishi M, Oikawa Y, Kawai T, Tanaka M, Shimada A, Itoh H. Insulin glulisine
may ameliorate nocturnal hypoglycemia related to insulin antibody--a case report. Diabetes Res Clin
Pract. 2011; 94: e53-4.
30) Vazeou A, Continuous blood glucose monitoring in diabetes treatment. Diabetes Res Clin Pract.
12
2011; 93: S125-30.
31) Bailey T, Bode BW, Christiansen MP, Klaff LJ, Alva S. The performance and usability of a factorycalibrated flash glucose monitoring system. Diabetes Technol Ther. 2015; 17: 787-94.
32) Mukai N, Ohara T, Hata J, Hirakawa Y, Yoshida D, Kishimoto H, Koga M, Nakamura U, Kitazono T,
Kiyohara Y, Ninomiya T. Alternative Measures of Hyperglycemia and Risk of Alzheimer's Disease
in the Community: The Hisayama Study. J Clin Endocrinol Metab. 2017; 102: 3002-10.
13
Figure legends
Figure 1: Comparison of GA between InsAb negative (open columns) and InsAb positive (shaded columns) diabetic patients, left panel for type 1 diabetes,
right panel for type 2 diabetes, respectively. The figure shows the individual plots of GA values. In left panel, in type 1 diabetes, n= 12 for InsAb negative
patients (GA= 23.4±1.6%), n= 4 for InsAb positive patients (GA= 31.4±12.4%). The unpaired Student’s t-test was performed for the comparison of two
groups. As a result, the P value is 0.03. In right panel, in type 2 diabetes, n=24 for InsAb negative patients (GA= 21.1±4.7%), n= 8 for InsAb positive patients
(GA= 29.5±10.3%). The unpaired Student’s t-test was performed for the comparison of two groups. As a result, the P value is 0.003. *: P < 0.05, **: P <
0.01, InsAb: insulin antibody, T1D: type 1 diabetes, T2D: type 2 diabetes.
Figure 2: Comparison of the GA/HbA1c ratio between InsAb negative (open columns) and InsAb positive (shaded columns) diabetic patients, left panel
for type 1 diabetes, right panel for type 2 diabetes, respectively. The figure shows the individual plots of GA/HbA1c values. In left panel, in type 1
diabetes, n= 12 for InsAb negative patients (GA/HbA1c= 2.99±0.22), n= 4 for InsAb positive patients (GA/HbA1c= 3.78±0.63). The unpaired Student’s
t-test was performed for the comparison of two groups. As a result, the P value is 0.001. In right panel, in type 2 diabetes, n=24 for InsAb negative
patients (GA/HbA1c= 3.36±0.79), n= 8 for InsAb positive patients (GA/HbA1c= 2.61±0.48). The unpaired Student’s t-test was performed for the
comparison of two groups. As a result, the P value is 0.003. *: P < 0.05, **: P < 0.01, InsAb: insulin antibody, T1D: type 1 diabetes, T2D: type 2 diabetes
14
Table 1 Clinical characteristics of study patients
Type
T1D
T1D
T2D
T2D
InsAb
12
24
Age (years)
62.2 ± 6.7
55.0 ± 22.4
0.316
67.2 ± 10.3
66.8 ± 18.4
0.936
Male (%)
4 (33.3)
2 (50.0)
0.582
7 (29.2)
4 (50.0)
0.298
BMI (kg/m2)
20.2 ± 1.4
18.6 ± 1.4
0.061
25.3 ± 2.2
25.0 ± 3.2
0.764
Duration of insulin therapy (years)
18.2 ± 12.7
2.8 ± 1.5
0.03
10.2 ± 8.2
2.5 ± 3.1
0.02
InsAb binding rate (%)
n.d.
78.9 ± 5.1
n.d.
80.3 ± 10.6
K1 (1/10 M)
n.d.
0.015 ± 0.006
n.d.
0.040 ± 0.039
R1 (10-8 M)
n.d.
70.3 ± 31.1
n.d.
61.6 ± 59.9
HbA1c (%)
7.8 ± 0.5
8.1 ± 2.3
0.68
8.0 ± 0.7
8.8 ± 2.1
0.131
MDI
CSII
Premixed insulin
Basal insulin only
11
DPP-4 inhibitors
11
GLP-1 receptor agonists
Sulfonylureas
-8
Insulin administration method
Antidiabetic medications
15
Biguanides
19
Thiazolidinediones
SGLT-2 inhibitors
Alpha-glucosidase inhibitors
10
InsAb: insulin antibody, T1D: type 1 diabetes, T2D: type 2 diabetes, K1: affinity constant, R1: binding site number, MDI: Multiple daily injection, CSII:
Continuous subcutaneous insulin infusion. The unpaired Student’s t-test was performed to compare two groups (Age, BMI, InsAb binding rate, K1, R1, and
HbA1c). In addition, the χ2 test was performed for the comparison of gender between two groups. P values less than 0.05 were considered statistically significant.
16
...