Alcohol-induced increase in BMP levels promotes fatty liver disease in male prediabetic stage Otsuka Long-Evans Tokushima Fatty rats.

Alcohol consumption exacerbates liver abnormalities in animal models, but whether it increases the severity of liver disease in early diabetic or prediabetic rats is unclear. To investigate the molecular mechanisms underlying alcohol-induced liver steatosis or hepatitis, we used a prediabetic animal model. Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Fatty (LETO) rats were pair-fed with an ethanol-containing liquid diet for 6 weeks. Compared with controls, OLETF and LETO rats displayed more pronounced liver steatosis and higher plasma levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SPGT), indicating liver injury. Ethanol-fed LETO (Pd-L-E) rats showed mild liver steatosis and no inflammation compared with ethanol-fed OLETF (Pd-O-E) rats. Although precursor and active SREBP-1 levels in the liver of ethanol-fed OLETF rats significantly increased compared with control diet-fed OLETF rats (Pd-O-C), those of Pd-L-E rats did not. Bone morphogenetic protein (BMP) and TGF-ß1 balance in Pd-O-E rats was significantly altered because BMP signaling was upregulated by inducing BMP2, BMP4, BMP7, BMP9, Smad1, and Smad4, whereas TGF-ß1, Smad3, and Erk were downregulated. Activation of TGF-ß/Smad signaling inhibited BMP2 and BMP9 expression and increased epithelial-mesenchymal transition (EMT) marker levels (Hepcidin, Snail, and Twist) in the liver of LETO rats. Livers of ethanol-fed OLETF rats showed increased levels of vimentin, FSP-1, α-SMA, MMP1, MMP13, and collagen III compared with rats of other groups, whereas EMT marker levels did not change. Thus, BMP exerted anti- and/or pro-fibrotic effects in ethanol-fed rats. Therefore, BMP and TGF-ß, two key members of the TGF-ß superfamily, play important but diverse roles in liver steatosis in young LETO and OLETF rats.

Effects of DA-9801 on the inflammation and apoptosis induced by angiotensin II in human dermal microvascular endothelial cells.

DA-9801, a plant-based drug used for the treatment of diabetic neuropathy, is known to improve angiotensin II (Ang II)-induced vascular endothelial cell dysfunction. However, the underlying mechanism is not fully understood. We aimed to determine whether the protective effect of DA-9801 against Ang II-induced endothelial cell dysfunction was mediated via inhibition of endothelial cell inflammation and apoptosis. Ang II-induced oxidative stress was attenuated by pretreatment of human dermal microvascular endothelial cells (HDMECs) with DA-9801. This prevented the Ang II-induced upregulation of NAD(P)H oxidase (the NOX4 and p22phox subunits) and reactive oxygen species. Further, pretreatment of HDMECs with DA-9801 ameliorated Ang II-mediated nuclear factor kappa B activity via prevention of the upregulation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. It also decreased the Ang II-stimulated increase in inducible nitric oxide synthase (NOS) and decreased endothelial NOS protein expression. DA-9801 decreased Ang II-induced upregulation of intercellular adhesion molecule 1, vascular adhesion molecule, and E-selectin in HDMECs. Moreover, TUNEL and annexin V-FITC fluorescence staining for apoptosis and the activities of caspases 9, 7, and 3 decreased in HDMECs pretreated with DA-9801, indicating that the drug enhanced anti-apoptotic pathways. Thus, DA-9801 modulated Ang II-induced endothelial cell dysfunction via inflammatory and apoptotic pathways.

Long-term insulin treatment leads to a change in myosin heavy chain fiber distribution in OLETF rat skeletal muscle.

The objective of this study was to investigate molecular and physiological changes in response to long-term insulin glargine treatment in the skeletal muscle of OLETF rats. Male Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats aged 24 weeks were randomly allocated to either treatment with insulin for 24 weeks or no treatment, resulting in three groups. Insulin glargine treatment in OLETF rats (OLETF-G) for 24 weeks resulted in changes in blood glucose levels in intraperitoneal glucose tolerance tests compared with age-matched, untreated OLETF rats (OLETF-C), and the area under the curve was significantly decreased for OLETF-G rats compared with OLETF-C rats (P < 0.05). The protein levels of MHC isoforms were altered in gastrocnemius muscle of OLETF rats, and the proportions of myosin heavy chain type I and II fibers were lower and higher, respectively, in OLETF-G compared with OLETF-C rats. Activation of myokines (IL-6, IL-15, FNDC5, and myostatin) in gastrocnemius muscle was significantly inhibited in OLETF-G compared with OLETF-C rats ( P < 0.05). MyoD and myogenin levels were decreased, while IGF-I and GLUT4 levels were increased, in the skeletal muscle of OLETF-G rats ( P < 0.05). Insulin glargine treatment significantly increased the phosphorylation levels of AMPK, SIRT1, and PGC-1α. Together, our results suggested that changes in the distribution of fiber types by insulin glargine could result in downregulation of myokines and muscle regulatory proteins. The effects were likely associated with activation of the AMPK/SIRT1/PGC-1α signaling pathway. Changes in these proteins may at least partly explain the effect of insulin in skeletal muscle of diabetes mellitus.

Metabolic profiling of serum and tissue from the rotator interval and anterior capsule in shoulder stiffness: a preliminary study.

BACKGROUND: Using mass spectrometry, we evaluated the metabolic profiles of patients who had rotator cuff tears with shoulder stiffness, or shoulder stiffness only, and compared these with samples from a control group. METHODS: This study enrolled 28 patients, including 10 patients with shoulder stiffness only (group I), nine patients with rotator cuff tear and stiffness (group II), and nine controls selected from patients diagnosed with impingement syndrome or long head of the biceps lesions without evident limitation of joint motion or rotator cuff tears. Serum and tissue from the rotator interval and anterior capsule were collected. In all, 82 samples were analyzed for metabolite profiling using the AbsoluteIDQ™p180 Kit. RESULTS: Comparison of 186 metabolites revealed that groups I and II had significantly higher concentrations of sphingolipids in serum (SM C24:1; group I = 65.16 µm, group II = 68.07 µm) than controls (55.37 µm, p = 0.005 & 0.015, respectively). Higher concentrations of sphingolipids were also present in the rotator interval tissue (SM C22:3) of groups 1 (0.0197 µm) and 2 (0.0144 µm) than controls (0.0081 µm, p = 0.012 & 0.014, respectively). The concentration of glycerophospholipid (PC aa C30:0) was higher in the anterior capsule tissue of groups I (0.850 µm) and II (1.164 µm) than controls (0.572 µm; p = 0.007) Total cholesterol was positively correlated with sphingolipid concentration in serum (SM C24:1, rho = 0.782, p = 0.008) and rotator interval tissue (SM C22:3, rho = 0.750, p = 0.017). There was no significant difference in the metabolites evaluated in groups I and II. CONCLUSION: Metabolic profiling showed that levels of lipid-related metabolites were increased in the anterior capsule tissue and rotator interval tissue of patients with shoulder stiffness. Sphingomyelin (SM C22:3) in the tissue of the rotator interval was positively correlated with the serum level of total cholesterol in patients with shoulder stiffness only. The level of glycerophospholipid (PC30:0) in the anterior capsule was positively correlated with the serum level of total cholesterol in patients who had rotator cuff tear with shoulder stiffness. The results indicate that serum total cholesterol may be related to shoulder stiffness. Future studies are needed to evaluate the role of serum cholesterol in the pathogenesis of shoulder stiffness. TRIAL REGISTRATION: KC12OISI0532. Registered Nov 15, 2012. approval by the Institutional Review Board of Seoul St. Mary's Hospital, the Catholic University of Korea.

High glucose and palmitate increases bone morphogenic protein 4 expression in human endothelial cells.

Here, we investigated whether hyperglycemia and/or free fatty acids (palmitate, PAL) aff ect the expression level of bone morphogenic protein 4 (BMP4), a proatherogenic marker, in endothelial cells and the potential role of BMP4 in diabetic vascular complications. To measure BMP4 expression, human umbilical vein endothelial cells (HUVECs) were exposed to high glucose concentrations and/or PAL for 24 or 72 h, and the effects of these treatments on the expression levels of adhesion molecules and reactive oxygen species (ROS) were examined. BMP4 loss-of-function status was achieved via transfection of a BMP4-specific siRNA. High glucose levels increased BMP4 expression in HUVECs in a dose-dependent manner. PAL potentiated such expression. The levels of adhesion molecules and ROS production increased upon treatment with high glucose and/or PAL, but this eff ect was negated when BMP4 was knocked down via siRNA. Signaling of BMP4, a proinflammatory and pro-atherogenic cytokine marker, was increased by hyperglycemia and PAL. BMP4 induced the expression of infl ammatory adhesion molecules and ROS production. Our work suggests that BMP4 plays a role in atherogenesis induced by high glucose levels and/or PAL.

Chronic Alcohol Consumption Results in Greater Damage to the Pancreas Than to the Liver in the Rats.

Alcohol consumption increases the risk of type 2 diabetes. However, its effects on prediabetes or early diabetes have not been studied. We investigated endoplasmic reticulum (ER) stress in the pancreas and liver resulting from chronic alcohol consumption in the prediabetes and early stages of diabetes. We separated Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type-2 diabetic animal model, into two groups based on diabetic stage: prediabetes and early diabetes were defined as occurrence between the ages of 11 to 16 weeks and 17 to 22 weeks, respectively. The experimental group received an ethanol-containing liquid diet for 6 weeks. An intraperitoneal glucose tolerance test was conducted after 16 and 22 weeks for the prediabetic and early diabetes groups, respectively. There were no significant differences in body weight between the control and ethanol groups. Fasting and 120-min glucose levels were lower and higher, respectively, in the ethanol group than in the control group. In prediabetes rats, alcohol induced significant expression of ER stress markers in the pancreas; however, alcohol did not affect the liver. In early diabetes rats, alcohol significantly increased most ER stress-marker levels in both the pancreas and liver. These results indicate that chronic alcohol consumption increased the risk of diabetes in prediabetic and early diabetic OLETF rats; the pancreas was more susceptible to damage than was the liver in the early diabetic stages, and the adaptive and proapoptotic pathway of ER stress may play key roles in the development and progression of diabetes affected by chronic alcohol ingestion.

Metabolic dysfunction-associated fatty liver disease increases the risk of type 2 diabetes mellitus in young Korean adults.

AIMS: To investigate the impact of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) on the risk of type 2 diabetes mellitus in young Korean adults. METHODS: Data were sourced from the Korean National Health Insurance Service-Health Screening Cohort, comprising adults aged 20-39 who underwent health examinations between 2009 and 2012. Participants were grouped based on the presence of MAFLD and nonalcoholic fatty liver disease (NAFLD), both individually and in combination. The categorizations included Neither-FLD, NAFLD-only, MAFLD-only, or Both-FLD. Incident diabetes was identified through claims data during the follow-up period. RESULTS: Among 6,232,656 participants, 676,747 (10.8 %) had MAFLD. During a median follow-up of 9.5 years, 182,291 incident diabetes cases were identified. Multivariate analysis revealed a significantly higher diabetes risk in the MAFLD group compared to those in the Non-MAFLD group (HR = 6.148, 95 % CI, 6.084-6.212). Notably, diabetes incidence was highest in FLI ≥ 60 subgroup with BMI ≥ 23 and metabolic syndrome. CONCLUSIONS: MAFLD is associated with a 6.1-fold increased diabetes risk in young adults, underscoring the urgent need for early intervention to mitigate this risk.

Inflammatory potential of diet and risk of mortality in normal-weight adults with central obesity.

BACKGROUND & AIMS: Inflammatory potential of diet may contribute to poor health outcomes in individuals with metabolic disorders. In a representative sample of the U.S. population, we investigated the association between consuming a pro-inflammatory diet and mortality risk in adults with normal range of body mass index (BMI) but with central obesity. METHODS: This prospective cohort study included 3521 adults 20-90 years of age with normal BMI who participated in the National Health and Nutrition Examination Survey III, 1988-1994 and did not have a history of cardiovascular disease (CVD) or cancer and did not change their dietary intake in the year preceding baseline measurements. Mortality from all causes, CVD, and cancer was ascertained from the National Death Index. Normal-weight central obesity (NWCO, n = 1777) was defined as those with BMI 18.5 to <25 kg/m2 and waist-to-hip ratio (WHR) ≥0.85 in women and ≥0.90 in men. Severe central obesity was defined as WHR ≥0.92 in women and ≥1.00 in men. The dietary inflammatory index (DII®) was computed based on baseline dietary intake using 24-h dietary recalls, and associations with mortality were estimated using multivariable Cox proportional hazards regression. RESULTS: In individuals with NWCO, DII score (i.e., more pro-inflammatory diet) was associated with increased risk of CVD mortality (HRT3 vs T1, 1.89 [95% CI, 1.01-3.53], P trend = 0.04; HR 1 SD increase 1.29 [95% CI, 1.06-1.57]). This association was stronger with more severe central obesity (HRT3 vs T1, 2.79 [95% CI, 1.10-7.03], P trend = 0.03; HR 1 SD increase 1.52 [95% CI, 1.05-2.21]). DII score was not associated with increased risk of mortality in normal-weight individuals without central obesity or with risk of cancer mortality in either group. CONCLUSION: Among individuals in the normal-weight range of BMI, a pro-inflammatory diet assessed by high DII scores was associated with increased risk of CVD mortality in those with central obesity.

Cumulative exposure to metabolic syndrome in a national population-based cohort of young adults and sex-specific risk for type 2 diabetes.

BACKGROUND: Metabolic syndrome is associated with type 2 diabetes and its prevalence is increasing worldwide in young adults. We aimed to determine whether cumulative exposure to metabolic syndrome is associated with type 2 diabetes risk in young adults. METHODS: Data of 1,376,540 participants aged 20-39 years without a history of type 2 diabetes and who underwent four annual health check-ups were collected. In this large-scale prospective cohort study, we evaluated the incidence rates and hazard ratios (HRs) of diabetes according to cumulative frequencies of metabolic syndrome over 4 years of consecutive annual health check-ups (burden score 0-4). Subgroup analyses were performed by sex and age. RESULTS: During 5.18 years of follow-up, 18,155 young adults developed type 2 diabetes. The incidence of type 2 diabetes increased with burden score (P < 0.0001). The multivariable-adjusted HRs for type 2 diabetes were 4.757, 10.511, 18.288, and 31.749 in participants with a burden score of 1 to 4, respectively, compared to those with 0. In subgroup analyses, the risk of incident diabetes was greater in women than men and in the 20-29 years age group than the 30-39 years age group. The HRs were 47.473 in women and 27.852 in men with four burden scores. CONCLUSION: The risk of type 2 diabetes significantly increased with an increase in the cumulative burden of metabolic syndrome in young adults. Additionally, the association between cumulative burden and diabetes risk was stronger in women and the 20s age group.

Transforming growth factor-ß induces epithelial to mesenchymal transition and suppresses the proliferation and transdifferentiation of cultured human pancreatic duct cells.

Pancreatic duct cells are considered a potential source of ß-cell regeneration, and transforming growth factor-ß (TGF-ß) has been suggested to perform an important role in these processes, but the underlying mechanism of the signal pathways, especially in humans, remains poorly understood. To evaluate the role of TGF-ß1, pancreatic duct cells were isolated from three brain-dead organ donors. Pancreatic cell clusters harvested after islet isolation were dispersed to single cells and cultured in monolayers, then treated with TGF-ß1. We analyzed the characteristics of the cultured cells, the TGF-ß1 intracellular signaling pathway, the proliferation, and transdifferentiation rates of the duct cells. We also evaluated the genes and protein expression patterns after TGF-ß1 treatment. After TGF-ß1 treatment, typical morphologic changes representative of EMT were observed and Erk1/2, JNK, and AKT phosphorylation, Ras downstream effectors, were increased. ß cell-specific transcription factors including PDX-1, Beta2/NeuroD, Ist-1, and NGN3 were markedly suppressed and the rate of transdifferentiation into ß cells was also suppressed. Genomic and proteomic analyses suggested that TGF-ß1 induces marked changes in a variety of structural genes and proteins associated with EMT. In conclusion, TGF-ß1 induces EMT in cultured human pancreatic duct cells, but suppresses its proliferation and transdifferentiation into ß cells. Our results are the first report of TGF-ß1 effects for EMT and ductal cell transdifferentiation and proliferation at the protein level in human pancreatic duct cells.

Cumulative exposure to impaired fasting glucose and future risk of type 2 diabetes mellitus.

AIMS: The status of metabolic abnormalities including impaired fasting glucose (IFG) can change over time, yet little is known about how exposure duration to IFG is related to diabetes risk. METHODS: Using nationally representative data from the Korean National Health Insurance system, 2,513,127 people who were free of diabetes and who received four consecutive annual health examinations commencing in 2006 or 2007 were followed up at the end of 2016. IFG was defined as fasting blood glucose levels of 100-125 mg/dL. Participants were classified numerically according to the cumulative number of IFG diagnoses. RESULTS: Over 4 years, 53% of the population participants remained normoglycemic, while 3% had persistent IFG and 44% had intermittent IFG. The risk of type 2 diabetes mellitus (DM) increased gradually with increasing IFG exposure score. Subjects with an IFG exposure score of 2, 3, or 4 had a 3.75- to 9.77-fold increased hazard ratio (HR) for incident diabetes (IFG exposure score 0 reference; score 2, HR 3.75, 95% confidence interval [CI] 3.67-3.83; score 3, HR 6.21, 95% CI 6.08-6.36; score 4, HR 9.77, 95% CI 9.53-10.02). CONCLUSIONS: Cumulative IFG exposure was associated with a higher risk of type 2 DM in a dose-response fashion.

Changes in metabolic syndrome status affect the incidence of end-stage renal disease in the general population: a nationwide cohort study.

Few studies have investigated the impact of a change in metabolic syndrome (MetS) components on clinical renal outcomes in the general population. Using nationally representative data from the Korean National Health Insurance System, 13,310,924 subjects who underwent two health examinations over 2 years and were free from end-stage renal disease (ESRD) from 2009 to 2012 were followed to the end of 2016. The subjects were divided into four groups according to the change in MetS components between the two visits over 2 years: no MetS (-/-), post-MetS (-/+), pre-MetS (+/-), and both MetS (+/+). After a median follow up of 5.11 years, 18,582 incident ESRD cases were identified. In the multivariate adjusted model, the hazard ratio (HR) and 95% confidence interval (CI) for the development of ESRD in the both-MetS (+/+) group compared with the no-MetS (-/-) group was 5.65 (95% CI, 5.42-5.89), which was independent of age, sex, and baseline estimated glomerular filtration rate. Additionally, the HR for the pre-MetS (+/-) group versus the no-MetS (-/-) group was 2.28 (2.15-2.42). In subgroup analysis according to renal function, the impact of a change in MetS on the incidence of ESRD was more pronounced in individuals with advanced renal dysfunction. Subjects with resolved MetS components had a decreased risk of ESRD, but not as low as those that never had MetS components. This provides evidence supporting the strategy of modulating MetS in the general population to prevent the development of ESRD.

Minichromosome maintenance protein 3 is a candidate proliferation marker in papillary thyroid carcinoma.

The proliferative capacity of tumor cells is a characteristic feature in the whole growing tumors. Many pathologists and clinicians have used the estimation of cell proliferation for prognostic information. Minichromosome maintenance protein 3 (MCM3) is known to have a role on the initiation and regulation of DNA replication during cell cycle. The aim of this study was to evaluate the potential applicability of one of the MCM proteins, MCM3, as a proliferation marker in papillary thyroid carcinoma (PTC) with correlation to clinicopathological parameters. We performed the immunohistochemical analysis for MCM3 and Ki-67 in 60 cases of PTC and Western blot analysis for MCM3 expression in 6 PTCs and normal thyroid tissues. The comparison of MCM3 labeling index (LI) to tumor size (P=0.031) and extrathyroidal extension (P=0.037) was statistically significant while that of Ki-67 LI to them was not. Moreover, a significant association was not observed between MCM3 and Ki-67, but the MCM3 LI was considerably higher. Western blot analyses revealed that the MCM3 protein expression levels were overexpressed in all PTCs. On the contrary, the levels of MCM3 were very low or absent in all normal thyroid tissues. Our results indicate that MCM3 may be a more reliable proliferation marker than Ki-67 in accessing the growth of tumor and evaluating tumor aggressiveness of PTC.

Gemigliptin Inhibits Interleukin-1ß-Induced Endothelial-Mesenchymal Transition via Canonical-Bone Morphogenetic Protein Pathway.

BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) contributes to inflammatory conditions inducing conversion of endothelial cells (ECs) into activated fibroblasts, promoting fibrotic diseases. Pro-inflammatory cytokine is the most potent inducer of EndMT. We investigated inhibition of interleukin-1ß (IL-1ß)-induced EndMT by gemigliptin, a dipeptidyl peptidase-IV inhibitor. METHODS: We exposed human umbilical vein endothelial cells (HUVECs) to 10 ng/mL IL-1ß/20 µM gemigliptin and analyzed the expression of endothelial, smooth muscle, mesenchymal, and osteoblastic markers, bone morphogenetic protein (BMP), Smad, and non-Smad signaling pathway proteins. RESULTS: Morphological changes showed gemigliptin blocked IL-1ß-induced EndMT, upregulated EC markers, and downregulated smooth muscle and mesenchymal markers. IL-1ß activation of HUVECs is initiated by the BMP/Smad and non-smad BMP signaling pathways. Gemigliptin inhibited IL-1ß induction of BMP2 and 7, activin receptor type IA, BMP receptor type IA, and BMP receptor type II. Reversal of IL-1ß-mediated inhibition of BMP-induced Smad1/5/8, Smad2, and Smad3 phosphorylation by gemigliptin suggests involvement of the Smad pathway in gemigliptin action. In the non-Smad BMP pathway, gemigliptin treatment significantly increased the deactivation of extracellular regulated protein kinase (ERK), p38, and JNK by IL-1ß. Gemigliptin treatment suppressed BMP-2-induced expression of key osteoblastic markers including osterix, runt-related transcription factor 2, and hepcidin during IL-1ß-induced EndMT. CONCLUSION: We demonstrated a novel protective mechanism of gemigliptin against fibrosis by suppressing IL-1ß-induced EndMT.

Combinations of metabolic syndrome components and the risk of type 2 diabetes mellitus: A nationwide cohort study.

OBJECTIVE: It remains unclear which specific combinations of metabolic syndrome (MetS) components confer a higher risk of type 2 diabetes mellitus (T2DM). This study examined the relation of each and combinations of MetS components with the risk of T2DM. METHODS: We studied the records of 19,475,643 adults aged ≥ 20 years with no history of T2DM from the database of the Korean National Health Insurance Service covering 2009 to 2012. The hazard ratios (HRs) and confidence intervals (CIs) of T2DM were estimated using Cox proportional hazards models. RESULTS: During a median follow-up of 5.13 years, 1,906,963 individuals were diagnosed with T2DM. The multivariable-adjusted HRs for T2DM were 1.86 for MetS, 1.821 for elevated fasting plasma glucose (FPG), 1.484 for elevated triglycerides, 1.415 for reduced high-density lipoprotein (HDL) cholesterol, 1.413 for elevated blood pressure (BP), and 1.17 for abdominal obesity compared with those without. In the combinations of two components excluding elevated FPG, subjects with elevated triglycerides and reduced HDL cholesterol had the highest risk of T2DM (HR 1.71; 95% CI, 1.695-1.725). In three components, the highest risk combination was elevated FPG, elevated triglycerides, and reduced HDL cholesterol (HR 3.342; 95% CI, 3.308-3.376). CONCLUSIONS: The combination of elevated triglycerides and reduced HDL cholesterol were more strongly associated with an increased risk of T2DM than other combinations except for elevated FPG.

BMI, Weight Change, and Dementia Risk in Patients With New-Onset Type 2 Diabetes: A Nationwide Cohort Study.

OBJECTIVE: This study examined the association between baseline BMI, percentage weight change, and the risk of dementia in patients newly diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using the South Korean National Health Insurance Service-National Health Screening Cohort database, we identified 167,876 subjects aged ≥40 years diagnosed with new-onset type 2 diabetes between 2007 and 2012. Their weight changes were monitored for ∼2 years after diagnosis, with follow-up assessments occurring for an average of 3.5 years. The hazard ratios (HRs) and Bonferroni-adjusted 95% CIs of all-cause dementia, Alzheimer disease (AD), and vascular dementia were estimated using multivariable Cox proportional hazards regression models. RESULTS: We identified 2,563 incident dementia cases during follow-up. Baseline BMI among patients with new-onset type 2 diabetes was inversely associated with the risk of all-cause dementia and AD, independent of confounding variables (P for trend <0.001). The percentage weight change during the 2 years after a diagnosis of type 2 diabetes showed significant U-shaped associations with the risk of all-cause dementia development (P < 0.001); the HRs of the disease increased significantly when weight loss or gain was >10% (1.34 [95% CI 1.11-1.63] and 1.38 [1.08-1.76], respectively). Additionally, weight loss >10% was associated with an increased risk of AD (HR 1.26 [95% CI 1.01-1.59]). CONCLUSIONS: A lower baseline BMI was associated with increased risks of all-cause dementia and AD in patients with new-onset type 2 diabetes. Weight loss or weight gain after the diagnosis of diabetes was associated with an increased risk of all-cause dementia. Weight loss was associated with an increased risk of AD.

Loss of beta-cells with fibrotic islet destruction in type 2 diabetes mellitus.

Recent morphologic analyses of human pancreases strongly suggest that a decreased beta-cell mass is observed from the early stages of diabetes and is caused by accelerated apoptosis of the beta-cells. In this article, we propose that fibrotic islet destruction might be one of the important pathogenic mechanisms of the limited capacity of beta-cell proliferation and accelerated apoptosis in diabetic patients. We have found that pancreatic stellate cells (PSCs) are involved in the progression of islet fibrosis in type 2 diabetes. High concentrations of glucose and insulin in islets contribute to PSC activation and proliferation through angiotensin II type 2 (ATII) signaling pathway, although the exact mechanisms remain to be confirmed. Angiotensin-converting enzyme inhibitors attenuate fibrotic islet destructions and that these have some beneficial effects on glucose tolerance. We suggest that PSCs might play a major role for the fibrotic islet destruction in patients with type 2 diabetes, and suppression of PSCs activation and proliferation might be one of the reasonable target to prevent and delay the progression of the type 2 diabetes mellitus.

Alpha-lipoic acid preserves skeletal muscle mass in type 2 diabetic OLETF rats.

BACKGROUND: Increased oxidative stress and impaired antioxidant defense are important mechanisms in the pathogenesis of diabetic myopathy. Alpha-lipoic acid (ALA) has been indicated as a weight-loss treatment in rodents and humans, but studies are limited. In the present study, we aimed to determine the influence of ALA, a potent biological antioxidant, on metabolic and growth processes in diabetic rat skeletal muscle. METHODS: Male 25-week-old type 2 diabetic rats (OLETF) were randomly divided into two groups, a control group (OLETF-C) and an ALA-treated group (OLETF-ALA) supplemented with 100 mg/kg ALA for 8 weeks. Age-matched, healthy, nondiabetic LETO (LETO-C) rats were used as controls. RESULTS: At 32 weeks of age, body weight was decreased by 6.8%, and the areas under the curve of IP-GTT, fasting glucose, and insulin were less in OLETF-ALA rats compared with OLETF-C rats. ALA significantly preserved muscle mass and enhanced muscle fiber cross-sectional area and fiber frequency percentage in the skeletal muscle of OLETF rats. Although the activation of myoD, myogenin, and myostatin in gastrocnemius muscle was significantly inhibited in OLETF-ALA rats relative to OLETF-C rats, there were no differences in the expression levels of muscle atrogin-1 and MuRF1 between the two groups. ALA treatment significantly increased the levels of phosphorylated 5'-AMPK, SIRT1, and PGC-1α, as well as the levels of phosphorylated AKT, mTOR, and p70S6 kinase in OLETF-ALA rats compared with OLETF-C rats. In contrast, the levels of phosphorylated p38 MAPK, IRS-1, and FOXO1 were decreased in OLETF-ALA rats compared with OLETF-C rats. CONCLUSIONS: ALA treatment preserved mass in the gastrocnemius muscles of OLETF rats. ALA significantly upregulated the AMPK/SIRT1/PGC-1α and AKT/mTOR/p70S6K signaling pathways in OLETF rat skeletal muscle. Therefore, ALA may be a potential therapeutic intervention for skeletal muscle loss in animal models of insulin resistance.

The Association between Pancreatic Steatosis and Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients.

BACKGROUND: Whether pancreatic steatosis has a local or systemic effect, like ectopic fat of other major organs, remains unknown. Data on the influence of pancreatic steatosis on microvascular complication are rare. Therefore, we investigated the relationship between pancreatic steatosis and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). METHODS: The attenuation of three pancreatic regions (head, body, and tail) and the spleen (S) in 186 patients with T2DM was measured using non-enhanced computed tomography imaging. We used three parameters for the assessment of pancreatic steatosis ('P' mean: mean attenuation of three pancreatic regions; P-S: difference between 'P' mean and 'S'; P/S: the 'P' mean to 'S' ratio). The presence of DR was assessed by an expert ophthalmologist using dilated fundoscopy. RESULTS: The average P mean was 29.02 Hounsfield units (HU), P-S was -18.20 HU, and P/S was 0.61. The three pancreatic steatosis parameters were significantly associated with the prevalence of DR in non-obese T2DM patients. In the non-obese group, the odds ratios of P mean, P-S, and P/S for the prevalence of DR, after adjustment for age, sex, and glycosylated hemoglobin level, were 2.449 (P=0.07), 2.639 (P=0.04), and 2.043 (P=0.02), respectively. CONCLUSION: In this study, pancreatic steatosis was significantly associated with DR in non-obese patients with T2DM. Further studies are necessary to clarify the causal relationship between pancreatic steatosis and the development of DR.

Publisher Correction: Normal-to-mildly increased albuminuria predicts the risk for diabetic retinopathy in patients with type 2 diabetes.

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