Later Stages Of Diabetes Research Articles

Construction of an Early Risk Prediction Model for Type 2 Diabetic Peripheral Neuropathy Based on Random Forest.

Diabetic peripheral neuropathy is a major cause of disability and death in the later stages of diabetes. A retrospective chart review was performed using a hospital-based electronic medical record database to identify 1020 patients who met the criteria. The objective of this study was to explore and analyze the early risk factors for peripheral neuropathy in patients with type 2 diabetes, even in the absence of specific clinical symptoms or signs. Finally, the random forest algorithm was used to rank the influencing factors and construct a predictive model, and then the model performance was evaluated. Logistic regression analysis revealed that vitamin D plays a crucial protective role in preventing diabetic peripheral neuropathy. The top three risk factors with significant contributions to the model in the random forest algorithm eigenvalue ranking were glycosylated hemoglobin, disease duration, and vitamin D. The areas under the receiver operating characteristic curve of the model ware 0.90. The accuracy, precision, specificity, and sensitivity were 0.85, 0.83, 0.92, and 0.71, respectively. The predictive model, which is based on the random forest algorithm, is intended to support clinical decision-making by healthcare professionals and help them target timely interventions to key factors in early diabetic peripheral neuropathy.

Piperazine ferulate inhibits diabetic nephropathy by suppressing AGE/RAGE-mediated inflammatory signaling in rats and podocytes.

Objective: Diabetic nephropathy (DN) is a serious complication that may occur during the later stages of diabetes, and can be further exacerbated by podocyte damage. Piperazine ferulate (PF) has well-defined nephroprotective effects and is used clinically in the treatment of chronic nephritis and other kidney diseases. However, the renoprotective effects and mechanisms of PF on DN are not clear. This study aims to investigate the protective effect of PF on DN and its mechanism of action, to inform the clinical application of PF in DN treatment. Methods: Network pharmacology was performed to predict the mechanism of action of PF in DN. Male Sprague Dawley rats were intraperitoneally injected with STZ (60mg/kg) to establish a DN model, and then assessed for renal injury after 12weeks of administration. In vitro, rat podocytes were treated with 25mmol/L glucose and cultured for 24h, followed by an assessment of cell injury. Results: Our results showed that PF significantly improved renal function, reduced renal pathological changes, decreased inflammatory response, and alleviated podocyte damage in DN rats. PF also attenuated glucose-induced podocyte injury in vitro. Regarding molecular mechanisms, our study demonstrated that PF downregulated the expression of genes and proteins related to AGE-RAGE-mediated inflammatory signaling. Conclusion: In summary, PF exerts its renoprotective effects by decreasing inflammation and protecting against podocyte injury through the inhibition of the AGE/RAGE/NF-κB/NLRP3 pathway. Overall, these data support the clinical potential of PF as a renoprotective agent in DN.

Cannabinoid Receptor 2-Centric Molecular Feedback Loop Drives Necroptosis in Diabetic Heart Injuries.

Diabetic heart dysfunction is a common complication of diabetes. Cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise time to intervene of particular cell death type remain largely unknown in the diabetic heart. This study aims to identify the particular cell death type that is responsible for diabetic heart dysfunction and to propose a promising therapeutic strategy by intervening in the cell death pathway. Type 2 diabetes models were established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. The type 1 diabetes model was established in streptozotocin-induced mice. Apoptosis and programmed cell necrosis (necroptosis) were detected in diabetic mouse hearts at different ages. G protein-coupled receptor-targeted drug library was searched to identify potential receptors regulating the key cell death pathway. Pharmacological and genetic approaches that modulate the expression of targets were used. Stable cell lines and a homemade phosphorylation antibody were prepared to conduct mechanistic studies. Necroptosis was activated after apoptosis at later stages of diabetes and was functionally responsible for cardiac dysfunction. Cannabinoid receptor 2 (CB2R) was a key regulator of necroptosis. Mechanically, during normal glucose levels, CB2R inhibited S6 kinase-mediated phosphorylation of BACH2 at serine 520, thereby leading to BACH2 translocation to the nucleus, where BACH2 transcriptionally repressed the necroptosis genes Rip1, Rip3, and Mlkl. Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. Cardiac re-expression of CB2R rescued diabetes-induced cardiomyocyte necroptosis and heart dysfunction, whereas cardiac knockout of Bach2 diminished CB2R-mediated beneficial effects. In human diabetic hearts, both CB2R and BACH2 were negatively associated with diabetes-induced myocardial injuries. CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R. Our study provides the integrative view of a novel molecular mechanism loop for regulation of necroptosis centered by CB2R, which represents a promising alternative strategy for controlling diabetic heart dysfunction.

Abstract 13062: In vivo Knockdown of Proapoptotic Mir-320 Restores Cardiac Function and Angiogenesis in a Mouse Model of Type 2 Diabetes

Background: Non-ischemic diabetic heart disease (NiDHD) is characterised by diastolic dysfunction and decreased or preserved systolic function, eventually resulting in heart failure. The fundamental mechanisms leading to NiDHD are still not known. microRNAs (miRNAs) plays a significant role in the development of NiDHD. Objective: To investigate the pathological role of cardiomyocyte enriched pro-apoptotic miR-320 in the development of NiDHD and to determine if therapeutic knockdown of miR-320 can restore impaired cardiac function and angiogenesis in the diabetic heart. Methods and Results: Cardiac tissue were collected from type-2 diabetic individuals undergoing cardiac surgery showed marked upregulation of miR-320, which was associated with downregulation of its direct target pro-survival insulin growth factor-1 (IGF-1) and anti-apoptotic protein Bcl-2. Analysis of cardiac tissue samples collected from type 2 diabetic mice (BKS.Cg-m+/+Leprdb/J) every 4wks, from 8 to 32wks of age showed activation of miR-320 and downregulation of IGF-1 at the later stages of diabetes. To determine if therapeutic knockdown of miR-320 is beneficial, high glucose cultured adult cardiomyocytes were treated with either locked nucleic acid (LNA) anti-precursor (pre)-miR-320 or scrambled (Scr) sequence. Results showed that LNA-anti-pre-320 significantly restored IGF-1 expression and reduced apoptotic cells death (3.1±05 in Scr vs 1.3±0.6 in LNA-anti-pre-320, P<0.01). Finally, to confirm if the effect can be translated in vivo , 24 weeks old type 2 diabetic mice with established systolic dysfunction were injected with LNA-anti-pre-320 once a week for 4wks. Echocardiography confirmed significant restoration of diastolic function and partial restoration of systolic function. Molecular analysis showed marked reduction in miR-320 expression, which was associated with recovery of IGF-1 and Bcl-2. Further, histological analysis confirmed improved angiogenesis and reduced fibrosis in the LNA-anti-pre-320 treated group. Conclusion: miR-320 is a late responding miRNA that aggravates apoptosis and cardiac dysfunction in diabetic heart, and that therapeutic knockdown of miR-320 is beneficial in partially restoring the deteriorated cardiac function.

PKR inhibitors suppress endoplasmic reticulum stress and subdue glucolipotoxicity-mediated impairment of insulin secretion in pancreatic beta cells.

Type 2 diabetes mellitus is characterized by insulin resistance and hypersecretion of insulin from the pancreas to compensate for decreased insulin sensitivity in the peripheral tissues. In later stages of the disease insulin-secreting beta cell degeneration commences and patients require insulin replacement therapy in order to accomplish proper regulation of their blood glucose. Endoplasmic reticulum (ER) stress in the beta cells is one of the factors contributing to this detrimental effect. Protein kinase R (PKR) is a cellular stress kinase activated by ER stress and contributing to degeneration of pancreatic islets. In order to determine whether inhibition of PKR activation by specific small molecule inhibitors of PKR ameliorates pancreatic insulin secretion capacity, we treated beta cells with two imidazole/oxindole-derived inhibitors of PKR kinase, imoxin (C16) and 2-aminopurine (2-AP), in the presence of ER stress. Our results demonstrate that PKR inhibition suppresses tunicamycin-mediated ER stress without altering the insulin production capacity of the cells. Palmitic acid-mediated suppression of insulin secretion, however, was subdued significantly by PKR inhibitor treatment through an ER stress-related mechanism. We suggest that PKR inhibitor treatment may be used to increase the insulin secretion capacity of the pancreas in later stages of diabetes.

A Method to Analyze Plantar Stiffness Variation in Diabetes Using Myotonometric Measurements

Abstract Diabetes mellitus is a group of metabolic disease, which has become globally prevalent, and affects a large population in socio-economically backward countries in Asian continent. Chronic diabetes can lead to ulceration in the plantar region and may result in amputation. Assessment of mechanical properties of plantar tissues can aid in early diagnosis of ulceration. Myotonometry, a technique to measure dynamic stiffness, is preferred due to its noninvasiveness, easy employability, and rapid investigation. In this study, an attempt has been made to analyze the changes in biomechanical properties of plantar soft tissue in diabetes. MyotonPro, a handheld device, is used for this purpose. 43 diabetic subjects with varied duration of diabetes are recruited. Site-specific mechanical properties of the plantar region for both the feet are acquired and statistical analysis is performed. Results show that the MyotonPro is able to differentiate the stages of diabetes. It is seen that there is a spatial variability in the mechanical properties of the plantar. Additionally, it is observed that there is a significant increment in the plantar stiffness value in the group with higher diabetic age (p < 0.05). Further, significant changes in dynamic mechanical properties are also observed in submetatarsal region. Additionally, a right–left asymmetry has been observed in frequency and stiffness values for later stages of diabetes. This study demonstrated the feasibility of MyotonPro in discriminating the stages of diabetic period. Thus, the proposed approach could be useful in early diagnosis of foot ulceration for various clinical conditions.

Correlation between the Activity of Aldehyde Dehydrogenase and Oxidative Stress Markers in the Saliva of Diabetic Patients.

BackgroundReactive aldehydes are involved in diseases associated with oxidative stress, including diabetes. Human salivary aldehyde dehydrogenase (hsALDH) presumably protects us from many toxic ingredient/contaminant aldehydes present in food.ObjectiveThis study aimed to probe the activity of hsALDH in patients with diabetes and than to correlate it with various oxidative stress markers in the saliva.MethodsThe saliva samples were collected from total 161 diabetic patients from Rajiv Gandhi Centre for Diabetes, Jawaharlal Nehru Medical College (JNMC), AMU, Aligarh, (India). HsALDH activity and markers of oxidative stress [8-hydroxydeoxyguanosine (8-OHDG), malondialdehyde (MDA) and advanced glycation end products (AGEs)] were measured in the saliva samples.ResultsPatients with early stage of diabetes had higher activity of hsALDH when compared with the control group. As the history of diabetes increases, the activity of the enzyme decreases and also higher oxidative stress markers (8-OHDG, MDA and AGEs) are detected in the saliva samples. Negative significant correlation between hsALDH activity and oxidative stress markers were observed (p <0.0001).ConclusionThe activity of hsALDH increases in early stages of diabetes most probably to counter the increased oxidative stress associated with diabetes. However, in later stages of diabetes, the activity of the enzyme decreases, possibly due to its inactivation resulting from glycation.

Hypoglycemic Drugs and Advanced Glycation Endproducts

Recent data showed that 9.1% of adults worldwide have diabetes, and 318 million adults have a high risk of developing diabetes in the future. Diabetes and its complications have serious impact on human health. In the early stages of diabetes, excessive advanced glycation endproducts (AGEs) accumulate in the body and bind to its receptor RAGE, which impairs glucose regulation. In the later stages of diabetes, increased blood glucose can accelerate the production of more AGEs. AGEs play a pivotal role in the development of diabetes and its complications. In recent years, AGEs have become one of the research hotspots. The search for potential drug targets that can block or reduce the accumulation of AGEs has attracted increasing attention. This review summarizes the role of AGEs and the effects of various hypoglycemic agents on AGEs from the perspective of mechanisms, in order to provide reference for the further search for targeted drugs against AGEs.

Diabetic Retinopathy: Recent Updates on Different Biomarkers and Some Therapeutic Agents.

Diabetic Retinopathy is a leading cause of sight-threatening complication, which occurs due to a number of physiological and metabolic abnormalities during later stages of diabetes. Many of these abnormal changes are consistent with altered oxidative stress, inflammation, genetic set up, advanced glycation end products, and hematological changes. So the altered levels of different biomolecules related to these changes serve as important biomarkers to assess better evaluation and early treatment of this disease. Some treatments like laser therapy may be fast and specific but are more expensive, limited and can result in severe contraindications. Several other novel treatment strategies have been evolved recently besides classical approaches like control over hyperglycemia, hypertension, lipid profile to control diabetic retinopathy. These precise treatments are based on targeting the elevated biomarkers in retina. Such treatments include use of anti-VEGF therapy, intravitreal corticosteroids, gamigliptin and flavonoids. The present review discusses the latest updates on diabetic retinopathy, common etiology, different biomarkers and current treatments. In conclusion, perfection and proper supervision of diabetes and early treatment of diabetic retinopathy are crucial in controlling the occurrence and severity of this disease.

Diabetes-associated alterations in the cecal microbiome and metabolome are independent of diet or environment in the UC Davis Type 2 Diabetes Mellitus Rat model.

The composition of the gut microbiome is altered in obesity and type 2 diabetes; however, it is not known whether these alterations are mediated by dietary factors or related to declines in metabolic health. To address this, cecal contents were collected from age-matched, chow-fed male University of California, Davis Type 2 Diabetes Mellitus (UCD-T2DM) rats before the onset of diabetes (prediabetic PD; n = 15), 2 wk recently diabetic (RD; n = 10), 3 mo (D3M; n = 11), and 6 mo (D6M; n = 8) postonset of diabetes. Bacterial species and functional gene counts were assessed by shotgun metagenomic sequencing of bacterial DNA in cecal contents, while metabolites were identified by gas chromatography-quadrupole time-off-flight-mass spectrometry. Metagenomic analysis showed a shift from Firmicutes species in early stages of diabetes (PD + RD) toward an enrichment of Bacteroidetes species in later stages of diabetes (D3M + D6M). In total, 45 bacterial species discriminated early and late stages of diabetes with 25 of these belonging to either Bacteroides or Prevotella genera. Furthermore, 61 bacterial gene clusters discriminated early and later stages of diabetes with elevations of enzymes related to stress response (e.g., glutathione and glutaredoxin) and amino acid, carbohydrate, and bacterial cell wall metabolism. Twenty-five cecal metabolites discriminated early vs. late stages of diabetes, with the largest differences observed in abundances of dehydroabietic acid and phosphate. Alterations in the gut microbiota and cecal metabolome track diabetes progression in UCD-T2DM rats when controlling for diet, age, and housing environment. Results suggest that diabetes-specific host signals impact the ecology and end product metabolites of the gut microbiome when diet is held constant.

Wear mechanisms and abrasion rates in selective laser sintering materials

Selective laser sintering offers very good mechanical material properties. The production in the powder bed gives total freedom in the layout without the need for support structures. One emerging application is the manufacturing of personalized shoes, be it for mass customization or in the medical field for patients with rheumatoid arthritis or later stages of diabetes. Because of this we are studying the wear and tribological behaviour of materials processed in this technology and we are looking for wear mechanisms that are unique to this process. We compared thermoplastic polyurethane as well as the defacto standard polyamide 12 under different loading scenarios to elicit different wear mechanisms. To account for the layerwise production process specimens build in different orientations were investigated and compared. A new wear mechanism was discovered and quantitative comparison of abrasion rates under different load conditions is given. The differences between building orientations were small and inconclusive.

Host diabetes status is the major regulator of gut microbiome in the UCD‐T2DM Rat

There is strong evidence in humans and in animal models that the gut microbiome is altered in obesity and/or the insulin resistant condition. Poor metabolic health is often linked to overnutrition and poor‐quality diets, and the gut microbiome is highly dependent on these factors. Less well appreciated is the potential role of host metabolic physiology in modifying gut microbial ecology. To address this question, we have used the UCD‐T2DM Rat model to test whether the gut microbiome is altered during the progression of diabetes when controlling for exogenous factors (sex, strain, age, diet and vivarium housing). Cecal microbial profiles were assessed using amplicon sequencing of 16S rRNA collected from age‐matched lean Sprague‐Dawley rats (LSD, n = 12), pre‐diabetic UCD‐T2DM rats (PD, n = 15), recently‐diabetic UCD‐T2DM rats (RD, n = 10), and 3‐months (D3M n = 11) and 6‐months (D6M n = 7) post‐diabetic UCD‐T2DM rats. LSD rats had significantly greater sample diversity (Shannon Index) at phylum level (P &lt; 0.05, ANOVA), but significantly lower sample richness (Chao1) at genus level (P &lt; 0.05, ANOVA) when compared to all UCD‐T2DM rat groups. β‐diversity was significantly different by group (P &lt; 0.05; PERMANVOA), with LSD rats distinctly clustered from all UCD‐T2DM rat groups in non‐metric dimensional scaling (NMDS) plots. A total of 30 genera were significantly altered between LSD and UCD‐T2DM rat groups, with Lactobacillus being the highest abundance genera that was greater in all UCD‐T2DM rat groups relative to LSD (1.7%, 7.6, 5.7%, 8.5%, and 13.0% in LSD, PD, RD, D3M, and D6M respectively). When only assessing UCD‐T2DM rat groups, there was a significant main effect of diabetes status, starting at bacterial class level and continuing through genus (P &lt; 0.05; PERMANOVA). Only 4 genera were altered between PD and RD groups, while only 3 genera differed between D3M and D6M. NMDS showed that rats from early stages of diabetes (PD plus RD) were discriminated from those in later stages of diabetes (D3M plus D6M). A total of 22 genera were significantly altered when comparing early diabetic groups between later stages. Genus altered with &gt; 1% median relative abundance included Bacteroides (PD: 1.3%, D6M: 0.9%), Lactobacillus (RD: 5.7%, D6M 13.0%), and an unassigned genera in the Clostridiaceae family (PD: 1.1%, D3M: 1.1%). In summary, the cecal gut microbiome in LSD rats was considerably different to UCD‐T2DM rats and may be due to alternative strain backgrounds. A major and novel finding was that significant gut microbe shifts were observed when comparing groups from pre‐ and early‐diabetes stages relative to those in later stages of diabetes, despite controlling for variables that typically confound microbiome studies of type 2 diabetes in humans. This indicates that the metabolic health of the host influences the micro‐ecology of the large intestine.Support or Funding InformationThis study was supported by USDA‐ARS Project 6026‐51000‐010‐05S.

Profiling of circulating microRNAs in children with recent onset of type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease that is clinically silent until the majority of β cells are destroyed. There is an unmet need for reliable and cost-effective biomarkers to predict and diagnose diabetes at an early stage. A number of stable microRNAs (miRNAs) have been reported in serum and plasma and are now being investigated as biomarkers of different diseases. We measured the levels of 745 miRNAs in sera of children with recent-onset T1D and age-matched controls using locked nucleic acid-enhanced (LNA-enhanced) quantitative PCR profiling. Thirty-five miRNAs were significantly different between the groups, and 27 miRNAs were elevated in T1D. Good discriminating power was obtained for 6 miRNAs (miR-454-3p, miR-222-3p, miR-144-5p, miR-345-5p, miR-24-3p, and miR-140-5p), which were not elevated at later stages of diabetes. In silico pathway analysis, based on inferred miRNA target genes, associated glycosaminoglycan biosynthesis as well as PI3K/Akt, MAPK, and Wnt signaling pathways with early stages of T1D. Among the 27 upregulated miRNAs in T1D, 2 miRNAs significantly correlated with hemoglobin A1c (HbA1c), as did 5 of 8 downregulated miRNAs. A total of 134 miRNAs significantly correlated with HbA1c when stratifying hyperglycemia-induced miRNAs from T1D-specific miRNAs. In conclusion, we have identified a serum miRNA pattern of recent-onset T1D and signaling pathways that may be involved in its pathogenesis.

Parenchymal and Stromal Cells Contribute to Pro-Inflammatory Myocardial Environment at Early Stages of Diabetes: Protective Role of Resveratrol.

Background: Little information is currently available concerning the relative contribution of cardiac parenchymal and stromal cells in the activation of the pro-inflammatory signal cascade, at the initial stages of diabetes. Similarly, the effects of early resveratrol (RSV) treatment on the negative impact of diabetes on the different myocardial cell compartments remain to be defined. Methods: In vitro challenge of neonatal cardiomyocytes and fibroblasts to high glucose and in vivo/ex vivo experiments on a rat model of Streptozotocin-induced diabetes were used to specifically address these issues. Results: In vitro data indicated that, besides cardiomyocytes, neonatal fibroblasts contribute to generating initial changes in the myocardial environment, in terms of pro-inflammatory cytokine expression. These findings were mostly confirmed at the myocardial tissue level in diabetic rats, after three weeks of hyperglycemia. Specifically, monocyte chemoattractant protein-1 and Fractalkine were up-regulated and initial abnormalities in cardiomyocyte contractility occurred. At later stages of diabetes, a selective enhancement of pro-inflammatory macrophage M1 phenotype and a parallel reduction of anti-inflammatory macrophage M2 phenotype were associated with a marked disorganization of cardiomyocyte ultrastructural properties. RSV treatment inhibited pro-inflammatory cytokine production, leading to a recovery of cardiomyocyte contractile efficiency and a reduced inflammatory cell recruitment. Conclusion: Early RSV administration could inhibit the pro-inflammatory diabetic milieu sustained by different cardiac cell types.

Changes in beta cell function occur in prediabetes and early disease in the Lepr (db) mouse model of diabetes.

Aims/hypothesisType 2 diabetes is a progressive disease that increases morbidity and the risk of premature death. Glucose dysregulation, such as elevated fasting blood glucose, is observed prior to diabetes onset. A decline in beta cell insulin secretion contributes to the later stages of diabetes, but it is not known what, if any, functional beta cell changes occur in prediabetes and early disease.MethodsThe Leprdb mouse (age 13–18 weeks) was used as a model of type 2 diabetes and a two-photon granule fusion assay was used to characterise the secretory response of pancreatic beta cells.ResultsWe identified a prediabetic state in db/db mice where the animals responded normally to a glucose challenge but have elevated fasting blood glucose. Isolated islets from prediabetic animals secreted more and were bigger. Insulin secretion, normalised to insulin content, was similar to wild type but basal insulin secretion was elevated. There was increased glucose-induced granule fusion with a high prevalence of granule–granule fusion. The glucose-induced calcium response was not changed but there was altered expression of the exocytic machinery. db/db animals at the next stage of disease had overt glucose intolerance. Isolated islets from these animals had reduced insulin secretion, reduced glucose-induced granule fusion events and decreased calcium responses to glucose.Conclusions/interpretationBeta cell function is altered in prediabetes and there are further changes in the progression to early disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3942-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Tissue-specific differences in the development of insulin resistance in a mouse model for type 1 diabetes.

Although insulin resistance is known to underlie type 2 diabetes, its role in the development of type 1 diabetes has been gaining increasing interest. In a model of type 1 diabetes, the nonobese diabetic (NOD) mouse, we found that insulin resistance driven by lipid- and glucose-independent mechanisms is already present in the liver of prediabetic mice. Hepatic insulin resistance is associated with a transient rise in mitochondrial respiration followed by increased production of lipid peroxides and c-Jun N-terminal kinase activity. At the onset of diabetes, increased adipose tissue lipolysis promotes myocellular diacylglycerol accumulation. This is paralleled by increased myocellular protein kinase C θ activity and serum fetuin A levels. Muscle mitochondrial oxidative capacity is unchanged at the onset but decreases at later stages of diabetes. In conclusion, hepatic and muscle insulin resistance manifest at different stages and involve distinct cellular mechanisms during the development of diabetes in the NOD mouse.

Streptozotocin diabetes attenuates the effects of nondepolarizing neuromuscular relaxants on rat muscles.

The hypothesis of this study was that diabetes-induced desensitization of rat soleus (SOL) and extensor digitorum longus (EDL) to non-depolarizing muscle relaxants (NDMRs) depends on the stage of diabetes and on the kind of NDMRs. We tested the different magnitude of resistance to vecuronium, cisatracurium, and rocuronium at different stages of streptozotocin (STZ)-induced diabetes by the EDL sciatic nerve-muscle preparations, and the SOL sciatic nerve-muscle preparations from rats after 4 and 16 weeks of STZ treatment. The concentration-twitch tension curves were significantly shifted from those of the control group to the right in the diabetic groups. Concentration giving 50% of maximal inhibition (IC50) was larger in the diabetic groups for all the NDMRs. For rocuronium and cisatracurium in both SOL and EDL, IC50 was significantly larger in diabetic 16 weeks group than those in the diabetic 4 weeks group. For SOL/EDL, the IC50 ratios were significantly largest in the diabetic 16 weeks group, second largest in the diabetic 4 weeks group, and smallest for the control group. Diabetes-induced desensitization to NDMRs depended on the stage of diabetes and on the different kind of muscles observed while was independent on different kind of NDMRs. The resistance to NDMRs was stronger in the later stage of diabetes (16 versus 4 weeks after STZ treatment). Additionally, when monitoring in SOL, diabetes attenuated the actions of neuromuscular blockade more intensely than that in EDL. Nonetheless, the hyposensitivity to NDMRs in diabetes was not relevant for the kind of NDMRs.

Serum Albumin Levels: A Simple Answer to a Complex Problem? Are We on the Right Track of Assessing Metabolic Syndrome?

Serum Albumin Levels: A Simple Answer to a Complex Problem? Are We on the Right Track of Assessing Metabolic Syndrome?

Aberrant production of extracellular matrix proteins and dysfunction in kidney endothelial cells with a short duration of diabetes.

Diabetic nephropathy is the most common cause of end-stage renal disease and is a major risk factor for cardiovascular disease. In the United States, microvascular complications during diabetic nephropathy contribute to high morbidity and mortality rates. However, the cell-autonomous impact of diabetes on kidney endothelial cell function requires further investigation. Male Akita/+ [autosomal dominant mutation in the insulin II gene (Ins2)] mice reproducibly develop diabetes by 4 wk of age. Here, we examined the impact a short duration of diabetes had on kidney endothelial cell function. Kidney endothelial cells were prepared from nondiabetic and diabetic mice (4 wk of diabetes) to delineate the early changes in endothelial cell function. Kidney endothelial cells from Akita/+ mice following 4 wk of diabetes demonstrated aberrant expression of extracellular matrix proteins including decreased osteopontin and increased fibronectin expression which correlated with increased α5-integrin expression. These changes were associated with the attenuation of migration and capillary morphogenesis. Kidney endothelial cells from Akita/+ mice had decreased VEGF levels but increased levels of endothelial nitric oxide synthase(eNOS) and NO, suggesting uncoupling of VEGF-mediated NO production. Knocking down eNOS expression in Akita/+ kidney endothelial cells increased VEGF expression, endothelial cell migration, and capillary morphogenesis. Furthermore, attenuation of sprouting angiogenesis of aortas from Akita/+ mice with 8 wk of diabetes was restored in the presence of the antioxidant N-acetylcysteine. These studies demonstrate that aberrant endothelial cell function with a short duration of diabetes may set the stage for vascular dysfunction and rarefaction at later stages of diabetes.

Insulin: Potential Negative Consequences of Early Routine Use in Patients With Type 2 Diabetes

The lack of adequate insulin secretion characterizes all hyperglycemic states. When insulin action is normal, as in type 1 diabetes, there is a near total loss of insulin secretory function. In type 2 diabetes, the abnormalities in insulin secretion are multiple. One of the initial defects is a loss of the early phase of meal-stimulated insulin secretion. This is followed by an inability of the β-cell to increase insulin secretion sufficient to overcome hepatic and peripheral insulin resistance. Type 2 diabetes is characterized by a progressive decrease in both β-cell mass and secretory function so that, in most individuals, absolute insulin deficiency occurs in the late stages of the disease. It would seem logical that the ideal treatment for type 2 diabetes should be early and continuing insulin therapy. Unfortunately, there are several characteristics of insulin treatment and insulin action in type 2 diabetes that limit the usefulness of insulin treatment and that suggest that chronic insulin therapy is best used in the later stages of diabetes when there is an absolute deficiency of insulin. In normal physiology, β-cell insulin secretion is coupled immediately with changes in the plasma glucose level (1). The secretory response is rapid (within a minute or two), and because the half-life of insulin is ~5 min, there is little lag time in the glucose regulatory system. Endogenously secreted insulin goes via the portal vein to the liver, where 30–80% of it is either metabolized or used (2). The portal vein-to-peripheral arterial insulin ratio is ~2:1. The administration of insulin exogenously eliminates the rapid regulation of plasma glucose, since the insulin must be taken up slowly and without regulation from the subcutaneous injection site. The kinetics are determined by the nature of the injected insulin formulation. Additionally, as illustrated in Fig. 1, it is necessary …