Teruo Shiba

Substrates for Insulin-Receptor Kinase

Several studies suggest that the tyrosine-specific protein kinase activity of the β-subunit of the insulin receptor is necessary to mediate the biological effects of insulin. This conclusion leads to the hypothesis that the effect of insulin is mediated through the tyrosine phosphorylation of cellular substrates by the insulin-receptor tyrosine kinase. In this review, the experimental evidence regarding insulin-stimulated phosphorylation of proteins both in vitro and in vivo is evaluated. In a cell-free system, tubulin, microtubuleassociated protein 2, tau, fodrin, calmodulin-dependent kinase, calmodulin, and lipocortins 1 and 2 were reported to be good substrates for insulin-receptor kinase. However, none were found to be tyrosine phosphorylated in an intact-cell system. In intact-cell systems, proteins of M, 185,000 (pp185), 120,000 (pp120), 240,000 (pp240), 15,000 (pp15), 60,000 (pp60), and 62,000 (pp62) as well as several others were reported to be tyrosine phosphorylated in an insulin-dependent fashion. However, the function or functional alteration of these proteins induced by insulin-stimulated tyrosine phosphorylation is not clear. Therefore, physiologically relevant substrates for the insulin-receptor kinase have not been established, and more work is necessary to verify the phosphorylation cascade hypothesis of insulin action.

HMG-CoA reductase inhibitor decreases small dense low-density lipoprotein and remnant-like particle cholesterol in patients with type-2 diabetes

Patients with type 2 diabetes are known to have abnormalities in their remnant metabolism and low density lipoprotein (LDL) subfraction pattern, with a preponderance of small dense LDL. The effects of pitavastatin, a newly synthesized 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, on lipoprotein profiles in patients with type 2 diabetes were determined. Thirty-three patients were treated with pitavastatin with a daily dose of 2 mg for 8 weeks. After treatment, triglyceride, total and LDL cholesterol were significantly reduced by 28.7 +/- 36.7%, 25.2 +/- 14.3% and 36.1 +/- 14.3%, respectively. Remnant-like particle cholesterol (RLP-C), an independent risk factor for CAD which is known to be elevated in diabetic patients, was also significantly reduced (-30.9 +/- 30.5%) by the treatment and this decrease correlated well with the decrease in triglyceride level. The proportion of small dense LDL, which is known for its atherogenisity, decreased from 29.9 +/- 26.2% to 19.7 +/- 22.7% and the mean LDL particle size significantly increased from 26.36 +/- 1.13 nm to 27.10 +/- 1.36 nm. Pitavastatin, which is known to improve triglyceride levels and cholesterol levels, also improves RLP-C level and LDL subfraction profiles, and this in turn may reduce the cardiovascular risk in patients with type 2 diabetes and dyslipidemia.

Serum superoxide dismutase activity correlates with the components of metabolic syndrome or carotid artery intima-media thickness

The activities of the enzymes to eliminate reactive oxygen species prevent the progression of atherosclerosis. We conducted a cross-sectional study among 3234 people that underwent total health check-up service, and studied the relationship between the serum superoxide dismutase (SOD) activity and risk factors of atherosclerosis or carotid artery intima-media thickness (IMT). Serum SOD activity negatively correlated with body mass index (BMI), systolic and diastolic blood pressure, serum triglyceride (TG) concentration and serum glucose concentration. Low serum SOD activity positively correlated with the carotid IMT thickening. But on the other hand, existence of carotid artery plaque positively correlated with serum SOD activity especially among men. Serum SOD activity negatively correlated with the components of metabolic syndrome and low serum SOD activity seems to be an independent risk of the thickening of carotid IMT. On the other hand, serum SOD activity level seems to elevate limitedly but reactively to the status of increased oxidative stress, such as carotid plaque formation.

Onset of diabetes with high titer anti-GAD antibody after IFN therapy for chronic hepatitis

A case of hyperglycemia induced by the injection of interferon-alpha was experienced in our hospital. This patient showed a sustained high titer of anti-GAD antibody after the onset of diabetes, suggesting that the involvement of immunological disturbance by IFN induces the onset of the disease. However, the susceptibility and the response of the immune system differs from patient to patient, and only limited destruction of beta-cells in the islet of Langerhans and normalization of glucose tolerance by CSII was induced in this patient.

Serum gliclazide concentration in diabetic patients: Relationship between gliclazide dose and serum concentration

Serum levels of gliclazide were determined by radioimmunoassay in seven healthy controls and in 18 diabetic in-patients receiving single oral dosing and consecutive dosing over 5 days. Following a single oral dose of 40 mg in the seven controls and eight diabetic patients, and 120 mg in ten diabetic patients, the serum levels of gliclazide peaked on average at 2 h, followed by a slow decline, the t1/2 being 16.5 h in the volunteers, 12.3 h in the diabetic patients receiving 40 mg, and 10.5 h in those receiving 120 mg. During consecutive administration, the serum levels both at fasting and at the peak reached a plateau in 2 days and no further accumulations were observed. The steady-state peak levels of gliclazide in the diabetic patients revealed a strongly positive correlation with the dose per m2 body surface area (r = 0.78, P less than 0.001), and their steady-state fasting levels correlated positively but weakly with the dose per m2 body surface area (r = 0.48, P less than 0.05). Thus, measuring either the fasting or the peak concentration of gliclazide will be useful for monitoring drug concentration in the serum. Pharmacokinetics of gliclazide will contribute to the elucidation of the relationship of serum level and clinical effectiveness in diabetic subjects.

Screening and follow-up of diabetic retinopathy using a new mosaic 9-field fundus photography system

AIM To evaluate the clinical usefulness of a newly developed fundus photographing system and assess its applicability to telemedicine. METHODS Nine overlapping 45 degrees fundus photographs were taken by a new camera equipped with nine internal fixation targets to provide standardized 9-field photographs. The digitally stored images were either edited in 3x3 form or reconstructed as collage (9F) and compared to the ophthalmological examination (OP) and single-field non-mydriatic photography (SC). In telemedicine, 9-field images derived from 61 adolescent diabetics were sent to ophthalmologists over an analog phone line. RESULTS The sensitivities of the examinations by 9F without and with mydriasis (78 and 82%) were equivalent to OP (84%) and superior to SC (64%). The diagnosis of severity by 9F was also comparable to those by OP, whereas SC tended to underestimate the severity. An average of 1 min 19 s was required to send one edited 9-field photography (average size 259+/-30 KB) over the Internet. Twelve of these eyes were diagnosed as diabetic retinopathy on a desktop monitor whereas SC gave only seven. CONCLUSION This new 9-field fundus photography system can be appropriate for the screening and follow-up of diabetic retinopathy in adult and adolescent diabetic subjects, especially when applied to telemedicine over the Internet.

Improvement of insulin resistance by a new insulin secretagogue, nateglinide—analysis based on the homeostasis model

Type 2 diabetes is a heterogeneous disorder characterized by defects in the early phase of insulin secretion after meals and in insulin resistance at its early stage. A new insulin secretagogue, nateglinide, has been shown to elicit an acute insulin release and to reduce postprandial hyperglycemia. We have treated 30 patients with type 2 diabetes using nateglinide and performed a standard meal test at breakfast, both before and after the treatment. Insulin resistance and beta-cell function was assessed by the HOMA model. Nateglinide, at 1 and 2 h after the test meal, significantly stimulated postprandial insulin secretion by 62.0 and 41.0% and improved blood glucose values by 17.3 and 21.9%, respectively, after the treatment. Fasting blood glucose (FBG) and glycohemoglobin was significantly reduced by 9.8 and 10.3%, respectively. The reduction was significantly larger in postprandial glucose than in FBG (P<0.0005). A significant correlation was found in the HOMA-insulin resistant (IR) index and in the changes of fasting IRI. When the patients were divided into three groups, forming a markedly insulin resistant (MIR) group, an IR group and a non-insulin resistant (NIR) group, HOMA-IR levels improved significantly, from 7.0 +/- 4.3 to 4.5 +/- 2.8 (P=0.026) in the MIR group and showed a tendency toward improvement in the IR group, from 2.9 +/- 0.7 to 2.3 +/- 1.1 (P=0.062), but failed to exhibit such a positive response in the NIR group, changing from 1.2 +/- 0.2 to 1.9 +/- 0.9 (P=0.21). HOMA-beta, on the other hand, improved significantly in the NIR group only, from 16.4 +/- 7.8 to 26.9 +/- 9.9 (P=0.017), but not in the IR nor MIR groups (M +/- S.D.). In conclusion, nateglinide improved the excessive excursion of postprandial glucose by the augmentation of early insulin secretion after a meal and differentially affected fasting insulin levels and HOMA-IR indexes, depending on the degree of insulin resistance.

Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins.

Background There exists a subpopulation of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C, representing a major risk of CVD. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks. Methods Lipid changes were assessed in a randomized, multicenter, 12-week, open-label study comparing a high-potency statin (10mg of atorvastatin or 1mg of pitavastatin) plus ezetimibe (EAT: n = 53) with a double dose of statin (20mg of atorvastatin or 2mg of pitavastatin) (DST: n = 56) in DM subjects who had failed to achieve the optimal LDL-C targets. Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C (remnant like particle cholesterol) and sd-LDL-C, two characteristic atherogenic risks of DM. Results The reduction of LDL-C (%), the primary endpoint, differed significantly between the two groups (-24.6 in EAT vs. -10.9 in DST). In the analyses of the secondary endpoints, EAT treatment brought about significantly larger reductions in sd-LDL-C (-20.5 vs. -3.7) and RLP-C (-19.7 vs. +5.5). In total, 89.4% of the patients receiving EAT reached the optimized treatment goal compared to 51.0% of the patients receiving DST. The changes in TC (-16.3 vs. -6.3) and non-HDL-C (-20.7 vs. -8.3) differed significantly between the two groups. Conclusion Ezetimibe added to high-potency statin (10 mg of atorvastatin or 1 mg of pitavastatin) was more effective than the intensified-dose statin (20 mg of atorvastatin or 2 mg of pitavastatin) treatment not only in helping T2DM patients attain more LDL-C reduction, but also in improving their atherogenic lipid profiles, including their levels of sd-LDL-C and RLP-C. We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response. Trial Registration The UMIN Clinical Trials Registry UMIN000002593

Delapril versus manidipine in hypertensive therapy to halt the type-2-diabetes-mellitus-associated nephropathy

Thirty-nine hypertensive patients with type 2 diabetes mellitus were followed under long-term treatment (mean, 20.7 months) with manidipine hydrochloride, a Ca antagonist, or delapril hydrochloride, an ACE inhibitor, at nine institutions. Both the treatments showed similar antihypertensive effects, although slight but significantly larger decreases were observed in systolic and mean blood pressures at months 12 and 24 in the patients treated with manidipine (P < 0.02). The urinary albumin excretion index (AEI) tended to increase throughout the study in both treatment groups, but no significant difference in AEI was observed between the two treatment groups at any time point. Overt albuminuria developed in four patients on manidipine but did not appear in any of the patients on delapril. The risk of progression to overt albuminuria was significantly different between manidipine and delapril groups (P = 0.011). No increase in serum creatinine (Cr) was observed with delapril. The average excretion indexes of tubular markers such as beta2-microglobulin, alpha1-microglobulin, and NAG tended to be higher in the patients on manidipine than in those on delapril. Taken in sum, these findings suggest that the ACE inhibitor delapril is more beneficial than the Ca antagonist manidipine in the treatment of diabetic renal diseases via mechanisms other than the blood pressure regulation, partly through their different effects on tubular function. In conclusion, delapril was significantly more effective than manidipine in inhibiting progression to overt albuminuria in hypertensive type 2 diabetes mellitus patients.

Knowledge and Demand for Information about Islet Transplantation in Patients with Type 1 Diabetes

This cross-sectional study based on self-administrated questionnaire was conducted to investigate knowledge, related factors, and sources of information regarding islet transplantation in patients with type 1 diabetes in Japan. Among 137 patients who provided valid responses, 67 (48.9%) knew about islet transplantation. Their main source of information was newspapers or magazines (56.7%) and television or radio (46.3%). However, 85.8% of patients preferred the attending physician as their source of information. Although more than half of the patients were correctly aware of issues related to islet transplantation, the following specific issues for islet transplantation were not understood or considered, and there was little knowledge of them: need for immunosuppressants, lifestyle and dietary adaptations, fewer bodily burdens, and complications. The experience of hypoglycaemia, a high level of academic background, frequent self-monitoring of blood glucose, and the use of continuous subcutaneous insulin infusion were related to higher knowledge about islet transplantation.