Osamu Funae

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

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.

Effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy in patients with type 2 diabetes, in relation to suppression of Nɛ-carboxymethyl lysine

OBJECTIVE We investigated the efficacy of epalrestat, an aldose reductase inhibitor, for diabetic peripheral neuropathy in Japanese patients with type 2 diabetes. METHODS A total of 38 type 2 diabetic patients (22 men and 16 women; mean ± S.E.M. age 63.3 ± 1.0 years; duration of diabetes 9.6 ± 0.8 years) with diabetic neuropathy were newly administered 150 mg/day epalrestat (EP group). Motor nerve conduction velocity (MCV), sensory nerve conduction velocity (SCV), and minimum F-wave latency were evaluated before administration of epalrestat and after 1 and 2 years. Serum N(ɛ)-carboxymethyl lysine (CML) as a parameter of advanced glycation end products (AGEs), lipid peroxide, and soluble vascular cell adhesion molecule (sVCAM)-1 as a parameter of angiopathy were measured before administration and after 1 year. We compared the results with those of 36 duration of diabetes-matched type 2 diabetic patients (mean ± S.E.M. duration of diabetes 8.2 ± 0.7 years) as control (C group). RESULTS The EP group showed significant suppression of deterioration of MCV (P<.01) and minimum F-wave latency (P<.01) in the tibial nerve and SCV (P<.05) in the sural nerve compared to those in the C group after 2 years. There was a significant difference in change in CML level between groups (-0.18 ± 0.13 mU/ml in the EP group vs. +0.22 ± 0.09 mU/ml in the C group, P<.05) after 1 year. CONCLUSIONS Epalrestat suppressed the deterioration of diabetic peripheral neuropathy, especially in the lower extremity. Its effects might be mediated by improvement of the polyol pathway and suppression of production of AGEs.

The Presence of Limited Joint Mobility Is Significantly Associated with Multiple Digit Involvement by Stenosing Flexor Tenosynovitis in Diabetics

Objective. Diabetes is associated with several disorders of the hand, including stenosing flexor tenosynovitis (SFTS). The feature of SFTS in diabetics is a higher prevalence of multiple digit involvement. We examined the magnitude of the tendency for involvement of more digits by SFTS in diabetic patients than in nondiabetic patients, and attempted to clarify the factors influencing multiple digit involvement by SFTS in diabetics. Methods. The study comprised 302 diabetic patients with SFTS and 235 nondiabetic patients with SFTS. The total number of digits exhibiting SFTS within the 1-year period following the initial visit to the Department of Orthopaedic Surgery was investigated in a prospective manner. We compared the difference in the frequency of multiple digit involvement by SFTS between diabetic and nondiabetic patients using the chi-squared test. Multiple regression analysis was performed to examine the contribution of independent variables [defined as 12 factors including age, sex, type of diabetes, estimated duration of diabetes, HbA1c values, carpal tunnel syndrome, Dupuytren contracture, limited joint mobility (LJM), de Quervains disease, diabetic retinopathy, diabetic nephropathy, and dyslipidemia] to the total number of digits affected by SFTS in diabetic patients. Results. Diabetic patients showed a significantly higher prevalence of multiple digit involvement than nondiabetic patients (p < 0.0001). Multiple regression analysis in diabetic patients revealed that the presence of LJM was positively associated with the prevalence of multiple digit involvement (r = 0.626, p < 0.0001). Conclusion. LJM in diabetics is closely associated with SFTS involving multiple digits.

Balance of GAD65-specific IL-10 production and polyclonal Th1-type response in type 1 diabetes.

It has been proposed that cytokine responses of memory CD4+ cells change from a T-helper 2 (Th2)-to a T-helper 1 (Thl)-dominant response as the disease progresses in non-obese diabetic (NOD) mice. However, the regulation of Thl/Th2 balance in spontaneous diabetes development in this model is not well understood. In this study, higher glutamic acid decarboxylase 65 (GAD65)-specific IL-10 production was observed at 10-12 weeks in NOD mice, and a marked increase of Thl-type response (IFN-γ production) upon polyclonal (anti-CD3 antibody) stimulation was observed just before diabetes development along with a decline of GAD65-specific IL-10 production. Moreover, there was a clear negative correlation between IL-10 level upon GAD65 stimulation and log(IFN-γ) level upon anti-CD3 antibody stimulation (r==0.999, p<0.001). These results suggest that the balance between GAD65-specific IL-10 production and polyclonal Thl-type response may regulate the onset of hyperglycemia in type 1 diabetes in NOD mice

Insulin-like Growth Factor-1 (IGF-1)-derived Peptide Protects against Diabetes in NOD Mice

Spontaneous diabetes in non-obese diabetic (NOD) mice results from β-cell destruction by autoreactive T lymphocytes. Here, we report the significance of insulin-like growth factor-1 (IGF-1) peptide as a tool for the prevention of type 1 diabetes. Female NOD mice were immunized with a subcutaneous injection of IGF-1, glutamic acid decarboxylase (GAD), insulin or IGF-1-derived peptides (residues 8-23, 24-41 or 50-70) in incomplete Freunds adjuvant (IFA) or with IFA only as the control group at 4 weeks of age, and observed up to 36–37 weeks of age. Diabetes onset was significantly suppressed and delayed in the IGF-1 group as compared to the GAD, insulin and control groups (p<0.05), and it was significantly suppressed and delayed in the (50-70)IGF-1 group as compared to the (8-23)IGF-1 and control groups (p<0.02). Although the degree of insulitis in all treated mice was not significantly different, a significant number of IL-4-producing cells in response to IGF-1 peptides were detected in (50-70)IGF-1-treated mice in intracellular cytokine assay. In conclusion, IGF-1 peptide 50-70 immunizations of NOD mice suppressed and delayed diabetes onset, probably through amplification of the Th2-type response. It was suggested that IGF-1 peptide 50-70 immunization can be used as a tool for prevention of type 1 diabetes.

Secretion of GIP in responders to acarbose in obese Type 2(NIDDM) patients.

Acarbose has been shown to reduce postprandial hyperglycemia and to improve lipid parameters in diabetics via its inhibitory effects on intestinal alpha-glucosidases. Response to acarbose may therefore be dependent upon gastric or pancreatic hormone function. To test this hypothesis, we treated 27 mild type 2 (NIDDM) Japanese diabetics who were mildly obese with low-dose acarbose (150 mg/day) for 3 months. We then performed a responder analysis to determine specific hormonal responses that may be associated with a good response to acarbose. At the end of the treatment period, a total of 15 evaluable patients was grouped as responders (n=6) and nonresponders (n=9) based on an effective decrease in postprandial glucose levels (>30 mg/day) and glycosylated hemoglobin (HbA1c) levels (>0.5%). There were no differences between the two groups in demographic variables or mean postprandial glucose levels at baseline. There was a small but significant increase in postprandial cholecystokinin (CCK) in responders, and fasting gastric inhibitory peptide (GIP) levels were significantly increased in responders and all patients after treatment. Serum leptin levels were reduced by treatment in our mildly obese responders and this was associated with a significant decrease in body weight. These results suggest that treatment with low-dose acarbose may reduce hyperglycemia in mild type 2 Japanese patients and may improve metabolic control by regulating hormones involved in glycemic control and digestive absorption. Acarbose may provide a safe adjunct to help treat insulin resistance in type 2 patients.

Assessment of energy expenditure using doubly-labeled water, physical activity by accelerometer, and reported dietary intake in male Japanese patients with type 2 diabetes: a preliminary study

The aim of the present study was to determine the total energy expenditure, physical activity and dietary intake of men with type 2 diabetes mellitus and control participants without type 2 diabetes mellitus who were matched for age and body mass index. The participants in the present study were 12 well‐controlled type 2 diabetes mellitus patients and 10 controls, aged 40–75 years, with a body mass index <30 kg/m2. Total energy expenditure under free‐living conditions was assessed using the doubly labeled water method, and physical activity was measured using a triaxial accelerometer. Dietary intake was assessed using a self‐recorded food intake diary during the measurement period. Participants were instructed to record their dietary intake over 3 days, including 2 weekdays. Total energy expenditure was not significantly different between the groups (P = 0.153), nor were energy (P = 0.969) or macronutrient intakes. In conclusion, when age and body mass index are matched, total energy expenditure and self‐reported energy intake are not significantly different between type 2 diabetes mellitus patients and healthy controls.