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Background: This study aimed to evaluate the changes in glycemic control and diabetic complications over time in Japanese patients with juvenile‐onset type 1 diabetes mellitus and to clarify the factors associated with the progression of diabetic complications. Methods: We tracked 129 patients with type 1 diabetes mellitus (21.8 ± 4.1 years old [mean ± SD] with a diabetes duration of 12.6 ± 5.7 years) for up to 19 years and analyzed data on glycated hemoglobin (HbA1c) and indicators related to the severity of diabetic complications (estimated glomerular filtration rate [eGFR], urinary albumin excretion rate [UAE], carotid intima‐media thickness [CIMT], and brachial‐ankle pulse wave velocity [baPWV]) using linear mixed model and decision tree analysis. Results: Although the HbA1c and UAE levels improved over time, the eGFR, CIMT, and baPWV worsened. Decision tree analysis showed that HbA1c and the glycoalbumin/HbA1c ratio for eGFR; HbA1c and systolic blood pressure for UAE; low‐density lipoprotein cholesterol/high‐density lipoprotein cholesterol ratio, glycoalbumin/HbA1c ratio, and body mass index (BMI) for CIMT; and HbA1c for baPWV were associated factors. Conclusions: In this retrospective observational study, glycemic control and albuminuria improved; however, renal function and arteriosclerosis worsened over time. HbA1c levels, glycemic excursion, and blood pressure are associated with nephropathy progression. HbA1c levels, glycemic excursion, lipid levels, and BMI are associated with the progression of atherosclerosis. [ABSTRACT FROM AUTHOR]

Aims/Introduction: To investigate whether the COVID‐19 pandemic affected behavioral changes and glycemic control in patients with diabetes and to conduct a survey of telemedicine during the pandemic. Materials and Methods: In this retrospective study, a total of 2,348 patients were included from 15 medical facilities. Patients were surveyed about their lifestyle changes and attitudes toward telemedicine. Hemoglobin A1c (HbA1c) levels were compared among before (from June 1 to August 31, 2019) and in the first (from June 1 to August 31, 2020) and in the second (from June 1 to August 31, 2021) year of the pandemic. A survey of physician attitudes toward telemedicine was also conducted. Results: The HbA1c levels were comparable between 2019 (7.27 ± 0.97%), 2020 (7.28 ± 0.92%), and 2021 (7.25 ± 0.94%) without statistical difference between each of those 3 years. Prescriptions for diabetes medications increased during the period. The frequency of eating out was drastically reduced (51.7% in 2019; 30.1% in 2020), and physical activity decreased during the pandemic (48.1% in 2019; 41.4% in 2020; 43.3% in 2021). Both patients and physicians cited increased convenience and reduced risk of infection as their expectations for telemedicine, while the lack of physician–patient interaction and the impossibility of consultation and examination were cited as sources of concern. Conclusions: Our data suggest that glycemic control did not deteriorate during the COVID‐19 pandemic with appropriate intensification of diabetes treatment in patients with diabetes who continued to attend specialized diabetes care facilities, and that patients and physicians shared the same expectations and concerns about telemedicine. [ABSTRACT FROM AUTHOR]

To evaluate whether continuous subcutaneous insulin infusion attenuates the progression of diabetic complications, we retrospectively extracted data from 35 individuals who had developed type 1 diabetes mellitus aged ≤20 years and whose treatment had been changed from multiple daily injections to continuous subcutaneous insulin infusion. The annual changes in estimated glomerular filtration rate, urinary albumin excretion rate, carotid intima‐media thickness and brachial‐ankle pulse wave velocity during each treatment period were calculated. Although mean glycated hemoglobin under the continuous subcutaneous insulin infusion treatment was lower than that under the multiple daily injection treatment, there were no significant differences in annual changes in diabetic nephropathy and atherosclerosis between the two treatment periods. This pilot study showed that, in Japanese patients with juvenile‐onset type 1 diabetes mellitus, there was no significant difference in the progression of diabetic nephropathy and atherosclerosis, at least in the early stage, between the two treatments. [ABSTRACT FROM AUTHOR]

Aims/Introduction: To investigate the basal insulin requirement in patients with type 1 diabetes who are on multiple daily injections (MDI) and to assess the patient characteristics that affect the percent of total daily basal insulin dose to the total daily insulin dose (%TBD/TDD). Materials and Methods: The subjects of this study were 67 inpatients with type 1 diabetes who were served diabetic meals of 25–30 kcal/kg standard body weight during several weeks of hospitalization. The basal insulin requirement was adjusted to keep the blood glucose level from bedtime to before breakfast within a 30 mg/dL difference. The bolus insulin dose before the meal was adjusted to keep the blood glucose level below 140 and 200 mg/dL before and 2 h after each meal, respectively. The total daily insulin dose (TDD), the percent of total daily basal insulin dose (TBD) to TDD (%TBD/TDD), and clinical characteristics were collected. Results: The median (Q1, Q3) of TDD was 33.0 (26.0, 49.0) units, and the %TBD/TDD was 24.1 ± 9.8%. The %TBD/TDD was positively correlated with the body mass index (BMI) and negatively correlated with the age at the onset and at the examination according to a univariate analysis. However, the %TBD/TDD was dependent on the BMI (β = 0.340, P = 0.004) and the age at examination (β = −0.288, P = 0.012) according to the multiple regression analysis. Conclusions: The average %TBD/TDD in patients with type 1 diabetes on MDI was approximately 24% under inpatient conditions. The basal insulin requirement was dependent on the BMI and the age at examination. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Thrombin exerts various pathophysiological functions by activating protease‐activated receptors (PARs). Recent data have shown that PARs influence the development of glomerular diseases including diabetic kidney disease (DKD) by regulating inflammation. Heparin cofactor II (HCII) specifically inactivates thrombin; thus, we hypothesized that low plasma HCII activity correlates with DKD development, as represented by albuminuria. Materials and Methods: Plasma HCII activity and spot urine biomarkers, including albumin and liver‐type fatty acid‐binding protein (L‐FABP), were determined as the urine albumin‐to‐creatinine ratio (uACR) and the urine L‐FABP‐to‐creatinine ratio (uL‐FABPCR) in 310 Japanese patients with diabetes mellitus (176 males and 134 females). The relationships between plasma HCII activities and those DKD urine biomarkers were statistically evaluated. In addition, the relationship between plasma HCII activities and annual uACR changes was statistically evaluated for 201/310 patients (115 males and 86 females). Results: The mean plasma HCII activity of all participants was 93.8 ± 17.7%. Multivariate‐regression analysis including confounding factors showed that plasma HCII activity independently contributed to the suppression of the uACR and log‐transformed uACR values (P = 0.036 and P = 0.006, respectively) but not uL‐FABPCR (P = 0.541). In addition, plasma HCII activity significantly and inversely correlated with annual uACR and log‐transformed uACR increments after adjusting for confounding factors (P = 0.001 and P = 0.014, respectively). Conclusions: The plasma HCII activity was inversely and specifically associated with glomerular injury in patients with diabetes. The results suggest that HCII can serve as a novel predictive factor for early‐stage DKD development, as represented by albuminuria. [ABSTRACT FROM AUTHOR]

Aims/Introduction: The present study aimed to clarify the prevalence and clinical characteristics of sarcopenia and dynapenia, which are muscle weakness with and without low muscle mass, respectively, in Japanese patients with type 1 diabetes mellitus and type 2 diabetes mellitus. Materials and Methods: This cross‐sectional study enrolled 1,328 participants with type 1 diabetes (n = 177), type 2 diabetes (n = 645) and without diabetes (n = 506). Sarcopenia was defined as a low grip strength and slow gait speed with low skeletal muscle mass index, whereas dynapenia was defined as low strengths of grip and knee extension with a normal skeletal muscle mass index. Participants without sarcopenia and dynapenia were defined as robust. Results: Among participants aged ≥65 years, sarcopenia and dynapenia were observed in 12.2% and 0.5% of individuals without diabetes, 42.9% and 11.4% of type 1 diabetes patients, and 20.9% and 13.9% of type 2 diabetes patients. In both type 1 diabetes and type 2 diabetes patients, sarcopenic patients were significantly older and thinner, and showed a significantly higher rate of diabetic neuropathy than robust patients. In patients with type 1 diabetes and type 2 diabetes, dynapenic patients were older, and showed a higher rate of diabetic neuropathy and lower estimated glomerular filtration rate than robust patients. Patients complicated with sarcopenia and dynapenia showed a significantly lower physical quality of life and higher rate of incidental falls than robust patients. Conclusions: Sarcopenia and dynapenia were more frequent in patients with type 1 diabetes and type 2 diabetes than in individuals without diabetes, which might contribute to their impaired quality of life and incidental falls. [ABSTRACT FROM AUTHOR]

Severe hypoglycaemia (SH) remains a challenge to people with type 1 diabetes (T1DM), and new‐generation basal insulins may improve patient outcomes. This post hoc meta‐analysis explored the risk of SH with insulin glargine 300 U/mL (Gla‐300) versus glargine 100 U/mL (Gla‐100) in a pooled population with T1DM from three randomized, multicentre, 6‐month similarly designed phase 3 trials: EDITION 4, EDITION JP 1 and EDITION JUNIOR. Endpoints included incidence and time to first occurrence of SH. Among 629 and 626 participants randomized to Gla‐300 and Gla‐100, respectively, glycated haemoglobin reductions were similar. Fewer participants experienced ≥1 SH event with Gla‐300 (6.2%) than with Gla‐100 (9.3%). From baseline to month 6, the risk of a first SH event was lower with Gla‐300: hazard ratio 0.65 [95% confidence interval (CI) 0.44–0.98; stratified log‐rank test P = 0.038]. SH event rates were numerically lower with Gla‐300 versus Gla‐100 from baseline to month 6 [relative risk (RR) 0.80 (95% CI 0.49–1.29); P = 0.356] and baseline to week 8 [RR 0.73 (95% CI 0.37–1.44); P = 0.369]. Thus, Gla‐300 demonstrated similar glycaemic control with lower risk of SH versus Gla‐100, particularly during the titration period. [ABSTRACT FROM AUTHOR]

Aim: To compare nasal glucagon (NG) with intramuscular glucagon (IMG) for the treatment of insulin‐induced hypoglycaemia in Japanese patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). Materials and methods: This phase 3, randomized, open‐label, two‐treatment, two‐period crossover non‐inferiority study enrolled Japanese adults with T1DM or T2DM on insulin therapy, with glycated haemoglobin levels ≤86 mmol/mol (≤10%). After ≥8 hours of fasting, hypoglycaemia was induced with human regular insulin (intravenous infusion). Patients received NG 3 mg or IMG 1 mg approximately 5 minutes after insulin termination. The primary endpoint was the proportion of patients achieving treatment success [plasma glucose (PG) increase to ≥3.9 mmol/L (≥70 mg/dL) or ≥1.1 mmol/L (≥20 mg/dL) increase from the PG nadir within 30 minutes of receiving glucagon]. Non‐inferiority was declared if the upper limit of the two‐sided 95% confidence interval (CI) of the mean difference in the percentage of patients achieving treatment success (IMG minus NG) was <10%. Results: Seventy‐five patients with T1DM (n = 34) or T2DM (n = 41) were enrolled; 72 patients (50 men, 22 women) received ≥1 study drug dose (T1DM, n = 33; T2DM, n = 39). Sixty‐eight patients completed the study and were evaluable. All NG‐ and IMG‐treated patients achieved treatment success (treatment arm difference: 0%; upper limit of two‐sided 95% CI 1.47%); NG met prespecified conditions defining non‐inferiority versus IMG. Glucagon was rapidly absorbed after both nasal and intramuscular administration; PG profiles were similar between administration routes during the first 60 minutes post dose. Study drug‐related treatment‐emergent adverse events affecting >2 patients were rhinalgia, increased blood pressure, nausea, ear pain and vomiting in the NG group, and nausea and vomiting in the IMG group. Conclusion: Nasal glucagon was non‐inferior to IMG for successful treatment of insulin‐induced hypoglycaemia in Japanese patients with T1DM/T2DM, supporting use of NG as a rescue treatment for severe hypoglycaemia. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Advanced glycation end‐products (AGEs), which are a major cause of diabetic vascular complications, accumulate in various tissues under chronic hyperglycemic conditions, as well as with aging in patients with diabetes. The loss of muscle mass and strength, so‐called sarcopenia and dynapenia, has recently been recognized as a diabetic complication. However, the influence of accumulated AGEs on muscle mass and strength remains unclear. The present study aimed to evaluate the association of sarcopenia and dynapenia with accumulated AGEs in patients with type 2 diabetes. Materials and Methods: We recruited 166 patients with type 2 diabetes aged ≥30 years (mean age 63.2 ± 12.3 years; body mass index 26.3 ± 4.9 kg/m2; glycated hemoglobin 7.1 ± 1.1%). Skin autofluorescence as a marker of AGEs, limb skeletal muscle mass index, grip strength, knee extension strength and gait speed were assessed. Results: Sarcopenia and dynapenia were observed in 7.2 and 13.9% of participants, respectively. Skin autofluorescence was significantly higher in patients with sarcopenia and dynapenia. Skin autofluorescence was the independent determinant for skeletal muscle mass index, grip strength, knee extension strength, sarcopenia and dynapenia. Conclusions: Accumulated AGEs could contribute to reduced muscle mass and strength, leading to sarcopenia and dynapenia in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Aims/Introduction: We investigated the safety of the batteries and power units used in insulin pumps in Japan. Materials and Methods: A self‐administered questionnaire was sent to the 201 members of the Association for Innovative Diabetes Treatment in Japan. Results: A total of 56 members responded, and among the 1,499 active devices, 66 had episodes of trouble related to the batteries and power units. The ratio of reported troubles to the number of insulin pumps was significantly higher in insulin pumps with a continuous glucose monitoring sensor compared with insulin pumps without a continuous glucose monitoring sensor (odds ratio 2.82, P < 0.05). The cause and the consequences varied. The brands of the batteries varied; alkaline batteries purchased at drug stores and other shops accounted for 19.7%. Termination of battery life within 72 h of use was reported most frequently (50.0%), suspension of the insulin pump (21.2%) and leakage of the battery fluid (4.5%) followed. A total of 53.2% of the reported insulin pumps needed to be replaced, and 37.1% of them recovered after replacement of the battery. Conclusions: As trouble related to the batteries and power units of insulin pumps was frequent, practical guidance should be provided to respective patients regarding the use of reliable batteries, and to be well prepared for unexpected insulin pump failure. [ABSTRACT FROM AUTHOR]

Abstract: Despite great strides in pharmacotherapy for diabetes, there is increasing concern over the risk of hypoglycemia in patients with diabetes receiving pharmacotherapy as they become increasingly older. This has prompted the Japan Diabetes Society (JDS) to initiate a survey on the current status of severe hypoglycemia in clinical settings. In July 2015, following approval from the JDS Scientific Survey/Research Ethics Committee, the JDS extended an invitation to executive educators, who represented a total of 631 healthcare facilities accredited by the JDS for diabetes education, to participate in the proposed survey. Of these, those who expressed their willingness to participate in the survey were sent an application form required for obtaining ethical approval at these healthcare facilities and were then asked, following approval, to enter relevant clinical data on an unlinked, anonymous basis in a web‐based registry. The current survey was fully funded by the JDS Scientific Survey/Research Committee. A case registry (clinical case database) was launched after facility‐specific information (healthcare facility database) was collected from all participating facilities and after informed consent was obtained from all participating patients. With severe hypoglycemia defined as the “presence of hypoglycemic symptoms requiring assistance from another person to treat and preferably venous plasma glucose levels at onset/diagnosis of disease or at presentation clearly less than 60 mg/dL (capillary whole blood glucose, less than 50 mg/dL)”, the current survey was conducted between April 1, 2014 and March 31, 2015, during which facility‐specific information was collected from a total of 193 facilities with a total of 798 case reports collected from 113 facilities. Of the 193 respondent facilities, 149 reported having an emergency department as well, with the median number of patients who required emergency transportation services to reach these facilities totaling 4,962 annually, of which those with severe hypoglycemia accounted for 0.34% (17). The respondent facilities accommodated a total of 2,237 patients with severe hypoglycemia annually, with the number of patients thus accommodated being 6.5 patients per site. A total of 1,171 patients were admitted for severe hypoglycemia, with the number of patients thus admitted being 4.0 per site, who accounted for 52.3% of all patients visiting annually for severe hypoglycemia. A review of the 798 case reports collected during the survey revealed that 240, 480 and 78 patients had type 1 diabetes, type 2 diabetes, and other types of diabetes, respectively; those with type 2 diabetes were shown to be significantly older (median [interquartile range], 77.0 [68.0–83.0]) than those with type 1 diabetes (54.0 [41.0–67.0]) (P < 0.001); and the BMI was shown to be significantly higher for those with type 2 diabetes (22.0 [19.5–24.8] kg/m2) than for those with type 1 diabetes (21.3 [18.9–24.0] kg/m2) (P = 0.003). It was also found that the median estimated glomerular filtration rate (eGFR) was significantly lower among those with type 2 diabetes (50.6 mL [31.8–71.1]/min/1.73 m2) than among those with type 1 diabetes (73.3 [53.5–91.1] mL/min/1.73 m2) (P < 0.001). Again, the median HbA1c value at onset of severe hypoglycemia was shown to be 7.0 (6.3–8.1)% among all patients examined, 7.5 (6.9–8.6)% among those with type 1 diabetes, and 6.8 (6.1–7.6)% among those with type 2 diabetes, with the HbA1c value at onset of hypoglycemia being significantly lower among those with type 2 diabetes (P < 0.001). Antecedent symptoms of severe hypoglycemia were shown to be present, absent and unknown in 35.5, 35.6, and 28.9% of all patients, respectively, with the incidence of symptomatic hypoglycemia being significantly lower among those with type 1 diabetes (41.0%) than among those with type 2 diabetes (56.9%). The antidiabetic agents used in those with type 2 diabetes were insulin preparations (292 patients including 29 receiving concomitant sulfonylureas [SUs]) (60.8%), SUs (159 insulin‐naïve patients) (33.1%), and no insulin preparations or SUs (29 patients) (6.0%). Of the 798 patients surveyed, 296 patients (37.2%) were shown to have required emergency transportation services for severe hypoglycemia before. Thus, the survey revealed, for the first time, the current status of treatment‐related severe hypoglycemia in Japan and clearly highlights the acute need for implementing preventive measures against hypoglycemia not only through education on hypoglycemia but through optimization of antidiabetic therapy for those at high risk of severe hypoglycemia or those with a history of severe hypoglycemia. [ABSTRACT FROM AUTHOR]

Accumulation of advanced glycation end-products ( AGEs) is thought to contribute to muscle weakness in a diabetic animal model. Skin autofluorescence is a proposed marker for accumulation of AGEs in the skin. We aimed to investigate the relationship between AGEs accumulation, sarcopenia and muscle function of Japanese patients with type 1 diabetes. A total of 36 patients with type 1 diabetes participated in the present cross-sectional study. Sarcopenia parameters (skeletal muscle mass index and knee extension strength) were compared with subcutaneous AGEs accumulation using skin autofluorescence. The prevalence of sarcopenia and impaired knee extension strength was 16.6% (men 0.0%, women 22.2%) and 47.2% (men 22.2%, women 55.6%), respectively. Knee extension strength was negatively correlated with skin autofluorescence ( r² = 0.14, P < 0.05), but not with skeletal muscle mass index. In conclusion, the AGEs accumulation might be one of the reasons of impaired lower limb muscle function in Japanese patients with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Aims/Introduction The aim of the present study was to examine the short- and long-term effect of sitagliptin on glucose tolerance after near normalization of glycemic control with insulin in poorly controlled type 2 diabetic patients. Materials and Methods We consecutively enrolled a total of 30 type 2 diabetic patients whose glycated hemoglobin levels (National Glycohemoglobin Standardization Program) were ≥7.4%, stopped all oral antidiabetic drugs and started insulin therapy. When fasting plasma glucose levels became <140 mg/dL, we carried out the first oral glucose tolerance test (OGTT). After 1-week sitagliptin treatment (50 mg/day), the second OGTT was carried out. Furthermore, we evaluated the long-term efficacy of sitagliptin on glucose tolerance after near normalization of glycemic control with insulin. Results After 1-week sitagliptin treatment, the area under the curve of insulin was markedly increased, and the area under the curve of glucagon and glucose was markedly decreased. Duration of diabetes and insulin secretory capacity were correlated with the effect of sitagliptin. Furthermore, interestingly, near normalization of glycemic control with insulin therapy for 1-2 weeks brought out the long-term effectiveness of sitagliptin on glucose tolerance for 24 weeks, which was not observed with other antidiabetic drugs. Conclusions These findings suggest that near normalization of glycemic control with insulin improves the clinical response to sitagliptin in poorly controlled type 2 diabetic patients. [ABSTRACT FROM AUTHOR]

Aims/Introduction To realize the effectiveness of a novel system for measuring glucose area under the curve ( AUC) using minimally invasive interstitial fluid extraction technology ( MIET), outpatients undergoing oral glucose tolerance tests ( OGTT) were investigated for the efficacy of screening for glucose intolerance using this system. Materials and Methods Fifty outpatients scheduled to undergo a 75-g OGTT for medical reasons were recruited to the study. An area of skin on the forearm was pretreated with microneedle arrays before the application of hydrogels for interstitial fluid extraction. Plasma glucose ( PG) levels were measured every 30 min for 2 h to calculate reference (actual) AUC. The AUC was predicted by MIET on the basis of glucose extracted by the hydrogel using sodium ion levels as the internal standard. Results Good correlation between MIET-predicted and reference AUCs obtained using PG levels was confirmed for a wide AUC range. By introducing a threshold level for AUC to separate glucose intolerance with peak glucose ≥180 mg/dL from normal glucose tolerance, the system was demonstrated to provide better screening accuracy compared with conventional methods that use Hb A1c and fasting PG levels. The results of a questionnaire-based survey administered to the subjects suggested that this system was readily accepted by the majority as a painless monitoring method. Conclusions The findings suggest that our glucose AUC measurement system using MIET would be useful for screening of glucose intolerance. In the future, this system may prove to be a useful aid as a screen for glucose intolerance before performing an OGTT for diagnosis. [ABSTRACT FROM AUTHOR]

The aim of the present study was to compare the usefulness of premeal rapid-acting and regular insulin in type 2 diabetes patients. A total of 56 type 2 diabetic patients were investigated during hospitalization. Premeal rapid-acting insulin was applied instead of other medications. Premeal insulin was titrated to adjust premeal and bedtime blood glucose levels to 81-120 mg/ dL. Premeal rapid-acting insulin was changed to regular insulin just before a meal at the same dosage if the postmeal blood glucose level was lower than the premeal blood glucose level. A total of 15 patients changed to regular insulin, and 41 patients continued rapid-acting insulin. The blood glucose level was comparable between these two groups. Body mass index was significantly lower in the patients using regular insulin. According to the multivariate logistic regression analysis, low body mass index was an independent variable accounting for the usefulness of regular insulin. Regular insulin, rather than rapid-acting insulin, is a suitable choice for premeal insulin in lean type 2 diabetic patients. [ABSTRACT FROM AUTHOR]

AbstractBackground: The clinical usefulness of the radiopaque marker method for detecting diabetic gastrointestinal motility disturbances, was evaluated by examining 21 type II diabetes subjects who did not have any neuropathic symptoms. Methods: After administration of a Sitzmark capsule®, markers were located using plain abdominal radiographs, and the transit time of the markers through seven areas of digestive tract was calculated by Arhan’s methods. The plasma concentration of acetaminophen at 45 min after oral administration was measured to evaluate gastric emptying time. The coefficient of variation of R-R intervals on the electrocardiograms (CVR-R) was measured to evaluate parasympathetic autonomic function. Results: In the diabetics, the average (± SD) transit time through upper digestive tracts was slightly but not significantly elongated compared with control subjects (14.4 ± 8.3 vs 9.9 ± 6.1 h). Significant elongation was observed in transit time through the lower digestive tracts or the whole gut (44.6 ± 20.9 and 57.9 ± 22.3 h, respectively) compared with control subjects (23.3 ± 8.5 and 33.2 ± 11.0 h). The transit time of the markers from stomach to small intestine was highly correlated (r = 0.693) with plasma concentration of acetaminophen. The transit time through either the whole colon (r = 0.564) or the whole gut (r = 0.630) was highly correlated with CVR-R. Conclusions: These findings suggest that the radiopaque marker method is a useful tool for detecting the sections of the digestive tract responsible for gut motility disturbances. In type II diabetics with no neuropathic symptoms, the lower digestive tracts may deteriorate prior to the impairment of upper digestive tracts. [ABSTRACT FROM AUTHOR]