Role of calpains in diabetes mellitus: A mini review

Type 2 diabetes mellitus (T2DM) is characterized by defects in haepatic glucose production, insulin action and insulin secretion, which can also lead to a variety of secondary disorders. The disease can lead to death without treatment and it has been predicted that T2DM will affect 215 million people world-wide by 2010. T2DM is a multifactorial condition whose precise genetic causes and biochemical defects have not been fully elucidated but at both levels, calpains appear to play a role. Positional cloning studies mapped T2DM susceptibility to CAPN10, the gene encoding the intracellular cysteine protease, calpain 10. Further studies have shown a number of non-coding polymorphisms in CAPN10 to be functionally associated with T2DM whilst the identification of coding polymorphisms, suggested that mutant calpain 10 proteins may also contribute to the disease. The presence of both calpain 10 and its mRNA have been demonstrated in tissues from several mammalian species whilst calpain 10 appears to be associated with pathways involved in glucose metabolism, insulin secretion and insulin action. It appears that other calpains may also participate in these pathways and here we present an overview of recent studies on calpains and their putative role in T2DM. (Mol Cell Biochem 261: 161–167, 2004)     

Role of calpains in diabetes mellitus: a mini review

Type 2 diabetes mellitus (T2DM) is characterized by defects in haepatic glucose production, insulin action and insulin secretion, which can also lead to a variety of secondary disorders. The disease can lead to death without treatment and it has been predicted that T2DM will affect 215 million people world-wide by 2010. T2DM is a multifactorial condition whose precise genetic causes and biochemical defects have not been fully elucidated but at both levels, calpains appear to play a role. Positional cloning studies mapped T2DM susceptibility to CAPN10, the gene encoding the intracellular cysteine protease, calpain 10. Further studies have shown a number of non-coding polymorphisms in CAPN10 to be functionally associated with T2DM whilst the identification of coding polymorphisms, suggested that mutant calpain 10 proteins may also contribute to the disease. The presence of both calpain 10 and its mRNA have been demonstrated in tissues from several mammalian species whilst calpain 10 appears to be associated with pathways involved in glucose metabolism, insulin secretion and insulin action. It appears that other calpains may also participate in these pathways and here we present an overview of recent studies on calpains and their putative role in T2DM.     

The in vitro retardation of porcine cataractogenesis by the calpain inhibitor,SJA6017

Calpain inhibitors show the potential to serve as non-surgical alternatives in treating diabetic cataract and other types of these disorders. Here, we have tested the recently developed calpain inhibitor, SJA6017, for its ability to inhibit cataractogenesis in porcine lenses. These lenses were incubated in increasing levels of extralenticular calcium (Ca²⁺; 5–30 mM). Atomic absorption spectroscopy was used to determine total internal lens Ca²⁺ and a correlation between porcine lens Ca²⁺ uptake and levels of lens opacification were found with a total internal lens Ca²⁺ level of 5.8 M Ca²⁺ g^–1 wet lens weight corresponding to the onset of catarctogenesis. A total internal lens Ca²⁺ level of 8.0 M Ca²⁺ g^–1 wet lens weight corresponded to cataract occupying approximately 70% of the lens cell volume. This degree of cataract was reduced by approximately 40%, when SJA6017 (final concentration 0.8 M) was included in the extralenticular medium, suggesting that the Ca²⁺-mediated activation of calpains may be involved in the observed opacification. Supporting this suggestion atomic absorption spectroscopy showed that the effect of SJA6017 (final concentration 0.8 M) on lens opacification was not due to the compound restricting porcine lens Ca²⁺ uptake. The results indicate that calpain-induced cataractogenesis is dependent on extracellular Ca²⁺ and the calpain inhibitor SJA6017 (0.8 M) had no significant effect on Ca²⁺ uptake by lens. Its inhibitory effect on lens opacification may be due to a direct action on the activity of calpain. (Mol Cell Biochem 261: 169–173, 2004)     

Redox treatment ameliorates diabetes mellitus-induced skin flap necrosis via inhibiting apoptosis and promoting neoangiogenesis

Intractable wound healing is the habitual problem of diabetes mellitus. High blood glucose limits wound healing by interrupting inflammatory responses and inhibiting neoangiogenesis. Oxidative stress is commonly thought to be a major pathogenic cause of diabetic complications. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, EDV) is a free radical scavenger which suppress oxidative stress. This study investigates whether EDV can reduce oxidative stress in wound healing HaCaT/human dermal fibroblasts cells (HDFs) in vitro and in vivo animal model. Cell viability and wound healing assays, FACS flow cytometry, and Hoechst 33342 staining were performed to confirm apoptosis and cytotoxicity in H₂O₂ and EDV-treated HaCaT and HDFs. A streptozotocin-induced hyperglycemic animal model was made in adult C57BL6 mice. Full-thickness skin flap was made on dorsomedial back and re-sutured to evaluate the wound healing process. EDV was delivered slowly in the skin flap with degradable fibrin glue. The flap was monitored and analyzed on postoperative days 1, 3, and 5. CD31/DAPI staining was done to detect newly formed blood vessels. The expression levels of NF-κB, bcl-2, NOX3, and STAT3 proteins in C57BL6 mouse tissues were also examined. The wound healing process in hyper- and normoglycemic mice showed a difference in protein expression, especially in oxidative stress management and angiogenesis. Exogenous H₂O₂ reduced cell viability in a proportion to the concentration via apoptosis. EDV protected HaCaT cells and HDFs from H₂O₂ induced reactive oxygen species cell damage and apoptosis. In the mouse model, EDV with fibrin resulted in less necrotic areas and increased angiogenesis on postoperative day 5, compared to sham-treated mice. Our results indicate that EDV could protect H₂O₂-induced cellular injury via inhibiting early apoptosis and inflammation and also increasing angiogenesis. EDV might be valuable in the treatment of diabetic wounds that oxidative stress has been implicated.     

Age-Related Features of Cataractogenesis in Salmon Fry. 2. Biochemical Features of Lens during Cataractogenesis

We studied biochemical features of the lipid and phospholipid composition and patter of fatty acid spectra in lenses of one and two year old salmons bearing cataracts. The lipid complex of lenses of diseased fish underwent significant changes. Cataractogenesis was accompanied by enhanced free radical oxidation and accumulation of malone dialdehyde in lenses of salmons of various ages. The intensification of oxidative processes was synchronized with the decreased level of antioxidant protection (reduced glutathione, vitamins A and E). The activity of Ca²⁺-dependent proteolytic enzymes in lenses was determined and its decrease in the case of cataract was shown.     

Recent advances in molecular biomarkers for diabetes mellitus: a systematic review

Context: Diabetes is a growing global metabolic epidemic. Current research is focussing on exploring how the biological processes and clinical outcomes of diabetes are related and developing novel biomarkers to measure these relationships, as this can subsequently improve diagnostic, therapeutic and management capacity.

Objective: The objective of this study is to identify the most recent advances in molecular biomarkers of diabetes and directions that warrant further research.

Methods: Using a systematic search strategy, the MEDLINE, CINAHL and OVID MEDLINE databases were canvassed for articles that investigated molecular biomarkers for diabetes. Initial selections were made based on article title, whilst final inclusion was informed by a critical appraisal of the full text of each article.

Results: The systematic search returned 246 records, of which 113 were unique. Following screening, 29 records were included in the final review. Three main research strategies (the development of novel technologies, broad biomarker panels, and targeted approaches) identified a number of potential biomarkers for diabetes including miR-126, C-reactive protein, 2-aminoadipic acid and betatrophin.

Conclusion: The most promising research avenue identified is the detection and quantification of micro RNA. Further, the utilisation of functionalised electrodes as a means to detect biomarker compounds also warrants attention.     

The association between serum selenium and gestational diabetes mellitus: A systematic review and meta-analysis

BackgroundResults of the studies about association between serum selenium concentration and gestational hyperglycemia are inconsistent. Some studies have demonstrated that women with gestational diabetes mellitus (GDM) have lower Se concentrations while contrary results are reported in other studies.AimThe aim of this study is to compare the serum Se concentration in women with GDM and normoglycemic pregnant women via a systematic review and meta-analysis.MethodsA computerized literature search on four databases (PubMed, Cochrane register of control trials, Scopus and Google scholar) was performed from inception through August 2013. Necessary data were extracted and random effects model was used to conduct the meta-analysis.ResultsSix observational studies (containing 147 women with GDM and 360 normoglycemic pregnant women) were found, which had compared serum Se concentration in women suffering from GDM with normal pregnant ones. Our meta-analysis revealed that serum Se concentration was lower in women with GDM compared to normoglycemic pregnant women (Hedges = −1.34; 95% CI: −2.33 to −0.36; P < 0.01). Stratified meta-analysis demonstrated that concentration of Se in the sera of women with GDM was lower than normal pregnant women both in second and third trimesters, but the result was not significant in second trimester (second trimester: Hedges = −0.68; 95% CI: −1.60−0.25; P = 0.15, third trimester: Hedges = −2.81; 95% CI: −5.21 to −0.42; P < 0.05). It was also demonstrated that serum Se status was lower in pregnant women with impaired glucose tolerance (IGT) compared to normoglycemic pregnant women (Hedges = −0.85; 95% CI: −1.18 to −0.52).ConclusionThe available evidences suggest that serum Se concentration is significantly lower in pregnant women with gestational hyperglycemia compared to normal pregnant women.     

长链非编码RNA与糖尿病及其并发症

长链非编码RNA起初被认定是基因转录"噪音",随着DNA元件百科全书的研究进展发现,lnc RNA能以RNA的形式在表观遗传、转录以及转录后水平调控基因的表达,参与多种重要的生命调控过程,与人类疾病的发生发展和预防都有着紧密联系。文章介绍lnc RNA的功能和特点,结合对lnc RNA的研究思路,并在已有研究的基础上综述lnc RNA与糖尿病及其并发症的关系,这些研究进展将为进一步理解糖尿病及其发生发展的分子医学基础提供依据。     

Hexokinase isoenzymes in diabetes

Hexokinase is present in the tissues in four isoenzymic forms. Cerebral tissue contains predominantly Type I hexokinase which is believed to be insulin-insensitive. In cerebral tissue about 60 to 70% of the hexokinase is bound to the particulate fraction. The changes in the distribution of hexokinase Type I and Type II together with the bound and free hexokinase have been studied in control, diabetic and diabetic animals treated with insulin. The results indicate that the presence of insulin is essential for the normal binding of the hexokinase to the particulate fraction. In heart tissue, Type II hexokinase bound to the pellet shows a significant decrease in diabetes, which is reversed on insulin administration.     

Changes in the subcellular distribution of brain and heart hexokinase isoenzymes during alloxan diabetes

Changes in the subcellular distribution of hexokinase activity from three brain regions and heart were studied during alloxan induced diabetes. There was an overall decrease in the particulate hexokinase with an increase in the soluble form, after different time intervals of the onset of diabetes. Administration of insulin to the diabetic rats showed a partial counteraction of the enzyme changes. A possible regulation of brain hexokinase by metabolite changes is proposed     

An infectious aetiology of insulin-dependent diabetes mellitus? Role of the secretor status

Abstract Studies of patients with insulin-dependent diabetes and their families have shown increased incidences of HLA markers B8, B15, DR3 and DR4. While these genetic predispositions are obviously important, additional factors such as environmental influences are presumed to trigger the events leading to the development of diabetes.
Infectious triggers, in particular several viruses, have been suggested. The evidence from epidemiological and in vitro studies for a viral aetiology is summarized here. The significance of the recent finding of an increased proportion of non-secretors among patients with insulin-dependent diabetes is discussed in the context of other 'autoimmune' diseases for which infectious aetiologies have been proposed.     

A review of the molecular pathways mediating the improvement in diabetes mellitus following caloric restriction

Lifestyle modification is the cornerstone of diabetes prevention and treatment. Weight loss through caloric restriction (CR) is effective in improving glycemic control, though it is difficult for patients to follow in practice, and remains critical to achieve optimal glucose homeostasis. In this review, we look at what is known about the molecular pathways involved in CR-induced insulin sensitivity and improved insulin resistance.     

Chymotrypsin-reactive antibodies in insulin-dependent diabetes mellitus

In a previous study (Frazieret al., 1990), it was demonstrated that two patients with type 1 (insulin-dependent) diabetes mellitus had antibodies in their serum which reacted with four 29 kDa pancreas-specific proteins on two-dimensional immunoblots. This paper reports on the purification and identification of these pancreatic proteins. The protein with the pI closest to pH7 was purified through the use of ammonium sulfate fractionation and ion-exchange chromatography. Gel filtration chromatography established that the protein's molecular weight was closer to 25 kDa. Amino acid composition and sequence analyses demonstrated homology between the protein and chymotrypsin. It is suggested that an abnormal regulation of chymotrypsin activity might be related to antibodies formed in some diabetic patients.     

Resveratrol effects in bladder cancer: A mini review

Bladder cancer has a high incidence worldwide and is the most common genitourinary cancer. The treatment of bladder cancer involves surgery and chemotherapy; however high failure rates and toxicity are observed. In this context, the search of new drugs aiming a more effective treatment is extremely necessary. Natural products are an important source of compounds with antiproliferative effects. Resveratrol is a naturally occurring plant polyphenol whose anticancer activity has been demonstrated in different types of cancer. This review summarizes the in vitro and in vivo studies using models of bladder cancer treated with resveratrol and discusses its different mechanisms of action.     

Role of mitochondrial DNA in diabetes Mellitus Type I and Type II

Morbidity and mortality from diabetes mellitus and associated illnesses is a major problem across the globe. Anti-diabetic medicines must be improved despite existing breakthroughs in treatment approaches. Diabetes has been linked to mitochondrial dysfunction. As a result, particular mitochondrial diabetes kinds like MIDD (maternally inherited diabetes & deafness) and DAD (diabetic autonomic dysfunction) have been identified and studied (diabetes and Deafness). Some mutations as in mitochondrial DNA (mtDNA), that encodes for a significant portion of mitochondrial proteins as well as mitochondrial tRNA essential for mitochondrial protein biosynthesis, are responsible for hereditary mitochondrial diseases. Tissue-specificity and heteroplasmy have a role in the harmful phenotype of mtDNA mutations, making it difficult to generalise findings from one study to another. There are a huge increase in the number for mtDNA mutations related with human illnesses that have been identified using current sequencing technologies. In this study, we make a list on mtDNA mutations linked with diseases and diabetic illnesses and explore the methods by which they contribute to the pathology's emergence.     

Association between shift work and risk of type 2 diabetes mellitus: a systematic review and dose-response meta-analysis of observational studies

ABSTRACT

To evaluate the association between shift work and risk of type 2 diabetes mellitus, we searched PubMed, EMBASE and Web of Science from their inception to June 8, 2019. Observational studies examining the relationship between shift work and type 2 diabetes were included. Subgroup analyses were conducted to explore whether specific characteristics would affect the relationship. A dose-response relationship was estimated by using generalized least squares trend regression. Finally, twelve cohort studies and nine cross-sectional studies were included (inter-rater agreement, k = 0.96). The result of meta-analysis indicated that shift work was associated with an increased risk of type 2 diabetes (relative risk = 1.10, 95% confidence interval = 1.05–1.14). Subgroup analyses demonstrated that female shift workers have increased risk of type 2 diabetes while male not observed, health care workers showed the highest risk compared with civil servants and manual workers, and night shift and rotating shift were associated with an increased risk of type 2 diabetes. Dose-response meta-analysis based on three cohorts among female workers indicated that there might be a positive association between duration of shift work and the risk of type 2 diabetes. In conclusion, shift work is positively associated with an increased risk of type 2 diabetes. Among female workers, with the years of exposure to shift work prolonged, the risk of type 2 diabetes might increase accordingly. In the future, more studies are needed to confirm the results of dose-response analysis.     

Spontaneous diabetes mellitus in captive Mandrillus sphinx monkeys: a case report

Case history The two obese mandrills (Mandrillus sphinx) showed clinical signs of depression, anorexia, hyperglycemia, hypertriglyceridemia, glucosuria, proteinuria and ketonuria. Septic bed sore wounds were noted on both fore and hind limbs. Results Histopathological study revealed severe islet amyloidosis in both mandrills. Immunohistochemical study using polyclonal anti-cat amylin antibody confirmed derivation of the islet amyloid from islet amyloid polypeptide (IAPP). Cardiomyopathy and myocardial fibrosis were also evident. Conclusions The present study documents diabetes mellitus in two obese mandrills. Diabetes in these animals had features very similar type 2 diabetes mellitus of humans, including the development of severe, IAPP-derived islet amyloidosis. The mandrill may, therefore, serve as an animal model of human type 2 diabetes mellitus.     

Plasma levels of trace element status in early pregnancy and the risk of gestational diabetes mellitus: A nested case-control study

PurposeWe investigated the impacts of plasma levels of magnesium (Mg), zinc (Zn), calcium (Ca), iron (Fe), copper (Cu), selenium (Se), and chromium (Cr) on GDM risk and the potential mediation effect of blood glucose levels on the relationship between trace elements and GDM risk.MethodsThis nested case-control study was based on data from a birth cohort study conducted in Wuhan, China in 2013−2016. A total of 305 GDM cases and 305 individually-matched controls were included in the study. Conditional logistic regression models were used to estimate the associations between plasma trace element concentrations and GDM risk. A mediation analysis was conducted to explore whether blood glucose levels act as a mediator between trace element levels and GDM risk.ResultsAn IQR increment in plasma levels of Fe and Cu was associated with a significant increase in GDM risk [OR = 2.04 (95 % CI 1.62, 2.57) and OR = 1.52 (95 % CI 1.25, 1.82)], respectively. On the other hand, an IQR increment in plasma levels of Zn and Ca was associated with a significant decrease in GDM risk [OR = 0.55 (95 % CI 0.43, 0.71) and OR = 0.72 (95 % CI 0.56, 0.92)], respectively. The mediation analysis showed significant mediation of the association between Cu and GDM risk via the FBG (%mediated: 19.27 %), 1 h-PBG (12.64 %), 2h-PBG (28.44 %) pathways.ConclusionsPlasma levels of Zn and Ca were negatively associated with GDM risk, while Fe and Cu were positively associated. Blood glucose levels act as a mediator between plasma trace element exposures and GDM risk.