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Recent scientific efforts have focused on the detrimental effects that obesity has on the metabolic function of skeletal muscles and whether exercise can improve this dysfunction. In this regard, adiponectin, with important metabolic functions (e.g. insulin-sensitizer and anti-inflammatory), has been recently described as a myokine that acts in an autocrine/paracrine manner. Earlier studies reported that muscle adiponectin could be induced by pro-inflammatory mediators (e.g. lipopolysaccharide), cytokines, and high-fat diets, providing a protective mechanism of this tissue against metabolic insults. However, when metabolic insults such as high-fat diets are sustained this protective response becomes dysregulated, making the skeletal muscle susceptible to metabolic impairments. Recent studies have suggested that exercise could prevent or even reverse this process. Considering that most scientific knowledge on adiponectin dysregulation in obesity is from the study of adipose tissue, the present review summarizes and discusses the literature available to date regarding the effects of obesity on skeletal muscle adiponectin induction, along with the potential effects of different exercise prescriptions on this response in an obesity context.

AimsPropolis is a naturally occurring anti-inflammatory bee derived protectant resin. We have previously reported that topically applied propolis reduces inflammation and improves cutaneous ulcer healing in diabetic rodents. The aim of this study was to determine if propolis shows efficacy in a pilot study of human diabetic foot ulcer (DFU) healing and if it is well tolerated.MaterialsSerial consenting subjects (n=24) with DFU ≥4week's duration had topical propolis applied at each clinic review for 6weeks. Post-debridement wound fluid was analyzed for viable bacterial count and pro-inflammatory MMP-9 activity. Ulcer healing data were compared with a matched control cohort of n=84 with comparable DFU treated recently at the same center.ResultsUlcer area was reduced by a mean 41% in the propolis group compared with 16% in the control group at week 1 (P

Background & Aims While type 2 diabetes is an independent risk factor for worsening of human non-alcoholic steatohepatitis (NASH) in clinical studies, it has not been systematically reported in any model whether diabetes exacerbates NASH. The study aim was to determine if diabetes causes NASH progression in a mouse model of diet induced obesity. Methods C57BL/6 mice were fed a high fat diet (HFD: 45% kcal fat) or standard chow (CHOW: 12% kcal fat) for 20weeks and some animals (HFD+DM or CHOW+DM) were also rendered diabetic by low dose streptozotocin for the final 5weeks, to model type 2 diabetes. Serum assays included circulating insulin, triglyceride, ALT and AST, glucose, and ultrasensitive CRP and results of insulin tolerance tests. Intrahepatic lipid, triglyceride, macrophage infiltration, and fibrosis were determined. Fibrosis markers collagen-I, collagen-III, CTGF, TIMP-1, and FAP were assessed by qPCR and CTGF and collagen-I by immunostaining. Results HFD mice were obese, insulin resistant and hyperinsulinaemic, with NASH features of elevated intrahepatic lipid and macrophages, but without fibrosis. In contrast, the HFD+DM mice exhibited fibrosis in addition to these NASH features. By ANOVA, Sirius red staining at perisinusoidal, portal tract and central vein sites, collagen-I , collagen-III , FAP , and TIMP-1 transcripts and collagen-I and CTGF protein were each significantly increased in HFD+DM, compared with CHOW alone. In a further experiment, insulin treatment protected against fibrosis and CRP increases in HFD+DM, showing that diabetes, not streptozotocin, causes the fibrosis. Conclusions This novel model indicates that diet-induced NASH fibrosis is exacerbated by diabetes and attenuated by insulin therapy.

Circulating matrix metalloproteinase (MMP) levels may correlate with diabetic complications. Whether they are changed in early diabetic cardiomyopathy is not known and was examined in this study. TIMP-1 and collagen degradation products were also measured. Results from subjects with and without diastolic dysfunction were compared with those obtained for patients with varying stages of diabetic renal disease. Patients with type 2 diabetes with or without diastolic dysfunction with varying degrees of renal disease were recruited for this study. Age-matched non-diabetic subjects served as controls. MMPs (-1, -3 and -7) and TIMP-1 were measured by ELISA, MMP-2 and -9 by zymography and collagen degradation products by radioimmunoassay. Differences in the pattern of MMPs/TIMPs and collagen degradation products were observed. The most consistent change was in totalMMP-7, which was increased in those with diastolic dysfunction and those with macroalbuminuria. MMP-7 correlated with cardiac function (p

Diabetic renal disease is characterized by accumulation of extracellular matrix, glomerulosclerosis, and tubulointerstitial fibrosis. Connective tissue growth factor (CTGF) is implicated in these changes, as it contributes to new matrix synthesis and is increased in the diabetic kidney. CTGF also inhibits mesangial matrix degradation through up-regulation of the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). In a non-human primate model of diabetes, we determined whether the level of renal CTGF protein before development of albuminuria correlated with renal matrix and TIMP-1 changes and whether renal CTGF predicts progression to albuminuria. Methods: In a group of diabetic (n=9) and control (n=6) baboons after a 5-year duration of diabetes, renal tissue CTGF and TIMP-1 were detected by immunohistochemistry and compared with glomerular basement membrane (GBM) thickness and mesangial volume measurements from electron photomicrographs of renal biopsies. Urinary albumin levels were measured at 5 and 10 years of diabetes. Results: GBM thickness, CTGF protein, and TIMP-1 protein were increased after 5 years of diabetes (each Pb.05). Tubular fibronectin scores correlated with tubular CTGF scores (r=0.72, P=.002). In diabetic animals, GBM thickness correlated with tubular and total CTGF levels (P=.002 and P=.04, respectively), whereas mesangial cell and total matrix volume correlated with glomerular TIMP-1 (P=.02 and P=.01, respectively). Tubular CTGF scores (P=.008) and GBM thickness (P=.03) at 5 years in diabetes each predicted the degree of albuminuria at 10 years. Conclusions: These results suggest that early increases in renal CTGF protein contribute to incipient diabetic nephropathy and that renal CTGF may have utility as an early marker for progression to dysfunction in the diabetic kidney.

Effects of glucose on matrix metalloproteinase and plasmin activities in mesangial cells: Possible role in diabetic nephropathy. Diabetic nephropathy is characterized by an accumulation of mesangium matrix that correlates well with the loss of kidney function. High glucose concentration is known to increase the synthesis of many matrix components. Recently, we have shown that degradation of matrix also decreases in diabetes. The major enzymes responsible for matrix degradation are the matrix metalloproteinases. The physiology of these enzymes is complex and their activity is tightly regulated at many levels. At the transcriptional level matrix metalloproteinase (MMP) expression is increased by protein kinase C (PKC) agonists, and some growth factors. In contrast transforming growth factor (TGF)-β can decrease MMP expression. Once synthesized, MMPs are secreted as inactive pro-enzymes that are activated by other MMPs or plasmin. To effect this, plasmin must be liberated from plasminogen in the pericellular environment. In turn, activated MMPs can be inhibited by binding to specific inhibitors known as tissue inhibitor of metalloproteinases (TIMP). Cell culture and animal studies have shown that high glucose (HG) decreases expression of MMPs and increases expression of TIMPs. HG can also affect MMP activation by decreasing plasmin availability and reducing expression of a membrane-bound MMP called MT1-MMP. How HG induces these changes remains to be fully elucidated. One possibility is that HG can increase TGF-β, which may in turn alter MMP promoter activity; this area is currently being studied in our laboratory.

Expansion of the glomerular mesangium is a consistent finding of diabetic nephropathy. Negatively charged proteoglycans are an integral part of the mesangium and their synthesis and degradation is disturbed in many forms of glomerulosclerosis. The metabolism of ascorbic acid (AA), which plays an important role in extracellular matrix regulation, is known to be abnormal in diabetes. The action of AA has also been shown to be inhibited by high glucose (HG) concentration. In this study we investigated the effect of AA and HG on proteoglycan (PG) synthesis by examining the incorporation of [ 35 S] sulphate into PG in the cellular, matrix and media components of rat mesangial cell (MC) cultures. MC were grown in 9 or 25 mM glucose for 8 days, with and without the addition of AA. Sulphation of PG was measured by adding 50 μCi of [ 35 S] sulphuric acid to the culture medium and precipitating 35 S-labelled PG with cetylpyridinium chloride. In this study AA was shown to have a stimulatory effect on the overall incorporation of [ 35 S] sulphate into cell and matrix PG and this was inhibited by 25 mM glucose. Correcting for protein synthesis and specific activity of [ 35 S] sulphate showed that HG inhibits AA stimulation by decreasing sulphation of the individual PG molecules. These findings may be of particular importance in the pathophysiology of nephropathy in diabetes, a condition where AA concentration is already compromised.

Mesangium enlargement is a central feature of diabetic nephropathy and almost certainly plays a pathogenic role in this condition. Previous studies have shown that mesangium degradation is reduced in a high glucose mileau. Plasmin has been shown to play an important role in extracellular matrix degradation, both directly and through its ability to activate the matrix metalloproteinases. We therefore investigated how high glucose concentration may affect the various components of the plasminogen cascade on mesangial cells and whether it impairs the ability of the mesangial cell to generate plasmin activity. Result showed decreased binding of plasminogen and the urokinase type plasminogen activator to the mesangial cell surface while the tissue type plasminogen activator and the plasminogen activator-1 associated with mesangial cells were increased. The net effect of these changes was a reduced capacity of mesangial cell layers to generate plasmin activity in a high glucose environment. We postulate that this may be of importance in the reduced mesangium degradation which occurs in diabetes.

Abnormalities of retinal pericytes and endothelial cells are prominent features of diabetic retinopathy. In this study, we used cultures of bovine retinal cells to examine the regulation of cell-associated proteoglycans, a class of highly sulfated macromolecules important in the regulation of cell growth. Bovine retinal pericytes and endothelial cells were radiolabeled with 35 SO 4 and cell-associated proteoglycans were removed from the cell surface, quantified, and characterized. The effects of high glucose concentration (25 m M ), phorbol 12,13-dibutyrate (PDBu, 0.1 μ M ), and ascorbic acid (0.1 m M ) on cell-associated proteoglycans and growth of these cells were studied. Our results showed that both the ionically bound and the membrane-intercalated forms of cell-associated proteoglycans are present on retinal cells. The predominant cell-associated proteoglycan of pericytes is chondroitin sulfate and for endothelial cells it is heparan sulfate. High glucose concentration and ascorbic acid increased the cell-associated proteoglycans on pericytes but reduced them on endothelial cells. In contrast to this divergent trend, high glucose concentration and ascorbic acid inhibited the growth of both pericytes and endothelial cells. The effects of high glucose on retinal cell-associated proteoglycans were mimicked by PDBu added in a manner to stimulate protein kinase C activity. We conclude that cell-associated proteoglycans are present on retinal pericytes and endothelial cells. High glucose concentration and ascorbic acid affect cell-associated proteoglycans of these two cell types in opposite directions, whereas both suppress the growth of the two cell types. Therefore, it is not likely that high glucose concentration and ascorbic acid change the rate of retinal cell growth directly by affecting cell-associated proteoglycan levels.

We studied the incorporation of dietary n - 3 fatty acids from marine oils into red cell membranes, using animal models of type 1 diabetes (streptozotocin-treated Wistar rats) and type 2 diabetes (gold-thioglucose-injected CBA/T6 mice). In type 1 diabetic rats, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were higher following marine oil supplementation, and the increase in EPA was significantly greater than in non-diabetic animals (3.4 +/- 1.4% vs. 0.8 +/- 1.6%). Marine oil supplementation also resulted in higher levels of EPA and DHA in mice, but the increases were quantitatively similar with and without type 2 diabetes. Improvement in glycosylated haemoglobin following n - 3 fatty acid feeding was only found in type 2 diabetes (6.5 +/- 2.9% vs. 9.5 +/- 1.2%). This was associated with a higher plasma insulin concentration (170 +/- 40 vs. 136 +/- 41 mU/ml). The theory that n - 3 fatty acids improve insulin sensitivity would have predicted a decrease in plasma insulin levels. Our results suggest that n - 3 fatty acids may modify insulin secretion.