Insulin-derived amyloidosis without a palpable mass at the insulin injection site: A report of two cases.

To date, almost all case reports of insulin-derived amyloidosis described the presence of a subcutaneous mass that was observable on physical examination. This report presents two cases of insulin-derived amyloidosis without palpable masses at insulin injection sites. In both cases, blood glucose concentrations improved, and the insulin dose could be reduced by an average of 45% after changing the insulin injection sites. The insulin absorption at the site was reduced to at most 40% of that at a normal site in one case. Magnetic resonance imaging and ultrasonography were useful to screen and differentiate insulin-derived amyloidosis without a palpable mass. This report showed that insulin-derived amyloidosis without a palpable mass can be present at the insulin injection site, and has similar clinical effects to insulin-derived amyloidosis with palpable masses.

Toxicity of insulin-derived amyloidosis: a case report.

BACKGROUND: Insulin-derived amyloidosis is a skin-related complication of insulin therapy that interferes with insulin therapy. Although toxicities of in vitro-formed insulin amyloid fibrils have been well studied, the toxicity of insulin-derived amyloidosis remains to be clarified. CASE PRESENTATION: A 58-year-old man with type 2 diabetes mellitus underwent a lower limb amputation due to diabetic gangrene. Several antibiotics including minocycline were administered for infection and sepsis. A hard mass at the insulin injection sites in the lower abdomen was discovered by chance four months later. Although no abnormal findings in the surface skin of the mass were observed, necrotic tissue was seen around the mass when a biopsy was performed. Histological and toxicity studies were performed for this patient and four other patients with abdominal masses at insulin injection sites. Histological and immunohistochemical studies showed that the masses had typical characteristics of amyloid deposits in all cases, whereas necrotic findings were seen adjacent to the amyloid deposit only in the case presented. Toxicity studies indicated that the amyloid tissue from the present case had significant cell toxicity compared to the control skin tissue or the amyloid tissues from the other four cases. CONCLUSIONS: This report showed that toxic insulin-derived amyloidosis can occur. In addition, this report suggested that toxic insulin-derived amyloidosis may cause necrosis in the surrounding tissue. Although the toxic amyloid deposit of insulin-derived amyloidosis was found in only one patient, no structural differences between toxic and non-toxic deposits were seen on histological and immunohistochemical studies.

Insulin-derived amyloidosis and poor glycemic control: a case series.

OBJECTIVES: Insulin-derived amyloidosis is a rare skin-related complication of insulin therapy. The purpose of this study was to show the effects of insulin-derived amyloidosis on blood glucose levels, insulin dose requirements, and insulin absorption. METHODS: Seven patients were found to have insulin-derived amyloidosis at the Tokyo Medical University Ibaraki Medical Center. The clinical characteristics and insulin therapy of the 7 patients were investigated. Insulin absorption was studied by comparing the serum insulin levels after insulin injections into insulin-derived amyloidosis sites versus injections into normal sites in 4 patients. RESULTS: When the insulin-derived amyloidosis was discovered, the mean hemoglobin A1c level was 9.3%, and the mean daily insulin dose was 57 units. After changing the injection sites to avoid the insulin-derived amyloidosis, the blood glucose concentrations improved, and the mean daily insulin dose could be reduced to 27 units (P = .035; 53% reduction). The insulin absorption at insulin-derived amyloidosis sites was 34% of that at normal sites (P = .030). CONCLUSIONS: Insulin-derived amyloidosis caused poor glycemic control and increased insulin dose requirements because of impairments in insulin absorption.

A trial to assess the amount of insulin antibodies in diabetic patients by surface plasmon resonance.

OBJECTIVE: To measure the amount and affinity of insulin antibodies, we performed a trial to establish a new method for quantitative and qualitative analysis of these antibodies by using surface plasmon resonance (BIAcore system). METHODS: Real-time detection of insulin antibody interaction and kinetic analysis were performed using the BIAcore system. PATIENTS OR MATERIALS: Eight diabetic patients with insulin antibodies and whose fasting total immunoreactive insulin levels were more than 100 microU/ml were selected. The patients with and without recurrent hypoglycemia were classified into hypoglycemic episode-positive or hypoglycemic episode-negative groups, respectively. Seven diabetic patients without insulin antibodies were selected as controls. RESULTS: In the 8 patients, the concentration of insulin antibodies ranged from 2.91 to 16.3 microg/ml and insulin antibodies were not detected in the control group. The apparent KD (dissociation constant) and kd (the dissociation rate constant) values of the patients were much larger than those seen for the anti-human insulin monoclonal antibody. The KD values were significantly higher in the hypoglycemic episode-positive group than in the hypoglycemic episode-negative group (p<0.05). No significant differences in the concentration, the ka (the association rate constant) and the kd values were noted between the groups. CONCLUSION: The data suggests that insulin antibodies of the patients have an apparently lower affinity status in sera as compared with that for the anti-human insulin monoclonal antibody, and dissociate easily from the immune-complex in the sera, especially in cases where there is recurrent hypoglycemia in the patients. Therefore insulin antibody characteristics are one of the causative factors in hypoglycemic episodes.

A study of urinary myo-inositol as a sensitive marker of glucose intolerance.

BACKGROUND: We assessed the possibility of using myo-inositol as a marker of glucose intolerance. METHODS: We measured urinary myo-inositol enzymatically before and 2 h after a 75-g oral glucose tolerance test in 564 volunteers, who were divided into four groups [normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus (DM)]. Furthermore, we classified NGT into NGT-A (2-h blood glucose <120 mg/dl and 2-h glucosuria <50 mg/dl) and NGT-B (remaining NGT subjects). We then compared deltamyo-inositol (myo-inositol/creatinine ratio: 2-h after glucose load--before load) of each group to investigate the relationship between glucose intolerance and deltamyo-inositol. RESULTS: The glucose tolerance of NGT-B appeared to have deteriorated compared with NGT-A as determined by blood glucose, insulin, and glucosuria. There was very little effect of gender or age on deltamyo-inositol in NGT-A. deltamyo-inositol was significantly higher than that in NGT-A (0.5+/-7.1 mg/g Cr) not only in IFG (8.7+/-19.5 mg/g Cr, P<0.0001), IGT (14.8+/-22.9 mg/g Cr, P<0.0001) and DM (79.5+/-37.1 mg/g Cr, P<0.0001), but in NGT-B (7.4+/-12.7 mg/g Cr, P<0.0001). With 2 mg/g Cr as a tentative cut-off for deltamyo-inositol to detect NGT-A, sensitivity and specificity were 68% and 72%, respectively. CONCLUSIONS: The deltamyo-inositol can be use of a non-invasive and sensitive marker for glucose intolerance.

Determination of urinary myo-inositol concentration by an improved enzymatic cycling method using myo-inositol dehydrogenase from Flavobacterium sp.

BACKGROUND: To determine myo-inositol more accurately, we improved the enzymatic cycling method. METHODS: We screened myo-inositol dehydrogenase (MIDH; EC.1.1.1.18) from Flavobacterium sp., which was highly specific to myo-inositol. We measured urinary myo-inositol/creatinine ratio 2 h after 75-g oral glucose tolerance test (2 h MI) of 71 volunteers, and investigated the relationship between diabetes and urinary myo-inositol concentration. RESULTS: The calibration curve was linear (r = 1.00) up to 2000 micromol/l, and the detection limit was 10 micromol/l. Within-run and between-run CVs were 0.5-1.1% and 0.4-1.3%, respectively. The 2 h MI of impaired fasting glycemia (IFG; 65.1 +/- 46.6 mg/g Cr, P < 0.005), impaired glucose tolerance (IGT; 85.0 +/- 73.7 mg/g Cr, P < 0.001) and diabetes (163.4 +/- 73.7 mg/g Cr, P < 0.0001) increased significantly compared with that of normal glucose tolerance (NGT; 24.0 +/- 14.4 mg/g Cr). From receiver operating characteristic analyses on 2 h MI, with 50 mg/g Cr as a tentative cutoff value to detect diabetes, the sensitivity and specificity were 100% and 77%, respectively. With 40 mg/g Cr as a tentative cutoff value to detect NGT, the sensitivity and specificity were 74% and 85%, respectively. CONCLUSIONS: The myo-inositol measurement method demonstrated high specificity and yielded accurate results. The results of clinical trials suggested that 2 h MI could not only determine diabetes but also distinguish IFG and IGT from NGT.

Assessment of diabetic autonomic neuropathy using twenty-four-hour spectral analysis of heart rate variability: a comparison with the findings of the Ewing battery.

A power spectral analysis of heart rate variability has been applied in order to assess diabetic autonomic neuropathy and high frequency spectra are thus considered to possibly reflect vagal nerve integrity in patients with diabetes mellitus. The purpose of this study was to investigate the relationship between the findings of high frequency spectra analysis and the results of the Ewing battery. We performed 24-hour power spectral analysis using an ambulatory ECG monitoring system and standard tests in order to assess diabetic autonomic neuropathy (Ewing battery) in 18 diabetic patients to compare their diagnostic values for diabetic autonomic neuropathy. We used the high frequency amplitude (high frequency spectra; 0.15-0.40 Hz) as a direct measure of vagal nerve integrity from each hourly spectral plot. All hourly high frequency spectra decreased along with the impaired assessment of the battery, especially during the night when the high frequency spectra showed a manifest increase in patients classified as normal according to the battery. High frequency spectra during the night while asleep (22:00-05:00) and during a 24-hour period significantly correlated with the results of the battery. These values markedly decreased even in patients classified as having early vagal damage when compared with those classified as normal. High frequency spectra during night closely reflected the intrinsic vagal nerve integrity in patients with diabetes mellitus. High frequency spectra during night or a 24-hour period is a simple and sensitive measure of diabetic autonomic neuropathy and is considered to be a useful modality for detecting even early changes in autonomic dysfunction.