[Show abstract][Hide abstract] ABSTRACT: Aims/Introduction
Islet amyloid polypeptide (IAPP) is a main component of islet amyloid in type 2 diabetes and cosecreted from β‐cell with insulin. Clinical evidence from the patients with S20G mutation of the IAPP gene, as well as experimental evidence that insulin could inhibit amyloid formation of IAPP, suggests that a gradual reduction of insulin could be related to the cytotoxicity associated with S20G‐IAPP through long‐term deterioration of β‐cells in type 2 diabetes. Our objective was to show an effect of human insulin on S20G‐IAPP associated cytotoxicity.
Materials and Methods
We analyzed the cytotoxicity associated with S20G‐IAPP by controlling human insulin expression using adenovirus vectors with micro ribonucleic acid specifically against human insulin in endocrine AtT‐20ins cells, which express human insulin permanently. Additionally, we carried out a follow‐up study of circulating IAPP and insulin in type 2 diabetic patients.
S20G‐IAPP expression was associated with a decrease in viability and an increase in terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate‐biotin nick end labeling‐positive cells in AtT‐20ins cells. Furthermore, downregulation of human insulin enhanced the cytotoxicity associated with S20G‐IAPP, and induced the cytotoxicity associated with wild‐type (WT)‐IAPP. Reduction of ubiquitin carboxy‐terminal hydrolase L1 activity enhanced cytotoxicity under the downregulation of human insulin expression in both S20G‐ and WT‐IAPP transduced cells. A 5‐year follow up of type 2 diabetic patients showed a disproportionate increase of serum fasting IAPP‐to‐insulin ratio from baseline.
Human insulin plays a protective role against the cytotoxicity associated with S20G‐IAPP, as well as WT‐IAPP. The findings could suggest long‐term deterioration of insulin secretion associates with IAPP linked cytotoxicity in type 2 diabetes.
[Show abstract][Hide abstract] ABSTRACT: Aims/Introduction
The Kir6.2 E23K polymorphism was studied with a special reference to secondary sulfonylurea (SU) failure in non‐obese patients with type 2 diabetes.
Materials and Methods
We recruited 278 non‐obese (body mass index ≤30.0 kg/m2) Japanese patients with type 2 diabetes who had a history of SU treatment (for 11.2 ± 6.3 years) and compared the frequency of the secondary SU failure among the genotypes of the polymorphism. Genotyping of the Kir6.2 E23K was carried out by polymerase chain reaction‐restriction fragment length polymorphism.
The genotype frequencies of the polymorphism were similar to those previously reported in Japanese patients with type 2 diabetes. The frequency with which patients deteriorated into secondary SU failure was significantly higher in those with the KK genotype than those with EE or EK genotypes. Among 214 patients who eventually received insulin therapy because of secondary SU failure, the period of SU treatment in those with the KK genotype was significantly shorter than those with the EE or EK genotype, although the period from diagnosis to the start of SU treatment was not significantly different.
These data suggest that the Kir6.2 E23K polymorphism is related to the acceleration of secondary SU failure in non‐obese Japanese patients with type 2 diabetes.
[Show abstract][Hide abstract] ABSTRACT: Aims/Introduction
In order to characterize the impaired vascular function in type 2 diabetes (DM) patients, we evaluated the flow‐mediated vascular dilation (FMD) with glyceryl trinitrate‐mediated vascular dilation (NMD) using ultrasonography.
Materials and Methods
A total of 111 DM patients and 42 healthy control participants were studied. The maximal dilatation of FMD and NMD (%FMD and %NMD, respectively), the beginning time (T) of dilatation after stimulation and the velocity (V) of the vascular dilatation were also measured.
Among DM patients, 49% had impaired %NMD, which affects the results of %FMD. In DM patients with normal %NMD, the %FMD was also significantly lower than that in control participants, although the T and the V were not impaired. In contrast, both the T and the V were disturbed in the DM patients with low %NMD. Multiple linear regression analysis showed that %NMD was independently correlated with albuminuria. Our results indicate that the impaired FMD in DM is be affected by low NMD, and impaired endothelial function already exists even in DM patients whose vascular smooth muscle function is still retained, and also albuminuria is the clinical feature of DM with low %NMD.
Examination of NMD, not only FMD, should be carried out as it offers the possibility of clarifying vascular function in DM patients.
[Show abstract][Hide abstract] ABSTRACT: In order to evaluate seasonal changes in hemoglobin A1c (HbA1c) values, we examined HbA1c values among 34,590 patients in 2010, and calculated the monthly average of HbA1c values through the year. HbA1c values were the highest in March and the lowest in October with a difference of 0.30%. The similar annual pattern was observed in HbA1c values from 2006 to 2009. Then we selected 453 diabetic patients whose treatment did not change through the year, and calculated average HbA1c values in four seasons each. There were also significant seasonal changes in diabetic patients, which were the highest in the spring and the lowest in the autumn, especially found in patients with insulin therapy. These effects may be caused by cold climate, decreased physical activity, over food intake and body weight gain in the winter. These seasonal changes in HbA1c should be concerned in the case of health service research, clinical trials and evaluation of the effects of medical treatment.
Rinsho byori. The Japanese journal of clinical pathology 07/2012; 60(7):599-604.
[Show abstract][Hide abstract] ABSTRACT: Aims/Introduction: In order to clarify the enhanced β‐cell dysfunction in type 2 diabetic patients carrying the S20G mutation of the islet amyloid polypeptide gene (S20G‐patients), we first estimated the decline of insulin secretion in Japanese type 2 diabetic patients without the S20G mutation (non‐S20G‐T2D‐patients) by long‐term observation, and then compared it with that of the S20G‐patients.
Materials and Methods: We followed 70 non‐S20G‐T2D‐patients (body mass index <30 kg/m2) for more than 10 years and six S20G‐patients for more than 5 years. We measured fasting C‐peptide (F‐CP) every 1–2 years and carried out a glucagon test at least once during the follow‐up period. F‐CP and a 5‐min value of C‐peptide after glucagon injection (5′‐CP) were used as the indices of insulin secretion. We excluded patients who had renal dysfunction and/or anti‐insulin antibodies in the insulin‐treated patients. The individual annual declines were calculated from the slopes of the regression lines between C‐peptide levels and duration (years after diagnosis).
Results: The mean individual annual declines of both F‐CP and 5′‐CP were significantly greater in the S20G‐patients than the non‐S20G‐T2D‐patients (F‐CP; 0.047 ± 0.026 vs 0.011 ± 0.037 nmol/L/year, P = 0.025, 5′‐CP; 0.139 ± 0.055 vs 0.022 ± 0.012 nmol/L/year, P = 0.008).
Conclusions: We established the annual decline of insulin secretion in the Japanese type 2 diabetic patients by the long‐term observation. The results show that the decline of insulin secretion is more rapid in the S20G‐patients than the non‐S20G‐T2D‐patients. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00102.x, 2011)
[Show abstract][Hide abstract] ABSTRACT: Clinical evaluation of insulin assay system reacting with only human insulin molecule (kit B) was performed by comparing it with conventional insulin assay system (kit A) cross-reacting with insulin analogue as well as human insulin preparation. In vitro, the kit B was confirmed to cross-react with only human insulin, not with insulin analogue preparations such as insulin aspart, lyspro and glargine. In non-insulin treated diabetic patients, postprandial and post-insulin injected serum immunoreactive insulin (IRI) concentrations measured by kit B were almost the same as those measured by the kit A. On the other hand, in diabetic patients treated with insulin analogue preparations, postprandial and post-insulin injected serum IRI levels measured by kit B were obviously low compared with those by kit A. After intravenous injection of insulin analogue preparations (0.1 unit/kg), insulin lyspro or insulin aspart, serum IRI levels measured by the kit B were not increased but gradually decreased in contrast to the obviously increased serum IRI level measured by the kit A. From these results, the kit B was confirmed not to measure the insulin analogue preparations in vitro and in vivo.
Rinsho byori. The Japanese journal of clinical pathology 07/2011; 59(7):662-7.
[Show abstract][Hide abstract] ABSTRACT: Monocyte chemoattractant protein-1 (MCP-1) is a cytokine thought to be an important factor in adipose tissue inflammation
in obese patients, but little is known about circulating MCP-1 in type 2 diabetic patients. We studied circulating MCP-1 levels
in type 2 diabetic patients and their correlation with insulin resistance and other clinical data including chronic complications.
In a preliminary study of 114 non-diabetic subjects, we found a significant correlation between serum MCP-1 level and estimated
glomerular filtration rate (eGFR). We thus enrolled 185 type 2 diabetic patients and 91 non-diabetic subjects with an eGFR
more than 60ml/min/1.73m2. There was no difference in serum MCP-1 levels between diabetic patients and non-diabetic subjects. Serum MCP-1 levels had
no significant correlation with high-molecular-weight adiponectin in type 2 diabetic patients. In a limited number of type
2 diabetic patients (N=112), serum MCP-1 levels had no significant correlation with homeostasis model assessment for insulin resistance (P=0.075). Serum MCP-1 level was higher in proliferative retinopathy patients than in non-retinopathy patients (P=0.028). Multiple regression analysis revealed that serum MCP-1 level was correlated with diabetic retinopathy (P=0.007). We conclude that circulating MCP-1 level has little correlation with insulin resistance but is linked with diabetic
retinopathy in type 2 diabetic patients.
KeywordsMonocyte chemoattractant protein-1–Insulin resistance–Diabetic retinopathy–Adiponectin
Diabetology International 12/2010; 1(2):78-82. DOI:10.1007/s13340-010-0013-8
[Show abstract][Hide abstract] ABSTRACT: Aims/Introduction: Islets in type 2 diabetes are characterized by deposition of islet amyloid polypeptide (IAPP) as well as β‐cell dysfunction. The unique amyloidogenic character of human (h)IAPP is associated with cytotoxicity. Autophagy is a ubiquitous system of cellular recycling that contributes to cell survival. Thus, we examined whether autophagy could ameliorate hIAPP‐associated cytotoxicity.
Materials and Methods: First, we used a COS‐1 cell model, lacking endogenous IAPP that might affect cytotoxicity related to exogenous hIAPP. Next, we used the mouse β‐cell line, MIN‐6 cells. Both cells were transfected with hIAPP or rat (r)IAPP expression constructs, or transfected with bicistronic vectors expressing green fluorescent protein (GFP) and either hIAPP or rIAPP for flow cytometry analysis. Cell viability and apoptosis markers were studied in relation to chemical or genetic modulation of autophagy.
Results: The viability of cells expressing hIAPP was significantly decreased as compared with those expressing rIAPP and the cleavage of pro‐caspase‐3 was elevated in hIAPP‐transfected cells. The formation of autophagosomes and the conversion of microtubule‐associated protein light chain 3B I to II were elevated in hIAPP‐expressing cells. The viability of hIAPP‐expressing cells was increased after treatment with rapamycin, an inducer of autophagy, and decreased after treatment with 3‐methyladenine, an inhibitor of autophagy. In MIN‐6 cells, annexin positive cells were increased by 3‐methyladenine and decreased by rapamycin using flow cytometry. Knocking down of the autophagy protein 5 gene decreased hIAPP‐transfected cell viability.
Conclusions: Autophagy is co‐localized with hIAPP expression and it plays a protective role in hIAPP‐associated apoptosis. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00065.x, 2010)
[Show abstract][Hide abstract] ABSTRACT: Chronic kidney disease (CKD) and metabolic syndrome have been recognized as risk factors for cardiovascular disease. However, there is no information comparing their impact on macroangiopathy in diabetic patients. Thus, we studied the prevalence of CKD and metabolic syndrome in Japanese type 2 diabetic patients and then compared their impact on peripheral arterial disease (PAD) in type 2 diabetic patients.
This study focused on Japanese type 2 diabetic patients without hemodialysis (n = 1014). Patients with albuminuria, including microalbuminuria and/or an estimated glomerular filtration rate less than 60 mL/min/1.73(2), were diagnosed as having CKD. PAD was defined as ankle-brachial blood pressure index less than 0.9.
The prevalence of CKD and metabolic syndrome was 47.1% and 39.6%, respectively. In four age- and duration-matched groups classified by the presence or absence of CKD and metabolic syndrome, the prevalence of PAD was significantly higher in groups with CKD alone than those with metabolic syndrome alone, and the high prevalence in the groups with CKD was not influenced by the coexistence with metabolic syndrome.
This study indicates that CKD has more powerful impact on PAD than metabolic syndrome in type 2 diabetic patients.
Metabolic syndrome and related disorders 07/2009; 7(4):323-6. DOI:10.1089/met.2008.0074 · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is growing interest in the use of transcranial sonography (TCS) of the substantia nigra (SN) in patients with Parkinson's disease (PD), as it has been reported that SN hyperechogenicity may be present in about 90% of PD patients. However, TCS of the SN has not been applied in Japanese patients, and its clinical potential has not been determined.
TCS of the SN was performed in patients with PD, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and essential tremor (ET), and age-matched controls. Ultrasound images of the SN were assessed using semi-qualitative estimation criteria by two investigators unaware of clinical diagnosis.
SN hyperechogenicity was observed in approximately 83% of accessible SNs in Japanese PD patients. In comparison, SN hyperechogenicity was less frequently observed in healthy subjects or in patients with PSP, MSA, and ET. However, the rate of successful recording of the SN by TCS decreased prominently with advancing age, particularly in females.
The present study confirmed that TCS of the SN is potentially useful in the investigation of Japanese patients, and it provides a better differential diagnosis between PD and atypical parkinsonism. The recording failure of TCS in aged, particularly female subjects, may limit the clinical potential of TCS of the SN in Japanese patients.
Internal Medicine 02/2007; 46(18):1527-31. DOI:10.2169/internalmedicine.46.0271 · 0.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This investigation was conducted to clarify the frequency and characteristics of ALS associated with extrapyramidal symptoms or signs in Wakayama prefecture. The questionnaires to survey ALS cases were mailed to all medical centers in Wakayama prefecture. A total of 252 cases were found to have motor neuron diseases. Among them, 204 cases fulfilled probable or definite according to El Escorial Criteria. In 10 of them, extrapyramidal signs were identified as follows: rigidity 50%, tremor 40% and akinesia 10%. Family history of ALS in these cases (20%) is higher than expected in usual ALS, and all of them are negative for SOD-1 mutation. Dementia and autonomic nervous symptoms were observed in several cases. Incidence of extrapyramidal signs in ALS resulted in 4.8%. The incidence of extrapyramidal signs is more frequent than expected by chance, suggesting that the degeneration of basal ganglia and/or substantia nigra may not be so rare in ALS.
Nō to shinkei = Brain and nerve 10/2006; 58(9):779-84.
[Show abstract][Hide abstract] ABSTRACT: We performed a pilot, crossover trial of zonisamide (ZNS) on essential tremor patients. Patients were randomly selected to start either ZNS or arotinolol treatment for 2 weeks. After a washout period, the patients were switched to an alternative drug. The assessment of tremor was carried out using the Fahn-Tolosa-Marin's clinical rating scale for tremor at baseline and 2 weeks after administration of each drug. There was a significant improvement after ZNS and arotinolol administration compared with the baseline. There was no significant difference in the antitremor effect between ZNS and arotinolol; however, ZNS was more effective for tremors of cranial nerve areas. Although the number of enrolled patients was limited in the present study, this open-label pilot study suggests that ZNS may have a therapeutic potential for essential tremor. A controlled trial of this drug in the future would be valuable.
[Show abstract][Hide abstract] ABSTRACT: We report a 75-year-old Japanese woman with probable dementia with Lewy bodies (DLB). At the age of 64, she showed left hand resting tremor, and gradually developed bradykinesia, and rigidity. She was diagnosed as having parkinsonism and took medication. At the age of 70, she showed hallucination and dementia. As she had developing cognitive dysfunction and hallucination and parkinsonism, she was diagnosed to have probable DLB. At the age of 75, after administration of donepezil, she showed severe psychosis and worsened parkinsonism, and was admitted to hospital. On neurological examination, she showed severe rigidity and akinesia, and behavioral immobility like "waxy flexibility" or motiveless resistance to maintenance of rigid posture against attempts to be moved. The phenomena, she presented as motor abnormalities, were thought to be catatonia. In consideration of clinical course, her catatonia and worsened parkinsonism was thought to be induced by donepezil and she was stopped the administration of donepezil. After treatment with trihexiphenizil, she had improvement of motor abnormalities and worsened parkinsonism. It is important to recognize that donepezil may induce catatonia on the patients of parkinsonism with severe dementia.
Nō to shinkei = Brain and nerve 11/2004; 56(10):881-4.
[Show abstract][Hide abstract] ABSTRACT: The present study aims to study sequential alterations occurring in both dopaminergic neurons and microglia in substantia nigra (SN) following intrastriatal injection of 1-methyl-4-phenylpridium ion (MPP+) in rats. Heme oxygenase-1 (HO-1), a marker of oxidative stress, first appeared in dopaminergic neurons in SN at 1 day post-lesion. Subsequently, microglia in SN exhibited morphological changes indicative of activation. At 7 days post-lesion, those findings increased severity and 7a significant reduction in the number of dopaminergic neurons was observed. The present finding suggests that extensive oxidative stress and secondary-induced neuroinflammation play a relevant role in MPP(+)-induced retrograde dopaminergic neuron degeneration. We hope that this model will be useful in developing a disease modifying therapy of Parkinson's disease.
[Show abstract][Hide abstract] ABSTRACT: Quetiapine has been suggested to be useful for the treatment of psychosis in patients with Parkinson's disease without prominent deterioration of motor functions. We present two patients with Parkinson's disease in whom administration of quetiapine for drug-induced psychosis caused characteristic stereotyped behaviors or punding. Since stereotyped behaviors are usually associated with excessive dopaminergic activity, it is clinically important to note that stereotyped behaviors or punding may be induced by an atypical antipsychotic drug for the treatment of psychosis in patients with Parkinson's disease.
[Show abstract][Hide abstract] ABSTRACT: We report a patient who presented progressive cerebellar ataxia associated with vitamin B(12) deficiency. Brain magnetic resonance imaging (MRI) demonstrated a diffuse leukoencephalopathy. Six months after the initiation of methylcobalamin therapy, there were clinical improvement and reduction in the MRI abnormalities.
Journal of the Neurological Sciences 01/2004; 216(1):183-4. DOI:10.1016/S0022-510X(03)00219-3 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the clinical significance of T2-low signal intensity in the cortex of patients presenting parkinsonism, T2-weighted magnetic resonance (MR) images of the cortex of patients with multiple system atrophy (MSA), Parkinson's disease (PD) and progressive supranuclear palsy (PSP), and compared with those of patients with amyotrophic lateral sclerosis (ALS) and age-matched normal controls. The MR images were gathered and presented randomly to three neurologists who were blind to information on the patients. There was a significant increase in the frequency of T2-low signal intensity in the cortex of patients with ALS and MSA. Particularly in those with MSA, the T2-low signal intensity was observed not only in the motor cortex but also in the frontal association cortex. The cortical T2-low signal intensity in MSA might reflect the spread of degenerative processes in the cortex.
Journal of the Neurological Sciences 08/2003; 211(1-2):85-8. DOI:10.1016/S0022-510X(03)00061-3 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Psychosis characterized by hallucination or delusion, which occurs during drug therapy of parkinsonian patients, is one of the limiting factors for the control of motor symptoms or complications. In the present study, we encountered three patients with Parkinson's disease (PD) at advanced stages; all three patients had severe psychosis and severe wearing-off phenomenon and one had severe orthostatic hypotension. Their psychotic symptoms were successfully treated by administration of quetiapine, resulting in the favorable control of motor fluctuations and elevation of therapeutic levels unless any aggravation of parkinsonism occurs. Although the measure against drug-induced psychosis is principally a reduction of the doses or withdrawal of causative drugs, the effective use of antipsychotic drugs, such as quetiapine, is helpful to suppress psychosis and allow the patient to adjust to antiparkinsonian drugs for the control of symptoms other than psychosis.
Nō to shinkei = Brain and nerve 06/2003; 55(5):413-7.