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A case of fulminant type 1 diabetes mellitus with exocrine pancreatic insufficiency and enhanced glucagon response to meal ingestion
diabetes research and clinical practice 82 (2008) e1–e4
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/diabres
Brief report
A case of fulminant type 1 diabetes mellitus with exocrine pancreatic insufficiency and enhanced glucagon response to meal ingestion Daisuke Yabe a,*, Akira Kuroe a, Michihiro Ohya a, Koin Watanabe a, Naomi Kitatani a, Masayuki Oku b, Takeshi Kurose a, Yutaka Seino a,* a b
Division of Diabetes and Clinical Nutrition, Kansai Electric Power Hospital, 2-1-7 Fukushima, Osaka 553-0003, Japan Oku Clinic, 3-8 Kashita-honmachi, Higashi-osaka 577-0834, Japan
article info
abstract
Article history:
Non-specific aggression to endocrine a and b cells as well as exocrine pancreas has been
Received 17 July 2008
suggested in fulminant type 1 diabetes (FT1DM), while its effect on glucagon secretion and
Received in revised form
exocrine function is unknown. Here, we report a FT1DM case with exocrine pancreatic
17 July 2008
insufficiency and enhanced glucagon response to meal ingestion. # 2008 Elsevier Ireland Ltd. All rights reserved.
Accepted 5 August 2008 Published on line 11 September 2008 Keywords: Fulminant type 1 diabetes Insulin Glucagon Exocrine pancreatic insufficiency
Fulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes characterized by a sudden onset with ketoacidosis, high plasma glucose levels with near normal HbA1c, undetectable C-peptide, elevated serum pancreatic enzymes, and the absence of islet-associated autoantibodies [1]. Although the etiology of FT1DM still remains unclear, association of class II HLA (e.g. DR4 and DQ4) and involvement of viral infection (e.g. human herpes virus 6, influenza virus B and enterovirus) have been suggested [2–5]. Reduction of not only insulin-producing b cells but also glucagon-producing a cells [6] and infiltration of T lymphocytes in exocrine pancreas [7] are outstanding findings in biopsied pancreata of FT1DM patients, suggesting non-specific aggression to the whole
pancreas in FT1DM unlike b-cell-specific damages in autoimmune type 1 diabetes. Here, we report a case of FT1DM with exocrine pancreatic insufficiency and increased glucagon response to meal ingestion.
1.
History and examination
A 51-year-old man was transferred to our hospital in a diabetic ketoacidosis. He suffered from fever, abdominal discomfort and diarrhea 2 weeks before. He had thirst, polydipsia and polyuria 3 days before admission, and visited a clinic and was given drugs for common cold. On the day of admission, he
* Corresponding authors. Tel.: +81 6 6458 5821; fax: +81 6 6458 6994. E-mail addresses: [email protected] (D. Yabe), [email protected] (Y. Seino). 0168-8227/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.08.004
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diabetes research and clinical practice 82 (2008) e1–e4
visited another clinic to be found that his fasting plasma glucose was more than 500 mg/dL and was advised to visit our hospital. On admission, his arterial blood pH was 7.268 and bicarbonate was 11.8 meq/L. He had markedly increased levels of plasma glucose (613 mg/dL) and total ketone bodies (2.0 mmol/L), while his HbA1c was relatively low (6.4%). Serum and urinary C-peptide was under the detection limit (<0.10 ng/ mL and <2.11 mg/day, respectively). Serum C-peptide was not detected 120 min after standard Japanese breakfast (580 kcal) ingestion (<0.10 ng/mL). Serum C-peptide after meal ingestion was under the detection limit even 6 months after the admission (Fig. 1). Anti-GAD 65 antibody was very low (0.7 U/mL) and became undetectable 1 month after the
admission. Other islet-associated autoantibodies (i.e. islet cell antibody, insulinoma-associated antigen-2 antibody and insulin autoantibody) were not detected. His serum pancreatic amylase, lipase and elastase 1 levels were high (1201, 1457 and 12,597 IU/L, respectively), which were normalized 1 month after the admission. Percent recovery of orally administered N-benzoyl-L-tyrosyl-PABA in the urine was repeatedly low (64.4 and 59.4%; normal range 73.4–90.4%), suggesting exocrine pancreatic insufficiency. Fasting plasma glucagon levels were lower (84 pg/mL) than those of age- and sex-matched healthy volunteers (110.4 19.4 pg/mL) and patients with type 2 diabetes (135.9 19.4 pg/mL), and they did not change even 6 months after the admission (69 pg/mL). However, glucagon
Fig. 1 – (A) Changes in plasma glucose (left), plasma glucagon (middle), and serum C-peptide (right) levels after meal ingestion. The fulminant type 1 diabetic subject (FT1DM, triangles) (n = 1; 51-year-old male), type 2 diabetic subjects controlled for diet and exercise (T2DM, squares) (n = 8; males in age 40–59), and age- and sex-matched healthy volunteers (control, circles) (n = 7; males in age 40–59) were fasted for 12 h prior to ingestion of standard Japanese breakfast (480 kcal for control and T2DM groups, and 580 kcal for the FT1DM subject). The FT1DM subject routinely received three times daily subcutaneous injections of lispro (8, 6, and 4 U before breakfast, lunch and dinner, respectively) and twice daily subcutaneous injections of glargine (8 and 8 U before breakfast and dinner, respectively). Injections of lispro and glargine were omitted on the morning of the meal test in the FT1DM patient. The T2DM subjects were only controlled for diet and exercise, and received no medication. Blood samples were collected at indicated time points after meal ingestion. Serum Cpeptide and plasma glucagon levels were measured using lumipulse presto C-peptide (Fujirebio Inc., Japan) and Glucagon kit ‘‘Daiichi-II’’ (TFB, Japan), respectively. Data for Control and T2DM groups are shown as mean W S.E.M. The purpose and potential risks of the study were explained to all the subjects, and their informed, voluntary, written consent was obtained before the study. The study protocol was approved by the Ethics Committee, Kansai Electric Power Hospital. (B) Glucagon response after meal ingestion. Areas under the glucagon response curves during the 120-min period after initiation of meal ingestion were calculated, and shown for each group as mean W S.E.M.
diabetes research and clinical practice 82 (2008) e1–e4
secretion in response to standard Japanese breakfast ingestion was markedly enhanced (Fig. 1). The patient had HLA-A*2402/ A*3101, B*5401/B*4003, Cw*0102/Cw*0304, DRB1*0405/*1405, and DQB1*0401/*0503. HLA-A24 and -B54 are associated with Japanese type 1 diabetes [8], and HLA-DR4 and -DQ4 are strongly associated with FT1DM [2]. Serum neutralizing titers of coxackievirus B3, coxackievirus B4 and echovirus 4 were elevated on the day of admission (32-, 128-, and 64-folds, respectively).
2.
3.
e3
Conclusion
The exocrine pancreatic insufficiency in the current FT1DM case suggest presence of relatively non-specific aggression to the endocrine b cells as well as the exocrine pancreatic cells, while existence of cellular damages to a cells is unknown. Future investigation of exocrine pancreatic function and glucagon secretion, possibly in conjunction with morphometrical assessment of pancreatic islets for a and b cells will help us to understand the pathophysiology of FT1DM.
Investigation Conflict of interest
Characteristics of the current case are similar to those of previously reported cases of FT1DM. In addition to diminished insulin secretion, exocrine pancreatic insufficiency is observed in our case, consistent with cellular damages to the endocrine b cells as well as the exocrine pancreatic tissue implicated in FT1DM [1]. It has been recently reported that not only b-cell mass but also a-cell mass are reduced in pancreata of FT1DM patients [6]. Although there are several reports on a-cell mass in type 1 diabetes [9,10], little is known about pathophysiology of the reduced a-cell mass in FT1DM. While we did not evaluate the morphology of a cells in the patient, fasting plasma glucagon levels were decreased compared to healthy volunteers and patients with type 2 diabetes. These results might be consistent with the reduction of a-cell mass reported in FT1DM patients [6]. However, it is also possible that the long-acting glargine injected on the evening prior to blood collection suppressed glucagon secretion as previously reported in patients with autoimmune type 1 diabetes whose glucagon levels were decreased by intravenous continuous administration of regular insulin [12]. In contrast to the relatively low fasting glucagon levels, there exists significant glucagon response to meal ingestion in the current case as indicated by an increased area under the glucagon response curve (Fig. 1B). The profile of glucagon response is similar to those of patients with autoimmune type 1 diabetes where levels of plasma glucagon reached peak approximately 60 min after the start of the meal and returned to baseline after 120 min [13]. The paradoxical increase of glucagon in hyperglycemic conditions, possibly due to impaired suppression of glucagon secretion by insulin and b cells as well as defective glucose-sensing in a cells, has been suggested for type 2 and autoimmune type 1 diabetes [14], and it could be also a common phenomenon in FT1DM that aggravates postprandial hyperglycemia. In addition, the acell mass might be also responsible for the enhanced glucagon response to meal ingestion in not only type 2 and autoimmune type 1 diabetes but also in FT1DM. Taken together, despite of relatively low plasma glucagon levels at baseline, it is uncertain whether a-cell damages and decreased a-cell mass do exist in the current case. Since the Japanese nationwide survey on FT1DM did not evaluate glucagon secretion and exocrine function [11], the prevalence of damages to endocrine a cells and exocrine pancreas in FT1DM remains unknown, and should be evaluated in future to better understand the pathophysiology of FT1DM.
There are no conflicts of interest.
references
[1] T. Hanafusa, A. Imagawa, Fulminant type 1 diabetes: a novel clinical entity requiring special attention by all medical practitioners, Nat. Clin. Pract. Endocrinol. Metab. 3 (1) (2007) 36–45. [2] A. Imagawa, T. Hanafusa, Y. Uchigata, A. Kanatsuka, E. Kawasaki, T. Kobayashi, et al., Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus, Diabetologia 48 (2) (2005) 294–300. [3] A. Imagawa, T. Hanafusa, H. Makino, J.I. Miyagawa, P. Juto, High titres of IgA antibodies to enterovirus in fulminant type-1 diabetes, Diabetologia 48 (2) (2005) 290–293. [4] H. Sano, J. Terasaki, C. Tsutsumi, A. Imagawa, T. Hanafusa, A case of fulminant type 1 diabetes mellitus after influenza B infection, Diabetes Res. Clin. Pract. 79 (3) (2008) e8–9. [5] N. Sekine, T. Motokura, T. Oki, Y. Umeda, N. Sasaki, M. Hayashi, et al., Rapid loss of insulin secretion in a patient with fulminant type 1 diabetes mellitus and carbamazepine hypersensitivity syndrome, J. Am. Med. Assoc. 285 (9) (2001) 1153–1154. [6] K. Sayama, A. Imagawa, K. Okita, S. Uno, M. Moriwaki, J. Kozawa, et al., Pancreatic beta and alpha cells are both decreased in patients with fulminant type 1 diabetes: a morphmetrical assessment, Diabetologia 48 (2005) 1560–1564. [7] A. Imagawa, T. Hanafusa, J. Miyagawa, Y. Matsuzawa, A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies, N. Engl. J. Med. 342 (5) (2000) 301–307. [8] T. Kobayashi, K. Tamemoto, K. Nakanishi, N. Kato, M. Okubo, H. Kajio, et al., Immunogenetic and clinical characterization of slowly progressive IDDM, Diabetes Care 16 (5) (1993) 780–788. [9] L. Orci, D. Baetens, C. Rufener, M. Amherdt, M. Ravazzola, P. Studer, et al., Hypertropy and hyperplasia of somatostatincontaining D-cells in diabetes, Proc. Natl. Acad. Sci. U.S.A. 73 (4) (1976) 1338–1342. [10] M. Waguri, T. Hanafusa, N. Itoh, J. Miyagawa, A. Imagawa, M. Kuwajima, et al., Histopathologic study of the pancreas shows a characteristic lymphocytic infiltration in Japanese patients with IDDM, Endocrine J. 44 (1) (1997) 23–33. [11] A. Imagawa, T. Hanafusa, Y. Uchigata, A. Kanatsuka, E. Kawasaki, T. Kobayashi, et al., Fulminant type 1 diabetes: a nationwide survey in Japan, Diabetes Care 26 (8) (2003) 2345–2352.
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diabetes research and clinical practice 82 (2008) e1–e4
[12] J.E. Gerich, M. Lorenzi, E. Tsalikian, N.V. Bohannon, V. Schneider, J.H. Karam, et al., Effects of acute insulin withdrawal and administration on plasma glucagon responses to intravenous arginine in insulin-dependent diabetic subjects, Diabetes 25 (10) (1976) 955–960.
[13] W.A. Mu¨ller, G.R. Faloona, E. Aguilar-Parada, R.H. Unger, Abnormal alpha-cell function in diabes, N. Engl. J. Med. 283 (3) (1970) 109–114. [14] B.E. Dunning, J.E. Gerich, The role of a-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications, Endocr. Rev. 28 (3) (2007) 253–283.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/diabres
Brief report
A case of fulminant type 1 diabetes mellitus with exocrine pancreatic insufficiency and enhanced glucagon response to meal ingestion Daisuke Yabe a,*, Akira Kuroe a, Michihiro Ohya a, Koin Watanabe a, Naomi Kitatani a, Masayuki Oku b, Takeshi Kurose a, Yutaka Seino a,* a b
Division of Diabetes and Clinical Nutrition, Kansai Electric Power Hospital, 2-1-7 Fukushima, Osaka 553-0003, Japan Oku Clinic, 3-8 Kashita-honmachi, Higashi-osaka 577-0834, Japan
article info
abstract
Article history:
Non-specific aggression to endocrine a and b cells as well as exocrine pancreas has been
Received 17 July 2008
suggested in fulminant type 1 diabetes (FT1DM), while its effect on glucagon secretion and
Received in revised form
exocrine function is unknown. Here, we report a FT1DM case with exocrine pancreatic
17 July 2008
insufficiency and enhanced glucagon response to meal ingestion. # 2008 Elsevier Ireland Ltd. All rights reserved.
Accepted 5 August 2008 Published on line 11 September 2008 Keywords: Fulminant type 1 diabetes Insulin Glucagon Exocrine pancreatic insufficiency
Fulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes characterized by a sudden onset with ketoacidosis, high plasma glucose levels with near normal HbA1c, undetectable C-peptide, elevated serum pancreatic enzymes, and the absence of islet-associated autoantibodies [1]. Although the etiology of FT1DM still remains unclear, association of class II HLA (e.g. DR4 and DQ4) and involvement of viral infection (e.g. human herpes virus 6, influenza virus B and enterovirus) have been suggested [2–5]. Reduction of not only insulin-producing b cells but also glucagon-producing a cells [6] and infiltration of T lymphocytes in exocrine pancreas [7] are outstanding findings in biopsied pancreata of FT1DM patients, suggesting non-specific aggression to the whole
pancreas in FT1DM unlike b-cell-specific damages in autoimmune type 1 diabetes. Here, we report a case of FT1DM with exocrine pancreatic insufficiency and increased glucagon response to meal ingestion.
1.
History and examination
A 51-year-old man was transferred to our hospital in a diabetic ketoacidosis. He suffered from fever, abdominal discomfort and diarrhea 2 weeks before. He had thirst, polydipsia and polyuria 3 days before admission, and visited a clinic and was given drugs for common cold. On the day of admission, he
* Corresponding authors. Tel.: +81 6 6458 5821; fax: +81 6 6458 6994. E-mail addresses: [email protected] (D. Yabe), [email protected] (Y. Seino). 0168-8227/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.08.004
e2
diabetes research and clinical practice 82 (2008) e1–e4
visited another clinic to be found that his fasting plasma glucose was more than 500 mg/dL and was advised to visit our hospital. On admission, his arterial blood pH was 7.268 and bicarbonate was 11.8 meq/L. He had markedly increased levels of plasma glucose (613 mg/dL) and total ketone bodies (2.0 mmol/L), while his HbA1c was relatively low (6.4%). Serum and urinary C-peptide was under the detection limit (<0.10 ng/ mL and <2.11 mg/day, respectively). Serum C-peptide was not detected 120 min after standard Japanese breakfast (580 kcal) ingestion (<0.10 ng/mL). Serum C-peptide after meal ingestion was under the detection limit even 6 months after the admission (Fig. 1). Anti-GAD 65 antibody was very low (0.7 U/mL) and became undetectable 1 month after the
admission. Other islet-associated autoantibodies (i.e. islet cell antibody, insulinoma-associated antigen-2 antibody and insulin autoantibody) were not detected. His serum pancreatic amylase, lipase and elastase 1 levels were high (1201, 1457 and 12,597 IU/L, respectively), which were normalized 1 month after the admission. Percent recovery of orally administered N-benzoyl-L-tyrosyl-PABA in the urine was repeatedly low (64.4 and 59.4%; normal range 73.4–90.4%), suggesting exocrine pancreatic insufficiency. Fasting plasma glucagon levels were lower (84 pg/mL) than those of age- and sex-matched healthy volunteers (110.4 19.4 pg/mL) and patients with type 2 diabetes (135.9 19.4 pg/mL), and they did not change even 6 months after the admission (69 pg/mL). However, glucagon
Fig. 1 – (A) Changes in plasma glucose (left), plasma glucagon (middle), and serum C-peptide (right) levels after meal ingestion. The fulminant type 1 diabetic subject (FT1DM, triangles) (n = 1; 51-year-old male), type 2 diabetic subjects controlled for diet and exercise (T2DM, squares) (n = 8; males in age 40–59), and age- and sex-matched healthy volunteers (control, circles) (n = 7; males in age 40–59) were fasted for 12 h prior to ingestion of standard Japanese breakfast (480 kcal for control and T2DM groups, and 580 kcal for the FT1DM subject). The FT1DM subject routinely received three times daily subcutaneous injections of lispro (8, 6, and 4 U before breakfast, lunch and dinner, respectively) and twice daily subcutaneous injections of glargine (8 and 8 U before breakfast and dinner, respectively). Injections of lispro and glargine were omitted on the morning of the meal test in the FT1DM patient. The T2DM subjects were only controlled for diet and exercise, and received no medication. Blood samples were collected at indicated time points after meal ingestion. Serum Cpeptide and plasma glucagon levels were measured using lumipulse presto C-peptide (Fujirebio Inc., Japan) and Glucagon kit ‘‘Daiichi-II’’ (TFB, Japan), respectively. Data for Control and T2DM groups are shown as mean W S.E.M. The purpose and potential risks of the study were explained to all the subjects, and their informed, voluntary, written consent was obtained before the study. The study protocol was approved by the Ethics Committee, Kansai Electric Power Hospital. (B) Glucagon response after meal ingestion. Areas under the glucagon response curves during the 120-min period after initiation of meal ingestion were calculated, and shown for each group as mean W S.E.M.
diabetes research and clinical practice 82 (2008) e1–e4
secretion in response to standard Japanese breakfast ingestion was markedly enhanced (Fig. 1). The patient had HLA-A*2402/ A*3101, B*5401/B*4003, Cw*0102/Cw*0304, DRB1*0405/*1405, and DQB1*0401/*0503. HLA-A24 and -B54 are associated with Japanese type 1 diabetes [8], and HLA-DR4 and -DQ4 are strongly associated with FT1DM [2]. Serum neutralizing titers of coxackievirus B3, coxackievirus B4 and echovirus 4 were elevated on the day of admission (32-, 128-, and 64-folds, respectively).
2.
3.
e3
Conclusion
The exocrine pancreatic insufficiency in the current FT1DM case suggest presence of relatively non-specific aggression to the endocrine b cells as well as the exocrine pancreatic cells, while existence of cellular damages to a cells is unknown. Future investigation of exocrine pancreatic function and glucagon secretion, possibly in conjunction with morphometrical assessment of pancreatic islets for a and b cells will help us to understand the pathophysiology of FT1DM.
Investigation Conflict of interest
Characteristics of the current case are similar to those of previously reported cases of FT1DM. In addition to diminished insulin secretion, exocrine pancreatic insufficiency is observed in our case, consistent with cellular damages to the endocrine b cells as well as the exocrine pancreatic tissue implicated in FT1DM [1]. It has been recently reported that not only b-cell mass but also a-cell mass are reduced in pancreata of FT1DM patients [6]. Although there are several reports on a-cell mass in type 1 diabetes [9,10], little is known about pathophysiology of the reduced a-cell mass in FT1DM. While we did not evaluate the morphology of a cells in the patient, fasting plasma glucagon levels were decreased compared to healthy volunteers and patients with type 2 diabetes. These results might be consistent with the reduction of a-cell mass reported in FT1DM patients [6]. However, it is also possible that the long-acting glargine injected on the evening prior to blood collection suppressed glucagon secretion as previously reported in patients with autoimmune type 1 diabetes whose glucagon levels were decreased by intravenous continuous administration of regular insulin [12]. In contrast to the relatively low fasting glucagon levels, there exists significant glucagon response to meal ingestion in the current case as indicated by an increased area under the glucagon response curve (Fig. 1B). The profile of glucagon response is similar to those of patients with autoimmune type 1 diabetes where levels of plasma glucagon reached peak approximately 60 min after the start of the meal and returned to baseline after 120 min [13]. The paradoxical increase of glucagon in hyperglycemic conditions, possibly due to impaired suppression of glucagon secretion by insulin and b cells as well as defective glucose-sensing in a cells, has been suggested for type 2 and autoimmune type 1 diabetes [14], and it could be also a common phenomenon in FT1DM that aggravates postprandial hyperglycemia. In addition, the acell mass might be also responsible for the enhanced glucagon response to meal ingestion in not only type 2 and autoimmune type 1 diabetes but also in FT1DM. Taken together, despite of relatively low plasma glucagon levels at baseline, it is uncertain whether a-cell damages and decreased a-cell mass do exist in the current case. Since the Japanese nationwide survey on FT1DM did not evaluate glucagon secretion and exocrine function [11], the prevalence of damages to endocrine a cells and exocrine pancreas in FT1DM remains unknown, and should be evaluated in future to better understand the pathophysiology of FT1DM.
There are no conflicts of interest.
references
[1] T. Hanafusa, A. Imagawa, Fulminant type 1 diabetes: a novel clinical entity requiring special attention by all medical practitioners, Nat. Clin. Pract. Endocrinol. Metab. 3 (1) (2007) 36–45. [2] A. Imagawa, T. Hanafusa, Y. Uchigata, A. Kanatsuka, E. Kawasaki, T. Kobayashi, et al., Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus, Diabetologia 48 (2) (2005) 294–300. [3] A. Imagawa, T. Hanafusa, H. Makino, J.I. Miyagawa, P. Juto, High titres of IgA antibodies to enterovirus in fulminant type-1 diabetes, Diabetologia 48 (2) (2005) 290–293. [4] H. Sano, J. Terasaki, C. Tsutsumi, A. Imagawa, T. Hanafusa, A case of fulminant type 1 diabetes mellitus after influenza B infection, Diabetes Res. Clin. Pract. 79 (3) (2008) e8–9. [5] N. Sekine, T. Motokura, T. Oki, Y. Umeda, N. Sasaki, M. Hayashi, et al., Rapid loss of insulin secretion in a patient with fulminant type 1 diabetes mellitus and carbamazepine hypersensitivity syndrome, J. Am. Med. Assoc. 285 (9) (2001) 1153–1154. [6] K. Sayama, A. Imagawa, K. Okita, S. Uno, M. Moriwaki, J. Kozawa, et al., Pancreatic beta and alpha cells are both decreased in patients with fulminant type 1 diabetes: a morphmetrical assessment, Diabetologia 48 (2005) 1560–1564. [7] A. Imagawa, T. Hanafusa, J. Miyagawa, Y. Matsuzawa, A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies, N. Engl. J. Med. 342 (5) (2000) 301–307. [8] T. Kobayashi, K. Tamemoto, K. Nakanishi, N. Kato, M. Okubo, H. Kajio, et al., Immunogenetic and clinical characterization of slowly progressive IDDM, Diabetes Care 16 (5) (1993) 780–788. [9] L. Orci, D. Baetens, C. Rufener, M. Amherdt, M. Ravazzola, P. Studer, et al., Hypertropy and hyperplasia of somatostatincontaining D-cells in diabetes, Proc. Natl. Acad. Sci. U.S.A. 73 (4) (1976) 1338–1342. [10] M. Waguri, T. Hanafusa, N. Itoh, J. Miyagawa, A. Imagawa, M. Kuwajima, et al., Histopathologic study of the pancreas shows a characteristic lymphocytic infiltration in Japanese patients with IDDM, Endocrine J. 44 (1) (1997) 23–33. [11] A. Imagawa, T. Hanafusa, Y. Uchigata, A. Kanatsuka, E. Kawasaki, T. Kobayashi, et al., Fulminant type 1 diabetes: a nationwide survey in Japan, Diabetes Care 26 (8) (2003) 2345–2352.
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diabetes research and clinical practice 82 (2008) e1–e4
[12] J.E. Gerich, M. Lorenzi, E. Tsalikian, N.V. Bohannon, V. Schneider, J.H. Karam, et al., Effects of acute insulin withdrawal and administration on plasma glucagon responses to intravenous arginine in insulin-dependent diabetic subjects, Diabetes 25 (10) (1976) 955–960.
[13] W.A. Mu¨ller, G.R. Faloona, E. Aguilar-Parada, R.H. Unger, Abnormal alpha-cell function in diabes, N. Engl. J. Med. 283 (3) (1970) 109–114. [14] B.E. Dunning, J.E. Gerich, The role of a-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications, Endocr. Rev. 28 (3) (2007) 253–283.