Metabolic features of neutrophilic differentiation of HL-60 cells in hyperglycemic environments.

INTRODUCTION: Chronic hyperglycemia affects neutrophil functions, leading to reduced pathogen killing and increased morbidity. This impairment has been directly linked to increased glycemia, however, how this specifically affects neutrophils metabolism and their differentiation in the bone marrow is unclear and difficult to study. RESEARCH DESIGN AND METHODS: We used high-resolution respirometry to investigate the metabolism of resting and activated donor neutrophils, and flow cytometry to measure surface CD15 and CD11b expression. We then used HL-60 cells differentiated towards neutrophil-like cells in standard media and investigated the effect of doubling glucose concentration on differentiation metabolism. We measured the oxygen consumption rate (OCR), and the enzymatic activity of carnitine palmitoyl transferase 1 (CPT1) and citrate synthase during neutrophil-like differentiation. We compared the surface phenotype, functions, and OCR of neutrophil-like cells differentiated under both glucose concentrations. RESULTS: Donor neutrophils showed significant instability of CD11b and OCR after phorbol 12-myristate 13-acetate stimulation at 3 hours post-enrichment. During HL-60 neutrophil-like cell differentiation, there was a significant increase in surface CD15 and CD11b expression together with the loss of mitochondrial mass. Differentiated neutrophil-like cells also exhibited higher CD11b expression and were significantly more phagocytic. In higher glucose media, we measured a decrease in citrate synthase and CPT1 activities during neutrophil-like differentiation. CONCLUSIONS: HL-60 neutrophil-like differentiation recapitulated known molecular and metabolic features of human neutrophil differentiation. Increased glucose concentrations correlated with features described in hyperglycemic donor neutrophils including increased CD11b and phagocytosis. We used this model to describe metabolic features of neutrophil-like cell differentiation in hyperglycemia and show for the first time the downregulation of CPT1 and citrate synthase activity, independently of mitochondrial mass.

Endogenous Biological Drivers in Diabetic Lower Limb Wounds Recurrence: Hypothetical Reflections.

An impaired healing response underlies diabetic foot wound chronicity, frequently translating to amputation, disability, and mortality. Diabetics suffer from underappreciated episodes of post-epithelization ulcer recurrence. Recurrence epidemiological data are alarmingly high, so the ulcer is considered in "remission" and not healed from the time it remains epithelialized. Recurrence may result from the combined effects of behavioral and endogenous biological factors. Although the damaging role of behavioral, clinical predisposing factors is undebatable, it still remains elusive in the identification of endogenous biological culprits that may prime the residual scar tissue for recurrence. Furthermore, the event of ulcer recurrence still waits for the identification of a molecular predictor. We propose that ulcer recurrence is deeply impinged by chronic hyperglycemia and its downstream biological effectors, which originate epigenetic drivers that enforce abnormal pathologic phenotypes to dermal fibroblasts and keratinocytes as memory cells. Hyperglycemia-derived cytotoxic reactants accumulate and modify dermal proteins, reduce scar tissue mechanical tolerance, and disrupt fibroblast-secretory activity. Accordingly, the combination of epigenetic and local and systemic cytotoxic signalers induce the onset of "at-risk phenotypes" such as premature skin cell aging, dysmetabolism, inflammatory, pro-degradative, and oxidative programs that may ultimately converge to scar cell demise. Post-epithelialization recurrence rate data are missing in clinical studies of reputed ulcer healing therapies during follow-up periods. Intra-ulcer infiltration of epidermal growth factor exhibits the most consistent remission data with the lowest recurrences during 12-month follow-up. Recurrence data should be regarded as a valuable clinical endpoint during the investigational period for each emergent healing candidate.

Prevalence of non-alcoholic fatty liver disease and liver fibrosis in a general population cohort from Argentina.

INTRODUCTION AND OBJECTIVES: South America is one of the regions with the highest rates of non-alcoholic fatty liver disease (NAFLD). This study aimed to assess the prevalence and severity of NAFLD in suburban Argentina. PATIENTS AND METHODS: The study involved a general community cohort of 993 subjects evaluated sequentially with a comprehensive lifestyle questionnaire, laboratory testing, abdominal ultrasound (US) and transient elastography with XL probe. NAFLD was diagnosed according to standard criteria. RESULTS: The prevalence of NAFLD by the US was 37.2% (326/875) overall, 50.3% in subjects with overweight/obesity, 58.6% with hypertriglyceridemia, 62.3% with diabetes/hyperglycemia and 72.1% with all three risk factors. Male gender (OR 1.42, 95% CI 1.03-1.47, p = 0.029), age (50-59 years: OR 1.98, 95 CI 1.16-3.39, p = 0.013 and ≥60 years: OR 1.86, 95% CI 1.13-3.09, p = 0.015), BMI (25-29: OR 2.87, 95% CI 1.86-4.51, p<0.001 and ≥30: OR 9.57, 95% CI 6.14-15.20, p<0.001), diabetes/hyperglycemia (OR 1.65, 95% CI 1.05-2.61, p = 0.029) and hypertriglyceridemia (OR 1.73, 95% CI 1.20-2.48, p = 0.002) were independent predictors of NAFLD. Among patients with steatosis, 22.2% (69/311) had ≥F2 fibrosis (overweight 25%, hypertriglyceridemia 32%, diabetes/hyperglycemia 34%). BMI (OR 5.22, 95% CI 2.64-11.74, p<0.001), diabetes/hyperglycemia (OR 2.12, 95% CI 1.05-4.29, p = 0.04) and hypertriglyceridemia (OR 1.94, 95% CI 1.03-3.68, p = 0.040) were independent predictors of liver fibrosis. CONCLUSIONS: This general population study from Argentina showed a high prevalence of NAFLD. Significant liver fibrosis was present in 22% of subjects with NAFLD. This information adds to the existing knowledge of NAFLD epidemiology in Latin America.

Effects of reducing postprandial hyperglycemia and metabolism of acetate wheat starch on healthy mice

Abstract Recently, the acetate wheat starch (AWS) has been prepared by acetylation with an acetyl content of 2.42%, containing of rapidly digestible starch (RDS), slowly digestible starch (SDS) and resistant starch (RS) with 25.0%; 22.9% and 34.5%, respectively. In this study, this kind of starch was continuously evaluated with the postprandial blood glucose response and determined short-chain fatty acids (SCFAs) metabolized from AWS in the gastrointestinal tract of healthy mice by HPLC. The result showed that the mice fed with AWS exhibited a very limited increase in blood glucose level and remained stable for 2 hours after meals efficiently comparing with the control group fed with natural wheat starch (NWS). Simultaneously, the content of SCFAs produced in the caecum of the mice fed with AWS was significantly higher than mice fed with NWS, especially with acetic and propionic acids by 28% and 26%, respectively. Thus, AWS has shown to limit the postprandial hyperglycemia in mice effectively through the resistance to amylase hydrolysis in the small intestine. When going into the caecum, it is fermented to form SCFAs providing a part of energy for the body's activities, avoiding rotten fermentation causing digestive disorders which are inherent restrictions of normal high cellulose and fiber food.

Daily glucose variation influenced by the use of corticosteroids in COVID-19 patients treated in Lima-Peru.

AIM: The pandemic has generated the need for COVID-19 patients to be treated as best as possible; however, the effect of these treatments on glycemic control has not yet been taken into account. This article aims to determine whether the daily variation of glucose is influenced by the use of corticosteroids in COVID-19 patients treated in Lima-Peru. METHODOLOGY: A prospective cohort study was undertook, in which glucose was measured four times a day in 53 patients hospitalized due to COVID-19. These values were associated with the use of corticosteroids and adjusted for other socio-educational variables, all by means of PA-GEE models. RESULTS: Nested multivariate analysis of daily glucose variation found that those using corticosteroids increased the daily average glucose as well as the first and last glucose measurements, this is, at 6am and 10pm, respectively (all p-values <0.026). An increase in glucose levels was also observed in those with diabetes (all p-values <0.001). In contrast, we found that there was a decrease in the last glucose measurement of the day in obese patients (p-value = 0.044). CONCLUSIONS: The patients who used corticosteroids for the treatment of COVID-19 increased the average glucose per day, especially in the first and last measurement.

Pterostilbene influences glycemia and lipidemia and enhances antioxidant status in the liver of rats that consumed sucrose solution.

AIMS: The present study investigated the potential effects of pterostilbene (PT) on glycemic and lipid profiles, fat storage, cardiovascular indices, and hepatic parameters of rats fed with sucrose solution. MAIN METHODS: 24 male Wistar rats received either drinking water or a 40% sucrose solution over a period of 140 days. After this period, animals were randomly allocated into four groups (n = 6): Control (C), C + Pterostilbene (PT), Sucrose (S), and S + PT. Pterostilbene (40 mg/kg) was given orally for 45 consecutive days. KEY FINDINGS: Pterostilbene did not influence morphometric and nutritional parameters. The insulin sensitivity index TyG was elevated in the C + PT group (p < 0.01) and reduced in S + PT group (p < 0.05). Basal glucose levels were lower in the S + PT group (p < 0.05), and the glycemic response was improved with PT treatment in glucose provocative tests. Conversely, rats from the C + PT group showed impaired glucose disposal during those tests. Lipid profile was partially improved by PT treatment. Hepatic oxidative stress in the S group was improved after PT treatment. In the C group, PT reduced SOD activity, glutathione levels, and increased catalase activity. Collagen content was reduced by PT treatment. SIGNIFICANCE: PT effects depends on the type of diet the animals were submitted. In rats fed with sucrose-solution, PT confirmed its positive effects, improving glucose and lipid profile, and acting as a potent antioxidant. The effects of PT on rats that consumed a normal diet were very discrete or even undesirable. We suggest caution with indiscriminate consume of natural compounds by healthy subjects.

Review: Insulin resistance and mitochondrial dysfunction following severe burn injury.

The insulin signaling pathway plays a pivotal role in glucose metabolism and metabolic homeostasis. Disruption of this pathway is commonly seen in critical illness such as following severe burn injuries where homeostatic control is lost, leading to "insulin resistance" with poor blood glucose control. The aberrant signaling pathways involved in insulin resistance following burn injury include increases in hyperglycemic stress hormones, pro-inflammatory cytokines and free radical production. Leakage of mitochondrial sequestered self-antigens and signaling between mitochondria and endoplasmic reticulum also contribute to insulin resistance. Greater understanding of molecular processes involved in burn-related insulin resistance could potentially lead to the development of novel therapeutic approaches to improve patient management.

Fructose consumption during pregnancy and lactation causes DNA damage and biochemical changes in female mice.

The consumption of fructose during pregnancy can cause hyperglycaemia and may stimulate production of reactive oxygen species; however, there are only a few studies reporting whether fructose consumption during pregnancy causes DNA damage. Therefore, the aim of this study was to evaluate the effects of fructose consumption on genetic and biochemical parameters in Swiss mice treated during pregnancy and lactation. For this, 15 couples of 60-day-old Swiss mice were divided into three groups of five couples: negative control (water) and two fructose groups (fructose dose of 10%/l and 20%/l). During this period, we evaluated food consumption, energy efficiency and body weight. Samples of blood were collected from the females before copulation, after the 15th day of conception and on the 21st day after the lactation period, for the glycaemic and lipid profiles as well as comet assay and micronucleus (MN) test. Comet assay and MN test evaluate DNA damage and clastogenicity, respectively. In the gestation and lactation period, the two fructose doses tested showed DNA damage as observed in the comet assay, which is associated with an increase in dietary intake, body weight, lipid profile and fasting glycaemia in females. Thus, it can be suggested that the high consumption of fructose during these periods is harmful for pregnancy and lactation.

The Intracellular Growth of M. tuberculosis Is More Associated with High Glucose Levels Than with Impaired Responses of Monocytes from T2D Patients.

Diabetes mellitus, a metabolic disease characterized by hyperglycemia and poor glucose control, is a risk factor for Mycobacterium tuberculosis (M. tuberculosis) infection and the development of active tuberculosis. To evaluate whether M. tuberculosis infection susceptibility is associated with an intrinsic factor in monocytes from type 2 diabetes (T2D) patients or it is associated with hyperglycemia per se, we analyzed TLR-2 and TLR-4 expression by flow cytometry and the cytokines IL-1ß, IL-6, IL-8, IL-10, and TNF-α by cytometric bead array assays, either stimulated with TLR-2 and TLR-4 ligands or infected with M. tuberculosis in the whole blood from T2D patients (n = 43) and healthy subjects (n = 26) or in CD14+ monocytes from healthy subjects cultured in high glucose (HG) (30 mM). The intracellular growth of M. tuberculosis was evaluated by CFU counts at 0, 1, and 3 days in both monocytes from T2D patients and monocytes from healthy subjects cultured in HG. We did not find significant differences in TLR expression, cytokine production, or growth of M. tuberculosis in monocytes from T2D patients compared with those in monocytes from healthy subjects. Despite these results, in vitro assays of monocytes cultured with 30 mM glucose led to significantly increased TLR-2 and TLR-4 basal expression compared to those of monocytes cultured with 11 mM glucose (P < 0.05). Conversely, the production of IL-6 by TLR-2 ligand stimulation, of IL-1ß, IL-6, and IL-8 by TLR-4 ligand stimulation, and of IL-8 by M. tuberculosis infection significantly decreased in monocytes cultured in HG (P < 0.05). Additionally, the intracellular survival of M. tuberculosis increased in monocytes in HG after day 3 of culture (P < 0.05). In conclusion, HG decreased IL-8 production and the intracellular growth control of M. tuberculosis by monocytes, supporting the hypothesis that hyperglycemia plays an important role in the impaired immune responses to M. tuberculosis in patients with T2D.

Lupeol, a Dietary Triterpene, Enhances Wound Healing in Streptozotocin-Induced Hyperglycemic Rats with Modulatory Effects on Inflammation, Oxidative Stress, and Angiogenesis.

Impaired wound healing is a debilitating complication of diabetes that leads to significant morbidity, particularly foot ulcers. Natural products have shown to be effective in treating skin wounds. Lupeol is known to stimulate angiogenesis, fibroblast proliferation, and expressions of cytokines and growth factors involved in wound healing. The study is performed to evaluate the wound healing activity of lupeol in streptozotocin-induced hyperglycemic rats by macroscopical, histological, immunohistochemical, immunoenzymatic, and molecular methods. Percentage of wound closure and contraction was increased in the lupeol-treated group when compared to the Lanette group. Histopathological observation revealed decreased inflammatory cell infiltration and increased proliferation of fibroblasts, vascularization, and deposition of collagen fibers after lupeol treatment. Immunohistochemical analyses showed decreased intensity of NF-κB and increased intensity of FGF-2, TGF-ß1, and collagen III. ELISA results revealed downregulated IL-6 levels and upregulated IL-10 levels in response to lupeol. The mRNA expression levels of Hif-1α, Sod-2, and Ho-1 were significantly increased in response to lupeol as compared to Lanette whereas Nf-κb and Vegf-A levels were decreased in relation to insulin and lupeol treatment. These findings indicate that lupeol possesses wound healing potential in hyperglycemic conditions and may be useful as a treatment for chronic wounds in diabetic patients.

Combined effects of arsenic exposure and diabetes on male reproductive functions.

BACKGROUND: It is known that exposure to either arsenic or hyperglycemia can induce male reproductive damages. However, their combined effects on male reproductive organs are still unclear. Therefore, the present study investigated morphological and functional parameters of the testis, epididymis, and spermatozoa in diabetic rats exposed to arsenate. MATERIALS AND METHODS: Diabetes was induced in male rats by intraperitoneal streptozotocin injection. While a set of healthy and diabetic animals received saline solution (negative control and diabetes control, respectively), the other set received 10 mg/L sodium arsenate (arsenic control and diabetes + arsenic groups, respectively) for 40 days in drinking water. Testosterone concentration, daily sperm production, sperm counts in the testis and epididymis, and sperm parameters were evaluated in the groups. Moreover, testis and epididymis were subjected to antioxidant enzymes analysis, micromineral determination, and histopathological evaluation. RESULTS: Arsenate exposure reduced serum testosterone concentration in healthy animals and worsened this reduction in diabetic rats. In addition, the number of spermatozoa in testis and epididymis tissues, as well as the daily sperm production, was decreased in these groups. Sperm parameters such as motility, morphology, and integrity of acrosomal and plasma membranes were impaired in health animals exposed to arsenate. The combination of diabetes and arsenate, in turn, increased only the percentage of spermatozoa with abnormal morphology. Moreover, the proportion of arsenic increased in the testis and epididymis of both groups receiving arsenate. Its bioaccumulation in these organs caused an imbalance in antioxidant enzymes activities and mineral content in healthy animals, enhancing these changes in diabetic rats. Testicular pathologies occurred mainly in animals co-exposed to diabetes and arsenate. CONCLUSION: Our results indicate that arsenate exposure enhances several damages to male reproductive functions in diabetic rats, mainly by impairing testosterone levels and inducing nitrosative stress in testis and epididymis.

Alendronate-induced gastric damage in normoglycemic and hyperglycemic rats is reversed by metformin.

Alendronate is a bisphosphonate widely used for the treatment of osteoporosis; however, one of its main adverse reactions is gastric ulcer. Metformin is an oral antihyperglycemic agent that has several beneficial effects, including healing, gastroprotective and anti-tumoral action. This study aimed to evaluate the gastroprotective activity of metformin in alendronate-induced gastric damage in normoglycemic and hyperglycemic rats. The treatment with 100 mg/kg of metformin showed a significant gastroprotective effect in damage induced by alendronate (50 mg/kg) in macroscopic analysis and the analysis of light microscopy and atomic force microscopy. The results suggested metformin decreased the inflammatory response by reducing the expression of proinflammatory cytokines (TNF-α, IL-1ß and IL-6), myeloperoxidase activity, and malondialdehyde levels. Also, the results suggested that metformin induces the maintenance of basal levels of collagen and increase the production of mucus. Interestingly, with the presence of the AMPK inhibitor (Compound C), metformin presented impairment of its gastroprotective action. The gastroprotective effect of metformin might be related to the activation of the AMPK pathway. These findings revealed that metformin has a gastroprotective action and may be considered a therapeutic potential for the prevention and treatment of gastric lesions induced by alendronate.

Microencapsulated feruloyl esterase-producing lactobacilli ameliorate lipid profile and glycaemia in high fat diet-induced obese mice.

The effect of oral administration of spray-dried microcapsules of feruloyl esterase (FE) producing Lactobacillus fermentum CRL1446 (Lf) and Lactobacillus johnsonii CRL1231 (Lj) on high fat diet-induced obese mice was investigated to evaluate whether these strains could be used as a biotherapeutic for obesity. Swiss albino mice were divided into a normal diet fed group receiving empty microcapsules (control), a high fat diet plus empty microcapsules (HFD group), HFD plus microcapsules with Lf (HFD-Lf group) and HDF plus microcapsules with Lj (HFD-Lj group). Microcapsules containing Lf or Lj at a dose of ~107 cells/day/mouse were given orally for 7 weeks. Body weight gain, adiposity index, plasma leptin, lipid profiles, glycaemia, insulinemia, oral glucose tolerance, intestinal FE, glutathione peroxidase and glutathione reductase (GR) activities were determined. Administration of lactobacilli (HFD-Lf and HFD-Lj groups) improved metabolic parameters (triglyceride, total cholesterol, low-density lipoprotein cholesterol levels) and cardiovascular risk indicators (37-46% decrease of atherogenic index), and reduced body weight gain (29-38%), adiposity index (42-62%), plasma leptin levels, liver weight and fat deposition in liver. Intestinal FE activities significantly increased in HFD-Lf (62%) and HFD-Lj group (48%), thus improving hepatic GR activity (42% increment) compared to HFD group. Moreover, L. johnsonii increased HDL-cholesterol and L. fermentum reduced blood glucose to levels similar to the control. These FE-producing lactobacilli have the potential to improve biomarkers involved in obesity by increasing intestinal FE activity.

Characterization of the Goto-Kakizaki (GK) Rat Model of Type 2 Diabetes.

The Goto-Kakizaki (GK) rat is a model of type 2 diabetes mellitus, produced originally by selective inbreeding for a hyperglycemic trait. These rats are characterized as having insulin resistance and an insulin secretory defect. Pancreatic islets from these mice show abnormal morphology in the distribution of glucagon-secreting α cells and insulin-secreting ß cells, which may affect paracrine functions involved in the secretory response. This chapter describes the characterization of GK rat islets using immunofluorescence microscopy and Western blot analyses to demonstrate the effects on islet architecture and how this translates to changes in expression of predominant islet proteins.

Cerebellar synaptopathy in streptozotocin-induced diabetic rats / Sinaptopatía cerebelosa en ratas diabéticas inducidas por estreptozotocina

SUMMARY: There is an increasing amount of evidence that supports the diabetic complications of the central nervous system structure and function. The cerebellum, which is one of the primary structure derived from the hindbrain, plays an important role in motor control, motor coordination, and non-motor functions, such as cognitive processing. The synapse is a critical structure that regulates neuronal communication, and well-defined afferent and efferent fibre connections in the cerebellum help in maintaining the proper working order. Thus, the present study sought to investigate the long-term effects of diabetes-induced synaptopathy in the cerebellum, using both histological and ultrastructural studies. Twenty Sprague-Dawley male rats were divided randomly into control and diabetic groups, and diabetes was then induced through a single intraperitoneal injection of streptozotocin (60 mg/kg body weight). Six month later, the rats were sacrificed and the cerebellum was removed. Light and electron microscopic examinations showed a degeneration of Purkinje cells (Neuron purkinjense) with shrunken cells, pyknotic nuclei, and synaptopathy, including the reduction in synapse density, number of synaptic vesicles, and maturation of synapses in the molecular layer of diabetic cerebellum. The disruptions in synaptic profiles, which observed in the diabetic condition, could be related to cerebellar dysfunction, thus leading to the defects in coordinated movement, balance, as well as cognitive learning and memory.

RESUMEN: Actualmente existe una creciente evidencia que apoya las complicaciones diabéticas de la estructura y función del sistema nervioso central. El cerebelo, una de las estructuras primarias del cerebro posterior, desempeña un papel importante en el control motor, la coordinación motora y las funciones no motoras, tanto como en el procesamiento cognitivo. La sinapsis es una estructura crítica que regula la comunicación neuronal y las conexiones de fibras aferentes y eferentes bien definidas en el cerebelo, ayudan a mantener el funcionamiento correcto. Por lo tanto, en el presente estudio se investigaron los efectos a largo plazo de la sinaptopatía inducida por la diabetes en el cerebelo, utilizando estudios histológicos y ultraestructurales. Veinte ratas SpragueDawley macho se dividieron al azar en grupos de control y diabetes, se indujó la diabetes a través de una inyección intraperitoneal única de estreptozotocina (60 mg / kg de peso corporal). Seis meses después, se sacrificaron las ratas y se extrajo el cerebelo. Los exámenes de microscopías óptica y electrónica mostraron una degeneración de las neuronas purkinjenses (células de Purkinje), con células reducidas, núcleos picnóticos y sinaptopatía, como también la densidad reducida de sinapsis, el número de vesículas sinápticas y la maduración de las sinapsis en la capa molecular del cerebelo de las ratas diabéticas. Las interrupciones en los perfiles sinápticos, que se observaron en la condición diabética, podrían estar relacionadas con la disfunción cerebelosa, lo que lleva a defectos en el movimiento coordinado, el equilibrio, así como al aprendizaje cognitivo y la memoria.

Sodium tungstate: Is it a safe option for a chronic disease setting, such as diabetes?

Diabetes is a complex metabolic disorder triggered by the deficient secretion of insulin by pancreatic ß cells, the resistance of peripheral tissues to the action of the hormone, or both, and is characterized by chronic hyperglycemia leading to organ damage and failure. Tight glycemic control represents the best therapy to delay or stop progression of diabetes, with many antidiabetic drugs being commercially available nowadays. However, no ideal normoglycemic agent has been developed as yet, and those already available still induce hypoglycemia and/or weight gain as major side effects, worsening glycemic control. In this respect, the inorganic salt sodium tungstate (Na2 WO4 ) has been proven to offer a good antidiabetic alternative in different animal models of diabetes, reducing body weight and normalizing glycemia without causing hypoglycemic episodes. The mechanisms of action mediating the potent antidiabetic actions but also the spectrum of undesirable effects of Na2 WO4 are still poorly understood. In fact, along with its beneficial effects, Na2 WO4 has been consistently reported to be toxic and even carcinogenic. Given that Na2 WO4 is accumulated in the kidneys for elimination, here, we discuss a possible association between long-term Na2 WO4 treatment and a higher risk of renal carcinogenesis in diabetic individuals.

Food restriction promotes damage reduction in rat models of type 2 diabetes mellitus.

There are several animal models of type 2 diabetes mellitus induction but the comparison between models is scarce. Food restriction generates benefits, such as reducing oxidative stress, but there are few studies on its effects on diabetes. The objective of this study is to evaluate the differences in physiological and biochemical parameters between diabetes models and their responses to food restriction. For this, 30 male Wistar rats were distributed in 3 groups (n = 10/group): control (C); diabetes with streptozotocin and cafeteria-style diet (DE); and diabetes with streptozotocin and nicotinamide (DN), all treated for two months (pre-food restriction period). Then, the 3 groups were subdivided into 6, generating the groups CC (control), CCR (control+food restriction), DEC (diabetic+standard diet), DER (diabetic+food restriction), DNC (diabetic+standard diet) and DNR (diabetic+food restriction), treated for an additional two months (food restriction period). The food restriction (FR) used was 50% of the average daily dietary intake of group C. Throughout the treatment, physiological and biochemical parameters were evaluated. At the end of the treatment, serum biochemical parameters, oxidative stress and insulin were evaluated. Both diabetic models produced hyperglycemia, polyphagia, polydipsia, insulin resistance, high fructosamine, hepatic damage and reduced insulin, although only DE presented human diabetes-like alterations, such as dyslipidemia and neuropathy symptoms. Both DEC and DNC diabetic groups presented higher levels of protein carbonyl groups associated to lower antioxidant capacity in the plasma. FR promoted improvement of glycemia in DNR, lipid profile in DER, and insulin resistance and hepatic damage in both diabetes models. FR also reduced the protein carbonyl groups of both DER and DNR diabetic groups, but the antioxidant capacity was improved only in the plasma of DER group. It is concluded that FR is beneficial for diabetes but should be used in conjunction with other therapies.

Effect of administration of high-protein diet in rats submitted to resistance training.

PURPOSE: Although there is limited evidence regarding the pathophysiological effects of a high-protein diet (HD), it is believed that this type of diet could overload the body and cause damage to the organs directly involved with protein metabolism and excretion. The aim of this study was to verify the effects of HD on biochemical and morphological parameters of rats that completed a resistance training protocol (RT; aquatic jump) for 8 weeks. METHODS: Thirty-two adult male Wistar rats were divided into four groups (n = 8 for each group): sedentary normal protein diet (SN-14%), sedentary high-protein diet (SH-35%), trained normal protein diet (TN-14%), and trained high-protein diet (TH-35%). Biochemical, tissue, and morphological measurements were made. RESULTS: Kidney (1.91 ± 0.34) and liver weights (12.88 ± 1.42) were higher in the SH. Soleus muscle weight was higher in the SH (0.22 ± 0.03) when compared to all groups. Blood glucose (123.2 ± 1.8), triglycerides (128.5 ± 44.0), and HDL cholesterol levels (65.7 ± 20.9) were also higher in the SH compared with the other experimental groups. Exercise reduced urea levels in the trained groups TN and TH (31.0 ± 4.1 and 36.8 ± 6.6), respectively. Creatinine levels were lower in TH and SH groups (0.68 ± 0.12; 0.54 ± 0.19), respectively. HD negatively altered renal morphology in SH, but when associated with RT, the apparent damage was partially reversed. In addition, the aquatic jump protocol reversed the damage to the gastrocnemius muscle caused by the HD. CONCLUSIONS: A high-protein diet promoted negative metabolic and morphological changes, while RT was effective in reversing these deleterious effects.

Hyperglycemic condition during puberty increases collagen fibers deposition in the prostatic stroma and reduces MMP-2 activity.

Puberty is an important period for the growth and maturation of the male reproductive system, and is also a critical window for endocrine or environmental interference. The physiological levels of circulating insulin and hyperglycemic control are important factors for a normal prostate growth. Hyperglycemia during puberty is reported to retard the growth of the prostate gland, with remarkable effects on the epithelial compartment. Here, we investigated the impact of hyperglycemia along with a simultaneous or late insulin replacement on the ventral prostate growth in rats during puberty, paying special attention to the deposition of collagen fibers and activities of gelatinase, matrix metalloproteinase-2 (MMP-2), and -9 (MMP-9). Hyperglycemia was induced by streptozotocin (STZ) administration in 40-day-old male Wistar rats. A subset of hyperglycemic rats underwent an early insulin replacement (three days after the STZ administration), and another subset underwent a late insulin replacement (twenty days after the STZ administration). Animals were euthanized at 60 and/or 80 days of age. The ventral prostatic lobe was processed for picrosirius red staining, type I and III collagen immunohistochemistry, and gelatin zymography. Hyperglycemic animals showed an increased area of collagen fibers in the prostate, which was composed both types of collagens. MMP-2 activity was significantly reduced in the hyperglycemic animals, while MMP-9 activity was very low and showed no alteration. The simultaneous and late insulin administration restored collagen content and MMP-2 activity. In conclusion, puberty is a critical window for prostate maturation and type-1 diabetes-induced hyperglycemia affects the ratio of the prostatic parenchymal and stromal growth, leading to fibrotic tissues by also MMP-2 down regulation.

Proinflammatory cytokine MIF plays a role in the pathogenesis of type-2 diabetes mellitus, but does not affect hepatic mitochondrial function.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in the pathogenesis of type 2 diabetes mellitus (T2DM). Although the effect of high glucose on liver function has been described, the role of MIF in hepatic mitochondrial function during T2DM has not been studied. OBJECTIVE: We examine the influence of MIF to hepatic mitochondrial function in T2DM mouse model. METHODS: WT and Mif-/- BALB/c mice were treated with a single dose of streptozotocin (STZ). After an 8-week follow-up, serum glucose, proinflammatory cytokines, C-reactive protein (CRP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme quantification, and liver histological analyses were performed. Liver mitochondria were extracted, and mitochondrial function was evaluated by oximetry, swelling and peroxide production. RESULTS: Following treatment with STZ, WT mice (WT/STZ) developed significant hyperglycemia and high serum levels of MIF, tumor necrosis factor (TNF)-α, interleukin-ß (IL-ß), and CRP. Liver damage enzymes ALT and AST were found at high levels. In contrast, Mif-/-STZ lacked serum MIF levels and showed smaller increases in blood glucose, less TNF-α, IL-1ß, CPR, ALT and AST, and failure to develop clinical signs of disease compared to the WT/STZ group. Mitochondria extracted from the Mif-/-STZ liver showed similar respiratory control (RC) to WT/STZ or healthy mice with glutamate/malate or succinate as substrates. The four respiratory chain complexes also had comparable activities. WT/STZ-isolated mitochondria showed low swelling with calcium compared to mitochondria from Mif-/-STZ or healthy mice. Peroxide production was comparable in all groups. CONCLUSION: These results show although high systemic levels of MIF contribute to the development of T2DM pathology, the liver mitochondria remain unaltered. Importantly, the absence of MIF reduced the pathology of T2DM, also without altering liver mitochondrial function. These support MIF as a therapeutic target for the treatment of this disease in humans.