Both hypo- and hyperglycaemia are associated with increased fracture risk in Japanese people with type 2 diabetes: the Fukuoka Diabetes Registry.

AIM: The impact of glycaemic control on fracture risk is controversial, which may be due to the possible presence of hypoglycaemia. The aim of this study was to separately investigate the impacts of severe hypoglycaemia and poor glycaemic control on fracture risk in people with type 2 diabetes. METHODS: Overall, 4706 Japanese participants (2755 men and 1951 postmenopausal women) with type 2 diabetes (mean age 66 years) were followed prospectively (a median of 5.3 years; follow-up rate, 97.6%), and were stratified by severe hypoglycaemia status and glycaemic control. The primary outcome was fractures at any anatomic site. RESULTS: Fractures occurred in 662 participants (249 men and 413 women). The age- and sex-adjusted incidence rates (expressed per 1000 person-years) were: 71.2 (multiple episodes of severe hypoglycaemia), 43.1 (one episode), 25.2 [HbA1c < 53 mmol/mol (< 7%) without severe hypoglycaemia], 28.7 [HbA1c 53 to < 64 mmol/mol (7% to < 8%) without severe hypoglycaemia], 27.7 [HbA1c 64 to < 75 mmol/mol (8% to < 9%) without severe hypoglycaemia] and 40.5 [HbA1c ≥ 75 mmol/mol (≥ 9%) without severe hypoglycaemia]. Multivariate-adjusted hazard ratios (95% confidence intervals) for fractures were 2.24 (1.56, 3.21) in those with multiple episodes of severe hypoglycaemia, and 1.42 (1.04, 1.95) in those with HbA1c ≥ 75 mmol/mol (≥ 9%) without severe hypoglycaemia, compared with those with HbA1c < 53 mmol/mol (< 7%) without severe hypoglycaemia. CONCLUSIONS: Both severe hypoglycaemia and poor glycaemic control were significantly related to an increased risk of fracture in people with type 2 diabetes, although severe hypoglycaemia conferred a stronger risk.

Preoperative Muscle Volume Predicts Graft Survival After Pancreas Transplantation: A Retrospective Observational Cohort Study.

BACKGROUND: Several studies have suggested that decreased muscle volume is associated with attenuation of immune function. The recipient's immune system is responsible for rejection of transplanted organs, which is a major cause of graft loss after transplantation. We aimed to determine whether muscle volume is correlated with graft survival after pancreas transplantation (PT). METHODS: Forty-three patients underwent PT for type 1 diabetes mellitus at our institution from August 2001 to May 2016. The quantity of skeletal muscle was evaluated using the psoas muscle mass index (PMI). The correlation between PMI and outcome after PT was assessed. RESULTS: A total of 32 and 11 recipients underwent simultaneous pancreas-kidney transplantation (SPK) and PT alone/pancreas after kidney transplantation, respectively. Patients with a surviving graft showed a significantly lower PMI than those with graft loss (P = .0451). We divided the recipients into two groups according to the PMI cutoff values, which were established using receiver operating characteristic curves. The cumulative graft survival rate was significantly higher in patients with a low PMI (P = .0206). A multivariate Cox regression analysis revealed that a low PMI (P = .0075) is an independent predictive factor for better graft survival. A low PMI was not a significant predictive factor for acute rejection, but was an independent predictive factor for graft survival after the first acute rejection (P = .0025). CONCLUSIONS: Our data suggest that muscle volume could be a predictor of graft survival after PT.

Laparoscopy-Assisted Spleen-Preserving Distal Pancreatectomy for Living-Donor Pancreas Transplantation.

BACKGROUND: Living pancreas transplantation plays an important role in the treatment of patients with severe type 1 diabetes. However, pancreatectomy is very invasive for the donor, and less-invasive surgical procedures are needed. Although some reports have described hand-assisted laparoscopic surgery for distal pancreatectomy in living-donor operations, less-invasive laparoscopy-assisted (LA) procedures are expected to increase the donor pool. We herein report the outcomes of four cases of LA spleen-preserving distal pancreatectomy (Warshaw technique [WT]) in living pancreas donors. PATIENTS AND METHODS: Four living pancreas donors underwent LA-WT at our institution from September 2010 to January 2013. All donors fulfilled the donor criteria established by the Japan Society for Pancreas and Islet Transplantation. RESULTS: The median donor age was 54 years. Two donors underwent left nephrectomy in addition to LA-WT for simultaneous pancreas-kidney transplantation. The median donor operation time for pancreatectomy was 340.5 minutes. The median pancreas warm ischemic time was 3 minutes. The median donor blood loss was 246 g. All recipients immediately achieved insulin independence. One donor required reoperation because of obstructive ileus resulting from a port-site hernia. Another donor developed a pancreatic fistula (International Study Group of Pancreatic Fistula grade B), which was controlled with conservative management. After a maximum follow-up of 73 months, no clinically relevant adverse events had occurred. These results were comparable with those of previous studies concerning living-donor pancreas transplantation. CONCLUSION: The LA-WT is a safe and acceptable operation for living-donor pancreas transplantation.

Association between eating rate and obesity: a systematic review and meta-analysis.

BACKGROUND: The association between eating rate and obesity has recently been reported. However, the findings remain inconclusive. OBJECTIVES: We undertook a systematic review with a meta-analysis of published epidemiological studies to provide a reliable close estimate of the association between eating rate and obesity. METHODS: A comprehensive search of MEDLINE, EMBASE and CINAHL was conducted to identify studies that reported quantitative estimates for indices of obesity based on the category of eating rate. Interventional studies or studies conducted using children as subjects were excluded. Two independent researchers extracted the data. A summary estimate was calculated using a random-effects model, and subgroup analyses were conducted to identify sources of heterogeneity. RESULTS: Data from 23 published studies were eligible for inclusion. The mean difference in body mass indices (BMIs) between individuals who ate quickly and those who ate slowly was 1.78 kg m(-2) (95% confidence interval (CI), 1.53-2.04 kg m(-2)). The pooled odds ratio of eating quickly on the presence of obesity was 2.15 (95% CI, 1.84-2.51). There was evidence of significant quantitative heterogeneity in the magnitudes of the association across studies (I2=78.4%, P-value for heterogeneity <0.001 for BMI, I2=71.9%, P-value for heterogeneity <0.001 for obesity), which may be partially explained by differences in the type of study population (a weaker association was observed for BMI in diabetic patients). CONCLUSIONS: Eating quickly is positively associated with excess body weight. Further studies are warranted to determine whether interventions to slow the speed of eating are effective for weight control.

Living donor kidney transplantation preceding pancreas transplantation reduces mortality in type 1 diabetics with end-stage renal disease.

BACKGROUND: Simultaneous pancreas-kidney transplantation (SPK) is a definitive treatment for type 1 diabetics with end-stage renal disease (ESRD). Because of the shortage of deceased donors in Japan, the mortality rate during the waiting period is high. We evaluated mortality risk in patients with type 1 diabetes waiting for SPK, and the benefit of living-donor kidney transplantation (LDK) preceding pancreas transplantation, which may reduce mortality in patients awaiting SPK. METHODS: This retrospective study included 71 patients with type 1 diabetes. Twenty-six patients underwent SPK, 15 underwent LDK, and 30 were waiting for SPK. Their cumulative patient and graft survival rates were retrospectively evaluated. Risk factors contributing to mortality in patients with type 1 diabetes awaiting SPK were evaluated with the use of a Cox proportional hazards model. RESULTS: The 5-year cumulative patient survival rates in the SPK and LDK groups were 100% and 93.3%, respectively (P = .19), and 5-year kidney graft survival rates were 95.7% and 100% (P = .46), respectively. The cumulative survival rate in patients awaiting SPK was 77.7% at 5 years after registration. Duration of dialysis was the only factor significantly associated with patient and graft survivals according to both univariate and multivariate analyses. CONCLUSIONS: Patient and graft survival rates were similar in the SPK and LDK groups, but the survival rate of patients awaiting SPK decreased over time. Duration of dialysis was an independent risk factor for patient and graft survival. LDK preceding pancreas transplantation may be an effective therapeutic option for patients with type 1 diabetes and ESRD.

Outcome of renal transplantation in patients with type 2 diabetic nephropathy: a single-center experience.

BACKGROUND: Renal transplantation has been established as a treatment for end-stage renal disease (ESRD) due to diabetic nephropathy. However, few studies have focused on the outcome after renal transplantation in patients with ESRD and type 2 diabetic nephropathy. To investigate the effect of renal transplantation on ESRD with type 2 diabetic nephropathy, we retrospectively analyzed patients who received renal transplantation at our facility. This study aimed to compare the outcome of renal transplantation for type 2 diabetic nephropathy with that for nondiabetic nephropathy. METHODS: We studied 290 adult patients, including 65 with type 2 diabetic nephropathy (DM group) and 225 with nondiabetic nephropathy (NDM group), who underwent living-donor renal transplantation at our facility from February 2008 to March 2013. We compared the 2 groups retrospectively. RESULTS: In the DM and NDM groups, the 5-year patient survival rates were 96.6% and 98.7%, and the 5-year graft survival rates were 96.8% and 98.0%, respectively, with no significant differences between the groups. There were no significant differences in the rates of surgical complications, rejection, and infection. The cumulative incidence of postoperative cardiovascular events was higher in the DM group than in the NDM group (8.5% vs 0.49% at 5 years; P = .002). CONCLUSIONS: Patient and graft survival rates after renal transplantation for type 2 diabetic nephropathy are not inferior to those for recipients without diabetic nephropathy. Considering the poor prognosis of patients with diabetic nephropathy on dialysis, renal transplantation can provide significant benefits for these patients.

Impact of eating rate on obesity and cardiovascular risk factors according to glucose tolerance status: the Fukuoka Diabetes Registry and the Hisayama Study.

AIMS/HYPOTHESIS: Medical nutrition therapy plays a critical role in the prevention and treatment of type 2 diabetes. However, appropriate measures of eating behaviours, such as eating rate, have not yet been clearly established. The aim of the present study was to examine the associations among eating rate, obesity and cardiovascular risk factors. METHODS: A total of 7,275 Japanese individuals aged ≥40 years who had normal fasting glucose levels, impaired fasting glucose or diabetes were divided into four groups according to self-reported eating rate: slow, medium, relatively fast and very fast. The associations between eating rate and various cardiovascular risk factors were investigated cross-sectionally. RESULTS: The proportions of participants who were obese or who had elevated waist circumference levels increased progressively with increases in eating rate (p for trend <0.001), regardless of glucose tolerance status. These associations remained significant after adjustment for potential confounders, namely, age, sex, total energy intake, dietary fibre intake, current smoking, current drinking and regular exercise (p for trend <0.001). Blood pressure and lipid levels also tended to increase in association with eating rate. HbA(1c) rose significantly as eating rate increased, even after multivariate adjustment, including BMI, in diabetic patients on insulin therapy (p = 0.02), whereas fasting plasma glucose did not increase significantly. CONCLUSIONS/INTERPRETATION: Our findings suggest that eating rate is associated with obesity and other cardiovascular risk factors and therefore may be a modifiable risk factor in the management of cardiovascular risk factors and diabetes.

Altered postural regulation of foot skin oxygenation and blood flow in patients with type 2 diabetes mellitus.

AIMS: Although skin oxygenation is an important factor in the development and healing of foot ulcers, its regulation was not fully understood. We studied changes in foot skin oxygenation and blood flow during postural changes in patients with type 2 diabetes mellitus. METHODS: Skin oxygenation was measured using transcutaneous oxygen pressure (TcPO(2)) and skin blood flow by laser Doppler flowmetry in 40 patients with type 2 diabetes mellitus without evidence of peripheral arterial disease and 13 healthy control subjects. RESULTS: TcPO(2) in the supine position was significantly lower in patients with type 2 diabetes mellitus compared with control, although skin blood flow was not different. In the sitting position, TcPO(2) significantly increased in control and diabetic patients. The postural change-related increase in TcPO(2) was significantly enhanced in diabetic patients. On the other hand, skin blood blow significantly decreased in the sitting position from the supine position in control subjects but remained stable in diabetic patients. Orthostatic drop in systolic blood pressure correlated negatively with TcPO(2) in the supine position while correlated positively with %change in TcPO(2) and blood flow by postural changes. CONCLUSIONS: The present study demonstrated the dissociated regulation of skin oxygenation and blood flow in response to leg dependency. Impaired postural vasoconstriction was associated with altered regulation of skin oxygenation probably due to sympathetic vascular dysfunction in diabetic patients.

The atypical antipsychotic clozapine impairs insulin secretion by inhibiting glucose metabolism and distal steps in rat pancreatic islets.

AIMS/HYPOTHESIS: Diabetogenic effects of some atypical antipsychotic drugs have been reported, although the mechanisms are not fully understood. We investigated the long-term effects of culturing isolated rat pancreatic islets with atypical antipsychotic clozapine. METHODS: Glucose- and non-glucose-stimulated insulin secretion, glucose metabolism and intracellular Ca(2+) concentration ([Ca(2+)](i)) were measured in islets cultured with or without clozapine. RESULTS: Although acute incubation or 3-day culture with clozapine did not affect glucose-stimulated insulin secretion, clozapine suppressed glucose-stimulated insulin secretion by 53.2% at 1.0 micromol/l (therapeutic concentration) after 7 days of culture. Islet glucose oxidation and [Ca(2+)](i) elevation by high glucose were not affected after 3 days of culture, but clozapine significantly inhibited islet glucose oxidation, ATP production, and [Ca(2+)](i) elevation by high glucose after 7 days of culture. Moreover, 7 days of culture with clozapine inhibited insulin secretion stimulated by: (1) membrane depolarisation induced by high K(+); (2) protein kinase C activation; and (3) mastoparan at 16.7 mmol/l glucose under stringent Ca(2+)-free conditions. Elevation of [Ca(2+)](i) by high K(+)-induced membrane depolarisation was similar in control and clozapine-treated islets. Clozapine, a muscarinic blocker, acutely inhibited carbachol-induced insulin secretion, as did atropine, whereas after 7 days of culture atropine did not have the inhibitory effect shown by clozapine after 7 days. The impairment of glucose-stimulated insulin secretion recovered 3 days after the removal of clozapine treatment. CONCLUSIONS/INTERPRETATION: The present study demonstrated that the atypical antipsychotic drug clozapine directly impaired insulin secretion via multiple sites including glucose metabolism and the distal step in insulin exocytosis in a long-term culture condition. These mechanisms may be involved in the form of diabetes mellitus associated with atypical antipsychotic drugs.

Orthostatic hypertension in patients with type 2 diabetes.

OBJECTIVE: The prevalence and clinical importance of orthostatic hypertension (OHT) in diabetic patients has not been elucidated, in contrast to orthostatic hypotension, which is occasionally found in diabetic patients with autonomic neuropathy. RESEARCH DESIGN AND METHODS: The prevalence and severity of orthostatic hypertension was investigated in 277 Japanese male patients with type 2 diabetes, including 90 hypertensive patients and 128 nondiabetic age-matched male subjects. Patients treated with antihypertensive drugs were excluded from the study. OHT was defined as an increase in diastolic blood pressure (DBP) from <90 to >or=90 mmHg and/or an increase in systolic blood pressure (SBP) from <140 to >or=140 mmHg after standing from supine position. Clinical profiles and several serum biochemical parameters were determined in addition to chest X-rays and electrocardiograms. RESULTS: The prevalence of OHT in normotensive and hypertensive diabetic patients was significantly higher than in control subjects (12.8 vs. 1.8%, P < 0.01, for normotensive patients; 12.6 vs. 11.1%, not significant, for hypertensive patients). Orthostasis induced a mean increase of 6.8 +/- 11.4 mmHg in SBP and 9.1 +/- 5.2 mmHg in DBP in diabetic patients with OHT compared with those without OHT (-1.0 +/- 9.0 and 3.8 +/- 6.6 mmHg, respectively). Vibration sensation in the lower limb was reduced in diabetic patients with OHT, but the percent coefficient of variation of RR interval, cardio-to-thoracic ratio on chest X-ray, and serum triglyceride levels were higher in these patients compared with normotensive diabetic patients without OHT. CONCLUSIONS: Orthostatic hypertension is a novel complication in normotensive diabetic patients and may associate with early stage neuropathy and development of sustained hypertension.

Sodium-coupled glucose transporter as a functional glucose sensor of retinal microvascular circulation.

To clarify the function of the Na(+)-coupled glucose transporter in the regulation of cellular tone of cultured retinal pericytes, we investigated the effects of extracellular glucose concentration on cell size. The surface area and diameter of cultured bovine retinal pericytes under different glucose concentrations were measured by using a light microscope with a digital camera. We also examined the effects of extracellular Na(+) and Ca(2+), inhibitors of the Na(+)-coupled glucose transporter and Na(+)-Ca(2+) exchanger, a Ca(2+) channel blocker, and nonmetabolizable sugars on cell size. The surface area and diameter of the cells changed according to extracellular glucose concentrations. alpha-Methyl glucoside, which enters the cell through the Na(+)-coupled glucose transporter, induced cellular contraction. However, the cells did not contract in response to 2-deoxyglucose, which enters the cell through a facilitated glucose transporter. Glucose-induced cellular contraction was abolished in the absence of extracellular Na(+) and Ca(2+). Moreover, phlorizin, an inhibitor of the Na(+)-coupled glucose transporter, and 2',4'-dichlorobenzamil-HCl, an inhibitor of the Na(+)-Ca(2+) exchanger, also abolished glucose-induced cellular contraction, whereas nicardipine, a Ca(2+) channel blocker, did not. Our results indicate that high extracellular glucose concentrations induce contraction of bovine retinal pericytes via Na(+) entry through a Na(+)-coupled glucose transporter, suggesting that the Na(+)-coupled glucose transporter may act as a functional glucose sensor of retinal microvascular circulation.>

Effects of medium containing heparin and theophylline on capacitation and metabolic enzyme activities of ejaculated spermatozoa from dogs with asthenozoospermia.

The percentages of motile sperm (%MO), hyperactivated sperm (%HA), and acrosome-reacted sperm (%AR) of four beagle dogs with asthenozoospermia (AS) and five normal beagle dogs were determined during 7 h of incubation. The metabolic enzyme activities of the sperm was examined after 0 and 4 h of incubation. The sperm were incubated in canine capacitation medium (CCM) and CCM containing either 20 microg ml(-1) heparin (HE), 10 microg ml(-1) theophylline (TH) or 20 microg ml(-1) HE + 10 microg ml(-1) TH in glass tubes at 38 degrees C under 5% CO2 in air. The %HA and %AR were determined by counting the sperm exhibiting star-spin like movement and by the triple stain technique. The spermatozoa in HE + TH CCM were homogenized and centrifuged, and the metabolic activities of hexokinase, fructokinase, glucose-6-phosphodehydrogenase (G6PD), and pyruvate kinase in the sperm cytosol in the supernatant was measured with a spectrophotometer. The mean %MO and %HA values of both AS and normal dogs in the four types of CCM were highest in HE + TH CCM, with a mean %HA in HE + TH CCM of 78 +/- 5% (S.E.) after 7 h of incubation. However, there was little difference in %AR among the four types of CCM. The mean activities of the four enzymes in the sperm of AS dogs before incubation was significantly lower than in the sperm of normal dogs (P < 0.05, 0.01). However, after 4 h of incubation the activities of all enzymes in the sperm of both AS and normal dogs was clearly higher in HE + TH CCM than in the control CCM. These findings indicate that HE and TH in the medium are effective inactivating metabolic enzymes, maintaining longer sperm motility, and efficiently inducing HA even of the sperm of AS dogs.