Leptin is an adipocyte-derived hormone that regulates a number of physiological functions, including energy homeostasis and immune function. In immune responses, leptin plays a role in the induction of inflammation. We investigated a role of leptin in Listeria monocytogenes infection using leptin receptor-deficient db/db mice and leptin-deficient ob/ob mice. These mutant mice were highly susceptible to L. monocytogenes, and the elimination of bacteria from the liver was inhibited. After infection, the induction of monocyte chemoattractant protein-1 (MCP-1) and KC mRNA in the liver of db/db mice and the MCP-1 mRNA expression in the liver of ob/ob mice was decreased compared with their heterozygote littermates. Leptin replacement in ob/ob mice resulted in improvement of anti-listerial resistance and the MCP-1 mRNA expression. The elimination of L. monocytogenes was significantly enhanced, and the expression of MCP-1 and KC mRNA was completely reversed in db/db mice by insulin treatment. These results suggest that leptin is required for host resistance to L. monocytogenes infection and that hyperglycemia caused by leptin deficiency is involved in the inefficient elimination of bacteria from the liver. Moreover, defect of MCP-1 expression in the liver may be involved in the attenuated host resistance in these mutant mice. Diabetes 54:182-189, 2005 L eptin is a small peptide hormone secreted primarily by the adipocyte. Leptin-deficient ob/ob mice (1,2) and receptor-deficient db/db mice (3) were characterized initially as diabetes-obesity syndromes (4). Moreover, these animals exhibit a severe dysregulation of reproductive and hormonal traits (5) as well as a disturbance of hematopoietic and immune functions (6).Lord et al. (7) first reported that leptin increases Thelper (Th)1 cytokine production and suppresses Th2 cytokine production. Implication of leptin in inflammatory responses, including experimental autoimmune encephalomyelitis (8) and experimental arthritis (9), was demonstrated. On the other hand, a recent study showed that neutrophils express leptin receptors and that leptin enhances oxidative species production by neutrophils (10). Moreover, ob/ob mice exhibit impaired host resistance to intratracheal gram-negative Klebsiella pneumoiae infection due to impaired alveolar macrophage phagocytosis and neutrophil complement-mediated phagocytosis (11,12).Diabetes is often identified as an independent risk factor for infections (13,14). We were interested in investigating the role of leptin and its correlation to host resistance to Listeria monocytogenes infection. L. monocytogenes is an intracellular-growing bacterium that is ordinarily nonpathogenic to healthy people; however, it is important as an opportunistic pathogen. The individuals at highest risk are pregnant women and their fetuses, new born infants, debilitated elderly people, and immunocompromized hosts including patients with diabetes (15). Host resistance to L. monocytogenes is controlled by cell-mediated immunity and regulated endogenous cytokines....

The frequency of diabetes mellitus has risen in Japan as the traditional diet has become increasing Americanized and society has aged. With this has come a rise in infectious diseases and complications elderly diabetic patients and a growing need for appropriate management to maintain their quality of life (QOL) and minimize medical measures. Subjects were 98 diabetic patients-60 men and 38 women hospitalized for intravenous antibiotic treatment of infectious disease from 2002 to 2005. We studied plasma glucose control, plasma and urinary protein levels related to nephropathy, and inflammatory responses to treatment. Subjects were divided into good (under 6.5%), fair (from 6.5% to 8.0%), poor (over 8.0%) and severe (over 10%) groups by HbA1c level on admission. We then compared white blood cell counts, CRP levels and the antibacterial medication periods. Those with poorly controlled plasma glucose control, hypoalbuminuria and interrupted or untreated diabetes required significantly longer antibacterial administration. Insulin was increased by the complications of infection, and decreased as infection ameliorated. Appropriate antibiotic administration is essential for diabetic patients with infectious disease, in addition to early intervention, strict plasma glucose control, continuous treatment, and maintenance of good nutrition. Such treatment improves QOL, shortens antibiotic administration, staves off antibiotic-resistant bacteria, and cuts medical costs.

Background: It is expected that GLP-1 Receptor Agonists (GLP-1RA) have not only glucose lowering effect but also weight loss and protection of diabetic kidney disease. On the other hand, sarcopenia and frailty is becoming important, because elderly diabetic patients increase in Japan. In the present study, we report about falling risk, dietary surveys and exercise therapy of diabetic patients treated with GLP-1RA. Methods: The questionnaire was tested in type 2 diabetic outpatients treated with GLP-1RA at our hospital (mean age 65.7 years). The control group was the diabetic outpatient treated without GLP-1RA in nearly the same age range (mean age 63.6 years). We measured hand grip strength and one-leg standing (OLS) time. Participants were defined as patients with a high risk of falling, If their hand grip strength was ≤30kg(male) or ≤20kg(female) and their OLS time was <20s. Especially if their OLS time was <5s, defined as patients with a severe high risk of falling. We also analyzed their dietary surveys in three days. Finally, we planned original exercise program to patients with a high risk of falling, and investigated the effect of this exercise every month. Result: A total of 194 cases (male, 61%; female, 39 %) were included in this study. The prevalence of patients with a high risk falling was 36.1%. In patients treated with GLP-1RA (92 cases) and without GLP-1RA (102 cases), the prevalence of patients with a high risk falling was 45.7% and 27.5%. In patient treated with GLP-1RA, the prevalence of patients with severe high risk falling was 27.5% in liraglutide group (51 cases) and was 36.6% in dulaglutide group (41 cases). Dietary surveys and the effect of exercise program are on-going. Conclusion: These findings show that type 2 diabetic patients treated with GLP-1RA are high risk group of falling compared with patients treated without GLP-1RA. Therefore, in use of GLP-1RA, we should be careful of sarcopenia and frailty involves in weight loss and muscle atrophy. Exercise and diet therapy are important. Disclosure S. Ikejima: None. S. Kondo: None. T. Sakai: None. H. Taniai: None. T. Takahashi: None. J. Umezu: None. M. Iseka: None. M. Inoue: None. H. Nishihara: None. K. Murata: None. A. Hirai: None.

Background: Recently, GLP-1 receptor agonists and SGLT2 inhibitors have been frequently used to reduce the risk of diabetic kidney disease (DKD). However, these therapies may cause anorexia, sarcopenia, and an increased fall-risk. Furthermore, sarcopenia frequently accompanies chronic renal disease. The following study describes a novel method of screening to identify patients at an increased fall-risk in type 2 diabetic patients with DKD. Methods: The procedure was tested in type 2 diabetic outpatients at our hospital. We measured outpatient one-leg standing (OLS) times with eye open and the timed up and go test (TUG), which were fall-risk assessment tools. OLS times of less than 20 seconds or TUG score of more than 11 seconds were predictive of a greater fall-risk. Furthermore, we used the ten time sit to stand test (TTSST) and toe grip strength test (TGST), grip strength, skeletal muscle mass index (SMI), and evaluated diabetic neuropathy. We also analyzed their dietary surveys about Salt and protein intake. We planned a novel exercise program for patients with a high fall-risk. Result: A total of 247 cases (147 males; 100 females) were included in this study. The prevalence of patients with OLS times of less than 20 seconds was 45.3%. Interestingly, 56.6% of patients who scored less than 11 seconds on the TUG also scored less than 20 seconds on their OLS time. The OLS time was significantly associated with impaired renal function. In patients with short OLS times (OLS time<5 seconds) and those with normal OLS times (OLS time≥20), eGFR (ml/min/1.73 m2) was 45.3 and 64.1 respectively. Short OLS times were also significantly associated with TTSST, TGST, SMI and DPN. Salt and protein intake was 7.4 g/day and 50.5 g/day. We are currently analyzing the effects of the exercise program. Conclusion: In summary, a patient’s OLS time, which can be quickly measured in the doctor’s office, was significantly shorter in type 2 diabetic patients with DKD, and was a useful screening procedure to predict fall-risk. Disclosure S. Ikejima: None. S. Kondo: None. T. Takahashi: None. M. Uema: None. J. Umezu: None. A. Hirai: None.

Background: Coronary CT angiography (CCTA) has been applied to detect vulnerable plaques having low attenuation of CT value and positive remodeling which have been associated with acute coronary syndrome. The present study was performed to establish a novel approach to qualitative and quantitative analysis of coronary plaque, especially early detection of high-risk plaque by visualizing intra-plaque localization of necrotic core and the evaluation of plaque stabilizing effect of optimal medical therapy (OMT) including anti-PCSK9 antibody. Methods: We developed color mapped CCTA. The vulnerable plaques are identified by red color (CT attenuation: 0-30) and yellow color (CT attenuation: 30-60). The effect of OMT including anti-PCSK9 antibody on the vulnerable plaques in diabetic patients was studied. Results: Color mapped CCTA clearly demonstrated the presence of necrotic core (red in yellow sign) in vulnerable plaque. After 12 months administration of anti-PCSK9 antibody, an improvement of vulnerable plaque e.g., disappearance of necrotic core in vulnerable plaque was observed. Conclusion: Color mapped CCTA provides a new insight into early detection of high-risk plaque by visualizing intra-plaque localization of necrotic core, also contributes to the evaluation of drugs which may improve vulnerable plaques. Disclosure A. Hirai: None. S. Kondo: None. T. Goto: None. K. Hirai: None. N. Kamiya: None. Y. Tanabe: None. I. Komesu: None. H. Moromizato: None. J. Nakazato: None. S. Ikejima: None. H. Sunagawa: None. T. Kido: None.

Repetitive injection of insulin causes subcutaneous amyloid deposits leading to impaired blood glucose control due to delayed absorption of the drugs. Amyloid deposits in abdominal wall is detected by CT examinations. Proper selection of the injection site avoiding amyloid deposits is essential. The present study was conducted to establish a novel method for the management of injection site avoiding amyloid deposits. The present study included 50 diabetic patients who were treated with insulin over 5 years. Two weeks CGM was performed using Free Style Libre Pro. In the case of significant day to day variation in blood glucose control, abdominal wall CT examination was performed. In front abdominal wall, 36 small circular zones were set to identify the site of injection, named “no-injection zone” which caused impaired blood glucose control due to delayed absorption of insulin by amyloid deposits. Site rotation seat was developed for the management of insulin injection site. Among 50 patients, 33 patients were shown to have “no-injection zone” (average; 8.5 zones). In the patients whose HbA1c is over 8% (n=15), a significant improvement in HbA1c from 9.0% to 7.8% was observed without any changes in daily dose of long-acting insulins by the management of injection site. The management of injection site using CGM, abdominal CT and site rotation seat improves blood glucose control. Disclosure H. Nishihara: None. T. Sudo: None. J. Sasaki: None. N. Hasegawa: None. M. Ishii: None. C. Koizumi: None. M. Hiraoka: None. S. Ikejima: None. A. Hirai: None. M. Suzuki: None.

Background: Older type 2 diabetic patients are at an increased risk of falling. On the other hand, the risk of sarcopenia increases in patients with chronic renal disease. In the present study, we reported about the risk of falling in type 2 diabetic patients with diabetic kidney disease (DKD). Methods: Participants were 111 outpatients with type 2 diabetes at our hospital (66.1±8.8 years old). We measured one-leg standing (OLS) time with eyes open and analyzed the date according to renal function. Participants were defined as patients with a high risk of falling, if their OLS time was less than 20s. In order to examine the cause of short OLS time, we measured the ten times sit to stand test (TTSTS) and toe grip strength test (TGST). Furthermore, we measured hand grip strength, the timed up and go test (TUG), skeletal muscle mass (Inbody S10, Biospace, Tokyo, Japan), and evaluated diabetic peripheral neuropathy (DPN) by DPN Check (HDN-1000, Omron, Tokyo, Japan). At last, we planned original physical therapy for patients. Result: A total of 101 cases (60 males; 51 females) were included in this study. The prevalence of patients with a high risk of falling was 60.0%. In patients without renal failure (eGFR ≥ 60 ml/min/1.73 m2), with mild renal failure (30 ≤ eGFR < 60), and with sever renal failure (eGFR < 30), the prevalence of patients with a high risk of falling was 48.1%, 67.9%, and 81.8 % respectively. Patients with a short OLS time tended to perform the TTSTS more slowly than patients with a normal OLS time. Short OLS time is also associated with TGST. Patients with DPN did badly on the TGST. Based on this result, we provided patients with a physical therapy program and diet therapy. Conclusion: These findings showed that the OLS time was significantly shorter in type 2 diabetic patients, especially those with advanced DKD. Therefore, exercise therapy, diet therapy including a good quality protein intake and management of complication including diabetic DPN are important for type 2 diabetic patients with DKD. Disclosure S. Ikejima: None. T. Takahashi: None. S. Kondo: None. J. Umezu: None. M. Uema: None. A. Hirai: None.

Purpose: Coronary plaque progression despite very low levels of LDL-C has been reported in the patients with coronary artery disease (CAD) who received intensive statin therapy (IST). CCTA has been applied to detect vulnerable coronary plaques having low attenuation of CT value. The best characterized function of PCSK9 is the binding to hepatic LDL receptors, leading to their degradation. PCSK9 is produced also in vascular smooth muscle cells constituting the atheriosclerotic lesion in addition to hepatocytes. PCSK9 promotes foam cell formation by suppressing the excretion of cholesterol from macrophages. Recently, statin is demonstrated to promote PCSK9 production. PCSK9 has been proposed to play a crucial role in the pathogenesis of IST resistance. The present study was performed to establish a novel therapeutic approach to IST resistant vulnerable plaque of coronary artery in diabetic patients. Methods: The present study included 1T2DM patients with non-FHC asymptomatic CAD who developed vulnerable plaques in coronary artery despite IST over 1 year. CCTA by use of 320-slice CT was applied to evaluate vulnerable plaques in coronary artery. During the administration of anti-PCSK9 antibody, changes in serum lipids and CT value of vulnerable coronary plaques were determined. Results: After the administration of anti-PCSK9 antibody, 72% decrease in serum LDL-C was observed. Also, improvement of vulnerable coronary plaque e.g., rise in the CT value of plaque (from 45.2 ± 12.0 HU to 107.5 ± 42.3 HU, p<0.0001) was observed in 6 months after administration of the drug. Conclusion: A significant improvement in vulnerable coronary plaques was observed in the patients with asymptomatic CAD who are resistant to IST after 6 months administration of anti-PCSK9 antibody. An analysis of the plaque quality by CCTA is useful method for the evaluation of the effect of the drug on vulnerable coronary plaques. Disclosure A. Hirai: None. K. Fujimura: None. S. Kondo: None. T. Sakai: None. S. Ikejima: None. H. Taniai: None. K. Hirai: None. K. Murata: None. A. Shirakami: None. K. Okuzaki: None. T. Kageyama: None.