Diabetic Human Subjects Research Articles

The effect of different training programs on antioxidant status, oxidative stress, and metabolic control in type 2 diabetes

We compared the effects of 12 weeks of 3 different exercise types on type 2 diabetic (T2DM) male and female human subjects, randomly divided into 4 groups: aerobic training (AT; n = 11), strength training (ST; n = 10), combined training (CBT; n = 10), and no training (NT; n = 12). Metabolic control, anthropometric parameters, lipid and hematological profiles, kidney and liver function markers, hormones, antioxidant enzymes, and oxidative stress markers were assessed prior to and after the training programs. At baseline, fasting blood glucose and hemoglobin A(1c) in the ST group were higher than in the NT group; after the training, we no longer observed differences in these groups, suggesting an improvement on these parameters. In the AT group, catalase and superoxide dismutase activity, nitrite concentration, levels of sulfhydryl groups, and peak rate of oxygen consumption were elevated after the training (p < 0.05). No changes were observed in antioxidant enzymes or oxidative stress markers in the ST group. The levels of sulfhydryl groups diminished in the NT group (p < 0.01) and increased in the CBT group (p < 0.05). These data demonstrate that the AT program for the T2DM subjects provided important upregulation in antioxidant enzymes and increased nitric oxide bioavailability, which may help minimize oxidative stress and the development of the chronic complications of diabetes. We propose that the beneficial effects observed in the metabolic parameters of the ST group occurred in response to the poor baseline metabolic health n this group, and not necessarily in response to the training itself.

Honey--a novel antidiabetic agent.

Diabetes mellitus remains a burden worldwide in spite of the availability of numerous antidiabetic drugs. Honey is a natural substance produced by bees from nectar. Several evidence-based health benefits have been ascribed to honey in the recent years. In this review article, we highlight findings which demonstrate the beneficial or potential effects of honey in the gastrointestinal tract (GIT), on the gut microbiota, in the liver, in the pancreas and how these effects could improve glycemic control and metabolic derangements. In healthy subjects or patients with impaired glucose tolerance or diabetes mellitus, various studies revealed that honey reduced blood glucose or was more tolerable than most common sugars or sweeteners. Pre-clinical studies provided more convincing evidence in support of honey as a potential antidiabetic agent than clinical studies did. The not-too-impressive clinical data could mainly be attributed to poor study designs or due to the fact that the clinical studies were preliminary. Based on the key constituents of honey, the possible mechanisms of action of antidiabetic effect of honey are proposed. The paper also highlights the potential impacts and future perspectives on the use of honey as an antidiabetic agent. It makes recommendations for further clinical studies on the potential antidiabetic effect of honey. This review provides insight on the potential use of honey, especially as a complementary agent, in the management of diabetes mellitus. Hence, it is very important to have well-designed, randomized controlled clinical trials that investigate the reproducibility (or otherwise) of these experimental data in diabetic human subjects.

Circulating Myostatin Decreases with Aerobic Exercise Training in Pre‐Diabetic but not Diabetic Human Subjects

Myostatin is a potent secreted inhibitor of skeletal muscle growth. We recently demonstrated that plasma myostatin decreased with aerobic exercise and a correlation with insulin sensitivity. We subsequently quantified myostatin in plasma samples from two exercise‐training cohorts to determine the effects of both endurance and resistance exercise on circulating myostatin levels in both insulin resistant (STRRIDE, n=100) and type 2 diabetic (DARE, n=360) human subjects. In both studies, fasting myostatin levels increased significantly (P&lt;0.05) whilst markers of insulin resistance (Si and HOMA‐IR) worsened in the control subjects (~ 6 months sedentary). In the STRRIDE cohort the most intense aerobic exercise group (65–80% VO2, 2200 kcal/week) showed the most significant decrease in plasma myostatin. There were no significant decreases in plasma myostatin in the aerobic and combined exercise training groups in the DARE cohort, however, there was a small but significant decrease in resistance training group. These findings confirm that plasma myostatin levels are responsive to exercise training in both insulin resistant and diabetic patients albeit to different exercise modalities. These findings support our hypothesis that myostatin is in the causal pathway of acquired insulin resistance with physical inactivity.

Adipose tissue macrophages inhibit adipogenesis of mesenchymal precursor cells via wnt-5a in humans

In patients with obesity and type 2 diabetes, adipose tissue is infiltrated by macrophages known to alter adipogenesis of mesenchymal precursor cells via secretion of proinflammatory cytokines. Recently, it has been shown that under certain conditions, immune cells can also express wnt-5a, a factor known to inhibit adipogenesis in humans. Therefore, in this study we aimed to investigate whether macrophages affect adipogenesis of mesenchymal precursor cells via wnt-5a. Wnt-5a was found to be expressed in adipose tissue macrophages in obese and type 2 diabetic human subjects in vivo by immunohistochemistry of adipose tissue biopsies. Furthermore, wnt-5a was detectable in circulating CD14(+) blood monocytes of human subjects with obesity and type 2 diabetes on RNA level by real-time PCR. Besides expression analysis in vivo, we also performed functional studies to explore the role of wnt-5a in low-grade inflammation of adipose tissue. In a cell culture experiment, macrophage-conditioned differentiation medium inhibited adipogenesis of 3T3-L1 cells. This inhibitory effect was restored by adding neutralising anti-wnt-5a antibodies. In conclusion, our data indicate that macrophages alter adipogenesis of 3T3-L1 cells not only via classical proinflammatory cytokines, but also via wnt signalling molecules.

Bone Marrow-Derived Mesenchymal Stem Cells Improve the Functioning of Neurotrophic Factors in a Mouse Model of Diabetic Neuropathy

Diabetic neuropathy is one of the most frequent and troublesome complications of diabetes. Although there has been a continuous increase in the incidence of diabetic neuropathy, treatments have yet to be found that effectively treat diabetic neuropathy. Neurotrophic factors are proteins that promote the survival of specific neuronal populations. They also play key roles in the regeneration of peripheral nervous system. Recent evidence from diabetic animal models and human diabetic subjects suggest that reduced availability of neurotrophic factors may contribute to the pathogenesis of diabetic neuropathy. One way to reverse this effect is to take advantage of the finding that bone marrow derived mesenchymal stem cells (BM-MSCs) promote peripheral nerve repair and the functioning of neurotrophic factors. Therefore, we speculated that treatment with BM-MSCs could be a viable therapeutic strategy for diabetic neuropathy. The present study was designed to examine the possible beneficial effect of BM-MSCs on functions of neurotrophic factors in diabetic neuropathy. To assess this possibility, we used an in vivo streptozotocin-induced diabetic neuropathy mouse model. Quantitative real-time polymerase-chain reacion showed that BM-MSCs significantly increase expression levels of neurotrophic factors. Also, BM-MSCs ameliorated nerve conduction velocity in streptozotocin-treated mice. These results may help to elucidate the mechanism by which BM-MSCs function as a cell therapy agent in diabetic neuropathy.

Effects of Dichrostachys glomerata spice on cardiovascular diseases risk factors in normoglycemic and type 2 diabetic obese volunteers

Previous in vivo and in vitro experimental studies have shown Dichrostachys glomerata (DG), a spice used in western Cameroon, to have potential antioxidant and hypoglycemic properties. The purpose of the present study was to evaluate the effects of orally administered DG on various cardiovascular disease risk factors in obese normoglycemic and obese type 2 diabetic human subjects. The study was an 8week randomized, double-blind, placebo-controlled design with obese and obese/diabetic participants (20 males, 72 females, ages 25–65). The subjects were randomly divided into four groups: 2 normoglycemic obese groups (active; placebo) and two type 2 diabetic obese groups (active; placebo). Capsules containing the active (400mg DG) or placebo formulation were administered 30–60min before lunch and dinner throughout the study period. A total of 7 anthropometric and hemodynamic as well as 7 biochemical measurements were taken at the beginning of the study and after 4 and 8weeks of treatment. All diabetic patients maintained their prior lifestyle intervention and dietary control for the duration of the study. Compared to the two placebo groups, the two active groups showed statistically significant differences on all 14 variables between Weeks 0 and 8. These included body weight, BMI, waist and hip circumference, body fat, blood pressure, blood cholesterol, triglycerides, glucose, and glycosylated hemoglobulin. The results confirm the hypothesis that DG appears to reduce cardiovascular disease risk factors in obese normoglycemic and obese type 2 diabetic human subjects.

Advanced glycation end products in diabetic and non-diabetic human subjects suffering from cataract

Advanced glycation end products (AGEs) play a pivotal role in loss of lens transparency, i.e., cataract. AGEs formation occurs as a result of sequential glycation and oxidation reaction between reducing sugars and protein. AGEs production takes place throughout the normal aging process but its accumulation is found to be more rapid in diabetic patients. In this study, we quantified AGEs and N-(carboxyethyl) lysine (CEL) in human cataractous lenses from non-diabetic (n=50) and diabetic patients (n=50) using ELISA. We observed significantly higher (p<0.001) levels of lens AGEs and CEL in diabetic patients with cataract as compared with their respective controls. The presence of AGEs and CEL was also determined by western blotting and immuno-histochemical analysis. Furthermore, isolated β-crystallin from cataractous lenses of non-diabetic and diabetic patients was incubated with different sugars to evaluate the extent of glycation in a time dependent manner. Our data indicated more pronounced glycation in patients suffering from diabetes as compared to non-diabetics subjects demonstrating the need to focus on developing normoglycemic approaches. Such studies may provide an insight in developing therapeutic strategies and may have clinical implications.

Kinetics of the Post-Onset Decline in Zinc Transporter 8 Autoantibodies in Type 1 Diabetic Human Subjects

Zinc transporter 8 (ZnT8) is a newly discovered islet autoantigen in human type 1A diabetes (T1D). The objective was to document changes in ZnT8 autoantibody (ZnT8A) titer and prevalence after onset of disease in relationship to 65 kDa glutamate decarboxylase antibody (GADA) and islet cell antigen antibody (IA2A). Autoantibody radioimmunoprecipitation assays were performed on sera from three groups: 21 individuals monitored every 3 months from diagnosis for 2.5 yr; 61 individuals monitored at six monthly intervals for 5-12 yr; and a cross-sectional study of 424 patients with T1D of 20-57 yr duration. Circulating C-peptide was determined as an index of residual β-cell function. ZnT8A titers declined exponentially from clinical onset of T1D with a t(1/2) ranging from 26 to 530 wk, similar to C-peptide (23-300 wk). Life-table analysis of antibody prevalence to 12 yr indicated that ZnT8A measured with either Arg325 or Trp325 probes persisted for a shorter interval than IA2A. Although prevalence of ZnT8A, IA2A, and GADA were comparable at disease onset (70.4 vs. 73.4 vs. 64%), only 6.7% of individuals remained ZnT8A positive after 25 yr compared with 19.5% for IA2A and 25.9% for GADA. Titers of ZnT8A and IA2A in seropositive individuals decreased progressively, whereas GADA remained elevated consistent with periodic reactivation of GADA humoral autoimmunity. ZnT8 humoral autoreactivity declines rapidly in the first years after disease onset and is less persistent than IA2A or GADA in the longer term. ZnT8A determination may be a useful measure of therapeutic efficacy in the context of immune-based clinical interventions.

Visfatin/PBEF/Nampt and Resistin Expressions in Circulating Blood Monocytes are Differentially Related to Obesity and Type 2 Diabetes in Humans

Low-grade inflammation is important in the development of obesity related pathologies such as insulin resistance and type 2 diabetes, and also cardiovascular disease. Visfatin/PBEF/Nampt and resistin are proinflammatory adipokines secreted from adipocytes, monocytes, and macrophages, and have been linked to atherosclerotic plaque formation, recently. The aim of the present study was to investigate if the expression of these molecules in circulating blood monocytes is altered in obese and/or type 2 diabetic human subjects. Monocytes were isolated by CD14-antibody based magnetic cell sorting from blood samples of 17 lean controls, 20 obese nondiabetic subjects, and 19 obese patients with type 2 diabetes. FACS analysis was performed to test purity of the cell preparations. Expression of the different adipokines was measured by multiplex real-time PCR on RNA-level. Visfatin/PBEF/Nampt was found to be very strongly expressed in monocytes, whereas resistin levels were significantly lower. Furthermore, visfatin/PBEF/Nampt expression was significantly upregulated in obese type 2 diabetic patients, whereas obese nondiabetics exhibited similar levels compared to lean controls, indicating that visfatin/PBEF/Nampt levels are related to type 2 diabetes rather than to obesity. In contrast, resistin expression displayed a different pattern being significantly increased in obese subjects compared to controls but not related to type 2 diabetes. These data suggest a differential role for these two proinflammatory adipokines in linking metabolic diseases to atherosclerosis with visfatin/PBEF/Nampt being more important in patients with type 2 diabetes and resistin in obese but nondiabetic human subjects.

Evaluation of Hypoglycemic and Hypolipidemic Activity of Buteamonosperma Fruit in Diabetic Human Subjects

Evaluation of the hypoglycemic activity of local Butea monosperma (Palas papra) fruit in normal and diabetic human volunteers was conducted. Sampling was accomplished in and around the city of Faisalabad, especially at the Khadija Mahmood Trust Hospital and at the University of Agriculture, Faisalabad, Pakistan. Volunteers were categorized into normal and diabetic subjects on the basis of their blood glucose levels. Male and female diabetic volunteers aged between 30 and 60 years participated in the study. All the diabetic volunteers suffered from diabetes type II, i.e. non-insulin-dependent diabetes mellitus (NIDDM). The subjects were divided into 5 groups as follows: Group A - Untreated normal subjects; Group B - Normal subjects who received powdered B. monosperma (3 g) in 30 mL of water for 30 days, orally; Group C - Control diabetic subjects; Group D - Diabetic subjects who received powdered (3 g) in 30 mL of water for 30 days, orally; and Group E - Diabetic subjects who received a 5-mg tablet b. I. d. of Daonil® (a standard oral antidiabetic drug) in 30 mL of water for 30 days. The oral administration of B. monosperma fruit to diabetic and normal subjects for 30 days decreased (P < 0.05) blood glucose, urine sugar, and plasma glycoprotein levels, as well as the lipid profile and the activity of liver enzymes. In conclusion, the powder of the medicinal plant B. monosperma fruit can be considered an effective and alternative treatment for diabetes.

The potential health benefits of legumes as a good source of dietary fibre

Dietary fibre has been shown to have important health implications in the prevention of risks of chronic diseases. The objective of the present study was to determine the potential health benefits of legumes as a good source of dietary fibre. Six to ten local legumes were studied as follows: cowpeas, mung beans, pole sitao, chickpeas, green peas, groundnuts, pigeon peas, kidney beans, lima beans and soyabeans. The following studies were conducted: (a) mineral availability, in vitro; (b) glycaemic index (GI) in non-diabetic and diabetic human subjects; (c) the cholesterol-lowering effect in human subjects with moderately raised serum cholesterol levels. The highest Fe availability among legumes was for lima beans (9.5 (sem 0.1)) while for Zn and Ca, the highest availability was for kidney beans (49.3 (sem 4.5)) and pigeon peas (75.1 (sem 7.1)), respectively. Groundnuts have the lowest Fe (1.3 (sem 1.1)), Zn (7.9 (sem 1.3)) and Ca (14.6 (sem 2.8)) availability. Legumes are low-GI foods ( < 55), ranging from 6 (chickpeas) to 13 (mung beans). Kidney beans showed significant reductions for both total (6 %) and LDL-cholesterol (9 %), and groundnuts for total cholesterol (7 %; P < 0.05). We conclude that mineral availability from legumes differs and may be attributed to their mineral content, mineral-mineral interaction and from their phytic and tannic acid content; legumes are considered low-GI foods and have shown potential hypocholesterolaemic effects. The above studies can be a scientific basis for considering legumes as functional foods.

Chronic type 1 diabetes in spontaneously hypertensive rats leads to exacerbated cardiac fibrosis

Diabetes in human subjects is often associated with hypertension. The aim of this study was to examine the development of cardiac fibrosis following induction of type 1 diabetes in genetically hypertensive rats. Diabetes was induced by streptozotocin (STZ) injection in 8-week-old normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) for a duration of 16 or 24 weeks. Aged-matched, nondiabetic WKY and SHRs were used as controls. At termination of treatment, the rats were anaesthetized, hearts arrested in diastole and perfusion fixed. A comprehensive examination of cardiac fibrosis throughout the right and left ventricles was undertaken in picrosirius red-stained sections, using image analysis and by undertaking collagen type I and type III immunohistochemistry. Induction of diabetes in the SHRs led to a marked increase in the levels of interstitial fibrosis in the left ventricle plus septum (LV+S) at both 16 and 24 weeks duration (59% and 43% increase, respectively) and also in the right ventricle after 24 weeks duration of diabetes (35% increase compared to the nondiabetic SHR). Exacerbated perivascular fibrosis was also observed in the LV+S in the diabetic-hypertensive rats at the later time point. These effects of induction of diabetes were not observed in the normotensive strain. Our findings clearly demonstrate elevations in cardiac fibrosis when type 1 diabetes is combined with hypertension. Our findings thus stress the importance of closely monitoring both blood pressure and glucose levels in type 1 diabetic patients in order to prevent myocardial collagen deposition.

Inability to assess the safety of chromium‐enriched yeast added for nutritional purposes as a source of chromium in food supplements and the bioavailability of chromium from this source, based on the supporting dossiers

EFSA JournalVolume 7, Issue 6 1083 StatementOpen Access Inability to assess the safety of chromium-enriched yeast added for nutritional purposes as a source of chromium in food supplements and the bioavailability of chromium from this source, based on the supporting dossiers European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author First published: 17 June 2009 https://doi.org/10.2903/j.efsa.2009.1083Citations: 1 Panel members: F. Aguilar, U.R. Charrondiere, B. Dusemund, P. Galtier, J. Gilbert, D.M. Gott, S. Grilli, R. Guertler, G.E.N. Kass, J. Koenig, C. Lambré, J-C. Larsen, J-C. Leblanc, A. Mortensen, D. Parent-Massin, I. Pratt, I.M.C.M. Rietjens, I. Stankovic, P. Tobback, T. Verguieva, R.A. Woutersen. Acknowledgement: The European Food Safety Authority wishes to thank the members of the Working Group A on Food Additives and Nutrient Sources added to Food for the preparation of this opinion: F. Aguilar, N Bemrah, P. Galtier, J. Gilbert, S. Grilli, R. Guertler, G.E.N. Kass, C. Lambré, J.C. Larsen, J-C. Leblanc, A. Mortensen, I. Pratt, I. Stankovic. Adoption date: 13 May 2009 Published date: 17 June 2009 Question number: EFSA-Q-2005-097, EFSA-Q-2005-120, EFSA-Q-2005-205, EFSA-Q-2006-211, EFSA-Q-2006-212, EFSA-Q-2006-213 AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References Davis CM, Vincent JB, 1997. Chromium in carbohydrate and lipid metabolism. Journal of Biological Inorganic Chemistry 2, 675– 679. Ding WJ, Qian QF, Hou XL, Feng WY, Chen CY, Chai ZF, Zhang BR, Wang K, 2002. A preliminary study of chromium distribution in chromium-rich brewer's yeast cell by NAA. Biological Trace Element Research 88 (2), 193– 199. EC (European Commission), 2002. Directive 2002/46/EC of the European Parliament and of the Council of 10 June 2002 on the approximation of the laws of the Member States relating to food supplements. OJ L 183, 12.07.2002, p. 51. EFSA (European Food Safety Authority), 2008a. Opinion of the Scientific Panel on Biological Hazards on the maintenance of the list of QPS microorganisms intentionally added to food or feed. The EFSA Journal 923, 1– 48. EFSA (European Food Safety Authority), 2008b. Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food on a request from the Commission on certain bisglycinates and glycinate nicotinate as sources for copper, zinc, calcium, magnesium and chromium. The EFSA Journal 718, 1– 266. Hegóczki J, Suhajda Á, Janzsó B, Vereczkey G, 1997. Preparation of chromium enriched yeasts. Acta Alimentaria 26 (4), 345– 358. Lamson DW and Plaza SM, 2002. The Safety and efficacy of high-dose chromium. Alternative Medicine Review 7 (3), 218– 35. Mertz W, 1969. Chromium occurrence and function in biological systems. Physiological Reviews 49 (2), 163– 239. Vinson JA and Bose P, 1984. The effect of a high chromium yeast on the blood glucose control and blood lipids of normal and diabetic human subjects. Nutritional Reports International 30 (4), 911– 918. Zetic VG, Stehlik-Tomas V, Grba S, Lutilsky L, Kozlek D, 2001. Chromium uptake by Saccharomyces cerevisiae and isolation of glucose tolerance factor from yeast biomass. Journal of Biosciences 26 (2), 217– 223. Citing Literature Volume7, Issue6June 20091083 ReferencesRelatedInformation

Development of a novel GLUT4 translocation assay for identifying potential novel therapeutic targets for insulin sensitization

GLUT4 (glucose transporter 4) plays important roles in glucose homoeostasis in vivo. GLUT4 expression and function are diminished in diabetic human and animal subjects. The goal of the present study is to develop a cell-based assay for identifying negative regulators of GLUT4 translocation as potential targets for the treatment of Type 2 diabetes. Traditional GLUT4 translocation assays performed in differentiated myocytes or adipocytes are difficult to perform, particularly in HTS (high-throughput screening) mode. In the present study, we stably co-expressed c-Myc and eGFP [enhanced GFP (green fluorescent protein)] dual-tagged recombinant GLUT4 with recombinant IRS1 (insulin receptor substrate 1) in HEK-293 cells (human embryonic kidney cells) (HEK-293.IRS1.GLUT4 cells). Insulin treatment stimulated both glucose uptake and GLUT4 translocation in these cells. GLUT4 translocation is quantified by a TRF (time-resolved fluorescence) assay in a 96-well HTS format. TRF assays confirmed insulin-stimulated GLUT4 translocation, which can be inhibited by PI3K (phosphoinositide 3-kinase) or Akt [also called PKB (protein kinase B)] inhibitors. Treatment with palmitate increased IRS1 serine phosphorylation and reduced insulin-stimulated Akt phosphorylation and GLUT4 translocation, indicating insulin resistance. Knockdown of PTEN (phosphatase and tensin homologue deleted on chromosome 10) and PTP1B (protein tyrosine phosphatase 1B) gene expression by siRNA (small interfering RNA) treatment significantly increased GLUT4 translocation only in cells treated with palmitate but not in untreated cells. Similar results were obtained on treatment with siRNA of JNK1 (c-Jun N-terminal kinase 1), S6K1 (ribosomal protein S6 kinase, 70 kDa, polypeptide 1) and PKC(theta) (protein kinase C theta). In summary, we have established and validated a novel GLUT4 translocation assay that is optimal for identifying negative regulators of GLUT4 translocation. In combination with more physiologically relevant secondary assays in myotubes and adipocytes, this assay system can be used to identify potential novel therapeutic targets for the treatment of Type 2 diabetes.

Interactions of hearing loss and diabetes mellitus in the middle age CBA/CaJ mouse model of presbycusis

Recently, we characterized the more severe nature of hearing loss in aged Type 2 diabetic human subjects [Frisina, S.T., Mapes, F., Kim, S., Frisina, D.R., Frisina, R.D., 2006. Characterization of hearing loss in aged type II diabetics. Hear. Res. 211, 103–113]. The current study prospectively assessed hearing abilities in middle age CBA/CaJ mice with Type 1 diabetes mellitus (T1DM) (STZ injection) or Type 2 diabetes mellitus (T2DM) (high fat diet), for a period of 6 months. Blood glucose, body weight and auditory tests (Auditory Brainstem Response-ABR, Distortion Product Otoacoustic Emissions-DPOAE) were evaluated at baseline and every 2 months. Tone and broad-band noise-burst responses in the inferior colliculus were obtained at 6 months. Body weights of controls did not change over 6 months (∼32 g), but there was a significant (∼5 g) decline in the T1DM, while T2DM exhibited ∼10 g weight gain. Blood glucose levels significantly increased: 3-fold for T1DM, 1.3-fold for T2DM; with no significant changes in controls. ABR threshold elevations were found for both types of diabetes, but were most pronounced in the T2DM, starting as early as 2 months after induction of diabetes. A decline of mean DPOAE amplitudes was observed in both diabetic groups at high frequencies, and for the T2DM at low frequencies. In contrast to ABR thresholds, tone and noise thresholds in the inferior colliculus were lower for both diabetic groups. Induction of diabetes in middle-aged CBA/CaJ mice promotes amplification of age-related peripheral hearing loss which makes it a suitable model for studying the interaction of age-related hearing loss and diabetes. On the other hand, initial results of effects from very high blood glucose level (T1DM) on the auditory midbrain showed disruption of central inhibition, increased response synchrony or enhanced excitation in the inferior colliculus.

PPARγ2Pro12Ala Polymorphism and Human Health

The nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPARγ) is an important transcription factor regulating adipocyte differentiation, lipid and glucose homeostasis, and insulin sensitivity. Numerous genetic mutations of PPARγ have been identified and these mutations positively or negatively regulate insulin sensitivity. Among these, a relatively common polymorphism of PPARγ, Pro12Ala of PPARγ2, the isoform expressed only in adipose tissue has been shown to be associated with lower body mass index, enhanced insulin sensitivity, and resistance to the risk of type 2 diabetes in human subjects carrying this mutation. Subsequent studies in different ethnic populations, however, have revealed conflicting results, suggesting a complex interaction between the PPARγ2 Pro12Ala polymorphism and environmental factors such as the ratio of dietary unsaturated fatty acids to saturated fatty acids and/or between the PPARγ2 Pro12Ala polymorphism and genetic factors such as polymorphic mutations in other genes. In addition, this polymorphic mutation in PPARγ2 is associated with other aspects of human diseases, including cancers, polycystic ovary syndrome, Alzheimer disease and aging. This review will highlight findings from recent studies.

A New Wound Healing Polyherbal Oil for the Treatment of Diabetic Ulcers

The effect of an ayurvedic formulation (SLS-003) in healing wounds in diabetic and non-diabetic human subjects was determined by monitoring the rate of reepithelialization, edema, erythema, scabbing and size of the ulcer. This study was a prospective, randomized, open label clinical trial with an evaluation period of 5–7 weeks in duration. The patients who participated in the trial were from diabetic unit undergoing treatment for type-2 diabetes. Of the 22 patients recruited for the study we completed the study with 11 patients. Ulcers were treated once daily until complete reepithelialization. The wound healing efficacy was recorded by measuring the wound diameter every 3–4 days and photographs prints were taken at appropriate time intervels. The percent reduction in ulcer size is determined through CAD and the other variables like eptithelialization, edema, erythema and scabbing were assessed through visual analog scale. There was about 50% reduction in ulcer size between zero day and 17th day. The effect of SLS-003 in reducing the edema was statistically significant (p < 0.001). The increased rate of reepithelialization between zero and day 17 was statistically significant (p < 0.05). Similar results were observed in erythema and scabbing. SLS-003 did not show any adverse effects during the treatment period. In conclusion, the results suggest that SLS-003 is effective in healing the wounds in both diabtetic and non-diabetic patients.

Effects of thiazolidinediones on blood pressure

Peroxisome-proliferator-activated receptor-gamma (PPAR-gamma) agonists (known as thiazolidinediones; TDZs) activate nuclear receptors that regulate gene expression; they were developed as insulin-sensitizing drugs to treat type 2 diabetes mellitus. Although the prototypic TZD troglitazone was withdrawn from the market due to hepatic toxicity, rosiglitazone and pioglitazone are mainstays in managing type 2 diabetes mellitus. TZDs exert their hypoglycemic effect by reducing insulin resistance, hence improving insulin sensitivity. However, TZDs also exhibit a broad range of cardiovascular actions, with the clinical consequence of reduction in blood pressure (BP), observed in animal models and human diabetic subjects. The magnitude of reduction appears to be about 4 to 5 mm Hg in systolic and 2 to 4 mm Hg in diastolic BP--sufficient to significantly reduce subsequent cardiovascular event rates. But these BP-reducing properties, which are not present with metformin or sulfonylureas, are particularly important when viewed in conjunction with hypoglycemic effects. A significant proportion of patients with type 2 diabetes mellitus and BP mildly above target range might be successfully treated for both processes with a single drug.

Plantar shear stress distributions: Comparing actual and predicted frictional forces at the foot–ground interface

Plantar shear stresses are believed to play a major role in diabetic ulceration. Due to the lack of commercial devices that can measure plantar shear distribution, a number of mathematical models have been developed to predict plantar frictional forces. This study assessed the accuracy of these models using a custom-built platform capable of measuring plantar stresses simultaneously. A total of 48 (38 healthy and 10 diabetic) human subjects (75±20 kg, 41±20 years, 32 males, 16 females) were recruited in the study. Plantar force data were collected for 2 s at 50 Hz. Two models (M1 and M2) reported in the literature by different groups were used to predict local shear stresses. Root mean squared errors (RMSE) were calculated to compare model data with the actual data, focusing on three parameters: location, magnitude and timing of peak shear components. RMSE values of estimated peak AP and ML shear locations were 3.1 and 2.2 cm for M1 and 3.1 and 2.1 cm for M2, respectively. Magnitude RMS error values for M1 were found to be 86.6 kPa in AP shear and 38.5 kPa in ML shear, whereas these values were determined to be 97.8 and 63.5 kPa, respectively by M2. Time to peak shear RMSE values averaged 17.2% in terms of the gait duration. In conclusion, distribution of plantar shear should be measured rather than predicted, particularly if one is interested in the magnitudes of shear components.

Role of Poly(ADP-Ribose) Polymerase-1 Activation in the Pathogenesis of Diabetic Complications: Endothelial Dysfunction, as a Common Underlying Theme

Hyperglycemia-induced overproduction of superoxide by mitochondrial electron-transport chain triggers several pathways of injury involved in the pathogenesis of diabetic complications [protein kinase C (PKC), hexosamine and polyol pathway fluxes, advanced glycation end product (AGE) formation] by inhibiting glyceraldehyde- 3-phosphate dehydrogenase (GAPDH) activity. Increased oxidative and nitrosative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP). PARP activation, on the one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport, and ATP formation. On the other hand, it inhibits GAPDH by poly(ADP-ribosy)lation. These processes result in acute endothelial dysfunction in diabetic blood vessels, which importantly contributes to the development of various diabetic complications. Accordingly, hyperglycemia-induced activation of PKC isoforms, hexosaminase pathway flux, and AGE formation is prevented by blocking PARP activity. Furthermore, inhibition of PARP protects against diabetic cardiovascular dysfunction in preclinical models. PARP activation is present in microvasculature of human diabetic subjects. The oxidative/nitrosative stress-PARP pathway leads to diabetes-induced endothelial dysfunction, which may be an important underlying mechanism for the pathogenesis of other diabetic complications (cardiomyopathy, nephropathy, neuropathy, and retinopathy). This review focuses on the role of PARP in diabetic complications and the unique therapeutic potential of PARP inhibition in the prevention or reversal of diabetic complications.