Diabetes mellitus is a complex metabolic disorder characterized by chronic hyperglycemia due to absolute or relative lack of insulin. Though great efforts have been made to investigate the pathogenesis of diabetes, the underlying mechanism behind the development of diabetes and its complications remains unexplored. Cumulative evidence has linked mitochondrial modification to the pathogenesis of diabetes and its complications and they are also observed in various tissues affected by diabetes. Proteomics is an attractive tool for the study of diabetes since it allows researchers to compare normal and diabetic samples by identifying and quantifying the differentially expressed proteins in tissues, cells or organelles. Great progress has already been made in mitochondrial proteomics to elucidate the role of mitochondria in the pathogenesis of diabetes and its complications. Further studies on the changes of mitochondrial protein specifically post-translational modifications during the diabetic state using proteomic tools, would provide more information to better understand diabetes.
Adipose Tissue ; metabolism ; Diabetes Complications ; Diabetes Mellitus ; metabolism ; pathology ; Humans ; Insulin ; metabolism ; Insulin-Secreting Cells ; cytology ; metabolism ; Liver ; metabolism ; Mitochondria ; metabolism ; Muscle, Skeletal ; metabolism ; Proteome ; metabolism ; Proteomics

This study was performed to investigate the changes of tear film and ocular surface in diabetic patients, as well as the ocular and systemic factors related to these changes. We assessed the scoring of keratoepitheliopathy, corneal sensitivity test, tear film break-up time (BUT), Schirmer test, and conjunctival impression cytology in 94 eyes of 47 patients with noninsulin-dependent diabetes mellitus and in 60 eyes of 30 normal subjects. The degree of keratoepitheliopathy was severe, and the corneal sensitivity, BUT, and tear secretion were significantly reduced in the diabetic patients. Conjunctival impression cytology showed a higher grade of conjunctival squamous metaplasia and lower goblet cell density in the diabetic patients. All parameters were related to the status of metabolic control, diabetic neuropathy, and stage of diabetic retinopathy. We think that diabetic patients with poor metabolic control, neuropathy, and advanced stage of retinopathy should be examined for tear film and ocular surface changes.
Adult ; Aged ; Comparative Study ; Corneal Diseases/etiology/*metabolism ; Diabetes Complications/*metabolism/pathology ; Epithelium, Corneal/*metabolism/pathology ; Female ; Goblet Cells/pathology ; Humans ; Male ; Middle Aged ; Risk Factors ; Tears/*metabolism

OBJECTIVETo investigate the role of the non-canonical Wnt signaling pathway in development of non-alcoholic steatohepatitis (NASH) related to type 2 diabetes mellitus (T2DM) using a rat model.

METHODSTwenty-four male Sprague-Dawley rats were randomly divided into two equal groups: control group, fed a stand diet; T2DM-NASH model group, fed a high sucrose and fat diet for 4 weeks and intraperitoneally injected with streptozotocin (30 mg/kg). Twelve weeks after model establishment, all rats were sacrificed. Serum levels of glucose, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by biochemical analysis. Liver pathological changes were assessed microscopically by hematoxylin-eosin and oil red O staining. The liver expression of Wnt5a and NF-kB p65 were detected by immunohistochemistry and western blotting (protein), and quantitative real-time PCR (mRNA).

RESULTSThe T2DM-NASH model group showed significantly higher levels of glucose (control group: 6.25 +/- 1.28 vs. 31.21 +/- 0.86 mmol/L, t = -36.204, P less than 0.01), ALT (31.00 +/- 3.69 vs. 301.50 +/- 8.62 U/L, t = -99.94, P less than 0.01), and AST (77.58 +/- 1.83 vs. 344.75 +/- 1.82 U/L, t = -358.85, P less than 0.01). The T2DM-NASH group also showed remarkable signs of steatosis and inflammation in hepatic tissues. The T2DM-NASH group had significantly higher integral optical density (IOD) detection of Wnt5a (control group: 1.15E4 +/- 577.45 vs. 4.04E5 +/- 2.42E4, t = -56.24, P less than 0.01) and NF-kB p65 (1.28E4 +/- 1.59E3 vs. 4.21E5 +/- 1.68E4, t = -83.895, P less than 0.01), as well as protein levels detected by western blot (Wnt5a: 4.21 +/- 0.34 vs. 1.00 +/- 0.25, t = 17.030, P less than 0.01; NF-kB p65: 4.93 +/- 0.76 vs. 1 +/- 0.13, t = 11.438, P less than 0.01). The hepatic mRNA levels followed the same trend (Wnt5a: 9.53 +/- 0.64 vs. 1.04 +/- 0.35, t = 20.165, P less than 0.01; NF-kB p65: 0.60 +/- 0.13 vs. 0.74 +/- 0.10, t = -1.802, P = 0.125). In the T2DM-NASH group, hepatic Wnt5a protein expression was positively correlated with ALT (r = 0.64, P less than 0.05), AST (r = 0.59, P less than 0.05), and NF-kB p65 protein expression (r = 0.58, P less than 0.05).

CONCLUSIONWnt5a may activate NF-kB to stimulate an inflammatory response leading to development of NASH related to T2DM.

Animals ; Diabetes Mellitus, Experimental ; complications ; metabolism ; Diabetes Mellitus, Type 2 ; complications ; metabolism ; Liver ; pathology ; Male ; Non-alcoholic Fatty Liver Disease ; etiology ; pathology ; Rats ; Rats, Sprague-Dawley ; Transcription Factor RelA ; metabolism ; Wnt Proteins ; metabolism ; Wnt Signaling Pathway ; Wnt-5a Protein

While long-standing diabetes is a risk factor of pancreatic cancer, new-onset diabetes could be a consequence of underlying pancreatic malignancy. About 30% to 50% of pancreatic cancer patients have new-onset diabetes. Because diabetes develops in preclinical or early stages of pancreatic cancer, it could serve as an excellent clue for early detection of pancreatic cancer. Insulin resistance associated with hyperglycemia and hyperinsulinemia by diabetogenic factors secreted from cancer cells have been suggested to be a possible mechanism of pancreatic cancer-induced diabetes. It is difficult to differentiate pancreatic cancer-induced diabetes from the more common type 2 diabetes. Although several clinical features and potential biomarkers have been investigated, optimal strategies and modalities to screen pancreatic cancer among the new-onset diabetes have not yet been fully determined.
Adiponectin/metabolism ; Age Factors ; Body Mass Index ; Cytokines/metabolism ; Diabetes Mellitus, Type 2/*complications/*diagnosis/pathology ; Humans ; Pancreatic Neoplasms/*complications/*diagnosis/pathology ; Tomography, X-Ray Computed

The aim of this study was to investigate the relationship between obesity, insulin resistance and atherosclerosis in type 2 diabetes mellitus (T2DM) patients. Total 530 patients with T2DM were included. To evaluate the severity of atherosclerosis, we measured the coronary artery calcification (CAC) score, intima-media thickness (IMT) of the common carotid artery, and the ankle-brachial pressure index (ABPI). Subjects were classified according to body mass index (BMI), a marker of general obesity, and waist-to-hip ratio (WHR), a marker of regional obesity. The insulin sensitivity index (ISI) was measured by the short insulin tolerance test. All subjects were classified into four groups, according to BMI: the under-weight group, the normal-weight (NW) group, the over-weight (OW) group, and the obese (OB) group. WHR and systolic blood pressure, triglycerides (TG), HDL-cholesterol (HDLC), free fatty acids (FFA), fibrinogen, and fasting c-peptide levels were significantly different between BMI groups. TG, HDL-C, FFA, fibrinogen and ISI were significantly different between patients with and without abdominal obesity. In the OW group as well as in the NW group, carotid IMT, ABPI and CAC score were significantly different between patients with and without abdominal obesity. This study indicates that abdominal obesity was associated with atherosclerosis in T2DM patients.
Aged ; Atherosclerosis/complications ; Blood Pressure ; Coronary Vessels/pathology ; Diabetes Complications ; Diabetes Mellitus, Type 2/*genetics ; Female ; Humans ; Insulin Resistance ; Korea ; Male ; Middle Aged ; Obesity/*complications/*genetics ; Triglycerides/metabolism ; Tunica Intima/pathology ; Tunica Media/pathology

The prevalence of diabetes mellitus (DM) and associated diseases such as cancers are substantially increasing worldwide. About 80% of the patients with pancreatic cancer have glucose metabolism alterations. This suggests an association between type 2 DM and pancreatic cancer risk and progression. There are hypotheses that show metabolic links between the diseases, due to insulin resistance, hyperglycemia, hyperinsulinemia, low grade chronic inflammation, and alteration in the insulin-insulin-like growth factor axis. The use of diabetes medications can influence the extent of carcinogenesis of the pancreas. This study briefly reviews recent literature on investigation of metabolic link of type 2 DM, risk of carcinogenesis of the pancreas and their association, as well as the current understanding of metabolic pathways implicated in metabolism and cellular growth. The main finding of this review, although there are discrepancies, is that according to most research long-term DM does not raise the risk of pancreatic cancer. The longest duration of DM may reflect hypoinsulinemia due to treatment for hyperglycemia, but recent onset diabetes was associated with increased risk for pancreatic cancer due to hyperinsulinemia and hyperglycemia. In conclusion, the review demonstrates that type 2 DM and the duration of diabetes pose a risk for pancreatic carcinogenesis, and that there is biological link between the diseases.
Diabetes Mellitus, Type 2/complications/epidemiology/metabolism/*pathology ; Humans ; Hyperglycemia/pathology ; Insulin/metabolism ; Insulin Resistance ; Insulin-Like Growth Factor I/metabolism ; Pancreatic Neoplasms/epidemiology/*etiology ; Risk Factors

OBJECTIVETo study the possible association between C-reactive (CRP) and insulin resistance (IR) as well as the pathogenesis of type 2 diabetes macrovascular complication.

METHODSSerum CRP was measured by ultrasensitive immuoturbidimetric, which was determined on type 2 diabetes (T2DM) with or without macrovascular complication (70 and 60 cases respectively) and on normal controls (90 cases). IR was estimated by homeostasis model assessment (HOMA-IR).

RESULTSResults showed that the concentration of CRP was higher in T2DM with or without macrovascular complications than that in the healthy subjects (P < 0.01), while it was higher in diabetic patients with macrovascular complications than that in diabetic patients without macrovascular complications (P < 0.01). In diabetic patients with macrovascular complications, person correlation analysis indicated that there existed positive correlations between CRP and FINS, HOMA-IR, triglyceride (TG) while stepwise linear regression showed that usCRP and HOMA-IR, TG having linear correlation.

CONCLUSIONCRP seemed to play a role in the initiation and progression of atherosclerosis in type 2 diabetes, possibly was by the way of IR.

C-Reactive Protein ; metabolism ; Case-Control Studies ; Diabetes Complications ; blood ; metabolism ; pathology ; Diabetes Mellitus, Type 2 ; complications ; metabolism ; physiopathology ; Female ; Homeostasis ; Homocysteine ; blood ; Humans ; Inflammation Mediators ; metabolism ; Insulin Resistance ; Linear Models ; Male ; Middle Aged

Pathogenesis of diabetic cardiomyopathy (DCM) is a complicate and chronic process that is secondary to acute cardiac responses to diabetes. One of the acute responses is cardiac cell death that plays a critical role in the initiation and development of DCM. Besides hyperglycemia, inflammatory response in the diabetic heart is also a major cause for cardiac cell death. Diabetes or obesity often causes systemic and cardiac increases in tumor necrosis factor-alpha, interleukin-18 and plasminogen activator inhibitor-1. However, how these cytokines cause cardiac cell death remains unclear. It has been considered to relate to oxidative and/or nitrosative stress. We have demonstrated that metallothionein as a potent antioxidant or stress protein significantly protected the heart from oxidative damage and cell death caused by these cytokines, leading to effective prevention of DCM. The direct link of the inhibition of oxidative stress and damage to the prevention of cardiac cell death was defined by addition of superoxide or peroxynitrite specific inhibitor to completely prevent cytokine-induced cardiac cell death. Cardiac cell death is induced by the inflammatory cytokines that is increased in response to diabetes. Inflammatory cytokine-induced cardiac cell death is mediated by oxidative stress and is also the major initiator for DCM development.
Animals ; Cardiomyopathies ; etiology ; Cell Death ; Diabetes Mellitus ; metabolism ; pathology ; Humans ; Inflammation ; pathology ; physiopathology ; Interleukin-18 ; metabolism ; Metallothionein ; metabolism ; Myocardium ; pathology ; Obesity ; complications ; metabolism ; pathology ; Oxidative Stress ; Tumor Necrosis Factor-alpha ; metabolism

Actins ; metabolism ; Animals ; Collagen Type III ; metabolism ; Collagen Type IV ; metabolism ; Desmin ; metabolism ; Diabetes Mellitus, Experimental ; complications ; Diabetic Nephropathies ; metabolism ; pathology ; HSP47 Heat-Shock Proteins ; metabolism ; Kidney Glomerulus ; metabolism ; pathology ; Male ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Vimentin ; metabolism

Thioredoxin-interacting protein (TXNIP), also known as vitamin D3-up-regulated protein (VDUP1), is an endogenous inhibitor of thioredoxin (Trx), which regulates the cellular reduction-oxidation (redox) state. TXNIP regulates cellular survival, apoptosis and inflammation induced by glucotoxicity, heat shock and mechanical pressure. The above functions of TXNIP are regulated by carbohydrate response element binding protein (ChREBP) and AMP-dependent protein kinase (AMPK). In recent years, numerous studies showed that TXNIP is involved in diabetes and diabetic complications. On the one hand, TXNIP functions in diabetes by increasing insulin resistance and hepatic gluconeogenesis. TXNIP expression is induced by high glucose, which is implicated in pancreatic beta cell glucotoxicity and endothelial cells dysfunction. TXNIP may contribute to the development and progression of diabetes and its vascular complications. TXNIP may be a new target for diabetes and its vascular complications therapy.
Apoptosis ; Carrier Proteins ; metabolism ; Diabetes Complications ; drug therapy ; metabolism ; Diabetes Mellitus ; drug therapy ; metabolism ; Endothelial Cells ; pathology ; Humans ; Inflammation ; Insulin Resistance ; Insulin-Secreting Cells ; pathology ; Vascular Diseases ; drug therapy ; metabolism