Higher Plasma Insulin Levels Research Articles

Nitric Oxide Overproduction Reduces Insulin Secretion from Isolated Islets in Fetal Hypothyroid Rats.

Thyroid hormones have developmental effects during fetal life. Fetal hypothyroidism leads to glucose intolerance and reduced insulin secretion capacity. Activity of nitric oxide synthases follows a heterogeneous pattern in hypothyroidism. Overactivity of constitutive nitric oxide synthase (NOS), inhibits glucose-stimulated insulin release. The aim of this study was to examine if reduction in insulin secretion in fetal hypothyroidism is due to overproduction of nitric oxide. Pregnant Wistar rats were divided into 2 groups; the experimental group consumed water containing 0.02% of 6-propyl-2-thiouracil till delivery, while the control group consumed tap water. After delivery serum thyroid hormones were measured. Intravenous glucose tolerance test was performed in 6-month old offspring (n=8). After 3 weeks recovery, pancreatic islets were isolated and insulin secretion, inducible and constitutive nitric oxide synthase activity were measured (n=4). Compared to controls, during intravenous glucose tolerance test, fetal hypothyroid rats had high plasma glucose concentration (p=0.003) and low plasma insulin levels (p=0.012) at 5-20 min and their insulin secretion from isolated islets at basal glucose concentration and in the presence of l-arginine was lower. The nitric oxide synthase inhibitor, NG-nitro-l-arginine methyl ester significantly improved insulin secretion in fetal hypothyroid rats at basal glucose concentration and in the presence of l-arginine. The results showed higher NOS activities in fetal hypothyroid rats (constitutive 17.60±1.09 vs. 47.34±4.44 and inducible 4.09±0.96 vs. 19.97±1.14 pmol/min/mg proteins, p=0.002). In conclusion, NO overproduction through NOS participates in decreased insulin secretion in fetal hypothyroid rats.

Longitudinal Changes in Body Fat and Its Distribution in Relation to Cardiometabolic Risk in Black South African Women.

Ethnic differences in body composition and cardiometabolic risk have been reported in cross-sectional studies. This study aimed to investigate changes in body composition over 5.5 years, and its association with cardiometabolic risk in premenopausal black South African (SA) women. Changes in body composition and body fat distribution (dual-energy x-ray absorptiometry and computerized tomography), fasting glucose, insulin, and lipid concentrations, were measured in 63 black SA women at baseline (age: 27 ± 8 years), and 5.5 years later. Body weight and fat mass (FM) increased by 6.9 ± 9.9 kg and 4.3 ± 6.9 kg, respectively, over the 5.5 years with a relative (%FM) increase in central and decrease in peripheral FM (all P < 0.05). Fasting glucose and lipid concentrations (except HDL-cholesterol) increased over the follow-up period (all P < 0.05). Both baseline and changes in body fat distribution were associated with cardiometabolic risk. Independent of baseline age, FM and insulin sensitivity, baseline trunk:leg was associated with reduced insulin sensitivity at follow-up (Matsuda index; β = -0.41, P = 0.002). Increasing trunk:gynoid ratio was associated with higher plasma insulin levels (β = 0.31, P = 0.023) and reduced insulin sensitivity (Matsuda index; β = -0.52, P < 0.001) at follow-up. Weight gain in free-living black SA women over 5.5 years was associated with a centralization of fat mass, which predicted an increase in cardiometabolic risk.

GLP-2 as Beneficial Factor in the Glucose Homeostasis in Mice Fed a High Fat Diet.

Glucagon like peptide-2 (GLP-2) is a gastrointestinal hormone released in response to dietary nutrients, which acts through a specific receptor, the GLP-2 receptor (GLP-2R). The physiological effects of GLP-2 are multiple, involving also the intestinal adaptation to high fat diet (HFD). In consideration of the well-known relationship between chronic HFD and impaired glucose metabolism, in the present study we examined if the blocking of the GLP-2 signaling by chronic treatment with the GLP-2R antagonist, GLP-2 (3-33), leads to functional consequences in the regulation of glucose metabolism in HFD-fed mice. Compared with animals fed standard diet (STD), mice at the 10th week of HFD showed hyperglycaemia, glucose intolerance, high plasma insulin level after glucose load, increased pancreas weight and β cell expansion, but not insulin resistance. In HFD fed mice, GLP-2 (3-33) treatment for 4 weeks (from the 6th to the 10th week of diet) did not affect fasting glycaemia, but it significantly increased the glucose intolerance, both fasting and glucose-induced insulin levels, and reduced the sensitivity to insulin leading to insulin-resistance. In GLP-2 (3-33)-treated HFD mice pancreas was significantly heavier and displayed a significant increase in β-cell mass in comparison with vehicle-treated HFD mice. In STD mice, the GLP-2 (3-33) treatment did not affect fasted or glucose-stimulated glycemia, insulin, insulin sensitivity, pancreas weight and beta cell mass. The present study suggests that endogenous GLP-2 may act as a protective factor against the dysregulation of the glucose metabolism that occurs in HFD mice, because GLP-2 (3-33) worsens glucose metabolism disorders.

Overexpression of Pref-1 in pancreatic islet β-cells in mice causes hyperinsulinemia with increased islet mass and insulin secretion

Preadipocyte factor-1 (Pref-1) is made as a transmembrane protein containing EGF-repeats at the extracellular domain that can be cleaved to generate a biologically active soluble form. Pref-1 is found in islet β-cells and its level has been reported to increase in neonatal rat islets upon growth hormone treatment. We found here that Pref-1 can promote growth of pancreatic tumor derived AR42J cells. To examine Pref-1 function in pancreatic islets in vivo, we generated transgenic mouse lines overexpressing the Pref-1/hFc in islet β-cells using rat insulin II promoter (RIP). These transgenic mice exhibit an increase in islet mass with higher proportion of larger islets in pancreas compared to wild-type littermates. This is in contrast to pancreas from Pref-1 null mice that show higher proportion of smaller islets. Insulin expression and insulin secretion from pancreatic islets from RIP-Pref-1/hFc transgenic mice are increased also. Thus, RIP-Pref-1/hFc transgenic mice show normal glucose levels but with higher plasma insulin levels in both fasting and fed conditions. These mice show improved glucose tolerance. Taken together, we conclude Pref-1 as a positive regulator of islet β-cells and insulin production.

Clinical features and causes of endogenous hyperinsulinemic hypoglycemia in Korea.

BackgroundEndogenous hyperinsulinemic hypoglycemia (EHH) is characterized by an inappropriately high plasma insulin level, despite a low plasma glucose level. Most of the EHH cases are caused by insulinoma, whereas nesidioblastosis and insulin autoimmune syndrome (IAS) are relatively rare.MethodsTo evaluate the relative frequencies of various causes of EHH in Korea, we retrospectively analyzed 84 patients who were diagnosed with EHH from 1998 to 2012 in a university hospital.ResultsAmong the 84 EHH patients, 74 patients (88%), five (6%), and five (6%) were diagnosed with insulinoma, nesidioblastosis or IAS, respectively. The most common clinical manifestation of EHH was neuroglycopenic symptoms. Symptom duration before diagnosis was 14.5 months (range, 1 to 120 months) for insulinoma, 1.0 months (range, 6 days to 7 months) for nesidioblastosis, and 2.0 months (range, 1 to 12 months) for IAS. One patient, who was diagnosed with nesidioblastosis in 2006, underwent distal pancreatectomy but was later determined to be positive for insulin autoantibodies. Except for one patient who was diagnosed in 2007, the remaining three patients with nesidioblastosis demonstrated severe hyperinsulinemia (157 to 2,719 µIU/mL), which suggests that these patients might have had IAS, rather than nesidioblastosis.ConclusionThe results of this study suggest that the prevalence of IAS may be higher in Korea than previously thought. Therefore, measurement of insulin autoantibody levels is warranted for EHH patients, especially in patients with very high plasma insulin levels.

Congenital Hyperinsulinism and Cochlear Hypoplasia in a Rare Case of Pallister-Hall Syndrome

Pallister-Hall syndrome (PHS) is characterized by a spectrum of anomalies, which include polydactyly, hypothalamic hamartoma, laryngotracheal cleft, bifid epiglottis, imperforate anus, and renal abnormalities. Hypoplastic cochlea is a rare reported association of PHS. A baby girl was born at 31 weeks gestation with birth weight of 1.2 kg. The endotracheal intubation was extremely difficult due to narrow trachea. She was noted to be dysmorphic and have recurrent hypoglycemic episodes requiring high concentration of glucose infusion. The investigations revealed an inappropriately high plasma insulin and C-peptide level during hypoglycemia with low free fatty acids and β-hydroxy butyrate suggestive of congenital hyperinsulinism (CHI). MRI of the brain revealed the presence of a large hypothalamic hamartoma. The cochlea was noted to be truncated bilaterally with reduced number of turns. The cytogenetic analysis revealed GLI3 mutation consistent with diagnosis of PHS. This is the first reported case of CHI in association with PHS. Our patient also had hypoplastic cochlea, which is a unique but rarely reported feature of PHS. Int J Clin Pediatr. 2015;4(2-3):154-157 doi: http://dx.doi.org/10.14740/ijcp196w

Acute enzymatic glycocalyx degradation results in reduced insulin sensitivity but normal glucose tolerance in conscious rats

Perturbation of the endothelial glycocalyx has been suggested to be an early event in the development of endothelial dysfunction during increased cardiovascular risk exposure. Previously, we showed in anesthetized rats that acute enzymatic degradation of the endothelial glycocalyx was associated with impaired insulin-mediated glucose disposal, suggesting a role of the glycocalyx in regulation of glucose homeostasis. In the current study, we tested the acute effect of enzymatic glycocalyx treatment on glucose tolerance and insulin sensitivity in conscious rats. In rats that had had their femoral artery and vein cannulated 1 week before the experiment, intravenous glucose and insulin tolerance tests were performed before and after acute degradation of the endothelial glycocalyx using an intravenous bolus of hyaluronidase. During the intravenous glucose tolerance test, glucose tolerance did not differ between the hyaluronidase-treated and control animals, but was associated with a 1.5-fold higher plasma insulin level in the former group. Further, glycocalyx treatment significantly decreased insulin-mediated glucose disposal during intravenous insulin tolerance tests, as observed from the reduced insulin-mediated glucose disposal rate from 3.3±0.1%/min in control rats to 2.6±0.2%/min in the hyaluronidase-treated rats. These results support a role for the endothelial glycocalyx in the regulation of peripheral insulin sensitivity. The reduction in insulin sensitivity during acute glycocalyx damage, however, does not have an immediate effect on glucose tolerance because of a compensatory increase in plasma insulin levels.

Impaired Oxidative Endoplasmic Reticulum Stress Response Caused by Deficiency of Thyroid Hormone Receptor α

Thyroid hormone receptor α (TRα) is critical to postnatal pancreatic β-cell maintenance. To investigate the association between TRα and the survival of pancreatic β-cells under endoplasmic reticulum (ER) stress, the expression of endogenous TRα was inhibited by infection with an adenovirus expressing double-stranded short hairpin RNA against TRα (AdshTRα). In control adenovirus-infected pancreatic β-cells, palmitate enhanced the expression of activating transcription factor 4 (ATF4) and heme oxygenase 1, which facilitates adaptation to oxidative ER stress. However, in AdshTRα-infected pancreatic β-cells, palmitate did not induce ATF4-mediated integrated stress response, and oxidative stress-associated apoptotic cell death was significantly enhanced. TRα-deficient mice or wild-type mice (WT) were fed a high fat diet (HFD) for 30 weeks, and the effect of oxidative ER stress on pancreatic β-cells was analyzed. HFD-treated TRα-deficient mice had high blood glucose levels and low plasma insulin levels. In HFD-treated TRα-deficient mice, ATF4 was not induced, and apoptosis was enhanced compared with HFD-treated WT mice. Furthermore, the expression level of 8-hydroxydeoxyguanosine, an oxidative stress marker, was enhanced in the β-cells of HFD-treated TRα-deficient mice. These results indicate that endogenous TRα plays an important role for the expression of ATF4 and facilitates reduced apoptosis in pancreatic β-cells under ER stress.

Factors associated with cognitive decline in older adults with type 2 diabetes mellitus during a 6‐year observation

Type 2 diabetes mellitus (T2DM) is a risk for cognitive decline in older adults. The current study was carried out to determine the factors associated with cognitive decline. The older T2DM patients (aged ≥65 years, mean age 79.2 ± 5.1 years) were observed for 6 years, and the mean values in clinical indicators of participants with and without cognitive decline over a 6-year period were compared. Then, multiple logistic analysis was carried out to determine the factors associated with cognitive decline. Separate analyses were also carried out for each of five cognitive assessments (Mini-Mental State Examination, word immediate and delayed recall, Stroop test, digit symbol substitution). In the composite of several cognitive assessments, higher age and a lower level of high-density lipoprotein cholesterol were associated with cognitive decline in older T2DM patients. Lower systolic blood pressure was associated with a decline in delayed word list recall. Higher plasma insulin level was associated with a decline in the Stroop test performance. Lower high-density lipoprotein cholesterol was significantly associated with general cognitive decline in older T2DM patients during our 6-year observation. Several other factors were also associated with cognitive assessments of various cognitive domains.

Factors influencing the incidence of high rigor temperature in beef carcasses in Australia

Beef carcasses undergoing rapid pH fall while the loin muscle temperature is still high are described as heat-shortened, heat-toughened or ‘high rigor temperature’ carcasses, with subsequent negative effects on quality traits. The aim of the study was to quantify the occurrence of high rigor temperature in beef carcasses across Australia and to identify the causative factors. Data was collected over 4–5 days at each of seven beef processing plants from 1512 beef carcasses. The beef carcasses were from both grass- and grain-fed cattle ranging in days on grain feeding from 0 (grass-fed) to 350 days and the category of cattle ranged from veal to ox and cow. Data collected on the day of slaughter included the duration of electrical inputs at the immobiliser, electrical stimulation and hide puller, longissimus muscle pH and temperature decline, hot carcass weight and P8 fat depth. At grading, ultimate pH, eye muscle area, wetness of the loin surface and colour score were also collected. The temperature at pH 6 was calculated and if it was &gt;35°C, the carcass was defined as ‘high rigor temperature’. Modelling of the data was conducted using GLMM and REML. The occurrence of high rigor temperature across all seven beef processing plants was 74.6% ranging from 56 to 94% between beef processing plants. Increasing days in the feedlot and heavier carcass weights were highly correlated and both caused an increase in the predicted temperature at pH 6 and in the % high rigor temperature (P &lt; 0.05 for both). Longer duration of electrical inputs at the hide puller, fatter grass-fed cattle and fatter male (castrate) carcasses had a higher temperature at pH 6 and higher % high rigor temperature. Modelling showed that if the time to reach pH 6 in the longissimus muscle was 65 v. 105 min, the % high rigor temperature carcasses reduced from 98 to 19% in grain-fed cattle and 93 to 7% in grass-fed cattle. Higher plasma insulin levels at slaughter were associated with a higher temperature at pH 6 (rigor temperature) (P &lt; 0.001). In conclusion, in order to reduce the incidence of high rigor temperature in grain-fed beef carcasses, methods for identifying high rigor temperature carcasses will be required and while some management strategies can be implemented now, others require further research.

The Unholy Alliance between Obesity, Type-2 Diabetes, the Sympathetic Nervous System, and Hypertension in Young/Middle-Aged Subjects

There is an obesity/type-2 diabetes (DM2)/hypertension epidemic in developed countries around the world. The purpose of this review is to examine the interrelationships between obesity, DM2 and hypertension in young/middleaged subjects, highlighting the importance of raised sympathetic nerve activity and treatment implications. Central obesity is associated with insulin-resistance, and high plasma insulin and leptin levels. Insulin and leptin act upon the mid-brain, resulting in increased sympathetic nerve activity and blood pressure. Chronically raised sympathetic nerve activity, independent of blood pressure, is a powerful predictor of myocardial infarction in the middle-aged. Weight-loss, via life-style change or bariatric surgery, results in blood pressure reduction. Anti-hypertensive agents that increase sympathetic nerve activity, e.g. diuretics, dihydropyridine calcium antagonists, and angiotensin receptor blockers (ARBs), do not reduce (and may increase) the risk of myocardial infarction in younger/middleaged subjects with hypertension and DM2. Beta-1 blockade, which is effective in regressing and stabilising coronary atheromataous plaque, is preferable to ACE-inhibition, and is the first-line treatment of choice.

Appetite loss may be induced by lower serum ghrelin and higher serum leptin concentrations in subarachnoid hemorrhage patients

BackgroundPatients with aneurysmal subarachnoid hemorrhage (SAH) typically develop appetite loss. However, the mechanisms regulating appetite are not understood. Ghrelin and leptin, both of which signal nutritional status and energy storage levels to the hypothalamus, are essential elements of the appetite system. Thus, the goal of this study was to investigate the relationship between appetite and ghrelin and leptin concentrations in patients with SAH.MethodsBlood plasma or serum profiles and appetite status were measured in 19 patients with SAH who underwent aneurysmal clipping within 48 hours of SAH onset. Appetite status was measured using dietary oral calorie intake. All outcome variables were measured at an early (day 3) and late (day 8) time point after SAH onset (day 0).ResultsOf the 19 patients studied, 6 (31.6%) showed lower dietary oral calorie intake at the late time point than at the early time point. In these patients with appetite loss, plasma hemoglobin (P < 0.02), albumin (P < 0.01), glucose (P < 0.01), plasma insulin (P < 0.04), and serum ghrelin (P < 0.03) concentrations were lower at the late time point than at the early time point. Serum leptin was higher at the late time point than at the early time point (P < 0.02).ConclusionIn SAH patients, appetite loss may be induced by lower serum ghrelin and higher serum leptin concentrations resulting from high plasma glucose and insulin levels due to a catecholamine surge following SAH.

The prospective estimation of blood serum free IGF-1, insulin concentration, and body mass index as a prognostic factor for breast cancer patients.

47 Background: Numerous epidemiologic findings suggest that an increase in IGF-1, insulin concentration and body mass index correlates with the risk of developing certain types of malignant tumors, including breast cancer. They may also have an influence on the cancer stage. The purpose of this study was to prospectively evaluate the correlation of body mass index (BMI), insulin, and free IGF-1 concentration with cancer stage. Methods: Prospective analysis has been conducted in 2011 in Cancer Center and Institute of Oncology in Gliwice, Poland. This study has been approved by Bioethics Committee according to national regulations. The pilot group included 138 patients with breast cancer treated with chemotherapy, 76% in adjuvant setting and 24% due to cancer dissemination. Results: Patients’ median weight was 70kg (range 52-106kg) and median BMI was 27 (range 18.8-40.8). Patients with HER2 overexpression had diabetes more frequently (8% vs. 0%), p=0.06. Patients with higher BMI more frequently had negative steroid receptor status (42% vs. 25%) p=0.06, and significantly more often were in postmenopausal period (81% vs. 52%), p=0.00029. Tumor stage was significantly more advanced in patients with lower physical activity, p=0.04. Tumor stage was insignificantly more advanced in patients with higher plasma insulin level, p=0.09. Multivariate analysis had shown that overweight patients with more advanced stage of breast cancer had negative steroid receptors more often, p=0.033. Patients with metastatic breast cancer often had higher insulin plasma levels in comparison to patients with early breast cancer (7% vs. 1%), p=0.09. The multivariate analysis also showed that patients with diabetes had more frequently more often overexpression of HER2 and were in a more advanced cancer stage, p=0.03. Conclusions: Hyperinsulinemia may be a risk factor for more advanced stage of disease. There is a possibility that the effect of being overweight on breast cancer stage is mediated by estrogen metabolism. This analysis is scheduled to be performed later in the project.

Antihyperglycemic effect of fermented Gastrodia elata blume in streptozotocin-induced diabetic mice

Gastrodia elata Blume (GE) has been used in traditional medicine as a sedative, an anti-convulsant and anti-epileptic drug. This study was performed to investigate antihyperglycemic effect of fermented-Gastrodia elata Blume (FGE) in streptozotocin (STZ)-induced type 1 diabetic mice. FGE was prepared by fermentation with Saccharomyces cerevisia. GE and FGE were orally administered at 20 or 100 mg/kg/day for 3 weeks to STZ (70 mg/kg)-induced diabetic mice. Administartion of FGE significantly reduced blood glucose levels in an oral glucose tolerance test (OGTT), fasting blood glucose (FBG), and glycosylated hemoglobin (HbA1c) compared to GE. In addition, FGE significantly decreased serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and at the same time markedly increased serum high density lipoprotein cholesterol (HDL-C) and plasma insulin levels. The results of this experimental study indicate that FGE possesses antihyperglycemic effect in STZ-induced diabetic mice.

Maternal metformin treatment decreases fetal inflammation in a rat model of obesity and metabolic syndrome

Obesity and metabolic syndrome are associated with systemic inflammation and increased perinatal morbidity. Metformin improves metabolic and inflammatory biomarkers in nonpregnant adults. Using in vivo and in vitro models, we examined the effect of metformin on maternal and fetal inflammation. Female Wistar rats (6-7 weeks old) were fed a normal diet (NORM) or a high-fat/high-sugar diet (HCAL) for 5-6 weeks to induce obesity/metabolic syndrome. After mating with NORM-fed male rats, one-half of the HCAL-fed female rats received metformin (300 mg/kg, by mouth daily). All dams continued their respective diets until gestational day 19, at which time maternal and fetal outcomes were assessed. Maternal and fetal plasma and placentas were analyzed for metabolic and inflammatory markers. Cultured human placental JAR cells were pretreated with vehicle or metformin (10 μmol/L-2.5 mmol/L) before tumor necrosis factor α (TNF-α; 50 ng/mL), and supernatants were assayed for interleukin-6 (IL-6). HCAL rats gained more prepregnancy weight than NORM rats (P = .03), had higher levels of plasma insulin and leptin, and exhibited dyslipidemia (P < .05). Fetuses that were exposed to the HCAL diet had elevated plasma IL-6, TNF-α, and chemokine (C-C motif) ligand 2 levels (P < .05) and enhanced placental TNF-α levels (P < .05). Maternal metformin did not impact maternal markers but significantly decreased diet-induced TNF-α and chemokine (C-C motif) ligand 2 in the fetal plasma. Finally, metformin dose-dependently reduced TNF-α-induced IL-6 and IκBα levels in cultured placental JAR cells. Diet induced-obesity/metabolic syndrome during pregnancy significantly enhanced fetal and placental cytokine production; maternal metformin reduced fetal cytokine levels. Similarly, metformin treatment of a placental cell line suppressed TNF-α-induced IL-6 levels by NFκB inhibitor.

8-Oxoguanine DNA Glycosylase (OGG1) Deficiency Increases Susceptibility to Obesity and Metabolic Dysfunction

Oxidative damage to DNA is mainly repaired via base excision repair, a pathway that is catalyzed by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). While OGG1 has been implicated in maintaining genomic integrity and preventing tumorigenesis, we report a novel role for OGG1 in altering cellular and whole body energy homeostasis. OGG1-deficient (Ogg1−/−) mice have increased adiposity and hepatic steatosis following exposure to a high-fat diet (HFD), compared to wild-type (WT) animals. Ogg1−/− animals also have higher plasma insulin levels and impaired glucose tolerance upon HFD feeding, relative to WT counterparts. Analysis of energy expenditure revealed that HFD-fed Ogg1−/− mice have a higher resting VCO2 and consequently, an increased respiratory quotient during the resting phase, indicating a preference for carbohydrate metabolism over fat oxidation in these mice. Additionally, microarray and quantitative PCR analyses revealed that key genes of fatty acid oxidation, including carnitine palmitoyl transferase-1, and the integral transcriptional co-activator Pgc-1α were significantly downregulated in Ogg1−/− livers. Multiple genes involved in TCA cycle metabolism were also significantly reduced in livers of Ogg1−/− mice. Furthermore, hepatic glycogen stores were diminished, and fasting plasma ketones were significantly reduced in Ogg1−/− mice. Collectively, these data indicate that OGG1 deficiency alters cellular substrate metabolism, favoring a fat sparing phenotype, that results in increased susceptibility to obesity and related pathologies in Ogg1−/− mice.

VAMP8 Deletion Delays the Onset of Streptozotocin-Induced Hyperglycemia

ObjectiveWe recently reported that vesicle-associated membrane protein (VAMP) isoform 8 deletion increased islet β-cell mass. We now sought to determine if VAMP8 deletion-induced increase in islet β-cell mass would provide protection against streptozotocin (STZ)-induced β-cell destruction, and subsequently alleviate STZ-induced diabetes. MethodsVAMP8 null mice (KO) and age-matched littermate controls (WT) were treated with single daily intraperitoneal injections of STZ (40 mg/kg body weight) for 5 consecutive days. Intraperitoneal glucose (2 g/kg body weight) tolerance tests were carried out to determine blood glucose and insulin levels. Pancreas samples were obtained for histological assessment of β-cell mass (β-cell area per pancreatic area), proliferative (Ki67) and apoptotic (TUNEL) activities. ResultsSTZ-treated VAMP8 KO mice compared to WT mice displayed delayed onset in hyperglycemia, superior glucose tolerance and higher plasma insulin levels. However, the number of TUNEL-positive cells was similar between WT and VAMP8 KO islets. The number of Ki67-positive cells and the ratio of β-cell area per pancreatic area showed a higher but insignificant trend in VAMP8 KO mice islets vs. WT mice islets. ConclusionsVAMP8 deletion did not appear to protect against β-cell destruction by STZ; nonetheless, the residual increase in basal β-cell mass attributed to enhanced glucose tolerance and delayed onset of hyperglycemia.

HEMOCHROMATOSIS AND FATTY LIVER DISEASE: BUILDING EVIDENCE FOR INSULIN RESISTANCE IN BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS)

Hemochromatosis in bottlenose dolphins (Tursiops truncatus) is associated with high postprandial plasma insulin levels, suggestive of insulin resistance. In humans, insulin resistance is associated with liver pathologies, including excessive iron deposition and nonalcoholic fatty liver disease. Dolphin liver tissues, in addition to excessive iron storage, were evaluated for other pathologies supportive of underlying insulin resistance. Archived liver tissues collected postmortem during 1985-2010 from 18 dolphins (median age 27.9 yr, range 0.7-51.4) that were part of the Navy Marine Mammal Program's managed collection were assessed for the presence and severity of hemosiderin deposition, fatty liver disease, and hepatitis. Demographics, clinical pathology values, and percentage weight loss were compared among dolphins with and without these changes. Twelve (66.7%) dolphins had mild to moderate hemosiderin deposition, 7 (38.9%) had mild to severe fatty liver disease, and 11 (61.1%) had mild to moderate hepatitis. Of the 12 dolphins with hemosiderosis, deposition occurred in the Kupffer cells among 11 (91.7%). Dolphins with fatty liver disease were more likely to have higher postprandial serum hyperglycemia (>140 mg/dl), leukocytosis (>11,000 cells/microl), and hyperglobulinemia (>3.5 g/dl). Unlike in many nonhuman terrestrial animals, fatty liver disease was not associated with rapid weight loss or hypoglycemia. Interestingly, there were no significant associations among dolphins with hemosiderosis, fatty liver disease, and hepatitis. This study supports that both hemochromatosis and fatty liver disease were present in the dolphin study population, and histopathology and clinical pathology among these animals suggest a nonhereditary, metabolic etiology. Bottlenose dolphin, fatty liver disease, hemochromatosis, hemosiderosis, hepatic lipidosis, hepatitis, Tursiops truncatus.

Decreased Skin-Mediated Detoxification Contributes to Oxidative Stress and Insulin Resistance

The skin, the body's largest organ, plays an important role in the biotransformation/detoxification and elimination of xenobiotics and endogenous toxic substances, but its role in oxidative stress and insulin resistance is unclear. We investigated the relationship between skin detoxification and oxidative stress/insulin resistance by examining burn-induced changes in nicotinamide degradation. Rats were divided into four groups: sham-operated, sham-nicotinamide, burn, and burn-nicotinamide. Rats received an intraperitoneal glucose injection (2 g/kg) with (sham-nicotinamide and burn-nicotinamide groups) or without (sham-operated and burn groups) coadministration of nicotinamide (100 mg/kg). The results showed that the mRNA of all detoxification-related enzymes tested was detected in sham-operated skin but not in burned skin. The clearance of nicotinamide and N 1-methylnicotinamide in burned rats was significantly decreased compared with that in sham-operated rats. After glucose loading, burn group showed significantly higher plasma insulin levels with a lower muscle glycogen level than that of sham-operated and sham-nicotinamide groups, although there were no significant differences in blood glucose levels over time between groups. More profound changes in plasma H2O2 and insulin levels were observed in burn-nicotinamide group. It may be concluded that decreased skin detoxification may increase the risk for oxidative stress and insulin resistance.

Glycemic control and anti-osteopathic effect of propolis in diabetic rats

The aim of the study was to explore the possibility that propolis can control diabetes mellitus and prevent diabetic osteopathy in rats. The study compared 60 streptozotocin (STZ)-induced diabetic rats, with ten nondiabetic rats used as a negative control. The experimental design comprised seven groups (n = 10 rats per group): (1) nondiabetic, used as a negative control; (2) nontreated, used as a positive control; (3) treated with insulin alone; (4) treated with a single dose of propolis alone; (5) treated with a double dose of propolis; (6) treated with insulin and a single dose of propolis; and (7) treated with insulin and a double dose of propolis. After 6 weeks of treatment, the rats were sacrificed. Ratios of femur ash to femur weight and of femur weight to body weight (FW/BW) were calculated and calcium (Ca), phosphorus (P), and magnesium (Mg) concentrations in femur ash were estimated and analyzed. Fasting blood glucose (FBG), plasma insulin and glucagon, serum thiobarbituric acid reactive substances (TBARS), plasma parathyroid hormone (PTH), and calcitonin levels were also estimated and analyzed. There was significant reduction in FBG in all diabetic treated rats. Similarly, higher plasma insulin levels were observed in diabetic rats treated with propolis and insulin than in nontreated diabetic rats, although plasma insulin was not comparatively higher in diabetic rats treated with insulin alone. Serum TBARS was significantly lower in the propolis treated rats than the diabetic nontreated rats. No differences in PTH and calcitonin levels were observed among treatment groups. The FW/BW ratio was significantly higher in diabetic treated groups than in control groups. Furthermore, diabetic rats treated with propolis and insulin had significantly higher Ca, P, and Mg concentrations in femoral ash than nontreated diabetic rats and diabetic rats treated with insulin alone. In conclusion, propolis has a remarkable effect on glucose homeostasis and bone mineralization.