Insulin-dependent State Research Articles

Practice guideline: Statement regarding treatment for suspected slowly progressive type 1 diabetes (SPIDDM; probable) cases (English version).

Insulin treatment should be introduced in patients with slowly progressive type 1 diabetes (SPIDDM; definite), according to the revised diagnostic criteria of SPIDDM (2023). In contrast, SPIDDM (probable) patients are in a non-insulin-dependent state; therefore, a more flexible treatment can be considered, although sulfonylurea agents should be avoided. Insulin treatment has been shown to maintain endogenous insulin secretion capacity in SPIDDM (probable); however, this does not mean that all SPIDDM (probable) patients should use insulin from the early phase. Dipeptidyl peptidase-4 inhibitors and biguanides might be the treatment of choice for SPIDDM (probable), but no evidence exists for other hypoglycemic agents. In any case, careful monitoring of the endogenous insulin secretion capacity should be carried out, and if a decrease in insulin secretion capacity is suspected, a change in treatment should be considered to prevent progression to an insulin-dependent state.

Prediction of future insulin-deficiency in glutamic acid decarboxylase autoantibody enzyme-linked immunosorbent assay-positive patients with slowly-progressive type 1 diabetes.

This study aimed to identify risk factors that contribute to the progression of slowly-progressive type 1 diabetes by evaluating the positive predictive value (PPV) of factors associated with the progression to an insulin-dependent state. We selected 60 slowly-progressive type 1 diabetes patients who tested positive for glutamic acid decarboxylase autoantibodies (GADA) at diagnosis from the Japanese Type 1 Diabetes Database Study. GADA levels in these patients were concurrently measured using both radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) techniques. Compared with the non-progressor group (fasting C-peptide [F-CPR] levels maintained ≥0.6 ng/mL), the progressor group showed a younger age at diagnosis, lower body mass index (BMI), lower F-CPR levels and a higher prevalence of insulinoma-associated antigen-2 autoantibodies (IA-2A). The PPV of RIA-GADA increased from 56.3 to 70.0% in the high titer group (≥10 U/mL), and further increased to 76.9, 84.2, 81.0 and 75.0% when combined with specific thresholds for age at diagnosis <47 years, BMI <22.6 kg/m2, F-CPR <1.41 ng/mL and IA-2A positivity, respectively. In contrast, the PPV of ELISA-GADA (71.8%) remained the same at 73.1% in the high titer group (≥180 U/mL), but increased to 81.8, 82.4 and 79.0% when evaluated in conjunction with age at diagnosis, BMI and F-CPR level, respectively. Our findings show that, unlike RIA-GADA, ELISA-GADA shows no association between GADA titers and the risk of progression to an insulin-dependent state. The PPV improves when age at diagnosis, BMI and F-CPR levels are considered in combination.

L’eterogeneità del diabete autoimmune

Autoimmune diabetes is a heterogeneous disease, encompassing both type 1 diabetes, characterized by fast progression towards an insulin-dependent state, and latent autoimmune diabetes in adults (LADA), considered a less severe form of autoimmune diabetes with a mild metabolic decompensation. An extensive genetic, phenotypic, and humoral heterogeneity is recognized even within the group of people with LADA. In this review, we discuss the pathological and clinical heterogeneity of autoimmune diabetes, highlighting the current understanding and gaps in knowledge.

Insulin-dependent diabetes mellitus in older adults: Current status and future prospects.

The recent increase in life expectancy has resulted in an increase in the number of older adults with diabetes mellitus. In addition to type 2 diabetes, in which aging is a well‐known risk factor, individuals with type 1 and other types of diabetes are also increasing owing to longevity in the general population and improved prognosis of the disease and comorbidities. Insulin‐dependent state in type 1 diabetes and other types of diabetes, such as diabetes after pancreatectomy, inevitably requires insulin treatment for survival; however, daily injection of insulin is often hampered in older adults due to impaired cognitive function or limited activities of daily living. In this review, we aimed to discuss the current situation of insulin‐dependent diabetes mellitus in older adults and highlight future prospects. Geriatr Gerontol Int 2022; 22: 549–553.

Adult-onset autoimmune diabetes identified by glutamic acid decarboxylase autoantibodies: a retrospective cohort study.

Patients with GAD antibodies (GADAb) showing clinical features of type 2 diabetes typically exhibit progression to an insulin-dependent state in several months or years. This condition is diagnosed as slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults, a subtype of adult-onset autoimmune diabetes. However, some patients diagnosed with adult-onset autoimmune diabetes do not progress to an insulin-dependent state. We conducted a retrospective cohort study to identify patients with non-insulin-dependent diabetes among those diagnosed with adult-onset autoimmune diabetes using measurable indicators in routine clinical practice. We surveyed data from the electronic medical records of all patients with GADAb from eight medical centres in Japan for selecting and analysing patients who matched the diagnostic criteria of SPIDDM. Overall, 345 patients were analysed; of these, 162 initiated insulin therapy (insulin therapy group), whereas 183 did not (non-insulin therapy group) during the follow-up period (median 3.0years). Patients in the non-insulin therapy group were more likely to be male and presented a later diabetes onset, shorter duration of diabetes, higher BMI, higher blood pressure levels, lower HbA1c levels, lower GADAb levels and lesser antidiabetic agent use than those in the insulin therapy group when GADAb was first identified as positive. A Cox proportional hazards model showed that BMI, HbA1c levels and GADAb levels were independent factors for progression to insulin therapy. Kaplan-Meier analyses revealed that 86.0% of the patients with diabetes having GADAb who presented all three factors (BMI ≥ 22kg/m2, HbA1c < 75mmol/mol [9.0%] and GADAb <10.0U/ml) did not require insulin therapy for 4years. Higher BMI (≥22kg/m2), lower HbA1c (<75mmol/mol [9.0%]) and lower GADAb levels (<10.0U/ml) can predict a non-insulin-dependent state for at least several years in Japanese patients with diabetes having GADAb.

Prediction and Prevention of Type 1 Diabetes.

Type 1 Diabetes (T1D) is one of the most common chronic autoimmune diseases in children. The disease is characterized by the destruction of beta cells, leading to hyperglycemia, and to a lifelong insulin-dependent state. Although several studies in the last decades have added relevant insights, the complex pathogenesis of the disease is not yet completely understood. Recent studies have been focused on several factors, including family history and genetic predisposition (HLA and non-HLA genes) as well as environmental and metabolic biomarkers, with the aim of predicting the development and progression of T1D. Once a child becomes symptomatic, beta cell mass has already reached a critical threshold (usually a residual of 20–30% of normal amounts), thus representing only the very late phase of the disease. In particular, this final stage follows two preceding asymptomatic stages, which have been precisely identified. In view of the long natural history and complex pathogenesis of the disease, many strategies may be proposed for primary, secondary, and tertiary prevention. Strategies of primary prevention aim to prevent the onset of autoimmunity against beta cells in asymptomatic individuals at high risk for T1D. In addition, the availability of novel humoral and metabolic biomarkers that are able to characterize subjects at high risk of progression, have stimulated several studies on secondary and tertiary prevention, aimed to preserve residual beta cell destruction and/or to prolong the remission phase after the onset of T1D. This review focuses on the major current knowledge on prediction and prevention of T1D in children.

Slowly progressive insulin-dependent (type 1) diabetes positive for anti-GAD antibody ELISA test may be strongly associated with a future insulin-dependent state.

Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM), believed to be caused by β-cell destruction through islet-cell autoimmunity, gradually progresses to an insulin-dependent state over time. Although the presence of anti-glutamic acid decarboxylase antibody (GADA) is required for the diagnosis of SPIDDM, a recent change in the GADA assay kit from radioimmunoassay (RIA) to enzyme-linked immunosorbent assay (ELISA) yields mismatched GADA test results between the two kits, leading to confusion in understanding the pathological conditions of SPIDDM in Japan. Thus, this study aimed to clarify the difference in the clinical characteristics of GADA-ELISA-positive and GADA-ELISA-negative patients originally diagnosed as SPIDDM by GADA-RIA test. As a result, 42 of 63 original GADA-RIA-positive SPIDDM patients (66.7%) were found to be GADA-ELISA-positive, whereas the remaining 21 patients (33.3%) were found to be GADA-ELISA-negative. In patients with shorter disease duration, GADA-ELISA-positive patients showed significantly lower serum C-peptide levels than GADA-ELISA-negative patients. Meanwhile, in patients with longer disease duration, serum C-peptide levels were comparably decreased in GADA-ELISA-positive and GADA-ELISA-negative patients. A significant inverse correlation between serum C-peptide level and disease duration was observed in GADA-ELISA-negative patients, but not in GADA-ELISA-positive patients, suggesting that insulin secretory capacity may be gradually impaired over time also in GADA-ELISA-negative SPIDDM patients. In conclusion, physicians should be aware that GADA-ELISA-positive SPIDDM may be strongly associated with a future insulin-dependent state. Meanwhile, physicians should be careful in treating GADA-ELISA-negative SPIDDM patients diagnosed as type 2 DM, and cautiously follow the clinical course, in accordance with SPIDDM.

What's in a Name? Classification of Diabetes Mellitus in Veterinary Medicine and Why It Matters.

Diabetes Mellitus (DM) is a syndrome caused by various etiologies. The clinical manifestations of DM are not indicative of the cause of the disease, but might be indicative of the stage and severity of the disease process. Accurately diagnosing and classifying diabetic dogs and cats by the underlying disease process is essential for current and future studies on early detection, prevention, and treatment of underlying disease. Here, we review the current etiology‐based classification of DM and definitions of DM types in human medicine and discuss key points on the pathogenesis of each DM type and prediabetes. We then review current evidence for application of this etiology‐based classification scheme in dogs and cats. In dogs, we emphasize the lack of consistent evidence for autoimmune DM (Type 1) and the possible importance of other DM types such as DM associated with exocrine pancreatic disease. While most dogs are first examined because of DM in an insulin‐dependent state, early and accurate diagnosis of the underlying disease process could change the long‐term outcome and allow some degree of insulin independence. In cats, we review the appropriateness of using the umbrella term of Type 2 DM and differentiating it from DM secondary to other endocrine disease like hypersomatotropism. This differentiation could have crucial implications on treatment and prognosis. We also discuss the challenges in defining and diagnosing prediabetes in cats.

Postprandial C-Peptide to Glucose Ratio as a Marker of β Cell Function: Implication for the Management of Type 2 Diabetes.

C-peptide is secreted from pancreatic β cells at an equimolar ratio to insulin. Since, in contrast to insulin, C-peptide is not extracted by the liver and other organs, C-peptide reflects endogenous insulin secretion more accurately than insulin. C-peptide is therefore used as a marker of β cell function. C-peptide has been mainly used to assess the presence of an insulin-dependent state for the diagnosis of type 1 diabetes. However, recent studies have revealed that β cell dysfunction is also a core deficit of type 2 diabetes, and residual β cell function is a key factor in achieving optimal glycemic control in patients with type 2 diabetes. This review summarizes the role of C-peptide, especially the postprandial C-peptide to glucose ratio which likely better reflects maximum β cell secretory capacity compared with the fasting ratio in assessing β cell function, and discusses perspectives on its clinical utility for managing glycemic control in patients with type 2 diabetes.

Predictive value of titer of GAD antibodies for further progression of beta cell dysfunction in slowly progressive insulin-dependent (type 1) diabetes (SPIDDM).

Whether the titer of glutamic acid decarboxylase antibodies (GADAs), especially a low titer, is a marker of progression of beta cell dysfunction in patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) is unclear. Patients were subdivided as follows: patients with high GADA titers [≥10U/ml (≥180 WHOU/ml): high GADA] (group 1, n=37); those with low GADA titers [<10 U/ml (<180 WHO U/ml): low GADA] (group 2, n=33); those without GADA and with islet cell antibodies (ICA) (group 3, n=8); those without both GADA and ICA and with insulinoma-associated antigen 2 antibodies (IA-2A) (group 4, n=6). We also allocated 198 type 2 diabetic patients without any GADA, ICA or IA-2A as group 5. Serum C-peptide responses to annual oral glucose tolerance tests (OGTTs) were followed up for a mean of 107months from entry. The proportion of patients progressing to an insulin-dependent state in groups 1, 2, 3 and 4 was significantly higher than in group 5. C-peptide responses in OGTTs of patients in groups 1 and 2 were decreased at a significantly higher rate than in group 5. Multivariate Cox proportional hazard analysis revealed that factors including high GADA, low GADA, onset age <45years, duration of diabetes <24months, body mass index (BMI) <22.0kg/m2, low degree of preserved beta cell function and ICA were independent risk factors for progression to an insulin-dependent state. SPIDDM patients with low GADA titers have a significantly higher risk of progression to an insulin-dependent state than type 2 diabetic patients, suggesting that the presence of GADA, irrespective of the titer, is a hallmark of beta cell failure. Other risk factors for further progression to an insulin-dependent state in SPIDDM patients were ICA, onset age, duration of diabetes, BMI and residual beta cell function.

Erratum to: Diagnostic criteria for slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) (2012): report by the Committee on Slowly Progressive Insulin-Dependent (Type 1) Diabetes Mellitus of the Japan Diabetes Society

Diagnostic criteria for slowly progressive insulin-dependent (Type 1) diabetes mellitus (SPIDDM) have been proposed by the Committee on Slowly Progressive Insulin-dependent (type 1) Diabetes Mellitus of the Japan Diabetes Society. Two criteria must be met for definitive diagnosis: the presence of glutamic acid decarboxylase antibodies (GADAb) and/or islet cell antibodies (ICA) at some time during the clinical course of the diabetes, and the absence of ketosis or ketoacidosis at the onset (or diagnosis) of diabetes mellitus and no need for insulin treatment to correct hyperglycemia immediately after diagnosis. It is still unclear whether insulinoma-associated antigen-2 autoantibodies (IA-2Ab), insulin autoantibodies (IAA), or zinc transporter 8 autoantibodies (ZnT8Ab) are essential markers for diagnosis for SPIDDM. Hence, the presence of IA-2Ab, IAA, and ZnT8Ab were excluded from these diagnostic criteria for SPIDDM. Furthermore, ketosis or ketoacidosis can be observed in cases in which SPIDDM is complicated by soft-drink ketosis. Supplementary information for diagnosis include: most SPIDDM patients will need insulin treatment more than 3 months after onset (or diagnosis) of diabetes mellitus and frequently progress to an insulin-dependent state; sometimes, for clinical reasons, early insulin treatment is started when GADAb or ICA are positive both for child and adult-onset cases; GADAb and/or ICA often become negative during the course of the disease; and a small proportion of patients might maintain endogenous beta-cell function more than 10 years after the onset (or diagnosis) of diabetes mellitus, irrespective of the titer of GADAb and ICA.

Glycemic control indicators in patients with neonatal diabetes mellitus.

Neonatal diabetes mellitus (NDM) is a type of diabetes mellitus caused by genetic abnormality which develops in insulin dependent state within 6 mo after birth. HbA1c is widely used in clinical practice for diabetes mellitus as the gold standard glycemic control indicator; however, fetal hemoglobin (HbF) is the main hemoglobin in neonates and so HbA1c cannot be used as a glycemic control indicator in NDM. Glycated albumin (GA), another glycemic control indicator, is not affected by HbF. We reported that GA can be used as a glycemic control indicator in NDM. However, it was later found that because of increased metabolism of albumin, GA shows an apparently lower level in relation to plasma glucose in NDM; measures to solve this problem were needed. In this review, we outlined the most recent findings concerning glycemic control indicators in neonates or NDM.

Slowly Progressive Type 1 Diabetes Treated with Metformin for Five Years after Onset

A 52-year-old man was diagnosed with slowly progressive type 1 diabetes (SPIDDM). We expected him to quickly progress to an insulin-dependent state due to a high anti-glutamic acid decarboxylase antibody titer (23.9 U/mL). At SPIDDM diagnosis, he was in a non-insulin-dependent state, with a fasting serum C-peptide immunoreactivity level of 2.5 ng/mL. Therefore, we prescribed metformin. His glycemic control remained stable, and his intrinsic insulin secretion capacity was maintained for five years. Although one case is insufficient to draw firm conclusions, this report suggests that metformin is a therapeutic choice for SPIDDM when the insulin secretion capacity is maintained.

Pioglitazone may accelerate disease course of slowly progressive type 1 diabetes

It has been reported that intervention with insulin in slowly progressive type 1 diabetic (SPIDDM) patients delays the progression to an insulin-dependent state compared to that with sulfonylureas. However, the rate of progression to SPIDDM with the use of insulin-sensitizing agents is unknown. The aim of this study was to determine the effect of insulin-sensitizing agents on SPIDDM patients. The enrolled SPIDDM patients were randomly allocated to a pioglitazone or metformin group. When the haemoglobin A1C level was more than 8% on two consecutive occasions, the case was considered to reach the end point. By 4 years post-intervention, all patients had reached the end point in the pioglitazone group, whereas only 20% of patients had reached the end point in the metformin group (p<0.05). Pioglitazone may accelerate the disease course of SPIDDM.

Fulminant type 1 diabetes mellitus associated with a reactivation of Epstein-Barr virus that developed in the course of chemotherapy of multiple myeloma.

A 70-year-old woman who was diagnosed with multiple myeloma underwent chemotherapy. Three months after beginning chemotherapy, she was readmitted to the hospital because of fever and hepatopathy. Her elevated Epstein-Barr virus (EBV) antibody levels showed that the hepatopathy was caused by reactivation of EBV. On the 18th hospital day, the levels of fasting plasma glucose (FPG; 451 mg/dL) and pancreatic enzymes were suddenly elevated. Elevation of HbA1c level (6.4%) was slight, as compared with that of the FPG level. Arterial blood gas analysis showed metabolic acidosis and diabetic ketoacidosis was suspected. The serum C-peptide level was below the detectable limit both before and after glucagon load, thereby suggesting an insulin-dependent state. These features were identical to the features for fulminant type 1 diabetes mellitus. The levels of EBV anti-viral capsid antigen immunoglobulin M decreased, and the clinical course was identical to that associated with reactivation of EBV infection. (J Diabetes Invest, doi: 10.1111/j.2040.1124.2010.00061.x, 2010).

Pancreas transplantation alone in children: a case report

Pancreas transplantation (PT) is a relatively uncommon therapy for non-uremic type 1 diabetes, as the severity of diabetes must warrant the risk of immunosuppression. In pediatric diabetic patients, who are less likely to display uremia because of the duration of diabetes, there is very little experience with pancreas transplantation alone (PTA). This report describes a 13-yr-old male PTA recipient. This patient was initially diagnosed with type 1 diabetes mellitus at the age of four yr. Following a multidisciplinary evaluation, PTA was found to be indicated based on a history of severe labile diabetes and hypoglycemic unawareness resulting in frequent episodes of hypoglycemia and hospital admissions. Because of the failure of medical management of the patient's diabetes, a whole organ bladder and systemic drained PTA was performed. Immunosuppression included thymoglobulin, tacrolimus, mycophenolate mofetil, and steroids. Early outcome was uneventful and patient was discharged 12 d after surgery normoglycemic and insulin-free. An episode of acute rejection (Maryland grade II) 20-d post-transplant was successfully treated with corticosteroids. A second and more severe episode of rejection (Maryland grade IV) occurred 13 months post-transplant, requiring treatment with thymoglobulin and conversion from steroid to sirolimus. On tacrolimus, sirolimus, and mycophenolic acid, he remains euglycemic and insulin-free 38 months after PTA. His quality-of-life is judged to be superior to his insulin dependent state prior to transplantation. According to the medical literature, this is the youngest patient ever to undergo PTA.

Transient Anti-GAD Antibody Positivity and Acute Pancreatitis with Pancreas Tail Swelling in a Patient with Susceptible Haplotype for Type 1 Diabetes Mellitus

A 57-year-old man was admitted to our hospital complaining of poor appetite. He had been diagnosed with diabetes mellitus and was anti-GAD antibody (GAD-Ab) negative 1 year previously, at the age of 56 years old. Abdominal CT revealed pancreas tail swelling; elastase-I level was elevated and he was diagnosed with pancreatitis. The level of GAD-Ab was increased and HLA haplotype was DRB1*0901-DQB1*0303, which is seen frequently in type 1 diabetic Japanese patients. However, his endogenous insulin secretion ability was not deteriorated. After elastase-I level and pancreas swelling improved, GAD-Ab returned to a normal range. One year after the onset of pancreas swelling, he was still not in an insulin-dependent state. In this case, transient GAD-Ab positivity with susceptible haplotype for type 1 diabetes mellitus might have been induced by a GAD antigen discharged from the destroyed islet due to pancreatitis.

Insulin Intervention in Slowly Progressive Insulin-Dependent (Type 1) Diabetes Mellitus

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. 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). 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. Insulin intervention to preserve beta-cell function is effective and safe for patients with SPIDDM or latent autoimmune diabetes in adults.

Immunopathological and Genetic Features in Slowly Progressive Insulin‐Dependent Diabetes Mellitus and Latent Autoimmune Diabetes in Adults

In 1982 we proposed the presence of a subtype of type 1 diabetes [slowly progressive insulin-dependent diabetes mellitus (SPIDDM)], which was characterized by persistently positive islet cell antibody, late age of onset, noninsulin-dependent diabetes, and slowly progressive beta cell failure. Since then many studies demonstrated that this subtype of type 1 diabetes is prevalent in many ethnic groups and was later called the latent autoimmune diabetes in adults (LADA). Recent epidemiological studies reported that about 10% of patients with apparent type 2 diabetes have at least one autoantibodies against islet-specific antigen with high potential to progress to insulin-dependent state. Between SPIDDM and LADA some differences are reported in terms of some genetic predispositions including HLA class II and class I genes, vitamin D receptor gene, and CTLA4 genes. Common features in SPIDDM and LADA including preserved beta cells at the onset of diabetes and weak T cell response to residual beta cells suggest that these subtypes of type 1 diabetes are suitable candidates for prevention treatment for further progression of beta cell failure.

A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese.

Pax4 is one of the transcription factors that play an important role in the differentiation of islet beta-cells. We scanned the Pax4 gene in 200 unrelated Japanese type 2 diabetic patients and found a missense mutation (R121W) in 6 heterozygous patients and 1 homozygous patient (mutant allele frequency 2.0%). The mutation was not found in 161 nondiabetic subjects. The R121W mutation was located in the paired domain and was thought to affect its transcription activity through lack of DNA binding. Six of seven patients had family history of diabetes or impaired glucose tolerance, and four of seven had transient insulin therapy at the onset. One of them, a homozygous carrier, had relatively early onset diabetes and slowly fell into an insulin-dependent state without an autoimmune-mediated process. This is the first report of a Pax4 gene mutation that exhibits loss of function and seems to be associated with type 2 diabetes. This work provides significant implications for the Pax4 gene as one of the predisposing genes for type 2 diabetes in the Japanese.