島田朗、川﨑英二、阿比留教生他. 緩徐進行1型糖尿病の診断基準（2023）―1型糖尿病における新病態の探索的検討委員会報告―. 糖尿病. 2023;66(7):587–591.
Imagawa A, Hanafusa T, Uchigata Y, Kanatsuka A, Kawasaki E, Kobayashi T, Shimada A, Shimizu I, Toyoda T, Maruyama T, Makino H.
Fulminant type 1 diabetes: a nationwide survey in Japan.
Diabetes Care. 2003 Aug;26(8):2345-52. doi: 10.2337/diacare.26.8.2345.
Abstract/Text
OBJECTIVE: To describe the clinical and immunologic characteristics of fulminant type 1 diabetes, a novel subtype of type 1 diabetes, we conducted a nationwide survey.
RESEARCH DESIGN AND METHODS: History and laboratory data, including islet-related autoantibodies, were examined in 222 patients with fulminant and nonfulminant type 1 diabetes in our hospitals in addition to another 118 patients with fulminant type 1 diabetes located outside our hospitals in Japan.
RESULTS: In our hospitals, of the 222 patients studied, 43 (19.4%) were diagnosed with fulminant type 1 diabetes, 137 (61.7%) were classified as having autoimmune type 1 diabetes, and 42 were type 1 diabetic subjects who were not fulminant and did not have anti-islet antibodies. An additional 118 fulminant patients outside our hospitals were enrolled, making a total of 161 fulminant type 1 diabetic subjects (83 male and 78 female subjects; 14 children/adolescents and 147 adults) identified from all over Japan. (In 2000, the average incidence was three cases per month.) Flu-like symptoms and pregnancy were more frequently observed in the fulminant than in the autoimmune group (P < 0.001). In the fulminant patients, 4.8% were positive for anti-GAD antibodies and none were positive for anti-islet antigen 2 antibodies.
CONCLUSIONS: Fulminant type 1 diabetes is a distinct subtype and accounts for approximately 20% of the ketosis-onset type 1 diabetes cases in Japan. Flu-like symptoms are characteristic of disease onset. Metabolic derangement is more severe in this subtype than in autoimmune type 1 diabetes.
Murao S, Kondo S, Ohashi J, Fujii Y, Shimizu I, Fujiyama M, Ohno K, Takada Y, Nakai K, Yamane Y, Osawa H, Makino H.
Anti-thyroid peroxidase antibody, IA-2 antibody, and fasting C-peptide levels predict beta cell failure in patients with latent autoimmune diabetes in adults (LADA)--a 5-year follow-up of the Ehime study.
Diabetes Res Clin Pract. 2008 Apr;80(1):114-21. doi: 10.1016/j.diabres.2008.01.024. Epub 2008 Mar 14.
Abstract/Text
OBJECTIVE: To clarify the natural course and factors involved in beta cell failure in Japanese latent autoimmune diabetes in adults (LADA) patients.
RESEARCH DESIGN AND METHODS: Insulin secretion in 57 LADA patients identified from among 4980 adult-onset diabetic patients in a hospital-based Ehime study were examined over a 5-year period. Postprandial serum C-peptide levels below 0.33 nmol/l were defined as beta cell failure. The involvement of clinical and immunological factors in the progression to beta cell failure were evaluated.
RESULTS: Forty-two of the fifty-seven LADA patients completed the 5-year follow-up. Eleven (26.2%) required insulin treatment and five (11.9%) progressed to beta cell failure. A Cox regression analysis revealed that positive anti-thyroid peroxidase antibody (TPOAb) and insulinoma-associated protein 2 (IA-2Ab) were associated with the need for insulin treatment (p<0.05 and p<0.01, respectively). Positive TPOAb, anti-thyroglobulin antibody (TGAb), IA-2 antibody (p<0.01 for each), and lower serum fasting C-peptide levels (p<0.05) were contributors to the progression to beta cell failure. Involvement of type 1 diabetes susceptible HLA class II genes was not evident.
CONCLUSIONS: Japanese LADA patients are a heterogeneous population. In addition to IA-2 antibody, presence of TPOAb and fasting C-peptide level could indicate an oncoming deterioration of beta cell function.
Awata T, Shimada A, Maruyama T, Oikawa Y, Yasukawa N, Kurihara S, Miyashita Y, Hatano M, Ikegami Y, Matsuda M, Niwa M, Kazama Y, Tanaka S, Kobayashi T.
Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S).
Diabetes Ther. 2017 Oct;8(5):1123-1134. doi: 10.1007/s13300-017-0299-7. Epub 2017 Sep 19.
Abstract/Text
INTRODUCTION: We tested the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitors are effective in preserving the β-cell function for long-term periods in patients with slowly progressive type 1 diabetes (SPIDDM) or latent autoimmune diabetes in adults (LADA).
METHODS: In the present open-label, randomized, controlled trial, 14 non-insulin-requiring diabetic patients with glutamic acid decarboxylase autoantibodies (GADAb) were randomly assigned to receive either sitagliptin (S group) or pioglitazone (P group). As a historical control, the Tokyo Study, in which non-insulin-dependent patients with SPIDDM were assigned to receive treatment by either insulin or sulfonylurea (SU), was used.
RESULTS: On average, the ∑C-peptide values during the oral glucose tolerance test through the follow-up periods showed a nonsignificant increase in the S group (n = 6, n = 5 at 48 months) compared to the P group (n = 5, n = 2 at 48 months). In comparison to the data in the Tokyo Study, treatment by sitagliptin significantly influenced the longitudinal changes in the ∑C-peptide values with a more increased direction than insulin or SU, especially in patients with 48 months of follow-up (p = 0.014 and p = 0.007, respectively). Although the titers of GADAb were not significantly different between the S and P groups during the study, the change ratio of the GADAb titers from baseline was significantly inversely correlated with the change ratio of the ∑C-peptide values from baseline in the S group (p = 0.003); in particular, when the GADAb titers decreased from baseline, the ∑C-peptide values frequently increased.
CONCLUSION: The present pilot trial suggests that treatment of SPIDDM/LADA by sitagliptin, a DPP-4 inhibitor, may be more effective in preserving the β-cell function than insulin treatment for at least 4 years, possibly through the immune modulatory effects of DPP-4 inhibitors.
CLINICAL TRIAL REGISTRATION: Japanese Clinical Trials Registry UMIN000003693.
島田朗、川﨑英二、阿比留教生他. 緩徐進行1型糖尿病疑い例への治療介入に関するステートメント. 糖尿病. 2023;66(12):807–814.
Kitabchi AE, Ayyagari V, Guerra SM.
The efficacy of low-dose versus conventional therapy of insulin for treatment of diabetic ketoacidosis.
Ann Intern Med. 1976 Jun;84(6):633-8. doi: 10.7326/0003-4819-84-6-633.
Abstract/Text
The effect of low-dose intramuscular insulin therapy was compared with that of high-dose insulin therapy by intravenous and subcutaneous routes in 48 patients with diabetic ketoacidosis. A simplified protocol was devised to compare efficacy of the two methods of therapy in a randomized manner. Plasma glucose dropped to less than 250 mg/dl in the low-dose group in 6.7 +/- 0.8 h and in the high-dose group in 4.5 +/- 0.8 h (P = not significant). The amount of insulin necessary to lower plasma glucose to 250 mg/dl was 263 +/- 45 U in the high-dose group and 46 +/- 5 U in the low-dose group. Twenty five percent in the high-dose group and none in the low-dose group developed hypoglycemia. Other biochemical and clinical variables in the two groups were comparable. No treatment complications were noted in the low-dose group. Our studies suggest that low-dose intramuscular insulin therapy is simple and as effective as high-dose therapy in the treatment of diabetic ketoacidosis without the risk of hypoglycemia and with a diminished incidence of hypokalemia. Furthermore, the favorable response of these patients to low-dose insulin therapy suggests the absence of insulin resistance in diabetic ketoacidosis.
Krentz AJ, Hale PJ, Singh BM, Nattrass M.
The effect of glucose and insulin infusion on the fall of ketone bodies during treatment of diabetic ketoacidosis.
Diabet Med. 1989 Jan-Feb;6(1):31-6. doi: 10.1111/j.1464-5491.1989.tb01135.x.
Abstract/Text
During the treatment of diabetic ketoacidosis intravenous glucose is infused when blood glucose has fallen to around 14 mmol l-1. The use of hypertonic (10%) glucose has been recommended in order to hasten the clearance of blood ketone bodies. In a randomized controlled study 17 patients presenting with severe diabetic ketoacidosis were allocated to one of two regimens of intravenous glucose and insulin when blood glucose had fallen to less than 14 mmol l-1. Nine patients were given 5% glucose containing 10 U l-1 insulin and 8 patients received 10% glucose with 40 U l-1 insulin. Fluid was infused at a rate of 250 ml h-1 for 6 h. At the start of the infusions blood glucose had fallen from levels at presentation to 12.8 +/- 1.1 mmol l-1 (mean +/- SE) in the group which subsequently received the low infusion rate and to 13.7 +/- 0.9 mmol l-1 in the subsequent high infusion rate group. With glucose/insulin infusion blood glucose after 6 h was 11.5 +/- 0.9 mmol l-1 (low infusion rate group) and 15.7 +/- 1.3 mmol l-1 (high infusion rate group). This difference between groups at 6 h was significant (p less than 0.05). Over the 6 h of infusion the fall in blood total ketone bodies was significantly greater in the group receiving the higher rate of glucose/insulin infusion (7.34 +/- 0.57 vs 5.18 +/- 0.57 mmol l-1; p less than 0.05). Despite the greater fall in total ketone bodies in this group there was no difference in the improvement in capillary blood pH or bicarbonate.(ABSTRACT TRUNCATED AT 250 WORDS)
Morris LR, Murphy MB, Kitabchi AE.
Bicarbonate therapy in severe diabetic ketoacidosis.
Ann Intern Med. 1986 Dec;105(6):836-40. doi: 10.7326/0003-4819-105-6-836.
Abstract/Text
Twenty-one adult patients with severe diabetic ketoacidosis entered a randomized prospective protocol in which variable doses of sodium bicarbonate, based on initial arterial pH (6.9 to 7.14), were administered to 10 patients (treatment group) and were withheld from 11 patients (control group). During treatment, there were no significant differences in the rate of decline of glucose or ketone levels or in the rate of increase in pH or bicarbonate levels in the blood or cerebrospinal fluid in either group. Similarly, there were no significant differences in the time required for the plasma glucose level to reach 250 mg/dL, blood pH to reach 7.3, or bicarbonate level to reach 15 meq/L. We conclude that in severe diabetic ketoacidosis (arterial pH 6.9 to 7.14), the administration of bicarbonate does not affect recovery outcome variables as compared with those in a control group.
Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C.
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
N Engl J Med. 1993 Sep 30;329(14):977-86. doi: 10.1056/NEJM199309303291401.
Abstract/Text
BACKGROUND: Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
METHODS: A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.
RESULTS: In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.
CONCLUSIONS: Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group.
Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus.
JAMA. 2002 May 15;287(19):2563-9. doi: 10.1001/jama.287.19.2563.
Abstract/Text
The purpose of this report is to summarize and integrate the findings of the Diabetes Control and Complications Trial (DCCT), a randomized controlled clinical trial, and the succeeding observational follow-up of the DCCT cohort in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, regarding the effects of intensive treatment on the microvascular complications of type 1 diabetes mellitus. The DCCT proved that intensive treatment reduced the risks of retinopathy, nephropathy, and neuropathy by 35% to 90% compared with conventional treatment. The absolute risks of retinopathy and nephropathy were proportional to the mean glycosylated hemoglobin (HbA(1c)) level over the follow-up period preceding each event. Intensive treatment was most effective when begun early, before complications were detectable. These risk reductions, achieved at a median HbA(1c) level difference of 9.1% for conventional treatment vs 7.3% for intensive treatment have been maintained through 7 years of EDIC, even though the difference in mean HbA(1c) levels of the 2 former randomized treatment groups was only 0.4% at 1 year (P<.001) (8.3% in the former conventional treatment group vs 7.9% in the former intensive treatment group), continued to narrow, and became statistically nonsignificant by 5 years (8.1% vs 8.2%, P =.09). The further rate of progression of complications from their levels at the end of the DCCT remains less in the former intensive treatment group. Thus, the benefits of 6.5 years of intensive treatment extend well beyond the period of its most intensive implementation. Intensive treatment should be started as soon as is safely possible after the onset of type 1 diabetes mellitus and maintained thereafter, aiming for a practicable target HbA(1c) level of 7.0% or less.
Mehta SN, Quinn N, Volkening LK, Laffel LM.
Impact of carbohydrate counting on glycemic control in children with type 1 diabetes.
Diabetes Care. 2009 Jun;32(6):1014-6. doi: 10.2337/dc08-2068. Epub 2009 Feb 24.
Abstract/Text
OBJECTIVE: To study the association between parent carbohydrate counting knowledge and glycemic control in youth with type 1 diabetes.
RESEARCH DESIGN AND METHODS: We assessed 67 youth ages 4-12 years with type 1 diabetes (duration >or=1 year). Parents estimated carbohydrate content of children's meals in diet recalls. Ratios of parent estimates to computer analysis defined carbohydrate counting knowledge; the mean and SD of these ratios defined accuracy and precision, respectively. A1C defined glycemic control.
RESULTS: Greater accuracy and precision were associated with lower A1C in bivariate analyses (P < 0.05). In a multivariate analysis (R(2)= 0.25, P = 0.007) adjusting for child age, sex, and type 1 diabetes duration, precision (P = 0.02) and more frequent blood glucose monitoring (P = 0.04), but not accuracy (P = 0.9), were associated with lower A1C. A1C was 0.8% lower (95% CI -0.1 to -1.4) among youth whose parents demonstrated precision.
CONCLUSIONS: Precision with carbohydrate counting and increased blood glucose monitoring were associated with lower A1C in children with type 1 diabetes.
Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R.
UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group.
Lancet. 1997 Nov 1;350(9087):1288-93. doi: 10.1016/s0140-6736(97)03062-6.
Abstract/Text
BACKGROUND: Autoantibodies to islet-cell cytoplasm (ICA) and glutamic acid decarboxylase (GADA) can occur in apparently typical, non-insulin dependent diabetes mellitus (type 2). We investigated whether the presence of either or both antibodies characterises a subtype of diabetes and provides better prediction of requirement for insulin therapy by 6 years' follow-up than clinical variables.
METHODS: We measured ICA and GADA at diagnosis of diabetes in a representative population of 3672 white patients with type 2 diabetes, aged between 25 and 65 years. The phenotype was assessed by age of onset, body-mass index, percentage haemoglobin A1c (HbA1c), and islet beta-cell function. We investigated the need for insulin therapy among 1538 patients not assigned insulin and followed up for 6 years from diagnosis.
FINDINGS: The proportion of patients with ICA and GADA decreased with increasing age at diagnosis (from 33 [21%] of 157 patients aged 25-34 [corrected] to 66 [4%] of 1769 aged 55-65 for ICA; from 53 [34%] to 122 [7%] for GADA). Among patients younger than 35 at diagnosis, those with ICA or GADA had lower body-mass index than those without (mean 24.9 [SD 6.0] vs 31.7 [7.3] kg/m2; p < 0.0001 and had higher percentage of HbA1c (9.7 vs 8.7%, p < 0.05). 94% of patients with ICA and 84% of those with GADA required insulin therapy by 6 years, compared with 14% of those without the antibodies (p < 0.0001). Among patients older than 55 at diagnosis, the difference between those with and without antibodies in body-mass index was smaller (27.2 [5.4] vs 28.6 [4.8] kg/m2, p < 0.001); 44% of those with ICA, 34% of those with GADA, and 5% with neither antibody required insulin therapy by 6 years (p < 0.0001). Among patients older than 45 years, body-mass index and HbA1c provided little predictive information for insulin requirement, whereas the positive predictive values of GADA (> or = 60 U/L) alone, or both GADA (> or = 20 U/L) and ICA (> 5 U/L), for insulin therapy were 52% and 68%.
INTERPRETATION: Among young adults with type 2 diabetes, the phenotype of those with ICA or GADA antibodies was similar to that of classic juvenile-onset insulin-dependent diabetes, and either phenotype or antibodies predicted insulin requirement. In older adults, the phenotype was closer to that of patients without antibodies and only the presence of antibodies predicted an increased likelihood of insulin requirement.
Maruyama T, Tanaka S, Shimada A, Funae O, Kasuga A, Kanatsuka A, Takei I, Yamada S, Harii N, Shimura H, Kobayashi T.
Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus.
J Clin Endocrinol Metab. 2008 Jun;93(6):2115-21. doi: 10.1210/jc.2007-2267. Epub 2008 Apr 8.
Abstract/Text
OBJECTIVE: We tested the hypothesis that insulin therapy rather than sulfonylurea (SU) treatment is preferable to reverse or preserve beta-cell function among patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) or latent autoimmune diabetes in adults.
METHODS: This multicenter, randomized, nonblinded clinical study screened 4089 non-insulin-dependent diabetic patients for glutamic acid decarboxylase autoantibodies (GADAb). Sixty GADAb-positive non-insulin-requiring diabetic patients with a 5-yr duration or shorter of diabetes were assigned to either the SU group (n = 30) or the insulin group (n = 30). Serum C-peptide responses to annual oral glucose tolerance tests were followed up for a mean of 57 months. The primary endpoint was an insulin-dependent state defined by the sum of serum C-peptide values during the oral glucose tolerance test (SigmaC-peptide) less than 4 ng/ml (1.32 nmol/liter).
RESULTS: The progression rate to an insulin-dependent state in the insulin group (three of 30, 10%) was lower than that in the SU group (13 of 30, 43%; P = 0.003, log-rank). Longitudinal analysis demonstrated that SigmaC-peptide values were better preserved in the insulin group than in the SU group. Multiple regression analysis demonstrated that insulin treatment, a preserved C-peptide response, and a low GADAb titer at entry were independent factors in preventing progression to an insulin-dependent state. Subgroup analysis suggested that insulin intervention was highly effective for SPIDDM patients with high GADAb titers [> or =10 U/ml (180 World Health Organization U/ml)] and preserved beta-cell function [SigmaC-peptide > or = 10 ng/ml (3.31 nmol/liter)] at entry. No severe hypoglycemic episodes occurred during the study.
CONCLUSIONS: Insulin intervention to preserve beta-cell function is effective and safe for patients with SPIDDM or latent autoimmune diabetes in adults.
