Differences in risk factors for the onset of albuminuria and decrease in glomerular filtration rate in people with Type 2 diabetes mellitus: implications for the pathogenesis of diabetic kidney disease.

AIMS: To determine differences in predictors of albuminuria and decreased estimated GFR in Japanese people with Type 2 diabetes mellitus without chronic kidney disease. METHODS: This single-centre observational cohort study involved 1802 Japanese people with Type 2 diabetes with normoalbuminuria and estimated GFR ≥ 60 ml/min/1.73 m(2) (740 women; mean ± sd age 58 ± 12 years). Two separate outcomes were evaluated: onset of albuminuria ( ≥ 30 mg/g creatinine, albuminuria cohort; n = 1655) and decrease in estimated GFR ( < 60 ml/min/1.73 m(2) ; estimated GFR cohort; n = 1777). A Cox proportional hazards model was used to identify significant predictors for each outcome. RESULTS: During a median follow-up period of 6.9 years for the albuminuria cohort and 8.0 years for the estimated GFR cohort, 181 and 316 individuals reached the respective outcome. The 5-year cumulative incidence of albuminuria was 8.3%, and that of decreased estimated GFR was 10.4%. In the multivariate Cox model, greater urinary albumin-to-creatinine ratio, presence of diabetic retinopathy and higher HbA1c levels were associated with both outcomes. Unique risk factors for onset of albuminuria were male gender and higher uric acid levels; those for decreased estimated GFR were older age, greater systolic blood pressure, and lower baseline estimated GFR and HDL cholesterol levels. CONCLUSIONS: Identification of both common and distinct predictive factors for onset of albuminuria and decreased estimated GFR support the hypothesis that both common and distinct pathophysiological mechanisms are involved in the development of these two manifestations of chronic kidney disease in diabetes.

Urinary type IV collagen as a predictor for the incidence of microalbuminuria in young patients with Type 1 diabetes.

AIMS: To clarify whether urinary type IV collagen-to-creatinine ratio is a predictor for the incidence of microalbuminuria in patients with Type 1 diabetes. METHODS: A longitudinal observational cohort study was conducted; the subjects included normoalbuminuric patients diagnosed with Type 1 diabetes before the age of 30 years and who were less than 40 years old at the start of the observation. In total, 225 patients were enrolled (age, mean ± SD: 25 ± 5 years; male: 32.9%). The endpoint was the incidence of microalbuminuria, defined as 30 mg/g Cr ≤ urinary albumin-to-creatinine ratio < 300 mg/g Cr. Patients were divided into two groups based on the median of urinary type IV collagen-to-creatinine ratio levels. RESULTS: During the median follow-up period of 8.8 years (range 1.0-12.8 years), 13 patients with high urinary type IV collagen-to-creatinine ratio progressed to microalbuminuria. Meanwhile, only one patient with low urinary type IV collagen-to-creatinine ratio reached the endpoint. Kaplan-Meier estimates for the time to reach the endpoint were significantly faster for patients with a high ratio than for those with a low ratio (log-rank test, P < 0.001). In the multivariate Cox hazard analysis, the hazard ratio for patients with high vs. low urinary type IV collagen-to-creatinine ratio was 13.51 (95% CI 1.59-115.02, P = 0.017). When urinary type IV collagen-to-creatinine ratio was treated as a continuous variable, logarithmically transformed urinary type IV collagen-to-creatinine ratio, but not baseline albumin-to-creatinine ratio, was independently associated with reaching the endpoint (hazard ratio 19.23, 95% CI 1.53-242.30, P = 0.022). CONCLUSIONS: Urinary type IV collagen may be an important predictor for the incidence of microalbuminuria in young patients with Type 1 diabetes.

Pancreatic islet cell surface glycoproteins containing Gal beta 1-4GlcNAc-R identified by a cytotoxic monoclonal autoantibody.

To investigate the autoimmune pathogenesis of spontaneously occurring diabetes mellitus in BB rats, spleen cells of newly diagnosed diabetic BB rats were fused with mouse myeloma cells. Hybridoma supernatants were screened for antibodies by indirect immunofluorescence and by 51Cr-release assays using the RINm5F rat insulinoma cell line. One clone, E5C2, produced an IgM kappa antibody that was cytotoxic for RINm5F cells, but not for other rat cell lines nor for primary rat islet cells. However, treatment of primary rat islet cells with neuraminidase exposed surface antigens and rendered the cells susceptible to complement-mediated lysis by antibody E5C2. Using immunostaining of glycolipids separated by thin-layer chromatography, hapten inhibition assays with defined carbohydrates, and Western blots, the antigens recognized by E5C2 on RINm5F cells were identified as glycoproteins with molecular weights of 60,000 and 68,000. The antibody recognizes a carbohydrate antigen containing the sequence Gal beta 1-4GlcNAc-R, which on RINm5F cells is predominantly hidden by covalently bound sialic acid. These studies raise the possibility that hidden antigenic determinants on islet cells exposed by a variety of means may be the target of autoimmune attack.

Comparison of the prevalence of chronic kidney disease in Japanese patients with Type 1 and Type 2 diabetes.

AIMS: The relationship between type of diabetes and risk of chronic kidney disease has not been studied in detail. We conducted this study to determine the prevalence of chronic kidney disease in Japanese adults with diabetes, with a particular emphasis on the comparison of Type 1 and Type 2 diabetes. METHODS: We studied 3,575 Japanese patients with diabetes, 504 with Type 1 (mean +/- SD age 38 +/- 13 years; 350 women and 154 men) and 3071 with Type 2 diabetes (60 +/- 13 years; 1187 women and 1884 men). Prevalence rates of albuminuria [urinary albumin/creatinine ratio (> or = 30 mg/g], decreased estimated glomerular filtration rate (eGFR < 60 ml/min/1.73 m(2)) and chronic kidney disease (defined as albuminuria and/or decreased eGFR) were compared between the two diabetic groups. RESULTS: The prevalence of albuminuria was higher in Type 2 than Type 1 diabetic patients by both Fisher's exact test (36.1 vs. 15.9%, P < 0.001) and multivariate logistic regression analysis [adjusted odds ratio (OR) = 1.482, 95% confidence interval (CI) = 1.050-2.091, P = 0.025]. The prevalence of decreased eGFR was also higher in Type 2 diabetic patients (25.2 vs. 7.9%, P < 0.001); however, the statistical significance disappeared after adjusting for covariates, including age (OR = 0.656, 95% CI = 0.395-1.088, P = 0.102). The prevalence of chronic kidney disease was also higher in Type 2 diabetic patients (46.0 vs. 19.1%, P < 0.001); however, the statistical significance disappeared in the multivariate analysis. CONCLUSIONS Type 2 diabetic patients are more than twice as likely as Type 1 diabetic patients to have chronic kidney disease due to an age-independent higher prevalence of albuminuria and age-dependent decreased eGFR.

Clinical and immunogenetic characteristics of fulminant type 1 diabetes associated with pregnancy.

OBJECTIVE: The objective of this study was to characterize the clinical and immunogenetic features of Japanese pregnancy-associated fulminant type 1 diabetes (PF). A group of patients with PF was compared with a group of patients of child-bearing age with fulminant type 1 diabetes that was not associated with pregnancy (NPF) in a nationwide survey conducted from 2000-2004. PATIENTS: The clinical characteristics of the 22 patients in the PF group were compared with those of the 48 patients in the NPF group. Human leukocyte antigen (HLA) class II DR and DQ genotyping of 17 PF and 20 NPF patients was performed. RESULTS: Arterial pH was significantly lower (P = 0.0366), and amylase values tended to increase in PF patients compared with NPF patients (P = 0.0515). In 22 PF patients, 18 developed disease during pregnancy (26.3 wk; range, 7-38), whereas four cases occurred immediately after delivery (10.5 d; range, 7-14 d). Twelve cases that developed during pregnancy resulted in stillbirth (67%), and five of the six fetal cases that survived were delivered by cesarean section. The haplotype frequency of HLA DRB1*0901-DQB1*0303 in PF was significantly higher than those in NPF (P = 0.0244) and controls (P = 0.0001), whereas that of DRB1*0405-DQB1*0401 in NPF was significantly higher than those in PF (P = 0.0162) and controls (P < 0.0001). CONCLUSIONS: The clinical symptoms of PF patients were more severe than those of NPF patients, and the prognosis of their fetuses was extremely poor. The type 1 diabetes-susceptible HLA class II haplotype is distinct in PF and NPF patients, suggesting that different HLA haplotypes underlie the presentation of PF or NPF.

Effect of poly(ADP-ribose) synthetase inhibitor administration to rats before and after injection of alloxan and streptozotocin on islet proinsulin synthesis.

Nicotinamide (10 mmol/kg) and 3-aminobenzamide (1.25 mmol/kg), poly(ADP-ribose) synthetase inhibitors, were injected intravenously to rats either 30 min before the intravenous administration of 12 mg/kg alloxan or 50 mg/kg streptozotocin ("pretreatment") or 5 min after the administration ("posttreatment"). Fifteen minutes after the injection of the diabetogenic agents, pancreatic islets were isolated from the rats and proinsulin synthesis was determined. Proinsulin synthesis was decreased in islets from rats treated with alloxan or streptozotocin. Pretreatment with poly(ADP-ribose) synthetase inhibitors was found to protect against alloxan- or streptozotocin-induced decrease in proinsulin synthesis. By posttreatment with poly(ADP-ribose) synthetase inhibitors, streptozotocin-induced decrease in proinsulin synthesis was also significantly reversed, whereas the decrease induced by alloxan was not.

Human monoclonal IgG1 insulin autoantibody from insulin autoimmune syndrome directed at determinant at asparagine site on insulin B-chain.

Purified human insulin autoantibody (IAA) collected from the serum of a man (T.H.) with insulin autoimmune syndrome was characterized. The TH-IAA was found to be of IgG1 (lambda-light-chain) subclass. In addition to the single-binding affinity of TH-IAA to human insulin that we have shown in previous studies, the TH-IAA binding to human insulin was completely inhibited by a mouse monoclonal anti-idiotypic antibody against TH-IAA. A competitive inhibition study with various insulins revealed an epitope of human insulin against TH-IAA. These findings suggest that TH-IAA is monoclonal and is directed at a determinant at B-3 (asparagine) on the human insulin B-chain.

Inducement of antibody that mimics insulin action on insulin receptor by insulin autoantibody directed at determinant at asparagine site on human insulin B chain.

We previously showed that purified human IgG1 insulin autoantibody (IAA) from the serum of male patient T.H. with insulin autoimmune syndrome is directed at a determinant at the asparagine site on the human insulin B chain. An anti-idiotypic antibody (anti-TH) that inhibited TH-IAA binding to human insulin was obtained by immunizing BALB/c mice with TH-IAA. Anti-TH bound to viable IM-9 cells and the purified insulin receptor from IM-9 cells. Anti-TH binding to IM-9 cells and the insulin receptor was inhibited by TH-IAA but not by human IgG. Moreover, incubation of HepG2 cells with anti-TH had an inhibitory effect on insulin binding to HepG2 cells. Anti-TH, like insulin, stimulated amino acid uptake in HepG2 cells. These findings indicate that the conformation of TH-IAA idiotope is a mirror image of the determinant on the insulin B chain, the binding site for TH-IAA on anti-TH is also related to the insulin binding site on the insulin receptor, and anti-TH mimics insulin action on the insulin receptor.

Comparison of diagnostic criteria of IGT, borderline, and GDM. Blood glucose curve and IRI response.

A 75-g oral glucose tolerance test (OGTT) was performed in 615 nonobese pregnant women (mean +/- SD age 29.7 +/- 4.3 yr) who were referred to the Division of Internal Medicine at our diabetes center because of glycosuria. Seventy-seven cases were found to have urinary glucose at the first trimester, 185 at the second trimester, and 353 at the third trimester. With their 75-g OGTT results, the diagnostic criteria of borderline (formulated by the Japan Diabetes Society), impaired glucose tolerance (IGT; defined by the World Health Organization [WHO]), and gestational diabetes mellitus (GDM; determined by the Japan Society of Obstetrics & Gynecology standards) were compared through blood glucose (BG) curves and immunoreactive insulin (IRI) responses. Borderline (fasting BG greater than or equal to 6.1 and less than 7.8 mM and 2-h BG greater than or equal to 6.7 and less than 11.1 mM) is neither diabetes nor normal. IGT is as referred to by the WHO. GDM exceeds two points of fasting BG greater than or equal to 5.6 mM, 1-h BG greater than or equal to 10.0 mM, or 2-h BG greater than or equal to 8.3 mM. Diabetes mellitus (DM) is as referred to by the Japan Diabetes Society (same as the WHO). The prevalence of abnormal glucose tolerance among all 615 pregnant women was 54.6% in borderline, 24.5% in IGT, 7.3% in GDM, and 3.4% in DM. The 2-h BG levels in IGT during the first trimester were higher than in borderline (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Differential immunogenetic determinants of polyclonal insulin autoimmune syndrome (Hirata's disease) and monoclonal insulin autoimmune syndrome.

The insulin autoimmune syndrome (IAS), or Hirata's disease, is characterized by the combination of fasting hypoglycemia, high concentration of total serum immunoreactive insulin, and presence of autoantibodies to native human insulin in serum. Autoantibody production is classified as monoclonal or polyclonal, with the majority of IAS cases classified as polyclonal. Previously, we observed a striking association between the human leukocyte antigen (HLA) class II alleles DRB1*0406/DQA1* 0301/DQB1*0302 and Japanese IAS patients with polyclonal insulin autoantibodies (IAAs) and T-cell recognition of human insulin in the context of DRB1*0406 molecules. Because of such a strong HLA association in IAS, we performed intra- and interethnic studies on IAS-associated DRB1 alleles and searched for the critical amino acid residue(s) for IAS pathogenesis. Glutamate at position 74 in the HLA-DR4 beta 1-chain was presumed to be essential to the production of polyclonal IAA in IAS, whereas alanine at the same position of the HLA-DR beta 1-chain might be important in the production of monoclonal IAA.

Existence of early-onset NIDDM Japanese demonstrating severe diabetic complications.

OBJECTIVE: To identify the clinical characteristics of early-onset NIDDM patients with severe diabetic complications. RESEARCH DESIGN AND METHODS: The clinical cases of a large number of diabetic patients who visited a diabetes center within the period 1970-1990 were reviewed. Of a total of 16,842 diabetic patients, 1,065 (6.3%) had early-onset NIDDM (diabetes diagnosed before 30 years of age). These 1,065 patients were divided into two groups, those who developed proliferative retinopathy before the age of 35 (n = 135) and those who did not (n = 930). Development of proliferative retinopathy, nephropathy, renal failure, blindness, and atherosclerotic vascular disease were compared between the two groups. RESULTS: The subgroup of 135 patients was characterized by poor glycemic control, often requiring insulin therapy and a higher familial prevalence of diabetes, and contained a greater proportion of women than the subgroup of 930 patients. Of the 135 patients, 99 (67%) developed proliferative retinopathy before the first visit. The 135 patients developed severe progressive complications in contrast to the 930 patients. A total of 81 patients (60%) developed diabetic nephropathy at a mean age of 31 years, 31 (23%) developed renal failure requiring dialysis at a mean age of 35 years, 32 (24%) became blind at a mean age of 32 years, and 14 (10%) developed atherosclerotic vascular disease at a mean age of 36 years. CONCLUSIONS: Some Japanese early-onset NIDDM patients develop severe diabetic complications in their youth. Most of them had no symptoms nor regular treatment regarding diabetes until they were noticed to have developed severe diabetic complications. Although the relevant prevalence and the pathogenetic mechanism underlying the rapid onset of the complications remain to be determined, prolonged inadequate treatment of and familial predisposition to diabetes may be contributing factors. Careful diabetes care in the twenties, not only for IDDM but also for NIDDM patients, is warranted.

High incidence of diabetic nephropathy in early-onset Japanese NIDDM patients. Risk analysis.

OBJECTIVE: Because early-onset Japanese NIDDM patients (diagnosed before age 30 years) can develop diabetic end-stage renal failure (ESRF) in their thirties, this study was performed to elucidate the incidence and determinants for the development of diabetic nephropathy. RESEARCH DESIGN AND METHODS: The incidence of diabetic nephropathy and its relationship to baseline characteristics and long-term metabolic control were determined in 426 early-onset Japanese NIDDM patients who were followed for a mean of 6.8 years. RESULTS: Of these 426 patients, 41 developed diabetic nephropathy manifested by persistent proteinuria (incidence rate [95%CI]/1,000 person-years; 14.1 [10.4-19.1]). Among patients whose mean HbA1c (measured by a high-performance chromatography method that is standardized and comparable to the one used in the Diabetes Control and Complications Trial study) was around 7% or less, few developed nephropathy. The incidence of nephropathy increased with increasing mean HbA1c level in a dose-dependent manner (chi 2 trend = 49.9, P < 0.0001). Diastolic blood pressure and duration of diabetes at entry had significant predictive effects independent of metabolic control. CONCLUSIONS: The incidence rate of diabetic nephropathy in early-onset Japanese NIDDM patients is potentially high, similar to or higher than that in Pima Indian NIDDM or Caucasian IDDM patients of comparable age. Diabetic nephropathy in NIDDM patients aged in their thirties or forties is likely to be an early feature that leads to ESRF, and this would contribute to the marked increase in the number of new patients with diabetic ESRF in Japan. NIDDM is a serious disease if near-normal glycemia is not achieved.

A syndrome of periodic adrenocorticotropin and vasopressin discharge.

An 8-yr-old girl is presented who had periodic attacks of vomiting, psychotic depression, drowsiness, and hypertension (160/110 mm Hg) for a period of 16 months after head injury. At the initiation of the attack, serum ACTH and vasopressin levels were prominently increased (610 pg/ml and 41 microunits/ml, respectively), followed by hypercortisolemia, hyponatremia, and hypoosmolality in plasma. Serum PRL also was elevated (91 ng/ml). Responses of GH and cortisol to insulin-induced hypoglycemia and those of TSH to TRH were reduced. Urinary excretion of epinephrine and norepinephrine were increased, while dopamine (DA) excretion was reciprocally decreased, resulting in a marked elevation of the epinephrine plus norepinephrine to DA ratio during the episodes (0.4-4.5); this was normalized on attack-free days (0.08-0.25). During the attack, the concentration of homovanillic acid, a major metabolite of DA in the brain, also was reduced in cerebrospinal fluids from 70 to 23 ng/ml. The administration of methyl-dopa and reserpine effectively suppressed the recurrence of the episode. Although the exact cause of this syndrome is unknown, a periodic metabolic dysfunction of catecholamine in the central nervous system might be postulated.

Patients with Graves' disease who developed insulin autoimmune syndrome (Hirata disease) possess HLA-Bw62/Cw4/DR4 carrying DRB1*0406.

The insulin autoimmune syndrome (IAS) is characterized by the following diagnostic criteria: severe spontaneous hypoglycemia without evidence of exogenous insulin administration, high levels of total serum immunoreactive insulin, and the presence of a high titer of antiinsulin antibody. Just before the onset of IAS, 13 of the 35 (37%) patients with IAS examined in this study had taken methimazole for the treatment of Graves' disease. To investigate the difference between the Graves' disease patients treated with methimazole who developed IAS and other IAS patients, HLA class II genes in both groups were analyzed by serological and DNA typing methods. All 13 patients with Graves' disease who developed IAS possessed a specific allelic combination, Bw62/Cw4/DR4 carrying DRB1*0406, whereas only 1 of 50 Graves' disease patients without IAS had Bw62/Cw4/DR4 (odds ratio, 891; P < 1 x 10(-10)) and carried not DRB1*0406 (odds ratio, 2727; P < 1 x 10(-10)), but DRB1*0405. Of the 22 IAS patients without Graves' disease, 13 had the combination Bw62/Cw4/DR4 carrying DRB1*0406 (odds ratio, 19.0; P < 0.07). Thus, it is highly likely that patients with Graves' disease develop IAS via treatment with methimazole when their Bw62/Cw4/DR4 carry DRB1*0406.

Worldwide differences in the incidence of insulin autoimmune syndrome (Hirata disease) with respect to the evolution of HLA-DR4 alleles.

The relationship between the geographic distribution of susceptibility genes to insulin autoimmune syndrome (IAS) and the incidence of insulin autoimmune syndrome was investigated in order to examine the distribution of the genetic background to susceptibility to certain diseases. The HLA-DR4 allele, DRB1*0406, is associated with increased susceptibility to IAS among Japanese, while the DRB1*0403 and DRB1*0407 alleles are not (the odds ratio of which are 1.6 and 1.1, respectively). The worldwide geographic distribution of the three DR*04 alleles showed that the distribution of DRB1*0403 encompassed that of DRB1*0406 and DRB1*0407. Taken together with the findings that Glu at position 74 in the DRB1 molecule is shared by the three DRB1*04 alleles, there are only a few differences between the DRB1 molecule-nucleotide sequences of DRB1*0403, DRB1*0406 and DRB1*0407, and that all the three DRB1*04 alleles are carried by the same class II haplotype, DQA1*0301/DQB1*0302, it may be considered that DRB1*0403 is the ancestral allele of DRB1*0406 and DRB1*0407. Therefore, populations with a higher prevalence of DRB1*0406 have a higher risk of developing IAS. The extremely low prevalence of IAS among Caucasians can be explained by the low prevalence of DRB1*0406 in this population. This is a good example of the association between the predisposition to risk of development of certain diseases and the evolution of susceptibility genes.

An investigation of Japanese subjects maps susceptibility to type 1 (insulin-dependent) diabetes mellitus close to the DQA1 gene.

Insulin-dependent diabetic and control subjects of Japanese origin were HLA-DRB1, -DQB1, and -DQA1 typed using restriction fragment length polymorphism analysis and sequence-specific oligonucleotide gene probing. The DQA1 allele DQA1*0301 was positively associated with the disease [48/52 (92%) diabetic patients versus 44/64 (69%) control subjects, Pc less than 0.03, RR = 4.97]. Alleles of the DRB1 and DQB1 genes showed no significant association with the disease. The frequency of DQB1 genotypes encoding the amino acid aspartic acid at position 57 of the DQ beta chain did not differ significantly between subjects with insulin-dependent diabetes mellitus (IDDM) and controls. These findings suggest that a susceptibility allele for IDDM in the Japanese is more closely associated with the DQA1 gene than the DQB1 gene.

Hypoglycaemia due to insulin autoimmune syndrome: report of two cases with characterisation of HLA alleles and insulin autoantibodies.

OBJECTIVE: Insulin autoimmune syndrome (IAS) has been reported mainly in Japan and so far only 27 IAS cases have been described from outside Asia. We describe two unrelated Portuguese patients with IAS and characterise their insulin autoantibodies and HLA alleles. PATIENTS: Patient 1, a 24-year-old white female suffered an episode of unconsciousness in the late postprandial state and blood glucose was found to be 33 mg/dl with serum insulin levels of >3980 microIU/ml (normal range 0-30 microIU/ml). She was receiving monthly injections of penicillin G for the prophylaxis of recurrent tonsillitis. Patient 2, was a 19-year-old white female, with episodes of sweating, hand tremor, weakness and hunger occurring in the postprandial state and blood glucose levels during the attacks of 28-56 mg/dl. Very high insulin levels (602-708 microIU/ml) were present. METHODS AND RESULTS: Anti-insulin antibodies, determined by a semi-quantitative method, were strongly positive in both patients (91.7% in patient 1 and 88.6% in patient 2; normal range < or =7%). Sephadex G-100 chromatography of the sera showed most of insulin immunoreactivity present in the void volume which was retained by an affinity column with anti-human-immunoglobulin G antibodies (87% and 95% from patients 1 and 2 respectively). Scatchard plot analysis and molecular typing of the DRB1 gene revealed a polyclonal antibody and DRB1*0406 in patient 1, and a monoclonal antibody and DRB1*0403 in patient 2. CONCLUSIONS: These two Portuguese patients with IAS had different HLA-DR4 subtypes and insulin autoantibodies: DRB1*0406 and a polyclonal antibody in a patient treated with penicillin, and DRB1*0403 and a monoclonal antibody in a patient with "idiopathic" IAS.

The immunoglobulin class, the subclass and the ratio of kappa:lambda light chain of autoantibodies to human insulin in insulin autoimmune syndrome.

The immunoglobulin class, subclass and the k:lambda light chain ratio of insulin autoantibodies were determined in the sera of twenty-four patients with insulin autoimmune syndrome. All sera proved to be of the IgG immunoglobulin class but exhibited various IgG1:IgG2:IgG3:IgG4 ratios. The ratio of k:lambda light chain ranged from 1:0.13 to 1:0.75 with the exceptions of two sera that were characterized as IgG1(k) and IgG1(lambda).

Longitudinal changes of serum insulin concentration and insulin antibody features in persistent insulin autoimmune syndrome (Hirata's disease).

In a 56-year-old woman with granulomas of gold thioglucose in her hips, who developed insulin autoimmune syndrome, the relationships among the frequency or severity of hypoglycemic attacks, serum insulin (IRI) concentration, and characteristics of insulin antibodies were investigated during the clinical course with steroid treatment and two resection operations for the gold-thioglucose granulomas. When hypoglycemia was severe, the total IRI level was elevated, and Scatchard analysis showed that a high-affinity (k1), low-capacity (b1) population of antibodies had a relatively low affinity constant and very high binding capacity compared with the same population of antibodies in insulin-treated diabetic patients. When the attacks were relieved by steroid treatment and/or granuloma resection operation, the total IRI level was decreased and the high-affinity (k1), low-capacity (b1) population of antibodies showed a higher affinity constant and a lower binding capacity than those during the attacks. This indicated that the antibodies changed their characteristics to release insulin into the serum. The k1/b1 population of insulin antibodies with the lower affinity constant and higher binding capacity may easily release human insulin into the serum, leading to hypoglycemia. The longitudinal change of the k1/b1 population suggests a clonal change of the B cells producing the insulin antibody in insulin autoimmune syndrome.

Insulin autoimmune syndrome in Japan.

Since 1970, 197 patients with insulin autoimmune syndrome (IAS) showing severe spontaneous hypoglycemia have been reported in Japan. This is characterized by a high titer of anti-insulin autoantibodies without evidence of exogenous insulin administration. IAS is the third leading cause of spontaneous hypoglycemia in Japan, while only 21 cases have been reported in Europe and the United States. High levels of the extractable native human insulin and of the characteristic insulin autoantibodies in the sera of the IAS patients have been proved. Recently a significant association of HLA-DRB1*0406/DQA1*0301/DQB1*0302 with this syndrome has been found in the IAS patients in Japan.