Reduced Plasma Insulin Levels Research Articles

Caloric Restriction Paradoxically Increases Adiposity in Mice With Genetically Reduced Insulin.

Antiadiposity effects of caloric restriction (CR) are associated with reduced insulin/IGF-1 signaling, but it is unclear whether the effects of CR would be additive to genetically reducing circulating insulin. To address this question, we examined female Ins1(+/-):Ins2(-/-) mice and Ins1(+/+):Ins2(-/-) littermate controls on either an ad libitum or 60% CR diet. Although Igf1 levels declined as expected, CR was unable to reduce plasma insulin levels in either genotype below their ad libitum-fed littermate controls. In fact, 53-week-old Ins1(+/-):Ins2(-/-) mice exhibited a paradoxical increase in circulating insulin in the CR group compared with the ad libitum-fed Ins1(+/-):Ins2(-/-) mice. Regardless of insulin gene dosage, CR mice had lower fasting glucose and improved glucose tolerance. Although body mass and lean mass predictably fell after CR initiation, we observed a significant and unexpected increase in fat mass in the CR Ins1(+/-):Ins2(-/-) mice. Specifically, inguinal fat was significantly increased by CR at 66 weeks and 106 weeks. By 106 weeks, brown adipose tissue mass was also significantly increased by CR in both Ins1(+/-):Ins2(-/-) and Ins1(+/+):Ins2(-/-) mice. Interestingly, we observed a clear whitening of brown adipose tissue in the CR groups. Mice in the CR group had altered daily energy expenditure and respiratory exchange ratio circadian rhythms in both genotypes. Multiplexed analysis of circulating hormones revealed that CR was associated with increased fasting and fed levels of the obesogenic hormone, glucose-dependent insulinotropic polypeptide. Collectively these data demonstrate CR has paradoxical effects on adipose tissue growth in the context of genetically reduced insulin.

Effect of pertussis toxin pretreated centrally on blood glucose level induced by stress.

In the present study, we examined the effect of pertussis toxin (PTX) administered centrally in a variety of stress-induced blood glucose level. Mice were exposed to stress after the pretreatment of PTX (0.05 or 0.1 µg) i.c.v. or i.t. once for 6 days. Blood glucose level was measured at 0, 30, 60 and 120 min after stress stimulation. The blood glucose level was increased in all stress groups. The blood glucose level reached at maximum level after 30 min of stress stimulation and returned to a normal level after 2 h of stress stimulation in restraint stress, physical, and emotional stress groups. The blood glucose level induced by cold-water swimming stress was gradually increased up to 1 h and returned to the normal level. The intracerebroventricular (i.c.v.) or intrathecal (i.t.) pretreatment with PTX, a Gi inhibitor, alone produced a hypoglycemia and almost abolished the elevation of the blood level induced by stress stimulation. The central pretreatment with PTX caused a reduction of plasma insulin level, whereas plasma corticosterone level was further up-regulated in all stress models. Our results suggest that the hyperglycemia produced by physical stress, emotional stress, restraint stress, and the cold-water swimming stress appear to be mediated by activation of centrally located PTX-sensitive G proteins. The reduction of blood glucose level by PTX appears to due to the reduction of plasma insulin level. The reduction of blood glucose level by PTX was accompanied by the reduction of plasma insulin level. Plasma corticosterone level up-regulation by PTX in stress models may be due to a blood glucose homeostatic mechanism.

Deficiency in apolipoprotein A-I ablates the pharmacological effects of metformin on plasma glucose homeostasis and hepatic lipid deposition

Recently, we showed that deficiency in apolipoprotein A-I (ApoA-I) sensitizes mice to diet-induced obesity, glucose intolerance and NAFLD. Here we investigated the potential involvement of ApoA-I in the pharmacological effects of metformin on glucose intolerance and NAFLD development. Groups of apoa1-deficient (apoa1-/-) and C57BL/6 mice fed western-type diet were either treated with a daily dose of 300mg/kg metformin for 18 weeks or left untreated for the same period. Then, histological and biochemical analyses were performed. Metformin treatment led to a comparable reduction in plasma insulin levels in both C57BL/6 and apoa1-/- mice following intraperitoneal glucose tolerance test. However, only metformin-treated C57BL/6 mice maintained sufficient peripheral insulin sensitivity to effectively clear glucose following the challenge, as indicated by a [3H]-2-deoxy-D-glucose uptake assay in isolated soleus muscle. Similarly, deficiency in ApoA-I ablated the effect of metformin on hepatic lipid deposition and NAFLD development. Gene expression analysis indicated that the effects of ApoA-I on metformin treatment may be independent of adenosine monophosphate-activated protein kinase (AMPK) activation and de novo lipogenesis. Interestingly, metformin treatment reduced mitochondrial oxidative phosphorylation function only in apoa1-/- mice. Our data show that the role of ApoA-I in diabetes extends to the modulation of the pharmacological actions of metformin, a common drug for the treatment of type 2 diabetes.

Impact of alogliptin and pioglitazone on lipid metabolism in islets of prediabetic and diabetic Zucker Diabetic Fatty rats

Prolonged exposure of pancreatic beta (β) cells to elevated glucose and free fatty acids (FFA) as occurs in type 2 diabetes results in loss of β cell function and survival. In Zucker Diabetic Fatty (ZDF) rats, β cell failure is associated with increased triacylglyceride (TAG) synthesis and disruption of the glycerolipid/FFA (GL/FFA) cycle, a critical arm of glucose-stimulated insulin secretion (GSIS). The aim of this study was to determine the impact of activation of PPARγ and increased incretin action via dipeptidyl-peptidase inhibition using pioglitazone and/or alogliptin, respectively, on islet lipid metabolism in prediabetic and diabetic ZDF rats. Transition of control prediabetic ZDF rats to diabetes was associated with reduced plasma insulin levels, reduced islet insulin content and GSIS, reduced stearoyl-CoA desaturase 2 (SCD 2) expression, and increased islet TAG, diacylglyceride (DAG) and ceramides species containing saturated FA. Treatment of prediabetic ZDF rats with a combination of pioglitazone and alogliptin, but not individually, prevented the transition to diabetes and was associated with marked lowering of islet TAG and DAG levels. Pioglitazone and alogliptin, however, did not restore SCD2 expression, the degree of FA saturation in TAG, DAG or ceramides, islet insulin content, or lower ceramide levels. These findings are consistent with activation of PPARγ and increased incretin action working in concert to restore GL/FFA cycle in β cells of ZDF rats. Restoration of the GL/FFA cycle without correcting islet FA desaturation, production of islet ceramides, and/or insulin sensitivity, however, may place these islets at risk for β cell failure.

RE-1 silencing transcription factor (REST): a regulator of neuronal development and neuronal/endocrine function.

RE-1 silencing transcription factor (REST) is a transcriptional repressor that has been proposed to function as a master negative regulator of neurogenesis, as REST target genes encode neuronal receptors, ion channels, neuropeptides and synaptic proteins. During neuronal differentiation, REST expression levels are reduced, allowing expression of selected REST target genes. The analysis of neural stem/progenitor cells that are either devoid of REST or overexpress REST revealed that REST is not the master regulator that is solely responsible for the acquisition of the neuronal fate. Rather, REST provides a regulatory hub that coordinately regulates multiple tiers of neuronal development in vitro. In addition, REST may play an important role for maintaining the integrity of adult neurons. REST confers oxidative stress resistance and is essential for maintaining neuronal viability. Furthermore, the concentration of REST has been reported to influence the pathogenic outcome by neuronal diseases, including stroke, epilepsy and Alzheimer's disease. Experiments performed with PC12 pheochromocytoma cells indicate that REST may function as a key regulator of the neurosecretory phenotype. Moreover, transgenic mice overexpressing REST in pancreatic β-cells showed impaired insulin secretion leading to significantly reduced plasma insulin levels. Based on the fact that REST plays a prominent role in controlling stimulus-induced secretion in endocrine cells, we propose that REST may also be important for neurotransmitter release via regulation of genes that encode important proteins of the exocytotic machinery.

Altered gene expression of amyloid precursor protein in the adipose tissue and brain of obese mice fed with long-term high-fat diet and streptozotocin-induced diabetic mice

Mid-life obesity is associated with increased risk of Alzheimer's disease (AD). Amyloid precursor protein (APP) and its processing are centrally involved in the etiology of AD. Our previous studies demonstrated that human APP is expressed in adipocytes, up-regulated with obesity, and correlated with adipokine expression. This study was to determine whether APP expression is also dysregulated in mouse models of obesity and diabetes. Six-week-old C57BL/6 mice were fed normal or high-fat diets (HFD) until 16, 26, 36, 47, or 77 weeks of age. We measured gene expression of APP and adipokines, levels of glucose and insulin, and area under the glucose curve (AUCglucose) during the glucose tolerance test. Using quantitative real-time polymerase chain reaction (PCR), we demonstrated that APP expression in subcutaneous adipose tissue (SAT) significantly increased in all HFD mice groups, and that it correlated with the levels of AUCglucose, insulin, and expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and chemokine (C-C motif) ligand 2 (CCL2) genes. Thiazolidinedione treatment significantly reduced plasma insulin levels and APP expression in SAT and epididymal adipose tissue. APP expression in the SAT and brain also decreased significantly in streptozotocin-induced diabetic mice, indicating an important role of insulin in the regulation of APP gene expression. These results demonstrate that adipose tissue APP expression is increased with obesity and regulated by insulin levels, suggesting that the regulation and role of APP are similar in humans and mice. Insights into APP regulation and processing in the adipose tissue may improve our understanding of obesity-related adipose tissue inflammation and the increased risk of AD in obese individuals.

Role of Adipose Triglyceride Lipase and Lipolysis in the Regulation of Insulin Secretion: Study in β-Cell-Specific ATGL-Deficient Mice

Previous studies have suggested that lipolysis-derived lipid signalling molecules play a role in the regulation of glucose-stimulated insulin secretion. To directly assess the role of lipolysis of β-cell endogenous lipid stores in glucose signalling for insulin secretion, β-cell-specific adipose triglyceride lipase (ATGL)-deficient mice (KO) were generated. β-cell-specific tamoxifen-inducible ATGL deletion in MIP-Cre-ER/ATGL-LoxP mice (KO) was compared to tamoxifen-injected-MIP-Cre-ER and -ATGL-LoxP mice (controls). Two weeks after tamoxifen treatment in 8-week-old mice, ATGL protein level was dramatically decreased in KO islets from both sexes. KO male mice showed a decrease in body weight gain compared to the controls, which became significant 6 weeks after tamoxifen injection. Fasting plasma levels of free fatty acids and triglycerides were unchanged in KO mice of both sexes. Male KO mice showed a 60% decrease in insulinemia without altered glycemia in fed and fasted states. They also showed a 70% reduction in plasma insulin levels in response to a glucose challenge and a trend toward glucose intolerance. However, despite similar ATGL deletion in female KO mice, none of these changes in glucose homeostasis and insulin secretory response were observed. These results demonstrate that lipolysis via ATGL is involved in glucose-stimulated insulin secretion, at least in male mice. Female mice are often protected from diabetes in various animal models due to estrogens and a number of compensatory processes. We are currently studying the compensatory mechanisms that occur in KO female mice as they may reveal signalling and compensatory pathways involved in insulin secretion.

Improvement of insulin resistance, blood pressure and interstitial pH in early developmental stage of insulin resistance in OLETF rats by intake of propolis extracts

Propolis, a resinous mixture collected from plants by the Apis mellifera bee, contains high level nutrient factors including vitamins, polyphenols, and amino acids that would be expected to improve insulin sensitivity. Insulin resistance would secondarily cause elevation of blood pressure and increase the risk of cardiovascular diseases. The purpose of this study is to investigate the effect of propolis extracts on blood glucose levels and blood pressures in an early developmental stage of insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. OLETF rats (10weeks old) were divided into three different groups: normal diet, 0.1% propolis diet, and 0.5% propolis diet. After 8weeks, blood glucose levels, blood pressures, plasma metabolic factors and hormones, and interstitial fluid pH were measured. Casual blood glucose levels were decreased associated with a reduction of plasma insulin levels in both propolis diet groups compared with normal diet group. Propolis decreased systolic blood pressure with no significant changes in plasma aldosterone levels. We also found that interstitial fluid pH in ascites, liver, and skeletal muscle was higher in rats fed propolis diet than rats fed normal diet. These data suggests that dietary propolis improves insulin sensitivity and blood pressures in the early stage of the process in development of insulin resistance, which may be mediated by suppression of metabolic acidosis.

Feeding spinach thylakoids to rats modulates the gut microbiota, decreases food intake and affects the insulin response.

Thylakoid membranes derived from green leaf chloroplasts affect appetite-regulating hormones, suppress food intake, reduce blood lipids and lead to a decreased body weight in animals and human subjects. Thylakoids also decrease the intestinal in vitro uptake of methyl-glucose in the rat. The aim of this study was to investigate the effect of dietary thylakoids on the gut microbiota composition, mainly the taxa of lactobacilli and bifidobacteria, in rats fed either a thylakoid-enriched diet or a control diet for 10d. At the same time, a glucose-tolerance test in the same rats was also performed. Food intake was significantly decreased in the thylakoid-fed rats compared with the control-fed rats over the 10-d study. An oral glucose tolerance test after 10d of thylakoid- or control-food intake resulted in significantly reduced plasma insulin levels in the thylakoid-fed rats compared with the control-fed rats, while no difference was observed for blood glucose levels. Analysis of gut bacteria showed a significant increase of lactobacilli on the ileal mucosa, specifically Lactobacillus reuteri, in the rats fed the thylakoid diet compared with rats fed the control diet, while faecal lactobacilli decreased. No difference in bifidobacteria between the thylakoid and control groups was found. Analyses with terminal restriction fragment length polymorphism and principal component analysis of faeces demonstrated different microbial populations in the thylakoid- and control-fed animals. These findings indicate that thylakoids modulate the gut microbial composition, which might be important for the regulation of body weight and energy metabolism.

Effects of Single Nucleotide Polymorphisms in KATP Channel Genes on Type 2 Diabetes in a Turkish Population

ATP-sensitive potassium (K(ATP)) channels of pancreatic β-cells play a key role in glucose-stimulated insulin secretion mechanism. The Kir6.2 protein, forming the K(ATP) channel pore inwardly, and the SUR1 protein that surrounds it forming the outside part of the channel were encoded by ABCC8 and KCNJ11 genes, respectively. Recent studies reported that the single nucleotide polymorphisms (SNPs) established in these genes are associated with defects in insulin secretion and type 2 diabetes mellitus (T2DM). We aimed to investigate the allele profiles and the risk alleles of the ABCC8 and KCNJ11 genes and to highlight the associations with the disease in patients in Konya region of Turkey where T2DM is common. In this study, 169 patients with T2DM and 119 healthy controls were included. A total of 29 SNPs in ABCC8 and KCNJ11 genes were screened by PCR-SSCP technique and sequenced. Biochemical parameters and genotype-phenotype relationships were analyzed using variance analysis. R1273R silent substitution in exon 31 and 16/-3t→c substitution in noncoding region of exon 16 of ABCC8 gene showed a significant association (OR 4.8 [95% CI 2.41-9.77], p <0.001 and OR 3.5 [95% CI 1.64-7.40], p <0.001 under dominant and recessive models, respectively). We detected a significant association between E/K heterozygote genotype and reduced plasma insulin level in patients with T2DM (p <0.05). ABCC8 exons 16 and 31 variants increase susceptibility to T2DM and KCNJ11 E23K decreases insulin secretion in a Turkish population.

Exercise reduces oxidative stress but does not alleviate hyperinsulinemia or renal dopamine D1receptor dysfunction in obese rats

Impairment of renal dopamine D1 receptor (D1R)-mediated natriuresis is associated with hypertension in humans and animal models, including obese Zucker rats. We have previously reported that treatment of these rats with antioxidants or insulin sensitizers reduced insulin levels and oxidative stress, restored D1R-mediated natriuresis, and reduced blood pressure. Furthermore, the redox-sensitive transcription factor, nuclear factor-κB (NF-κB), has been implicated in impairment of D1R-mediated natriuresis during oxidative stress. In this study, we investigated the effect of exercise on insulin levels, oxidative stress, nuclear translocation of NF-κB, blood pressure, albuminuria, and D1R-mediated natriuresis. The exercise protocol involved treadmill exercise from 3 wk of age for 8 wk. Exercise reduced oxidative stress, nuclear translocation of NF-κB, and albuminuria. However, exercise did not reduce plasma insulin levels or blood pressure. Also, selective D1R agonist (SKF-38393)-mediated increases in sodium excretion and guanosine 5'-O-(3-thiotriphosphate) binding were impaired in obese rats compared with lean rats, and exercise did not restore this defect. We conclude that, while exercise is beneficial in reducing oxidative stress and renal injury, reducing insulin levels may be required to restore D1R-mediated natriuresis in this model of obesity and metabolic syndrome. Furthermore, this study supports previous observations that restoring D1R function contributes to blood pressure reduction in this model.

Apolipoprotein A-I Mimetic Peptides Prevent Atherosclerosis Development and Reduce Plaque Inflammation in a Murine Model of Diabetes

OBJECTIVETo determine the effect of the apolipoprotein A-I (ApoA-I) mimetic peptide, D-4F, on atherosclerosis development in a pre-existing diabetic condition.RESEARCH DESIGN AND METHODSWe induced hyperglycemia in 6-week-old apoE−/− female mice using streptozotocin. Half of the diabetic apoE−/− mice received D-4F in drinking water. Ten weeks later, plasma lipids, glucose, insulin levels, atherosclerotic lesions, and lesion macrophage content were measured.RESULTSDiabetic apoE−/− mice developed ∼300% more lesion area, marked dyslipidemia, increased glucose levels, and reduced plasma insulin levels when compared with nondiabetic apoE−/− mice. Atherosclerotic lesions were significantly reduced in the D-4F–treated diabetic apoE−/− mice in whole aorta (1.11 ± 0.73 vs. 0.58 ± 0.44, percentage of whole aorta, P < 0.01) and in aortic roots (36,038 ± 18,467 μm2/section vs. 17,998 ± 12,491 μm2/section, P < 0.01) when compared with diabetic apoE−/− mice that did not receive D-4F. Macrophage content in atherosclerotic lesions from D-4F–treated diabetic apoE−/− mice was significantly reduced when compared with nontreated animals (78.03 ± 26.1 vs. 29.6 ± 15.2 P < 0.001, percentage of whole plaque). There were no differences in glucose, insulin, total cholesterol, HDL cholesterol, and triglyceride levels between the two groups. Arachidonic acid, PGE2, PGD2, 15-HETE, 12-HETE, and 13-HODE concentrations were significantly increased in the liver tissue of diabetic apoE−/− mice compared with nondiabetic apoE−/− mice and significantly reduced by D-4F treatment.CONCLUSIONSOur results suggest that oral D-4F can prevent atherosclerosis development in pre-existing diabetic mice and this is associated with a reduction in hepatic arachidonic acid and oxidized fatty acid levels.

The appearance of dermcidin isoform 2, a novel platelet aggregating agent in the circulation in acute myocardial infarction that inhibits insulin synthesis and the restoration by acetyl salicylic acid of its effects

Hyperglycemia with severe reduction of plasma insulin level is frequently associated with acute ischemic heart disease. Since insulin is reported to be an anti thrombotic humoral factor, the mechanism of the impaired insulin synthesis was investigated. The plasma from the patients with acute myocardial infarction (AMI) was analyzed by SDS-polyacrylamide gel electrophoresis. Dermcidin isoform 2 (dermcidin) was determined by enzyme linked immunosorbent assay. Insulin synthesis was determined by in vitro translation of glucose induced insulin mRNA synthesis in the pancreatic β cells. Nitric oxide (NO) was determined by methemoglobin method. SDS-polyacrylamide gel electrophoresis of AMI plasma demonstrated the presence of a novel protein band of Mr 11 kDa that was determined to be dermcidin. Addition of 0.1 μM dermcidin inhibited insulin synthesis by >65 fold compared to control through the inhibition of NO synthesis in the pancreatic cells. The oral administration of 150 mg acetyl salicylic acid (aspirin) to the AMI patients increased the plasma insulin level from 13 (median) to 143 μunits/dl (median) with concomitant decrease of plasma dermcidin level from 112 to 9 nM in these patients within 12 h. It was also found that while the injection of 3.0 ± 0.05 (n = 10) nmol dermcidin with 0.25 ± 0.03 μmol ADP/g body weight caused coronary thrombus in mice, ADP itself at this concentration failed to produce thrombus. These results indicated that dermcidin was a novel platelet aggregating agent, and potentiated the ADP induced thrombosis in the animal model as well as acutely inhibited glucose induced insulin synthesis.

Lipid mobilization in subcutaneous adipose tissue during exercise in lean and obese humans. Roles of insulin and natriuretic peptides

The aim of this study was to evaluate the relative contributions of various hormones involved in the regulation of lipid mobilization in subcutaneous adipose tissue (SCAT) during exercise and to assess the impact of obesity on this regulation. Eight lean and eight obese men performed a 60-min cycle exercise bout at 50% of their peak oxygen uptake on two occasions: during intravenous infusion of octreotide (a somatostatin analog) or physiological saline (control condition). Lipolysis in SCAT was evaluated using in situ microdialysis. One microdialysis probe was perfused with the adrenergic blockers phentolamine and propranolol while another probe was perfused with the phosphodiesterase and adenosine receptor inhibitor aminophylline. Compared with the control condition, infusion of octreotide reduced plasma insulin levels in lean (from approximately 3.5 to 0.5 microU/ml) and in obese (from approximately 9 to 2 microU/ml), blunted the exercise-induced rise in plasma GH and epinephrine levels in both groups, and enhanced the exercise-induced natriuretic peptide (NP) levels in lean but not in obese subjects. In both groups, octreotide infusion resulted in higher exercise-induced increases in dialysate glycerol concentrations in the phentolamine-containing probe while no difference in lipolytic response was found in the aminophylline-containing probe. The results suggest that insulin antilipolytic action plays a role in the regulation of lipolysis during exercise in lean as well as in obese subjects. The octreotide-induced enhancement of exercise lipolysis in lean subjects was associated with an increased exercise-induced plasma NP response. Adenosine may contribute to the inhibition of basal lipolysis in both subject groups.

Simultaneous presence of Ins2C96Y mutation uncovers the insulin resistance phenotype in the adipose tissue of PPARγP465L female mice

Mutations in Peroxisome Proliferator Activated Receptor‐γ (PPARγ) affect adipose tissue and insulin sensitivity. The heterozygous PPARγP467L (L/+) mutation was originally identified in insulin resistant patients. Yet, L/+ mice have normal plasma glucose and insulin sensitivity. They have mild hyperinsulinemia and increased pancreatic islet mass, especially on high‐fat diet. We hypothesized that L/+ mutation leads to insulin resistance; however the hyperinsulinemia in mice compensates for it to retain normal plasma glucose. Thus, we introduced Ins2C96Y (akita, A/+) mutation, which reduces plasma insulin, in L/+ mice. Unlike +/+;A/+ littermates, male L/+;A/+ mice have dramatically reduced life span. When compared with +/+;A/+ mice, female L/+;A/+ mice have significant hyperglycemia, smaller pancreatic islets, reduced plasma insulin levels and upregulated gluconeogenesis. In an Insulin Tolerance Test, female L/+;A/+ mice have a smaller reduction in plasma glucose indicating impaired sensitivity to insulin. Adipose tissue explants from L/+;A/+ mice have impaired glucose uptake in response to exogenous insulin. Thus, insulin resistance phenotype can indeed be attributable to L/+ mutation. Our data also provides an excellent mouse model to study diabetes in the context of gender specific physiology.

Plasma corticosterone, insulin and glucose changes induced by brief exposure to isoflurane, diethyl ether and CO2 in male rats

The impact of anesthetic agents on endocrine and metabolic factors is an important issue. The present study has compared the effects of a short-term exposure to diethyl ether, isoflurane, or CO2 on plasma corticosterone, insulin and glucose concentrations since the duration of anesthetic exposure may have an effect on those factors. Male rats were divided into fed and fasted groups. The experimental rats were briefly exposed to diethyl ether, isoflurane, or CO2 (the degree of anesthesia was identical), while a control group was not exposed to the anesthetics. In the fed rats, diethyl ether exposure increased the levels of plasma glucose. CO2 exposure decreased plasma corticosterone and increased plasma glucose levels. Isoflurane exposure caused no changes in plasma corticosterone, glucose, or insulin levels. In the fasted rats, diethyl ether exposure increased plasma corticosterone and reduced plasma insulin levels. The plasma corticosterone and insulin levels were significantly increased by CO2) exposure. Isoflurane exposure decreased plasma insulin levels. A brief exposure to either diethyl ether or CO2 changed the plasma corticosterone, glucose, and insulin levels in fed and/or fasted rats. However, isoflurane exposure had the least effect on the concentration of these factors in both the fed and fasted states.

Effects of a grapeseed procyanidin extract (GSPE) on insulin resistance

Flavonoids are beneficial compounds against risk factors for metabolic syndrome, but their effects and the mechanisms on glucose homeostasis modulation are not well defined. In the present study, we first checked the efficacy of grapeseed procyanidin extract (GSPE) for stimulating glucose uptake in insulin-resistant 3T3-L1 adipocytes. Results show that when resistance is induced with chronic insulin treatment, GSPE maintain a higher stimulating capacity than insulin. In contrast, when dexamethasone is used as the resistance-inducing agent, GSPE is less effective. Next we evaluated how effective different GSPE treatments are at improving glucose metabolism in hyperinsulinemic animals (fed a cafeteria diet). GSPE reduced plasma insulin levels. The lower dose (25 mg GSPE/kg body weight per day) administered for 30 days improved the HOmeostasis Model Assessment-insulin resistance index. This was accompanied by down-regulation of Pparg2, Glut4 and Irs1 in mesenteric white adipose tissue. Similarly, a chronic GSPE treatment of insulin-resistant 3T3-L1 adipocytes down-regulated the mRNA levels of those adipocyte markers, although cells were still able to respond to the acute stimulation of glucose uptake. In summary, 25 mg/kg body weight per day of GSPE has a positive long-term effect on glucose homeostasis, and GSPE could be targeted at adipose tissue, where it might directly stimulate glucose uptake. This work also highlights the need to carefully consider the bioactive dose, since a higher dose does not necessarily correlate to a greater positive effect.

Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lep ob/ob mice

It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic β-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL ( Lep ob / ob / HSL − / − ) and explored the role of HSL in pancreatic β-cells in the setting of obesity. Lep ob / ob / HSL − / − developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep ob / ob / HSL + / + in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep + / + background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep ob / ob islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep ob / ob mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.

Insulinostatic activity of cerebellin — Evidence from in vivo and in vitro studies in rats

Cerebellin (CER) is a neuromodulatory hexadecapeptide that originates from the precursor protein precerebellin (Cbln1). Four highly homologous isoforms of Cbln are known (Cbln1–Cbln4), which are expressed in the central nervous system (CNS) and in peripheral tissues. CER modulates synaptic structure formation in the CNS, whereas in the peripheral tissues CER regulates catecholamine secretion. Cbln is also expressed in the pancreas; however, its function in the pancreas is unknown. Here, we demonstrate the role of CER in regulating insulin secretion in vivo and in vitro. We identified Cbln1 and Cbln3 transcripts in rat pancreatic islets and detected Cbln-immunoreactivity, predominantly located in the periphery of the rat endocrine pancreas. In vivo, CER reduced plasma insulin levels in rats after 1 and 2 h. CER decreased insulin secretion from isolated rat pancreatic islets at high (11 mM), but not at low (3.33 mM) glucose concentration. CER inhibited stimulated insulin secretion from clonal rat insulinoma (INS-1) cells, reduced forskolin-induced production of cAMP and intracellular calcium concentration. Our study demonstrates for the first time that Cbln1 and Cbln3 are expressed in the rat endocrine pancreas. Furthermore, we identify CER as an insulinostatic factor, which decreases intracellular cAMP production and calcium in INS-1 cells.

The late gestation fetal cardiovascular response to hypoglycaemia is modified by prior peri‐implantation undernutrition in sheep

Undernourished late gestation fetuses display asymmetric growth restriction, suggestive of a redistribution of nutritional resources. The modification of fetal organ blood supply in response to acute hypoxia is well characterized, but it is not known whether similar responses occur in response to acute reductions in nutrition, or if such late gestation responses can be influenced by early gestation nutrition. In pregnant sheep, total nutrient requirements were restricted during the peri-implantation period (PI40, 40%; PI50, 50% of total, days 1-31) or in late gestation (L, 50% total, days 104-postmortem). Control animals were fed 100% nutrient requirements. Fetal organ blood flows were measured at baseline, and during acute fetal hypoglycaemia induced by maternal insulin infusion at 125 dGA. Baseline heart rate was increased in PI40 fetuses. During hypoglycaemia, an initial rise in fetal heart rate was followed by a slower fall. Fetal femoral artery blood flow decreased, and adrenal blood flow and femoral vascular resistance increased in all fetuses during hypoglycaemia. These changes were accompanied by increased fetal plasma adrenaline and cortisol, and reduced plasma insulin levels. The maximum femoral artery blood flow response to hypoglycaemia occurred earlier in PI50 and PI40 compared with control fetuses. The late gestation fetal cardiovascular response to acute hypoglycaemia was consistent with a redistribution of combined ventricular output away from the periphery and towards central organs. One element of the peripheral vascular response was modified by peri-implantation nutrient restriction, indicating that nutritional challenges early in gestation can have an enduring impact on cardiovascular control.