Prevalence and characteristics of diabetic symmetric sensorimotor polyneuropathy in Japanese patients with type 2 diabetes: the Japan Diabetes Complication and its Prevention Prospective study (JDCP study 10).

Aim/introduction: This study aims to investigate the prevalence and characteristics of diabetic symmetric sensorimotor polyneuropathy (DSPN) in patients with type 2 diabetes registered in the Japan Diabetes Complication and its Prevention Prospective (JDCP) study. Materials and methods: In the study, 6338 patients with diabetes who had been treated by diabetes specialists were registered in 2007-2009. Of these, patients with type 2 diabetes who could be evaluated for DSPN were analyzed using t test, chi-square test, and logistic regression analyses. DSPN was diagnosed using the Simple Diagnostic Criteria for Diabetic Polyneuropathy proposed by the Diabetic Neuropathy Study Group in Japan. Results: Of the total participants, 5451 patients (mean age 61.4 years old and duration of diabetes 10.8 years) were analyzed. Based on the criteria, 35.8% of patients were diagnosed with DSPN. The prevalence of sensory symptoms was 25.8%. The following factors increased risk for DSPN: age [odds ratio (OR) 1.57, 95% confidence intervals (CI) 1.42-1.73], duration of diabetes (OR 1.32, 95% CI 1.21-1.43), body mass index (OR 1.19, 95% CI 1.09-1.30), systolic blood pressure (OR 1.06, 95% CI 1.01-1.10), hemoglobin A1c (OR 1.15, 95% CI 1.09-1.22), biguanides (OR 1.22, 95% CI 1.06-1.39), and insulin therapy (OR 1.59, 95% CI 1.36-1.84). The following factors decreased risk for DSPN: total cholesterol (OR 0.98, 95% CI 0.96-1.00) and exercise therapy (OR 0.85, 95% CI 0.73-0.98). Conclusions: The baseline survey clarified the prevalence and characteristics of DSPN in Japanese patients with type 2 diabetes. The survey also revealed the risk factors of DSPN.

Prevalence and characteristics of diabetic symmetric sensorimotor polyneuropathy in Japanese patients with type 2 diabetes: The Japan Diabetes Complication and its Prevention Prospective study (JDCP study 10).

This study aimed to investigate the prevalence and characteristics of diabetic symmetric sensorimotor polyneuropathy (DSPN) in patients with type 2 diabetes registered in the Japan Diabetes Complication and its Prevention Prospective study. In the study, 6,338 patients with diabetes who had been treated by diabetes specialists were registered in 2007-2009. Of these, patients with type 2 diabetes who could be evaluated for DSPN were analyzed using the t-test, χ2 -test and logistic regression analyses. DSPN was diagnosed using the Simple Diagnostic Criteria for Diabetic Polyneuropathy proposed by the Diabetic Neuropathy Study Group in Japan. Of the total participants, 5,451 patients (mean age 61.4 years, duration of diabetes 10.8 years) were analyzed. Based on the criteria, 35.8% of patients were diagnosed with DSPN. The prevalence of sensory symptoms was 25.8%. The following factors increased the risk for DSPN: age (odds ratio [OR] 1.57, 95% confidence interval [CI] 1.42-1.73), duration of diabetes (OR 1.32, 95% CI 1.21-1.43), body mass index (OR 1.19, 95% CI 1.09-1.30), systolic blood pressure (OR 1.06, 95% CI 1.01-1.10), hemoglobin A1c (OR 1.15, 95% CI 1.09-1.22), biguanides (OR 1.22, 95% CI 1.06-1.39) and insulin therapy (OR 1.59, 95% CI 1.36-1.84). The following factors decreased the risk for DSPN: total cholesterol (OR 0.98, 95% CI 0.96-1.00) and exercise therapy (OR 0.85, 95% CI 0.73-0.98). The baseline survey clarified the prevalence and characteristics of DSPN in Japanese patients with type 2 diabetes. The survey also showed the risk factors of DSPN.

Prevalence of nonalcoholic fatty liver disease and its association with age in patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a risk factor for nonalcoholic fatty liver disease (NAFLD). AIM: To determine the prevalence and clinical correlates of NAFLD in a large cohort of patients with T2DM. METHODS: Four hundred thirty-seven participants with T2DM who consulted at Meijo Hospital from April 2019 to September 2020 and underwent computed tomography (CT) were assessed. The mean age was 74 ± 13 years, and 269 were men. Hepatic attenuation minus splenic attenuation (CTL-S) less than 1 Hounsfield unit was considered fatty liver. NAFLD was defined as fatty liver in the absence of significant alcohol consumption and hepatitis virus infection. A multiple logistic regression was used to assess the independent factors associated with NAFLD. RESULTS: NAFLD was identified in 25.2% of the participants. Young age (odds ratio [OR] = -0.945; 95% confidence interval [CI]: 0.922-0.969), higher hemoglobin levels (OR = 1.501, 95%CI: 1.278-1.764), lower high-density lipoprotein (HDL) cholesterol levels (OR = 0.971, 95%CI: 0.953-0.989), and the absence of dialysis (OR = 0.109, 95%CI: 0.014-0.856) were independent predictors of NAFLD. CONCLUSION: NAFLD was detected with CT in 25.2% of the participants. NAFLD was associated with younger age, higher hemoglobin levels, lower HDL cholesterol levels, and an absence of dialysis.

Effect of re-coaching on self-injection of insulin in older diabetic patients - Impact of cognitive impairment.

AIMS: We investigated the effect of re-coaching on self-injection of insulin and impact of cognitive function in 100 older diabetic patients. METHODS: We examined patients on a variety of skills and knowledge regarding self-injection of insulin and evaluated the effect of re-coaching the patients after 3months and 4years. We also investigated the influence of cognitive impairment (CI) on coaching. RESULTS: Skills scores for self-injection of insulin and HbA1c improved significantly 3months after re-coaching. In 51 patients followed-up for 4years, skills scores were maintained during the 4years, while knowledge scores improved after 3months but then returned to the baseline level. In the group of patients with CI as determined by the Mini-Mental Status Examination, skills scores were similar to those in the group without CI, while knowledge scores were significantly lower as compared with those in the group without CI at any time point. Skills scores were maintained during the 4years regardless of CI. CONCLUSION: The present study showed that re-coaching in skills for self-injection of insulin was effective in improving and maintaining insulin treatment in older diabetic patients, even if patients had CI.

Factors Associated with Changes in Brain Atrophy during a Three-Year Observation in Elderly Diabetic Patients: Effect of Renal Impairment on Hippocampal Atrophy.

BACKGROUND/AIMS: We conducted a 3-year longitudinal study concerning factors associated with changes in brain atrophy in elderly diabetic patients. METHODS: We evaluated hippocampal and global brain atrophy using automatic voxel-based morphometry of structural magnetic resonance images, 4 cognitive function tests, and cerebral small vessel disease (SVD) in 66 diabetic patients. RESULTS: During the 3-year follow-up, hippocampal and global brain atrophy advanced, and cognitive functions worsened. For changes in hippocampal atrophy, changes in estimated glomerular filtration rate (eGFR), albuminuria, and being an ApoE ε4 carrier were independent factors; change in the number of silent brain infarctions was an independent factor for changes in global brain atrophy. A significant association of changes in eGFR and albuminuria with hippocampal atrophy remained after adjusting for confounders including SVD. Both types of brain atrophy at baseline were significantly correlated with cognitive impairment at baseline and especially associated with changes in delayed word recall during the follow-up after adjusting for confounders. CONCLUSION: Changes in eGFR and albuminuria during follow-up were independent risk factors for hippocampal atrophy, which was associated with decline in delayed word recall, suggesting that management of chronic kidney disease may prevent the progression of hippocampal atrophy.

Case of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet.

We present a case of a 32-year-old diabetic woman with Prader-Willi syndrome who developed severe ketoacidosis caused by a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a novel class of antihyperglycemic agents, during a strict low-carbohydrate diet. At admission, a serum glucose level of 191 mg/dL was relatively low, though laboratory evaluations showed severe ketoacidosis. This is the first report of ketoacidosis caused by a SGLT2 inhibitor. It is necessary to not only pay attention when using a SGLT2 inhibitor in patients following a low-carbohydrate diet, but also to start a low-carbohydrate diet in patients treated with a SGLT2 inhibitor because of a high risk for developing ketoacidosis.

Therapeutic efficacy of bone marrow-derived mononuclear cells in diabetic polyneuropathy is impaired with aging or diabetes.

AIMS/INTRODUCTION: Recent studies have shown that cell transplantation therapies, such as endothelial precursor cells, bone marrow-derived mononuclear cells (BM-MNCs) and mesenchymal stem cells, are effective on diabetic polyneuropathy through ameliorating impaired nerve blood flow in diabetic rats. Here, we investigated the effects of BM-MNCs transplantation in diabetic polyneuropathy using BM-MNCs derived from adult (16-week-old) diabetic (AD), adult non-diabetic (AN) or young (8-week-old) non-diabetic (YN) rats. MATERIALS AND METHODS: BM-MNCs of AD and AN were isolated after an 8-week diabetes duration. The BM-MNCs were characterized using flow cytometry analysis of cell surface markers and reverse transcription polymerase chain reaction of several cytokines. BM-MNCs or saline were injected into hind limb muscles. Four weeks later, the thermal plantar test, nerve conduction velocity, blood flow of the sciatic nerve and capillary-to-muscle fiber ratio were evaluated. RESULTS: The number of CD29(+)/CD90(+) cells that host mesenchymal stem cells in BM-MNCs decreased in AD compared with AN or YN, and transcript expressions of basic fibroblast growth factor and nerve growth factor in BM-MNCs decreased in AD compared with AN or YN. Impaired thermal sensation, decreased blood flow of the sciatic nerve and delayed nerve conduction velocity in 8-week-diabetic rats were significantly ameliorated by BM-MNCs derived from YN, whereas BM-MNCs from AD or AN rats did not show any beneficial effect in these functional tests. CONCLUSIONS: These results show that cytokine production abilities and the mesenchymal stem cell population of BM-MNCs would be modified by aging and metabolic changes in diabetes, and that these differences could explain the disparity of the therapeutic efficacy of BM-MNCs between young and adult or diabetic and non-diabetic patients in diabetic polyneuropathy.

Irbesartan attenuates production of high-mobility group box 1 in response to lipopolysaccharide via downregulation of interferon-ß production.

High-mobility group box 1 (HMGB1) is suggested to participate in development of local and systemic inflammatory disorders. Irbesartan (IRB), an angiotensin II type1 receptor blocker, is widely used for treatment of hypertension, especially in patients with diabetic nephropathy. The effect of IRB on lipopolysaccharide (LPS)-induced HMGB1 and nitric oxide (NO) production was examined using RAW 264.7 macrophage-like cells. IRB inhibited LPS-induced HMGB1 production. IRB also reduced LPS-induced expression of an inducible NO synthase, and inhibited LPS-induced NO production. The expression levels of IFN-ß protein and mRNA, which is a key molecule in MyD88-independent pathway of LPS signaling, were exclusively inhibited by IRB. Peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor were not involved in the inhibitory action of IRB on LPS-induced HMGB1 and NO production. Collectively, IRB was suggested to inhibit LPS-induced HMGB1 production via downregulation of IFN-ß production in the MyD88-independent pathway.

Effect of renal impairment on cognitive function during a 3-year follow up in elderly patients with type 2 diabetes: Association with microinflammation.

AIMS/INTRODUCTION: We investigated the effect of renal impairment on cognitive function during a 3-year follow up in elderly type 2 diabetic patients, and an association with microinflammation. MATERIALS AND METHODS: Four cognitive function tests - Mini-Mental State Examination (MMSE), word recall, Digit Symbol Substitution (DSS) and Stroop Color Word - were carried out in 67 patients. Renal impairment was defined as the presence of albuminuria and a decline in estimated glomerular filtration (eGFR) <60 mL/min/1.73 m(2). Inflammatory markers, such as highly sensitive C-reactive protein (hs-CRP), tumor necrotizing factor-α (TNF-α), interleukin (IL)-1ß and IL-6, were measured at baseline. RESULTS: At baseline, cognitive decline was found in patients with renal impairment. The DSS test was independently associated with eGFR decline, whereas MMSE tended to be associated with albuminuria after adjusting for confounding factors. Regarding changes in cognitive function and renal impairment, changes in urinary albumin to creatinine ratios were strongly and independently associated with changes in word recall scores. In patients with persistent eGFR decline, there was a tendency toward a greater decrease in MMSE and DSS scores, whereas in those with newly detected albuminuria, there was a tendency toward a greater decrease in word recall scores. Increased baseline levels of hs-CRP, TNF-α and IL-6 were associated with renal impairment and cognitive function, especially DSS tests, respectively. However, the increased levels were not independent predictors for cognitive decline. CONCLUSIONS: The present study showed a reciprocal relationship between cognitive decline and renal impairment, especially progression of albuminuria. Thus, monitoring treatment using renal biomarkers will be important for preserving both renal and cognitive function.

Spironolactone inhibits production of proinflammatory mediators in response to lipopolysaccharide via inactivation of nuclear factor-κB.

The effect of spironolactone (SPIR) on lipopolysaccharide (LPS)-induced production of proinflammatory mediators was examined using RAW 264.7 macrophage-like cells and mouse peritoneal macrophages. SPIR significantly inhibited LPS-induced production of nitric oxide (NO), tumor necrosis factor-α and prostaglandin E2. The inhibition was not mediated by cell death. SPIR reduced the expression of an inducible NO synthase mRNA in response to LPS. SPIR significantly inhibited phosphorylation of p65 nuclear factor (NF)-κB in response to LPS. Furthermore, SPIR inhibited phosphorylation of IκB kinase (IKK) as an upstream molecule of NF-κB in response to LPS. LPS did not induce the production of aldosterone in RAW 264.7 cells. Taken together, SPIR is suggested to inhibit LPS-induced proinflammatory mediators via inactivation of IKK/NF-κB in LPS signaling.

Significant modulation of the hepatic proteome induced by exposure to low temperature in Xenopus laevis.

The African clawed frog, Xenopus laevis, is an ectothermic vertebrate that can survive at low environmental temperatures. To gain insight into the molecular events induced by low body temperature, liver proteins were evaluated at the standard laboratory rearing temperature (22°C, control) and a low environmental temperature (5°C, cold exposure). Using nano-flow liquid chromatography coupled with tandem mass spectrometry, we identified 58 proteins that differed in abundance. A subsequent Gene Ontology analysis revealed that the tyrosine and phenylalanine catabolic processes were modulated by cold exposure, which resulted in decreases in hepatic tyrosine and phenylalanine, respectively. Similarly, levels of pyruvate kinase and enolase, which are involved in glycolysis and glycogen synthesis, were also decreased, whereas levels of glycogen phosphorylase, which participates in glycogenolysis, were increased. Therefore, we measured metabolites in the respective pathways and found that levels of hepatic glycogen and glucose were decreased. Although the liver was under oxidative stress because of iron accumulation caused by hepatic erythrocyte destruction, the hepatic NADPH/NADP ratio was not changed. Thus, glycogen is probably utilized mainly for NADPH supply rather than for energy or glucose production. In conclusion, X. laevis responds to low body temperature by modulating its hepatic proteome, which results in altered carbohydrate metabolism.

Does cerebral small vessel disease predict future decline of cognitive function in elderly people with type 2 diabetes?

AIMS: We conducted a 3-year longitudinal study concerning an association between cognitive function and cerebral small vessel disease (SVD) seen on magnetic resonance imaging (MRI) in elderly type 2 diabetic patients. METHODS: Four cognitive function tests--MMSE, word recall, Digit Symbol Substitution (DSS), and Stroop Color Word (Stroop)--were performed in 67 diabetic patients twice in 2006 and 2009. SVD was diagnosed as silent brain infarct (SBI) and white matter lesions (WMLs) according to MRI. RESULTS: Number of SBI was significantly correlated with a decline in DSS and Stroop tests, while WMLs grade was only associated with it in DSS tests after adjustment for age, gender, education years, the presence of hypertension and dyslipidemia, and smoking. Severity of SVD at baseline was stronger associated with cognitive function after the 3-year follow-up than at baseline. WMLs progression was associated with more rapid decline of DSS tests compared to a group without progression. CONCLUSIONS: SVD seen on MRI is a good marker for predicting future cognitive decline, and monitoring of treatment through the use of such markers is expected to maintain a good quality of life for elderly diabetic patients.

Association of resistin polymorphism, its serum levels and prevalence of stroke in Japanese type 2 diabetic patients.

UNLABELLED: Aims/Introduction: Resistin, an inflammatory cytokine, might be involved in the development of atherosclerosis. In a recent paper, we showed that resistin polymorphism might be a risk marker for stroke susceptibility in Japanese type 2 diabetic patients. We tested whether the serum resistin levels might be also a risk marker of stroke independently from RETN polymorphism. MATERIALS AND METHODS: Type 2 diabetic outpatients from our hospitals were enrolled. Patients (n = 89) with a history of coronary heart disease and stroke, and randomly selected controls (n = 178) matched for sex and age, but without a history of coronary heart disease and stroke, were examined for polymorphism -420 (C>G) and cytokines levels. RESULTS: Serum resistin levels were significantly higher in patients with cardiovascular diseases (CVD) than in those without CVD (P = 0.024), and were highest in patients with stroke among the CVD. In multiple logistic regression analysis, serum resistin levels was an independent risk marker of stroke even after adjusted by RETN polymorphism, age, sex, body mass index, HbA1c, systolic and diastolic blood pressure, triglyceride, low density lipoprotein cholesterol, high density lipoprotein cholesterol, creatinine, history of coronary heart disease, treatment of insulin, sulfonylurea and aspirin (odds ratio 1.33, 95% confidence interval [CI] 1.02-1.73, P = 0.039). The enrolled patients were divided by their serum resistin levels (high or low group) and their genotypes (CC, CG, GG at -420) into six groups. Patients with the GG genotype and high resistin levels showed the highest odds ratio, 5.69 (95% CI 1.24-26.1), compared with the group with CC and low levels. CONCLUSIONS: The results suggest that serum resistin levels might be a good marker of susceptibility to stroke as well as RETN polymorphism. (J Diabetes Invest, doi: 10.1111/j.2040-1124.00040.x, 2010).

Polymorphism in resistin promoter region at -420 determines the serum resistin levels and may be a risk marker of stroke in Japanese type 2 diabetic patients.

Resistin, which appears to be related to insulin resistance, is secreted mainly from macrophages in human and some of its polymorphisms have been reported. Based on recent in vitro studies, resistin may be associated with atherosclerosis by mediating endothelial hyperactivity. We investigated whether resistin polymorphism at -420C>G is associated with serum resistin levels and diabetic macroangiopathy (coronary heart disease, arteriosclerosis obliterans, and stroke) in 349 Japanese type 2 diabetic patients (DM) and 286 non-diabetic controls (non-DM). Serum resistin levels in DM with a history of stroke were significantly higher than those without, 19.6+/-2.1 and 12.4+/-0.5 ng/ml (P<0.001), respectively. Furthermore, the levels were significantly increased in a genotype-dependent manner (CC, CG, GG) based on the polymorphism at -420C>G (P<0.001) in both DM and non-DM. The prevalence of stroke in DM significantly increased according to the presence of mutations (P<0.035). In multivariate logistic-regression analysis, individuals with the CG or GG genotypes were significantly more likely to have had a stroke than individuals with the CC genotype (vs. CG; OR 2.99, P=0.024, vs. GG; OR 4.49, P=0.010). These data suggested that the genotyping of resistin polymorphism at -420(C>G) can be a risk marker for stroke susceptibility in Japanese type 2 diabetic patients.

Metformin prevents methylglyoxal-induced apoptosis of mouse Schwann cells.

Methylglyoxal (MG) is involved in the pathogenesis of diabetic complications via the formation of advanced glycation end products (AGEs) and reactive oxygen species (ROS). To clarify whether the antidiabetic drug metformin prevents Schwann cell damage induced by MG, we cultured mouse Schwann cells in the presence of MG and metformin. Cell apoptosis was evaluated using Hoechst 33342 nuclear staining, caspase-3 activity, and c-Jun-N-terminal kinase (JNK) phosphorylation. Intracellular ROS formation was determined by flow cytometry, and AMP-activated kinase (AMPK) phosphorylation was also examined. MG treatment resulted in blunted cell proliferation, an increase in the number of apoptotic cells, and the activation of caspase-3 and JNK along with enhanced intracellular ROS formation. All of these changes were significantly inhibited by metformin. No significant activation of AMPK by MG or metformin was observed. Taken together, metformin likely prevents MG-induced apoptotic signals in mouse Schwann cells by inhibiting the formation of AGEs and ROS.

Effects of basic fibroblast growth factor on experimental diabetic neuropathy in rats.

Basic fibroblast growth factor (bFGF) stimulates angiogenesis and induces neural cell regeneration. We investigated the effects of bFGF on diabetic neuropathy in streptozotocin-induced diabetic rats. Diabetic rats were treated with human recombinant bFGF as follows: 1) intravenous administration, 2) intramuscular injection into thigh and soleus muscles with cross-linked gelatin hydrogel (CGH), and 3) intramuscular injection with saline. Ten or 30 days later, the motor nerve conduction velocity (MNCV) of the sciatic-tibial and caudal nerves, sensitivity to mechanical stimuli, sciatic nerve blood flow (SNBF), and retinal blood flow (RBF) were measured. Delayed MNCV in the sciatic-tibial and caudal nerves, hypoalgesia, and reduced SNBF in diabetic rats were all ameliorated by intravenous administration of bFGF after 10, but not 30, days. Intramuscular injection of bFGF with CGH also improved sciatic-tibial MNCV, hypoalgesia, and SNBF after 10 and 30 days, but caudal MNCV was not improved. However, intramuscular injection of bFGF with saline had no significant effects. bFGF did not significantly alter RBF in either normal or diabetic rats. These observations suggest that bFGF could have therapeutic value for diabetic neuropathy and that CGH could play important roles as a carrier of bFGF.