Takahiro Kanatsuna

Defect of the First-Phase Insulin Secretion to Glucose Stimulation in the Perfused Pancreas of the Nonobese Diabetic (NOD) Mouse

To investigate the development of impaired insulin secretion in type I diabetes mellitus, the pancreata of ICR and NOD mice (10–50 wk of age) were perfused. According to insulin responses to 30 mM glucose and to 19 mM arginine, we classified the NOD mice into four groups: those having normal insulin secretion to glucose and to arginine similar to that of control ICR mice (group 1); those with a defect in the first-phase insulin secretion to glucose stimulation but with almost normal insulin secretion to arginine, total insulin release to glucose being significantly smaller than that of group 1 (group 2); those having only a small insulin response to either stimulus, but a fasting plasma glucose level still within the normal range (group 3); and those being overtly diabetic, showing no insulin response to either stimulus (group 4). The severity of insulitis and insulin concentration of the pancreas in each group of NOD mice was well correlated with the insulin release from the perfused pancreas. These results indicate that the initial sign of B-cell damage in NOD mice is a defect of the first phase of glucose-induced insulin secretion, which is followed by a total loss of ability to respond to glucose or arginine stimulation.

Reduced norepinephrine turnover in brown adipose tissue of pre-obese mice treated with monosodium-L-glutamate

Norepinephrine (NE) turnover, an index of sympathetic nervous system (SNS) activity, was measured in interscapular brown adipose tissue (IBAT), heart and pancreas of 3-weeks-old pre-obese monosodium-L-glutamate (MSG) mice and at 6-weeks-old mildly obese MSG mice. In IBAT, rates of NE turnover were slower not only in 3-weeks-old MSG mice but also in older obese MSG mice than in their saline controls. In heart, rates of NE turnover were slower in 6-weeks-old mildly obese MSG mice, but not in pre-obese MSG mice. No significant difference in NE turnover in pancreas was observed at either age. The low NE turnover in IBAT of MSG-treated mice prior to the onset of gross obesity suggests that low SNS activity may be an initial contributor to their high energy efficiency and resultant obesity.

Creatol, a creatinine metabolite, as a useful determinant of renal function.

Analysis of creatol (CTL, 5-hydroxycreatinine), an oxidative creatinine (Cr) metabolite, in serum and urine of human subjects has indicated that CTL is a useful determinant of renal function. The existence itself of serum CTL (s-CTL) could be a diagnostic sign for chronic renal failure (CRF): in all normal subjects, s-CTL was undetectable, but s-CTL was detectable in sera of all patients with CRF (s-Cr: > 2.0 mg/dl). And the s-CTL values increased in proportion to the severity of CRF in such patients. Furthermore, the molar ratio (CTL/Cr) in both urine and serum increased significantly in proportion to the severity of CRF. Our results indicated not only hyperproduction of CTL but also higher oxygen stress in patients according to the progression of CRF. The diagnostic importance of the CTL value and the CTL/Cr ratio are discussed.

Leukocyte-endothelial cell adhesion molecule 1 (LECAM-1) polymorphism is associated with diabetic nephropathy in type 2 diabetes mellitus

BACKGROUND/AIMS Glomerular infiltration with monocytes/macrophages has been implicated in the pathogenesis of diabetic nephropathy. In this study, we evaluated the relationship between the genetic polymorphism in leukocyte-endothelial adhesion molecule-1 (LECAM-1) and diabetic nephropathy in patients with type 2 diabetes mellitus. METHODS We determined the frequency of the LECAM-1 P213S genotype in 102 diabetic patients with diabetic nephropathy, 90 diabetic patients with no evidence of diabetic nephropathy, and 200 healthy control individuals. RESULTS The frequency of the LECAM-1 213PP genotype and P allele in patients with diabetic nephropathy was significantly higher than that in patients without nephropathy (genotype 68% vs. 53%, chi(2)=6.78, P=.034; allele 83% vs. 72%, chi(2)=6.26, P=.012). The LECAM-1 P213 genotype was associated with a 1.86-fold increased risk for nephropathy independently of other risk factors. CONCLUSION The data suggest that the LECAM-1 213PP genotype is a genetic risk factor for the development of nephropathy in type 2 diabetes mellitus.

Insulin Release from Column-Perifused Isolated Islets of Uremic Rats

In order to examine the insulin secretion in chronic renal failure, isolated pancreatic islets either from uremic rats or from control rats were mixed into a short column of Bio-Gel P-2 polyacrylamide beads and perifused. Uremic rats had higher concentrations of blood urea nitrogen, serum creatinine, and immunoreactive insulin and lower concentration of plasma 1,25-(OH)2D3 than control rats. Although the basal insulin release in the presence of 5.0 mM glucose showed no difference between uremic and control rats, the initial insulin release in the presence of 16.2 mM glucose was significantly lower (p less than 0.05) in uremic than in controls rats. The insulin content in islets was not different between both groups. These findings suggest that there might be impairment of the initial insulin secretion without changes of insulin content in pancreatic islets in uremia.

Relationship between erythrocyte sorbitol content and diabetic microangiopathy in patients with non-insulin-dependent diabetes mellitus: the study of a diet loading test

To determine whether erythrocyte sorbitol content could become an indicator of diabetic microangiopathy, we studied the relationship between the changes in erythrocyte sorbitol content in response to diet loading and diabetic microangiopathy in patients with non-insulin-dependent diabetes mellitus. The increase of change in erythrocyte sorbitol content (delta Sor) after diet loading (420 kcal) significantly correlated with that of plasma glucose levels (delta BS). The patients with less than or equal to 40 m/s of motor or sensory nerve conduction velocity (MCV and SCV) had significantly higher delta Sor and delta Sor/delta BS values than those with greater than 40 m/s of MCV and SCV; nevertheless, there were no significant differences in delta BS between the two groups. Furthermore there was a significant negative correlation between nerve conduction velocity and delta Sor and Delta Sor/delta BS values. On the other hand, the patients with nephropathy or retinopathy showed no significant increase in delta Sor or delta Sor/delta BS compared with patients without these complications. The results demonstrated that delta Sor and delta Sor/delta BS could become indicators of the presence or severity of diabetic neuropathy. Furthermore the more significant participation of alteration in the polyol pathway in the pathogenesis of neuropathy than of the other microangiopathies was suggested.

Islet cell surface antibodies preferentially inhibit glucose-stimulated insulin release in vitro

The effect of islet surface antibodies (ICSA) on in vitro insulin release was studied. Isolated rat islets were incubated in the presence of immunoglobulin preparations from patients with insulin-dependent and non-insulin-dependent diabetes mellitus (IDDM, NIDDM) and healthy subjects, and stimulated with D-glucose, L-arginine or tolbutamide. After incubation, the amount of insulin release from the rat islets was determined. The immunoglobulin preparations from 5 newly diagnosed IDDM patients who were positive for ICSA, and from 5 age-matched healthy subjects were examined. Even in the absence of complement or lymphocytes, immunoglobulin fractions positive for ICSA significantly inhibited low and high concentrations of glucose-stimulated insulin release compared with normal control (P less than 0.02), but had little influence on insulin release after stimulation with tolbutamide. Arginine-stimulated insulin release was almost the same in ICSA-positive immunoglobulin fractions and the control. Immunoglobulin fractions negative for ICSA either from four patients with recently diagnosed IDDM or from four newly diagnosed NIDDM patients had only negligible effect on insulin release after stimulation with glucose. These results suggest that ICSA in IDDM patients, even in the absence of complement or lymphocytes, may preferentially interfere with the mechanisms of glucose-stimulated insulin release in the pancreatic B cells.

A case of central nervous system dysfunction in systemic lupus erythematosus with serum antineuronal antibody

中枢神経症状を合併する全身性エリテマトーデス(CNS-SLE)は頻度が高く,また予後も悪いことより最近注目されている.その発症には免疫学的機序が関与するといわれ,一般に免疫複合体沈着による脈絡叢障害説と抗神経細胞抗体による直接障害説がある.今回我々はSLEの経過中に昏睡,全身痙攣などの重篤な症状を呈したにもかかわらず,ステロイド薬の大量投与にて寛解しえたCNS-SLEの症例で免疫組織学的に検討の結果,抗神経細胞抗体(IgG)を確認した.患者は41才,女性. 8年来,顔面蝶形紅斑,手指足趾の凍瘡様皮疹をくり返し,昭和57年秋より上記症状の増悪とともに脱毛傾向を認め,血液検査などからSLEの疑診を受けた.ステロイド薬は投与されず外来にて経過を観察したところ,翌年3月25日突然意識消失状態となり,その後昏迷状態のまま入院した.入院12時間後より昏睡に陥り全身痙攣も頻発した.入院時諸検査よりCNS-SLEと診断しprednisolone 200mg/dの大量投与を行ない意識障害は著明に改善し,第8病日には清明となつた.本症例では全経過を通じて血中免疫複合体は陰性のためその沈着による脈絡叢障害は否定的であり,また蛍光抗体間接法を用いた免疫組織学的検索にて抗神経細胞抗体を認めたので,今回の発症には自己抗体としての抗神経細胞抗体の関与が強く示唆された.

Glucose intolerance in chronic renal failure

慢性腎不全に耐糖能異常が存在することはよく知られているが, その成因については不明な点が少なくない. インスリン抵抗性もその一因と考えられているが, この点をさらに明らかにするためにインスリン受容体の面から検討した. 未透析腎不全患者10名, 透析患者12名および正常者6名を対象に赤血球のインスリン受容体を検討し, 0.5g/kgのIVGTTを行い, K値 (血糖消失率) およびΣIRI (IRIの総和) を求めた. K値は未透析群 (1.32±0.30) では正常群 (1.92±0.25), 透析群 (1.82±0.34) と比べて低値を示したが, 正常群と透析群との間には差がなかった. ΣIRIは未透析群 (445±78μU/ml), 透析群 (420±80μU/ml) は正常群 (260±38μU/ml) と比べて高値を示したが, 未透析群と透析群との間には差がなかった. インスリン特異結合率 (赤血球2.4×109個/mlへの0.2ng/mlの125I-インスリン) は未透析群 (3.99±0.76%) は低値を示したが, 正常群 (5.50±0.69%) と透析群 (5.11±0.80%) との間には有意差がなかった. Scatchard解析より, 未透析群におけるインスリン特異結合率の低下はインスリン受容体数の減少によるものと思われた (正常群64個/cell; 透析群58個/cell; 未透析群45個/cell).さらに, 耐糖能異常とインスリン受容体との関係を明らかにするために, インスリン特異結合率とK値および空腹時IRI, ΣIRIとの関係をみたが, 透析群において特異結合率とK値との間に正の相関を認めた. このことより, 未透析腎不全患者の耐糖能異常はインスリン受容体数の低下によるものと思われ, 透析療法はインスリン受容体レベルでの改善により耐糖能障害を正常化させるものと思われた.