Insulin-mediated Effects Research Articles

Acute effects of insulin and insulin-induced hypoglycaemia on carotid body chemoreceptor activity and cardiorespiratory responses in dogs.

What is the central question of this study? What are the effects of insulin and insulin-induced hypoglycaemia on carotid body chemoreceptor activity in vivo and how do carotid body chemoreceptor stimulation-mediated cardiorespiratory responses in beagle dogs compare during euglycaemia and insulin-induced hypoglycaemia? What is the main finding and its importance? Intracarotid insulin administration leads to sustained increase in carotid body chemoreceptor activity and respiratory response with significant cardiovascular effects. Insulin-induced hypoglycaemia exacerbated NaCN-mediated carotid body chemoreceptor activity and respiratory response with enhanced cardiovascular reflex response. These findings suggest that insulin-induced hypoglycaemia augments the carotid body chemoreceptors to initiate the adaptive counter-regulatory responses to restore the normoglycaemic condition. The carotid body chemoreceptors (CBC) play an important role in the adaptive counter-regulatory response to hypoglycaemia by evoking the CBC-mediated sympathetic neuronal system to restore normoglycaemia. Ex vivo studies have shown varied responses of insulin-induced hypoglycaemia on CBC function, and several in vivo studies have indirectly established the role of CBCs in restoring normoglycaemia in both animals and humans. However, a direct effect of insulin and/or insulin-induced hypoglycaemia on CBC activity is not established in animal models. Therefore, the aim of this study was to evaluate in vivo effects of insulin and insulin-induced hypoglycaemia on CBC activity and cardiorespiration in a preclinical large animal model. The carotid sinus nerve (CSN) activity and cardiorespiratory responses to sodium cyanide (NaCN; 25µg/kg) were compared before (euglycaemic) and after (hypoglycaemic) intracarotid administration of insulin (12.5-100µU/dogs) in beagle dogs. Insulin administration increased CSN activity and minute ventilation ( E ) with significant (P<0.0001) effects on heart rate and blood pressure. Insulin-mediated effects on CSN and cardiorespiration were sustained and the change in E was driven by tidal volume only. Insulin significantly (P<0.0001) lowered blood glucose level. NaCN-mediated CSN activity and E were significantly (P<0.0001) augmented during insulin-induced hypoglycaemia. The augmented E was primarily driven by respiratory frequency and partially by tidal volume. The cardiovascular reflex response mediated through CBC stimulation was significantly (P<0.0001) exacerbated during insulin-induced hypoglycaemia. Collectively, these results demonstrate direct effects of insulin and insulin-induced hypoglycaemia on CBC chemosensitivity to potentiate CBC-mediated neuroregulatory pathways to initiate adaptive neuroendocrine and cardiorespiratory counter-regulatory responses to restore normoglycaemia.

Predictors of laminitis development in a cohort of nonlaminitic ponies.

Quantifying risk factors for laminitis development requires improvement. To identify the most useful physical examination, metabolic and management factors to predict laminitis development in client-owned, nonlaminitic ponies. Prospective cohort study. Physical examination, metabolic and management data were collected from a pony cohort 6 monthly for up to 4years. Ponies were monitored for the development of laminitis. Metabolic data included basal plasma concentrations of ACTH ([ACTH]), adiponectin ([adiponectin]), triglycerides and glucose. Serum insulin concentrations ([insulin]) were measured in the unfasted basal state ([insulin]T0) and 60minutes ([insulin]T60) after administration of corn syrup (0.3ml/kg). Separate multivariable Cox proportional-hazards models were developed for physical, management/signalment and metabolic data and later combined into two final models. Low-, medium- and high-laminitis risk categories were defined based on basal or T60 [insulin]. Overall, 374 ponies (age 5-32years) and 891 pony-years were included in the main analysis. Laminitis incidence (95% confidence interval (CI)) was 4.8 (3.5-6.5) cases/100 pony-years. Laminitis development was associated with numerous univariable factors. Significant (P<.05) factors retained in the final multivariable models included [insulin]T0, [insulin]T60, [adiponectin] and divergent hoof growth. [ACTH] was not independently associated with laminitis. Based on [Insulin]T0, low- (<21.6 µIU/ml), medium- (21.6-45.2 µIU/ml) and high-risk (>45.2µIU/ml) categories encompassed 70, 20 and 10% of the population and had estimated 4-year laminitis incidences (95%CI) of 6 (2-9)%, 22 (10-33)% and 69 (48-82)% respectively. Based on [Insulin]T60 the low- (<53.4µIU/ml), medium- (53.4-153µIU/ml) and high-risk (≥153µIU/ml) categories comprised 60, 30 and 10% of the population and had estimated 4-year laminitis incidences (95%CI) of 3 (0-6)%, 20 (10-29)% and 73 (52-84)% respectively. Results may not apply to different insulin assays, geographical regions, breeds or management types. [Insulin]T0 or [insulin]T60 best quantify the risk of future laminitis development in nonlaminitic ponies.

Androgen-Dependent Prostate Cancer Cells Reprogram Their Metabolic Signature upon GLUT1 Upregulation by Manganese Superoxide Dismutase.

Prostate cancer is the second leading cause of cancer in men across the globe. The prostate gland accounts for some unique glycolytic metabolic characteristics, which causes the metabolic features of prostate tumor initiation and progression to remain poorly characterized. The mitochondrial superoxide dismutase (SOD2) is one of the major redox metabolism regulators. This study points out SOD2 as one major regulator for both redox and glycolytic metabolism in prostate cancer. SOD2 overexpression increases glucose transporter GLUT-1 and glucose uptake. This is not an insulin-mediated effect and seems to be sex-dependent, being present in male mice only. This event concurs with a series of substantial metabolic rearrangements at cytoplasmic and mitochondrial level. A concomitant decrease in glycolytic and pentose phosphate activity, and an increase in electron transfer in the mitochondrial electronic chain, were observed. The Krebs Cycle is altered to produce amino-acid intermediates by decreasing succinate dehydrogenase. This in turn generates a 13-fold increase in the oncometabolite succinate. The protein energy sensor AMPK is decreased at basal and phosphorylated levels in response to glucose deprivation. Finally, preliminary results in prostate cancer patients indicate that glandular areas presenting high levels of SOD2 show a very strong correlation with GLUT-1 protein levels (R2 = 0.287 p-value < 0.0001), indicating that in patients there may exist an analogous phenomenon to those observed in cell culture and mice.

Constant hepatic ATP concentrations during prolonged fasting and absence of effects of Cerbomed Nemos® on parasympathetic tone and hepatic energy metabolism

ObjectiveBrain insulin-induced improvement in glucose homeostasis has been proposed to be mediated by the parasympathetic nervous system. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) activating afferent branches of the vagus nerve may prevent hyperglycemia in diabetes models. We examined the effects of 14-min taVNS vs sham stimulation by Cerbomed Nemos® on glucose metabolism, lipids, and hepatic energy homeostasis in fasted healthy humans (n = 10, age 51 ± 6 yrs, BMI 25.5 ± 2.7 kg/m2). MethodsHeart rate variability (HRV), reflecting sympathetic and parasympathetic nerve activity, was measured before, during and after taVNS or sham stimulation. Endogenous glucose production was determined using [6,6-2H2]glucose, and hepatic concentrations of triglycerides (HCL), adenosine triphosphate (ATP), and inorganic phosphate (Pi) were quantified from 1H/31P magnetic resonance spectroscopy at baseline and for 180 min following stimulation. ResultstaVNS did not affect circulating glucose, free fatty acids, insulin, glucagon, or pancreatic polypeptide. Rates of endogenous glucose production (P = 0.79), hepatic HCL, ATP, and Pi were also not different (P = 0.91, P = 0.48 and P = 0.24) between taVNS or sham stimulation. Hepatic HCL, ATP, and Pi remained constant during prolonged fasting for 3 h. No changes in heart rate or shift in cardiac autonomic function from HRV towards sympathetic or parasympathetic predominance were detected. ConclusionNon-invasive vagus stimulation by Cerbomed Nemos® does not acutely modulate the autonomic tone to the visceral organs and thereby does not affect hepatic glucose and energy metabolism. This technique is therefore unable to mimic brain insulin-mediated effects on peripheral homeostasis in humans.

Insights into the Hexose Liver Metabolism-Glucose versus Fructose.

High-fructose intake in healthy men is associated with characteristics of metabolic syndrome. Extensive knowledge exists about the differences between hepatic fructose and glucose metabolism and fructose-specific mechanisms favoring the development of metabolic disturbances. Nevertheless, the causal relationship between fructose consumption and metabolic alterations is still debated. Multiple effects of fructose on hepatic metabolism are attributed to the fact that the liver represents the major sink of fructose. Fructose, as a lipogenic substrate and potent inducer of lipogenic enzyme expression, enhances fatty acid synthesis. Consequently, increased hepatic diacylglycerols (DAG) are thought to directly interfere with insulin signaling. However, independently of this effect, fructose may also counteract insulin-mediated effects on liver metabolism by a range of mechanisms. It may drive gluconeogenesis not only as a gluconeogenic substrate, but also as a potent inducer of carbohydrate responsive element binding protein (ChREBP), which induces the expression of lipogenic enzymes as well as gluconeogenic enzymes. It remains a challenge to determine the relative contributions of the impact of fructose on hepatic transcriptome, proteome and allosterome changes and consequently on the regulation of plasma glucose metabolism/homeostasis. Mathematical models exist modeling hepatic glucose metabolism. Future models should not only consider the hepatic adjustments of enzyme abundances and activities in response to changing plasma glucose and insulin/glucagon concentrations, but also to varying fructose concentrations for defining the role of fructose in the hepatic control of plasma glucose homeostasis.

Metformin and breast cancer: basic knowledge in clinical context.

Although preclinical work is vital in unraveling the molecular tenets which apply to metformin action in breast cancer, it is by nature unable to capture the host's response to metformin in terms of insulin-mediated effects and related changes in the hormonal and metabolic asset at the systemic level. The latter might sound seemingly paradoxical when considering the inveterate use of metformin in dysmetabolisms and pathologic conditions with underlying hormonal disruption. Bridging the gap between the molecular target and characteristics of breast cancer patients may help lab-based experiments and clinical work converge into one or more well characterized sub-populations instead of a sub optimally selected one. An appropriate patient selection is the main key to the most suitable outcome interpretation and amelioration, in an attempt to meet our patients needs midway between overestimation of benefits and efficacy dilution for any given intervention and/or co-intervention.

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

Metformin, an oral biguanide widely used to treat diabetes, has considerable potential and is in clinical trials as an experimental preventive or therapeutic agent for a range of cancers. Direct actions targeting cellular pathways, particularly via AMP-activated protein kinase and through inhibiting mitochondrial ATP synthesis, or systemic mechanisms involving insulin and insulin-like growth factors have been much studied in vitro and in preclinical models. Epidemiologic and retrospective studies also provide clinical evidence in support of metformin as an antitumor agent. Preoperative window-of-opportunity trials confirm the safety of metformin in women with primary breast cancer, and demonstrate reduction in tumor cell proliferation and complex pathways of gene suppression or overexpression attributable to metformin. Confirmation of insulin-mediated effects, independent of body mass index, also supports the potential benefit of adjuvant metformin therapy. Neoadjuvant, adjuvant, and advanced disease trials combining metformin with established anticancer agents are under way or proposed. Companion biomarker studies will utilize in vitro and preclinical understanding of the relevant molecular pathways to, in future, refine patient and tumor selection for metformin therapy.

Differentiating the Role of Testosterone and Insulin-Mediated Effects on Lipid Metabolism in a Rodent Model of Prediabetes and Polycystic Ovary Syndrome

Differentiating the Role of Testosterone and Insulin-Mediated Effects on Lipid Metabolism in a Rodent Model of Prediabetes and Polycystic Ovary Syndrome

Crosstalk between metabolic and neuropsychiatric disorders

Evidence supporting the concurrence of metabolic disturbances (e.g. insulin resistance, diabetes and obesity) and neuropsychiatric disorders has been demonstrated in both human and animal studies, suggesting the possibility that they have shared pathophysiological mechanisms. During the past decade, our understanding for the role of insulin in both normal and abnormal central nervous system (CNS) processes has become increasingly refined. Evidence indicates that insulin is a pleiotropic peptide, critical to neurotrophism, neuroplasticity, and neuromodulation. Moreover, the role of insulin underscores its importance in the development of several neuropsychiatric disorders, including, but not limited to, mechanisms involved in the pathogenesis and progression towards diabetes, obesity, and neurodegenerative disorders, such as Alzheimer's disease. This review focuses on the insulin-mediated effects on normal and abnormal brain function and discusses why targeting insulin-related pathways in the brain may emerge as a new approach for refining treatment of neurological and psychiatric disorders.

Adipocyte cell size enlargement involves plasma membrane area increase

The adipocyte enlargement is associated with an increase in the cytoplasmic lipid content, but how the plasma membrane area follows this increase is poorly understood. We monitored single-cell membrane surface area fluctuations, which mirror the dynamics of exocytosis and endocytosis. We employed the patch-clamp technique to measure membrane capacitance (Cm), a parameter linearly related to the plasma membrane area. Specifically, we studied whether insulin affects membrane area dynamics in adipocytes. A five-minute cell exposure to insulin increased resting Cm by 12±4%; in controls the change in Cm was not different from zero. We measured cell diameter of isolated rat adipocytes microscopically. Twenty-four hour exposure of cells to insulin resulted in a significant increase in cell diameter by 5.1±0.6%. We conclude that insulin induces membrane area increase, which may in chronic hyperinsulinemia promote the enlargement of plasma membrane area, acting in concert with other insulin-mediated metabolic effects on adipocytes.

Diet-Induced Hyperinsulinemia Accelerates Growth of Androgen-Independent PC-3 Cells In Vitro

We investigated the effect of insulin and diet-induced hyperinsulinemia on the growth of the PC-3 cells in vitro and discerned the growth promoting effect of insulin in the androgen-independent cells. Sprague-Dawley rats were kept on a high-fat diet for 4 wk for the induction of insulin resistance and hyperinsulinemia. Insulin alone or serum of the rats kept on either normal-pellet diet or high-fat diet was used to stimulate the serum-starved PC-3 cells growth in culture. S961, a high-affinity insulin-receptor antagonist, was used to confirm the insulin-mediated effects. Significant impairment in the glucose disposal rate and increase in the serum glucose and insulin levels was observed in the high-fat-diet-fed rats. The media supplemented with the serum of the high-fat-diet-fed rats accelerated the growth of the PC-3 cells in comparison to that of normal-pellet-diet-fed rats. Insulin treatment led to accelerated growth of the serum-starved PC-3 cells in a dose-dependent manner and inhibited by the S961 pretreatment. Insulin and serum of the diet-induced hyperinsulinemic rats promote the growth of androgen-independent prostate cancer PC-3 cells. Further, our results provide support for the concept that diet-associated elevation in insulin level may augment the growth of prostate cancer cells.

Insulin inhibits hepatocyte iNOS expression induced by cytokines by an Akt-dependent mechanism

Hepatocyte inducible nitric oxide synthese (iNOS) expression is a tightly controlled pathway that mediates hepatic inflammation and hepatocyte injury in a variety of disease states. We have shown that cyclic adenosine monophosphate (cAMP) regulates cytokine-induced hepatocyte iNOS expression through mechanisms that involve protein kinase B/Akt. We hypothesized that insulin, which activates Akt signaling in hepatocytes, as well as signaling through p38 and MAPK p42/p44, would regulate iNOS expression during inflammation. In primary rat hepatocytes, insulin inhibited cytokine-stimulated nitrite accumulation and iNOS expression in a dose-dependent manner. Inhibition of MAPK p42/p44 with PD98059 had no effect on iNOS activation, whereas SB203580 to block p38 reversed insulin's inhibitory effect. However, insulin did not increase p38 activation and inhibition of p38 signaling with a dominant negative p38 plasmid had no effect on cytokine- or insulin-mediated effects on iNOS. We found that SB203580 blocked insulin-induced Akt activation. Inhibition of Akt signaling with LY294002 or a dominant negative Akt plasmid increased cytokine-stimulated nitrite production and iNOS protein expression and blocked the inhibitory effects of insulin. NF-κB induces iNOS expression and can be regulated by Akt, but insulin had no effect on cytokine-mediated IκBα levels or NF-κB p65 translocation. Our data demonstrate that insulin inhibits cytokine-stimulated hepatocyte iNOS expression and does so through effects on Akt-mediated signaling.

S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats

Impairment in the insulin receptor signaling and insulin mediated effects are the key features of type 2 diabetes. Here we report that S961, a peptide insulin receptor antagonist induces hyperglycemia, hyperinsulinemia (∼18-fold), glucose intolerance and impairment in the insulin mediated glucose disposal in the Sprague–Dawley rats. Further, long-term S961 treatment (15day, 10nM/kg/day) depletes energy storage as evident from decrease in the adiposity and hepatic glycogen content. However, peroxysome-proliferator-activated-receptor-gamma (PPARγ) agonist pioglitazone significantly (P<0.001) restored S961 induced hyperglycemia (196.73±16.32 vs. 126.37±27.07mg/dl) and glucose intolerance (≈78%). Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. Further, results of the present study reconfirms and provide direct evidence to the crucial role of insulin receptor signaling in the glucose homeostasis and fuel metabolism.

Growth Hormone Regulation of p85α Expression and Phosphoinositide 3-Kinase Activity in Adipose Tissue

Phosphoinositide (PI) 3-kinase is involved in insulin-mediated effects on glucose uptake, lipid deposition, and adiponectin secretion from adipocytes. Genetic disruption of the p85alpha regulatory subunit of PI 3-kinase increases insulin sensitivity, whereas elevated p85alpha levels are associated with insulin resistance through PI 3-kinase-dependent and -independent mechanisms. Adipose tissue plays a critical role in the antagonistic effects of growth hormone (GH) on insulin actions on carbohydrate and lipid metabolism through changes in gene transcription. The objective of this study was to assess the role of the p85alpha subunit of PI 3-kinase and PI 3-kinase signaling in GH-mediated insulin resistance in adipose tissue. To do this, p85alpha mRNA and protein expression and insulin receptor substrate (IRS)-1-associated PI 3-kinase activity were measured in white adipose tissue (WAT) of mice with GH excess, deficiency, and sufficiency. Additional studies using 3T3-F442A cells were conducted to confirm direct effects of GH on free p85alpha protein abundance. We found that p85alpha expression 1) is decreased in WAT from mice with isolated GH deficiency, 2) is increased in WAT from mice with chronic GH excess, 3) is acutely upregulated in WAT from GH-deficient and -sufficient mice after GH administration, and 4) is directly upregulated by GH in 3T3-F442A adipocytes. The insulin-induced increase in PI 3-kinase activity was robust in mice with GH deficiency, but not in mice with GH excess. In conclusion, GH regulates p85alpha expression and PI 3-kinase activity in WAT and provides a potential explanation for 1) the insulin hypersensitivity and associated obesity and hyperadiponectinemia of GH-deficient mice and 2) the insulin resistance and associated reduced fat mass and hypoadiponectinemia of mice with GH excess.

Acute effects of wortmannin on insulin's hemodynamic and metabolic actions in vivo

Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, was systemically infused during a hyperinsulinemic euglycemic clamp to investigate its effects in vivo. Rats were infused under anesthesia with saline, 10 or 20 mU.min-1.kg-1 insulin, wortmannin (1 microg.min-1.kg-1)+saline, or wortmannin+insulin (10 mU.min-1.kg-1); wortmannin was present for 1 h before and throughout the 2-h clamp. Femoral blood flow (FBF), glucose infusion rate to maintain euglycemia (GIR), glucose appearance (Ra), glucose disappearance (Rd), capillary recruitment by 1-methylxanthine metabolism (MXD), hindleg glucose uptake (HLGU), liver, muscle, and aorta Akt phosphorylation (P-Akt/Akt), and plasma insulin concentrations were determined. Plasma insulin increased from 410+/-49 to 1,680+/-430 and 5,060+/-230 pM with 10 and 20 mU.min-1.kg-1 insulin, respectively. Insulin (10 and 20 mU.min-1.kg-1) increased FBF, MXD, GIR, Rd, and HLGU as well as liver, muscle, and aorta P-Akt/Akt and decreased Ra (all P<0.05). Wortmannin alone increased plasma insulin to 5,450+/-770 pM and increased Ra, Rd, HLGU, and muscle P-Akt/Akt without effect on blood glucose, FBF, MXD liver, or aorta P-Akt/Akt. Wortmannin blocked FBF, MXD, and liver P-Akt/Akt increases from 10 mU.min-1.kg-1 insulin. Comparison of wortmannin+10 mU.min-1.kg-1 insulin and 20 mU.min-1.kg-1 insulin alone (both at approximately 5,000 pM PI) showed that wortmannin fully blocked the changes in FBF and Ra and partly those of GIR, Ra, Rd, HLGU, and muscle P-AKT/Akt. In summary, wortmannin in vivo increases plasma insulin and fully inhibits insulin-mediated effects in liver and aorta and partially those of muscle, where the latter may result from inhibition of insulin-mediated increases in blood flow and capillary recruitment.

Glucosamine induces resistance to insulin-like growth factor I (IGF-I) and insulin in Hep G2 cell cultures: biological significance of IGF-I/insulin hybrid receptors.

IGF-I stimulates insulin-like actions directly through its receptor, and it also enhances sensitivity to insulin-mediated effects in vivo. These studies were undertaken to analyze the role of IGF-I, insulin, and insulin/IGF-I hybrid receptors (HRs) in mediating IGF-I and insulin signaling in cells that had been made insulin-resistant by treatment with glucosamine. Human HepG2 cells, which express IGF-I receptors, insulin receptors (IRs), and IGF-I/insulin HRs, were exposed to 20 mM glucosamine; and the effects of IGF-I and insulin in stimulating glycogen synthesis were determined. An overnight exposure to glucosamine markedly attenuated the effects of insulin and IGF-I in stimulating glycogen synthesis. To determine which receptors were mediating this effect, the ability of insulin and IGF-I to stimulate phosphorylation of their respective receptors was analyzed. An 18-h exposure to glucosamine (20 mM) caused a 75% reduction in the ability of IGF-I to phosphorylate its receptor but no change in receptor abundance. Glucosamine also caused a major reduction in insulin-stimulated receptor phosphorylation, although, unlike IGF-I, there was also a 50% reduction in IR abundance. Exposure to glucosamine also resulted in a reduction in the ability of IGF-I or insulin to stimulate phosphorylation of insulin IGF-I/HRs. The combination of insulin plus IGF-I was a more potent stimulus of HR phosphorylation than either agent alone, and this combination was also more potent in partially reversing the inhibitory effect of glucosamine. Taken together, these findings indicate that glucosamine induces a loss of sensitivity to stimulation of insulin, IGF-I, or HR tyrosine kinase activity by insulin or IGF-I. Although insulin is able to partially reverse the effect of glucosamine on IR phosphorylation, it has a very minimal effect on glucosamine-induced inhibition of HR phosphorylation. However, the combination of IGF-I and insulin induces a major increase in HR phosphorylation, even in the presence of glucosamine, suggesting that it is improving the sensitivity of the HR to insulin activation.

Insulin-mediated effects of alcohol intake on serum lipid levels in a general population: The Hisayama Study

To determine whether the beneficial effects of alcohol on lipid concentrations are mediated by insulin levels, we performed a cross-sectional analysis in 2103 nondiabetic men and women aged 40 to 79 years from a general Japanese population in Hisayama. The multivariate-adjusted sum of fasting and 2-hour postloading insulin levels and the insulin resistance index significantly decreased with elevating alcohol intake levels in men ( P < 0.01 for the trend) but not in women. No dose-response relations between alcohol intake and glucose levels were observed. In both sexes, high-density lipoprotein cholesterol (HDLC) significantly increased with elevated alcohol intake ( P < 0.01), whereas total cholesterol and low-density lipoprotein cholesterol (LDLC) were inversely correlated with alcohol intake ( P < 0.01). In contrast, triglycerides (TGs) levels in men showed a J-shaped relation to alcohol dose, with moderate drinkers (10–29 g/d) having the lowest levels. Estimates using regression models indicated that for men, 10% of the alcohol-induced increase in HDLC and 2% of the alcohol-induced decrease in LDLC were insulin mediated. It was also estimated for male subjects that 36% of the reduction in TGs due to low to moderate alcohol intake was mediated by low levels of insulin and that this insulin-mediated pathway reduced the positive alcohol-TG relation by 13% in cases of moderate to heavy drinking. Our data suggest that regular alcohol consumption dose-dependently increased insulin sensitivity among male nondiabetics, but the insulin-mediated beneficial effects of alcohol on lipid concentrations were relatively small.

Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress

The stress system coordinates the adaptive responses of the organism to stressors of any kind. 1 1 “Stress” is defined as a state of disharmony or threatened homeostasis. The concepts of stress and homeostasis can be traced back to ancient Greek history, however, the integration of these notions with related physiologic and pathophysiologic mechanisms and their association with specific illnesses are much more recent. In the present overview, we focus on the cellular and molecular infrastructure of the physiologic and behavioral adaptive responses to stress and we define the pathophysiologic effects of the dysregulation of the stress response, which may result in vulnerability to several disease entities, such as anxiety or depression and chronic inflammatory processes. The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus–norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary–adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic β-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The end-hormones of the hypothalamic–pituitary–adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and β-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5′ deiodinase, which converts the relatively inactive tetraiodothyronine (T 4) to triiodothyronine (T 3), contributing further to the suppression of reproductive, growth and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing “low turnover” osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation ( immune CRH). CRH antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, potentiators of CRH secretion/action may be useful to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli.

Hormonal Regulation of Stearoyl Coenzyme-A Desaturase 1 Activity and Gene Expression in Primary Cultures of Chicken Hepatocytes

Previous studies have provided evidence for the important role of liver stearoyl-CoA desaturase (SCD) in excessive adiposity in the chicken and suggest that the difference in SCD activity between fat and lean chickens could be explained by a difference in SCD1 gene expression. In the present study, the regulation of SCD1 gene expression was analyzed as the result of insulin and glucagon action, using primary cultures of 6-week-old chicken hepatocytes. Insulin increased SCD1 activity and mRNA levels, whereas glucagon decreased dramatically both the enzyme activity and the mRNA levels. Nuclear run-on transcription assays and mRNA stability investigations demonstrated that insulin and glucagon effects on SCD1 gene expression was primarily transcriptional. Furthermore, the results indicated that the glucagon-mediated inhibition of SCD1 gene transcription was more potent than just counteracting the insulin-mediated effect. These data represent the first demonstration that the glucagon effect on the SCD1 gene expression is primarily transcriptional. Moreover, among hepatic genes involved in lipid metabolism in chicken, SCD1 is the first gene shown to be regulated at the transcriptional level by insulin, in the absence of triiodothyronine. These data point out the potency of the growing chicken hepatocyte culture model in contrast with the embryonic cell culture model as regards the investigations of the insulin effect on gene expression.

Insulin resistance — Not hyperinsulinemia — Is pathogenic in essential hypertension

A correlation between essential hypertension and insulin resistance/hyperinsulinemia is well documented, and there is adequate reason to believe that this association is causal. The common presumption that hyperinsulinemia mediates this connection is based on studies demonstrating various pressor effects of insulin, such as sodium retention, activation of the sympathetic nervous system, and stimulation of renin output. However, a consideration of physiological parameters in essential hypertensives indicates that these insulin-mediated pressor effects are unlikely to play a crucial pathogenic role in most cases of essential hypertension. Moreover, physiological elevation of insulin following a meal is typically associated with a reduction of blood pressure in hypertensives and the elderly. Euglycemic insulin clamps tend to reduce blood pressure in elderly subjects, and prolonged maintenance of hyperinsulinemia in animals does not raise blood pressure. In fact, insulin has long been known to have direct vasodilatory or antipressor effects on resistance vessels, and there is recent evidence that insulin reduces vascular resistance in skeletal muscles to facilitate glycogen storage after a meal. I propose that essential hypertensives experience a net deficit of insulin activity in vascular muscle, and that, in conjunction with other genetic or acquired defects of electrolyte transport, this leads to an increase in basal vascular tone and a hypersensitivity to pressor agents. Correction of insulin resistance usually aids blood pressure control, and in addition may mitigate the excess cardiovascular risk associated with hypertension.