Characteristics of subjects classified by oral glucose tolerance test among patients with alcohol dependence BMI, body mass index; HDL-cholesterol, high density lipoprotein-cholesterol; LDL-cholesterol, low density lipoprotein-cholesterol; GOT, glutamate oxaloacetate transaminase; GPT, glutamate pyruvate transaminase; γ-GTP, γ-glutamyl transferase; HOMA-IR, homeostasis model assessment-insulin resistance; HOMA-β, homeostasis model assessment-β-cell function (*, p<0.05 and **, p<0.01 compared with NGT).
Appetite regulating peptides, particularly ghrelin and leptin in alcohol dependence are significantly related with abnormal glucose tolerance or insulin resistance which contribute to Type 2 diabetes mellitus (T2DM) [1-5]. Available evidence consistently indicates that altered levels of ghrelin and leptin are linked to overall diabetogentc effects of chronic alcohol comsumption, and have important mediating roles in the deteriorated pathophysiology of T2DM in alcoholic patients . Moreover, these peptides in the regulation of food seeking behavior have a similar mechanism of controlling of alcohol craving behavior [7, 8]. Threrefore, alterations of the peptides modulating numerous metabolic processes could present an intriguing biological mechanism on the relationship between chronic alcohol consumption and risk of T2DM. However, the manner in which the peptides contribute to the development or maintenance of T2DM with alcohol dependence is not clear. This review describes ghrelin and leptin implicated in the elevated risk of developing T2DM with chronic use of alcohol that attributes to the impact of glucose and insulin metabolism. Additionally, to identify whether these two peptides are relevant to the increase in the clustering of metabolic disturbance and progression of T2DM, the background information on the peptides, their role in glucose homeostasis and insulin function in addition to their mechanism of action are discussed. This review on the relationship between chronic use of alcohol and T2DM may further clarify the role of the peptides and provides an insight into the effects of chronic alcohol use in the pathophysiology of T2DM.
2. Pathophysiology of T2DM
T2DM, known as “non-insulin-dependent DM,” is a complex, multifactorial metabolic disorder. Characteristic features of T2DM include chronic hyperglycemia and declining pancreatic β-cell effectiveness, leading to the absence of a first-phase insulin response to nutrient ingestion. Further, slower glucose absorption and higher fasting glucose levels occur from factors such as a reduced insulin-mediated glucose uptake in muscle, impaired hepatic insulin sensitivity, defective insulin action and/or secretion in liver and a disruption of secretary function of adipocytes [9-11]. Glucose levels rise and hyperglycemia develops from deteriorated insulin secretion . Mechanistically, the manifestation of T2DM features a relative decrease in insulin secretion suggesting that this may be in accordance with a decreased β-cell mass failing to compensate for peripheral insulin resistance [13-16]. In the last two decades, declining pancreatic β-cell effectiveness has been a criterion for the development of hyperglycemia and T2DM; its progressive character also determines the course of the disease . Impaired glucose-stimulated insulin secretion, defective β-cell gene expression and disrupted mitochondrial ultrastructure is thought to be due to lipid accumulation and ‘lipoapoptosis’ is observed in pancreatic β-cells from type 2 diabetic animals . This is also supported by reports that chronic, high glucose administration generates the combination of hyperglycemia and chronic dislipidemia, termed ‘glucolipotoxicity,’ driving a vicious cycle by which metabolic abnormalities impair insulin secretion, which further aggravates metabolic disturbances in β-cell lines and isolated rat islets .
There is mounting evidence that chronically elevated circulating levels of glucose and fatty acids, critical characteristics of T2DM, contribute to relentless β-cell function decline, by endorsing glucolipotoxicity, which induces endoplasmic reticulum (ER) stress [20, 21], oxidative stress [22, 23], mitochondrial dysfunction [23, 24] and islet inflammation [25, 26]. Several studies have provided evidence that prolonged exposure to increased concentrations of fatty acids is associated with reduction of glucose induced insulin secretion , impairment of insulin gene expression [28, 29] and induction of β-cells death [30, 31]. Importantly, lipoapoptosis only occurs in the presence of concomitant elevation in insulin secretion [32, 33]. Thus, hyperglycemia and hyperlipidemia have been postulated to conduct to the worsening of insulin secretary capacity and β-cell mass observed in T2DM . It is to note, that during feeding, insulin secretion occurs in two phases. An elevation of insulin synthesis in pancreatic β-cells following an initial rapid release of insulin (i.e. first phase) to nutrient ingestion occurs primarily in response to elevated circulating glucose concentrations. The insulin level stimulates glucose uptake into striated muscle tissues through glucose transport type 4 (GLUT-4) for utilization as a source of energy and into adipose tissues for glycerol synthesis; it also affects liver cells thereby activating glycogen formation. Consequently, glucose utilization by these different tissues contributes to a decrease in concentrations of glucose in blood. Long term release of insulin occurs in response to continuously high glucose concentrations as part of the second phase of insulin response. On the other hand, during this period of hypoglycemia there is an altered interaction between pancreatic islets and glucagon-producing α cells, causing increased plasma glucagon, and residual β-cell function largely preserves the first-line defence against hypoglycemia in T2DM .
3. Interplay between alcohol consumption and T2DM
Chronic, heavy alcohol consumption, an independent risk factor for T2DM [35-37], disrupts glucose homeostasis and is associated with development of insulin resistance [38-40].
3.1. Epidemiological evidence
The association between alcohol consumption and DM was demonstrated early in 1971 by Phillips et al. . This study suggested that alcohol with doses of 266 to 513 ml produced glucose intolerance and insulin resistance in three of six healthy subjects. Later, this relationship was also demonstrated in a cross-sectional health screening survey of 636 individuals with negative urine glucose, suggesting that alcohol dependence was one of the malignant factors in individuals with impaired glucose tolerance diagnosed by performing a 75-g oral glucose tolerance test (OGTT) . Moreover, alcohol consumption influenced fasting plasma glucose levels along with obesity after analysis of 434 pairs of adult female nondiabetic twins . These results implied that alcohol might impair fasting and postprandial glycemic controls and thus may be a risk factor for T2DM, sharing common genetic factors. Indeed, alcohol consumption within the past week appears to be an independent risk factor of the development of T2DM after a 10 year, prospective population-based study . This significant association was observed only in men and remained significant after adjusting for other hazards of T2DM.
However, there also have been studies with negative or opposite findings explaining the relationship between alcohol consumption and the development of T2DM. Alcohol consumptions of 5-14.9g/d and more than 15g/d were associated with a decreased relative risk of DM in women . In a later study worked on younger women, light to moderate drinking (<14.9g/d) was also associated with a lower risk of T2DM compared to lifelong abstinence, whereas heavy drinking showed a significantly increased diabetic risk . Similarly, moderate amount of alcohol consumption (30.0-49.9 g/d) was associated with reduced risk of the development of DM in 41,810 male health professionals . Lowering the incidence of T2DM by light to moderate drinking, T2DM was also observed in older adults . On the other hand, no effect of alcohol consumption on the development of T2DM was reported in large population-based survey . The aforementioned results suggest the presence of possible influencing factors, such as gender [44, 50] and amount of alcohol consumption [46, 50].
Regarding drinking patterns, Conigrave et al.  found that more frequent drinking is more protective against T2DM. A later study  also showed that binge drinking for 1-3 days increased the risk of T2DM compared to non-drinking, while drinking the same amount over a week did not increase the risk. Meanwhile, there has been controversy on the type of alcoholic beverage and the risk of T2DM. Some studies noted protective effects of wine on T2DM than other alcoholic beverages . However, other studies presented no significant difference with various alcoholic liquors [48, 51]. In addition, obesity may also influence the relationship between alcohol consumption and T2DM. A systematic review of studies in Japanese showed that alcohol consumption is a risk factor for DM, whereas moderate drinking is associated with a reduced diabetic risk in higher body mass index (BMI) men in some studies . Although the mediating effects of obesity are supported by a positive association between alcohol intake, adiponectin levels and insulin sensitivity [54, 55], more studies will be needed to confirm this issue.
To date, 3 meta-analyses were performed in an attempt to draw a possible conclusion. Carlson et al.  analyzed data from 13 cohorts and suggested a U-shaped relationship between the amount of alcohol consumption and risk of T2DM. Moderate drinking, corresponding to about 5-30g/d was associated with a reduced risk of DM (relative risk: RR=0.72, 95% CI=0.67-0.77) in both men and women. This U-shaped relationship in both sexes was also demonstrated in a meta-analysis by Koppes et al.  in which lowest risk was in alcohol drinkers of 6-48g/d. Drinkers of ≥48g/d showed equal RR to that of nondrinkers. In their study, adjustment for confounding factors including diagnostic measures of T2DM (self-reported versus tested) and BMI (low- versus high-BMI) was performed. Results of a self-reported diagnosis were associated with lower RR than using a diagnostic test, whereas BMI did not affect the RR of T2DM. A third meta-analysis of Bauliunas et al.  additionally identified a deleterious effect of heavy drinking (≥60 g/d for men and ≥50g/d for women) in addition to the protective effect of moderate drinking in both sexes.
3.2. Alcohol consumption and risk of T2DM
Along with the epidemiological data on the relationship between alcohol consumption and T2DM, studies exploring underlying mechanisms between them have been performed. Most directly, alcohol can induce acute and chronic pancreatitis and result in DM as in T1DM . However, there is a growing body of evidence suggesting that the diabetogenic effect of alcohol does not seem to be mediated by decreased insulin secretion . The priming effect of ethanol-enhanced insulin secretion in pancreatic β-cells might be caused by an early defence mechanism used to compensate for alcohol-inhibited basal insulin secretion. In contrast, a limited number of studies have reported deleterious effects of alcohol on β-cells in which alcohol inhibited insulin secretion .
Excessive heavy alcohol use increases ROS production and may be a mechanism of pancreatic β-cells dysfunction in T2DM. The reason is that ROS production is one of the earliest events in glucose intolerance through mitochondrial dysfunction and β-cells are very sensitive to oxidative stress . Previous studies of alcohol dependence have shown that alcohol elevated the level of β-cell apoptosis and increased insulin resistance in the liver and skeletal muscle, which is among the earliest detectable alterations in humans with T2DM . In addition, the mechanisms by which this occurs are often multifactorial and quite complex, involving many cell signaling pathways. A common result of DM is hyperglycemia, which in turn contributes to the progression and maintenance of an overall oxidative environment . In obesity, oxidative stress is now recognized to be an important feature in dysregulation of adipokines and inflammation .
Among potential mediators of alcohol-induced insulin resistance including acetate, lactate, acetaldehyde, free fatty acids and triglycerides, hepatic insulin sensitizing substance (HISS) and glutathione need to be considered. Alcohol suppresses the release or action of HISS and meal-induced insulin sensitization in rats . Moreover, in animal models, acute alcohol administration also reduces glutathione  which is important for HISS release . As with acute alcohol consumption, hepatic glutathione and HISS seem to be involved. In contrast to the acute alcohol effect, chronic ethanol consumption increased hepatic glutathione levels and HISS release in cases of moderate dose, whereas decreased glutathione and HISS were reported at high doses .
On the other hand, results on the effect of chronic ethanol consumption on insulin sensitivity showed that insulin sensitivity was improved [66, 69-72] or unchanged [73-75] after chronic alcohol consumption. The mechanism by which chronic alcohol consumption enhances insulin sensitivity also remains elusive. Alcohol consumption is proposed to increase plasma adiponectin levels, which subsequently lowers plasma TNF-α, which interferes with insulin signaling . Taken together, alcohol might induce alterations in insulin resistance mediated by lipids, inflammation oxidative stress and altered metabolism. Moreover, the effect of alcohol on insulin sensitivity may be influenced by periods of and amount of alcohol consumption. Impaired suppression of hepatic glucose production by insulin is likely due to impaired insulin signaling in liver after chronic alcohol exposure. For instance, chronic ethanol consumption decreases tyrosine phosphorylation of insulin receptor substrate-1 as well as activities of PI 3-kinase and Akt (protein kinase B) in the liver .
3.3. Ghrelin and leptin correlated with risk of T2DM in alcoholic patients
It has been investigated that ghrelin may be associated with β-cell hypofunction and the first-phase insulin secretion defects in T2DM and exert to regulate glucose homeostasis with glucagon and insulin . Additionally, abnormal glucose tolerance and insulin resistance, which are main characteristics of T2DM, through performing 75g OGTT seemed to be affected by leptin as well as, the levels of leptin were higher in diabetic patients independently of body fat mass when it compared with healthy control patients . Thus, ghrelin and leptin have been regarded to have influence on T2DM. Valuable efficacy of plasma ghrelin and leptin levels by the development of T2DM in patients with alcohol dependence were changed . The data showed that ghrelin levels did not differ among the groups, even though there was a tendency towards decreased ghrelin levels; whereas the leptin level increased significantly with development of T2DM (Fig. 1).
The demographic characteristics of each group were shown in Table 1. The three groups exhibited similar values of age, height, weight, BMI and lipid profiles such as HDL-cholesterol, LDL-cholesterol, and triglyceride. Fasting glucose concentration and hemoglobin A1c, HOMA-IR in the DM group had significantly higher levels than NGT and Pre-DM groups.
|Alcohol use disorder identification test||21.7 ± 1.09||21.17 ± 1.61||24.3 ± 1.23|
|Alcohol dependency scale||42.29 ± 1.38||38.86 ± 1.74||43.83 ± 1.79|
|Onset age of problematic drinking (years)||36.58 ± 1.89||37.56 ± 1.68||40.05 ± 2.88|
|Age (years)||47.35 ± 1.37||48.87 ± 1.57||52.77 ± 1.84|
|Weight (kg)||66.83 ± 1.46||65.39 ± 1.25||63.96 ± 1.92|
|Height (cm)||169.57 ± 0.81||167.76 ± 0.8||167.38 ± 0.85|
|BMI (kg/m2)||23.19 ± 0.42||23.2 ± 0.36||22.77 ± 0.57|
|HDL-Cholesterol (mg/dl)||56.91 ± 2.27||51.08 ± 2.36||55.19 ± 4.44|
|LDL-Cholesterol (mg/dl)||113.09 ± 3.87||104.63 ± 4.95||101.96 ± 4.72|
|Triglyceride (mg/dl)||115.02 ± 10.31||135.33 ± 13.06||139.88 ± 15.54|
|GOT (IU/l)||69.5 ± 11.53||71.7 ± 9.19||52.54 ± 6.96|
|GPT (IU/l)||40.93 ± 5.25||50.07 ± 8.66||34 ± 6.19|
|γ-GTP (IU/l)||178.87 ± 45.33||205.07 ± 32.64||254.96 ± 67.99|
|Fasting Glucose (mg/dl)||86.09 ± 1.05||91.48 ± 1.45||124.19 ± 7.01**|
|Fasting Insulin (μU/ml)||4.8 ± 0.84||4.73 ± 0.69||6.22 ± 1.4|
|HemoglobinA1c (%Hb A1c)||5.5 ± 0.05||5.64 ± 0.08||7.13 ± 0.36**|
|HOMA-IR||1.02 ± 0.17||1.05 ± 0.15||1.87 ± 0.36*|
|HOMA-β||83.56 ± 18.56||66.13 ± 11.55||54.91 ± 14.87|
Moreover, this study demonstrated that leptin was significantly correlated with BMI, fasting insulin concentration and HOMA-IR reflecting insulin resistance (Table 2). The BMI was similar in the groups and the subjects were regarded as a non-obese group. The leptin produced by adipocytes increased in proportion to fat mass [79, 80]. The plasma leptin levels are highly correlated with BMI in both obese and normal weight subjects . In spite of the correlation between BMI and leptin, covarying for BMI in our statistical analyses did not alter our findings.
Leptin also has been shown to be correlated with insulin concentration and insulin sensitivity [82-84]. The direct relationship between leptin and insulin seemed to be mutual. Insulin also had a role in the regulation of leptin concentrations . Among all patients with chronic alcoholism, significant quadratic association of leptin level with insulin concentration and HOMA-IR were observed using simple regression analysis (Fig. 2, Table 3).
In conclusion, leptin can play a role in the pathogenesis of T2DM in patients with alcohol dependence. Chronic alcohol consumption might produce leptin resistance, which produces a significant correlation between leptin and the fasting insulin concentration, β-cell function and insulin resistance. However, more study will be needed to determine the mechanism of the relationship between alcohol intake and leptin resistance.
4. Role of the appetite regulating peptides in alcohol dependence and prevalence of T2DM
The neuropeptide, ghrelin secreted from cells of the gastric oxyntic glands in stomach, and leptin excreted from white adipose cells, have received attention due their roles in the neurobiology of alcohol dependence [2, 6]. Many studies have suggested that ghrelin and leptin predominantly produce variations of glucose and insulin concentrations, which may initiate metabolic disorders [86, 87]. In addition, recent research regarding neuroendocrinological alterations of ghrelin and leptin in patients with alcohol dependence has showed that chronic use of alcohol represents a potentially crucial risk factor for T2DM prevalence as ghrelin reduces insulin secretion stimulated by the increased level of blood glucose in the β cells of pancreas, while in contrast, leptin increases insulin secretion and action [88-90]. In regards to the diabetogenic effects of chronic use of alcohol, development of pancreatic β-cell dysfunction, insulin resistance, obesity, impairment of liver function in glucose metabolism have been noted . Indeed, alcoholic patients with T2DM have repeatedly been found to have deregulation of the ghrelin and leptin systems, as indicated by impaired insulin secretion, increased hepatic glucose production and decreased peripheral glucose utilization [38-40]. Moreover, these peptides are regarded to have an influence on T2DM-mediated alcohol cravings and relapses in alcoholism during alcohol abstinace [91-94]. Therefore, it is conceivable that alterations of appetite peptides provoked by chronic alcohol use might contribute to the development of T2DM, including defective glucose tolerance and impaired insulin resistance.
The decreases in ghrelin are paralleled by increases in leptin and rises in insulin [87, 95]. Leptin, which is elevated in the plasma of obese subjects, controls fat cell secretary productions on ghrelin secretion due to leptin-related decreases in ghrelin levels. [96-98]. It has been suggested that leptin is significantly associated with BMI and alcohol consumption, influencing fasting insulin concentration and HOMA-IR, and the passible mechamism of alcohol leptin interaction may be attributable to a direct noxious effect of alcohol on the pancreatic islet cells, or may reflect a truncal fat pattern related to heavy use of alcohol . Thus, the adverse effect of heavy use of alcohol on serum insulin concentrations, a risk for DM, seems to be partially mediated through its effect on BMI. Interestingly, it has been proposed that elevated peripheral insulin resistance may produce increased leptin concentrations regardless of body fat profiles, suggesting that leptin released from fat tissue in alcohol dependence patients may be abundant irrespective of body fat content . Therefore, altered leptin concentrations in alcoholic patients contribute to the incidence of T2DM mainly due to chronic alcohol consumption rather than body fat mass.
In the clinical studies, increases of mean body weights and leptin concentrations resulted from therapeutic treatment of insulin for 1 year in T2DM patients. , suggesting that insulin prompted leptin secretion, which was believed to exert influence on the increased body weight. Further, decrease of insulin-stimulated glucose utilization in skeletal muscle was exibited by long periods of leptin exposure. This is to the fact that insulin-stimulated p38 mitogen-activated protein kinase (MAPK) activation was inhibited and GLUT4 activation was decreased by leptin . Leptin also can interfere with insulin signaling and induce gluconeogenesis in hepatocytes directly . Insulin-stimulated glucose uptake into isolated adipocytes was inhibited by chronic alcohol feeding via vitiation of the fusion of GLUT4 vesicles at the plasma membrane of rats. Chronically fed with alcohol sustains insulin signaling through PI 3-kinase in adipocytes  but results in the disruption of insulin mediated Cbl/TC10 signaling pathway which leads to attenuated insulin-stimulated glucose transport . Thus, a combination of decreased GLUT4 expression and impaired insulin-stimulated GLUT4 trafficking to the plasma membrane contributes to reduced glucose uptake in response to insulin in adipocytes. Hence, the possibility that ghrelin and leptin can be related with deteriorated pathophysiology of T2DM, aligned with defective insulin signaling pathway, including change in kinase activity, glucose transporter translocation and intracellular enzyme activity, in alcoholic patients exists.
5. Ghrelin in glucose and insulin homeostasis
Ghrelin was originally isolated from the stomach, but ghrelin has also been identified in other peripheral tissues, such as the gastrointestinal tract, pancreas, ovary and adrenal cortex [3, 103-105]. Regulation of ghrelin secretion, as well as its biological effects, appears to be opposite those of leptin and antagonize leptin’s effects in appetite regulation [95, 106-108]. A suppressive role of ghrelin in insulin secretion from pancreatic islets is supported by the observation that ghrelin inhibits glucose-stimulated insulin secretion and disrupts glucose tolerance in normal subjects . There is evidence that ghrelin may have proliferative or protective roles on β-cells  and stimulates insulin secretion, which primarily occurs in response to increased circulating glucose levels, whereas insulin reduces plasma ghrelin in normal controls and T2DM patients . Moreover, ghrelin may be associated with β-cell hypofunction and first-phase insulin secretion defects in T2DM as well as regulates glucose homeostasis with glucagon and insulin . Furthermore, it has been noted that deficiency of the genes encoding ghrelin and its receptor (GHS-R1a) enhances insulin levels, increases glucose-stimulated insulin secretion, improves peripheral insulin sensitivity and prevents high-fat diets from inducing obesity . Similarly, ghrelin receptor antagonists which inhibit ghrelin signaling have been shown to improve the diabetic condition by promoting glucose-dependent insulin secretion . Ghrelin can also inhibit the activity of glucose-sensing neurons in the dorsal vagal complex of rats, indicating that ghrelin manipulates the sensitivity of glucose-sensing neurons [114, 115].
The pathophysiological role of ghrelin in glucose homeostasis was strengthened by the fact that ghrelin may decline endogenous glucose production through suppression of insulin secretory capacity , while reinforcing insulin action on glucose disposal . A recent study demonstrated that acylated ghrelin has a positive correlation with insulin resistance, as indicated by the increased insulin and glucose concentrations, whereas correlation between des-acylated ghrelin and HOMA-IR was shown to be negative . On the other hand, it has been reported that fasting ghrelin levels at any other point might be impossible to use for predicting the development of impaired glucose regulation . The reduction of ghrelin levels were shown to be associated independently with T2DM, agreeing with the results of studies demonstrating that ghrelin has an inverse correlation with insulin resistance evaluated by HOMA-IR . Moreover, increases in ghrelin during chronic alcohol use suggested that a role of ghrelin may contribute significantly to the overall alcohol response. It has likewise been reported that ghrelin is not only a regulator of glucose and insulin metabolism in the central nervous system (CNS), but also a modulator of those in the periphery. In the periphery, ghrelin has been shown to stimulate hepatic glucose production  and inhibit insulin release from pancreatic islets [121, 122]. Peripheral ghrelin produced in the gastrointestinal tract [103, 123] reaches ghrelin-receptors in the anterior pituitary and potentially in the mediobasal and mediolateral hypothalamus through the general circulation to stimulate GH release and to regulate energy homeostasis . Therefore, it can be postulated that decreases in ghrelin concentrations as well as facilitation of the development of perturbations in glucose metabolism resulting from deregulation of the CNS and the periphery might lead to perseverance of T2DM. Besides, low blood ghrelin concentrations appears to influence growth hormone/insulin like growth facor-1-axis which may, in turn, affect increased insulin resistance and ultimately manifest T2DM .
6. Leptin in glucose and insulin homeostasis
Leptin, an adipocyte-derived anorexic peptide plays a primary role in regulation of energy homeostasis including food intake and energy expenditure involved in obesity, regulating overall metabolism and particularly glucose metabolism. Leptin is transported across the blood brain barrier (BBB) by binding to its receptor in the arcuate nucleus of the hypothalamus to regulate glucose metabolism via central leptin signaling, which modulates sympathetic and neuroendocrine activities [126, 127], as well as though peripheral signaling in insulin-sensitive tissues such as liver and muscle [128, 129]. A previous study demonstrated that serum leptin was positively correlated with fasting blood glucose in obese patients with DM, suggesting that resistance to insulin and leptin may have participated in increasing food intake in T2DM. Additionally, leptin has to be considered as a possible regulator of the gastrohypothalamic axis involved in short-term feeding regulation  and may have a central role in islet cell growth and insulin secretion . In addition, several other appetite-related hormones such as anorexigenic neuropeptides, alpha-melanocyte-stimulating hormone (alpha-MSH), proopiomelanocortin (POMC), cocaine and amphetamine regulated transcript (CART) and corticotropin-releasing hormone (CRH) are stimulated by leptin. Conversely, orexigenic neuropeptides NPY, melanin-concentrating hormone (MCH), orexins and agouti-related peptide (AgRP) are inhibited by leptin which suppresses food intake and enhances energy expenditure through these central interactions, which is associated with T2DM [132-135].
In the brain, obesity and T2DM typified by both insulin and leptin resistance, on account of either reduced BBB transport or impaired neuronal capacity to sense peripheral signals, causes increased concentrations of anorexigenic neuropeptides and reduced concentrations of orexigenic ones . It has been postulated that leptin resistance might be due to defective leptin transport across the BBB . Leptin enters the brain by a satiable transport system and that capacity of leptin transport is lower in obese individuals, thereby providing a mechanism for leptin resistance . The development leptin resistance most likely involves a period of excess caloric intake, resulting in a disturbance of the leptin system, leading to sustained defects. The hypothalamus exposed to high leptin levels becomes less sensitive to leptin, resulting in a sustained increase in leptin levels . Leptin resistance may also have functional implications in peripheral tissues expressing leptin receptors, such as pancreatic β cells, where insulin is synthesized and secreted; leptin may also affect hepatocytes, muscle and adipose tissue, where insulin exerts its function . In all these tissues, an effect of leptin has been demonstrated on insulin secretion and on insulin-induced activities such as glucose utilization [83, 141]. Also, increased leptin levels, probably reflecting leptin resistance, was shown to be strongly related to insulin resistance . Moreover, peripheral leptin inhibits insulin secretion in pancreatic β-cells , whereas insulin stimulates leptin production in adipocytes . Therefore, reciprocal interaction of leptin and insulin called ‘adipo-insular axis’ is central under physiological conditions.
However, in few studies, glucose and insulin levels were able to increase circulating leptin levels, indicating that the capacity of leptin to suppress insulin secretion in pancreatic β-cell might be a possible involvement of T2DM [143, 144]. Interestingly, reduced leptin sensitivity of the pancreatic β-cell occurs concurrently with hyperinsulinemia resulting from not only decreased insulin sensitivity, but also increased insulin secretion, and consequently hyperleptimia as part of a vicious cycle that promotes both and insulin resistance ). Leptin has been shown to increase whole-body glucose utilization, decrease glycogen stores and inhibit insulin-stimulated glucose uptake , implying that increased leptin levels contribute to increased glycemia and altered glucose homeostasis . Therefore, the capacity of leptin to suppress insulin secretion in pancreatic β-cell suggests a possible involvement in T2DM. Moreover, obese
7. Inverse interactions between leptin and ghrelin
Leptin is important for the negative feedback regulation of ghrelin in states of moderate body weight increase, whereas recombinant leptin administration is ineffective on altering ghrelin levels in healthy subjects . There is currently evidence that ghrelin and leptin exert antagonistic effects via their specific receptors in the CNS and in peripheral tissues. Ghrelin increases appetite and food intake via centrally mediating actions but, peripherally it modulates pancreatic β-cells function as well as glucose and lipid metabolism . The satiety inducing effects of leptin include the suppression of ghrelin secretion to induce anorexic effects . Adipogenic as well as orexigenic effects of ghrelin are also most likely mediated by a specific central network of neurons that is also mediated by leptin [124, 151-153].
In the brain, ghrelin may transfort the BBB and bind to its receptors in the hypothalamus after secretion into the bloodstream from the stomach [105, 154, 155]. Ghrelin reaches the brain via the vagal nerve and nucleus tractus solitarus [154, 156] and is released locally in the hypothalamus, where it may directly affect various hypothalamic nuclei [154, 157]. In addition, central ghrelin may affect the energy centre in the hypothalamus and both ghrelin and leptin stimulate and suppress, respectively hypothalamic neurons containing various neuropeptides, resulting in anorexic or orexic effects on energy balance. Ghrelin thus stimulates the activity of neurons expressing NPY, AgRP and orexin [158-160] and inhibits POMC neurons and CRH-producing neurons . The interaction between ghrelin and leptin in the hypothalamus indicates that these peptides have different effects in the hypothalamic neurons producing various orexigenic and anorexigenic peptides, presenting more or less opposing effects on energy balance.
In hepatocytes, ghrelin reduces and leptin augments insulin signal transduction, resulting in increased and decreased glucose production, respectively . In pancreatic β-cells, insulin release was stimulated by ghrelin but inhibited by leptin administration . Insulin was postulated to act indirectly via ghrelin and leptin to suppress appetite . However, attenuated suppressive action of insulin on ghrelin and particular association between insulin resistance and leptin resistance were shown in T2DM [5, 142]. Thus, leptin seems to the major determinant of ghrelin effects on progression of metabolic syndromes.
The studies discussed here demonstrate that the role of appetite regulating peptides, ghrelin and leptin, in alcohol patients with T2DM may be of high importance for clinical research and practice. The extensive functional interactions between these peptides, which may contribute significantly to the overall defecting glucose tolerance with regard to alcoholism, may have a new insight into mechanism of T2DM. Therefore, understanding of mechanisms underlying the pivotal relations between ghrelin, leptin and glucose homeostasis during chronic use of alcohol represents an additional therapeutic intervention for T2DM.Acknowledgement
This study was supported by a grant of the Korea Health 21R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A111378).
Increased circulating leptin levels in chronic alcoholism. Journ. Nicolas J. M. Fernandez-Sola J. Fatjo F. Casamitjana R. Bataller R. Sacanella E. et al. 2001 25 1 83 8
Ghrelin levels are increased in alcoholism. Journ. Kraus T. Schanze A. Groschl M. Bayerlein K. Hillemacher T. Reulbach U. et al. 2005 29 12 2154 7
Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion. Journ. Date Y. Nakazato M. Hashiguchi S. Dezaki K. MS Mondal Hosoda. H. et al. 2002 51 1 124 9
Insulin-resistant patients with type 2 diabetes mellitus have higher serum leptin levels independently of body fat mass. Journ. Fischer S. Hanefeld M. Haffner S. M. Fusch C. Schwanebeck U. Kohler C. et al. 2002 39 3 105 10
Differential association of basal and postprandial plasma ghrelin with leptin, insulin, and type 2 diabetes. Journ. Erdmann J. Lippl F. Wagenpfeil S. Schusdziarra V. 2005 54 5 1371 8
The change of plasma ghrelin and leptin levels by the development of type 2 diabetes mellitus in patients with alcohol dependence. Journ. Ju A. Cheon Y. H. Lee K. S. Lee S. S. Lee W. Y. Won W. Y. et al. 2011 35 5 905 11
Journ. Thiele T. E. Navarro M. Sparta D. R. Fee J. R. Knapp D. J. Cubero I. Alcoholism obesity overlapping. neuropeptide pathways?. 2003 37 6 321 37
Kalra SP, Kalra PS.Overlapping and interactive pathways regulating appetite and craving. Journ. 2004 23 3 5 21
Kahn CR. Banting Lecture. Insulin action, diabetogenes, and the cause of type II diabetes.Journ. 1994 43 8 1066 84
Current views on type 2 diabetes. Journ.; Lin Y. Sun Z. 204 1 1 11
Current views on type 2 diabetes. Journ. Lin Y. Sun Z. 2010 204 1 1 11
Reaven GM.Role of insulin resistance in human disease (syndrome X): an expanded definition. Journ. 1993 44 121 31
Rhodes ET, Ferrari LR, Wolfsdorf JI.Perioperative management of pediatric surgical patients with diabetes mellitus. Journ. 2005 101 4 986 99table of contents.
Journ. Kumari M. Brunner E. Fuhrer R. Minireview mechanisms. by which. the metabolic. syndrome diabetes impair. memory 2000B 228 32
Role of sulfhydryl inhibitors in the pathogenesis of diabets mellitus. Journ. Falkmer S. 1962Suppl 154 106 7
Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Journ. Butler A. E. Janson J. Bonner-Weir S. Ritzel R. Rizza R. A. Butler P. C. 2003 52 1 102 10
Journ. Harmon J. S. CE Gleason Tanaka. Y. Poitout V. Robertson R. P. Antecedent hyperglycemia. not hyperlipidemia. is associated. with increased. islet triacylglycerol. content decreased insulin. gene m. R. N. A. level in. Zucker diabetic. fatty rats. 2001 50 11 2481 6
Journ. Unger R. H. Orci L. Lipoapoptosis its. mechanism its diseases. 2002 202 EOF 12 EOF
Long-term exposure of beta-INS cells to high glucose concentrations increases anaplerosis, lipogenesis, and lipogenic gene expression. Journ. Roche E. Farfari S. Witters L. A. Assimacopoulos-Jeannet F. Thumelin S. Brun T. et al. 1998 47 7 1086 94
The role for endoplasmic reticulum stress in diabetes mellitus. Journ. Eizirik D. L. Cardozo A. K. Cnop M. 2008 29 1 42 61
The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Journ. Marchetti P. Bugliani M. Lupi R. Marselli L. Masini M. Boggi U. et al. 2007 50 12 2486 94
Wajchenberg BL.beta-cell failure in diabetes and preservation by clinical treatment. Journ. 2007 28 2 187 218
Islet beta cell failure in type 2 diabetes. Journ. Prentki M. Nolan C. J. 2006 116 7 1802 12
Transient oxidative stress damages mitochondrial machinery inducing persistent beta-cell dysfunction. Journ. Li N. Brun T. Cnop M. Cunha D. A. Eizirik D. L. Maechler P. 2009 284 35 23602 12
Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. Journ. Maedler K. Sergeev P. Ris F. Oberholzer J. Joller-Jemelka H. I. Spinas G. A. et al. 2002 110 6 851 60
Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Journ. Cnop M. Welsh N. Jonas J. C. Jorns A. Lenzen S. Eizirik D. L. 2005Suppl 2:S 97 107
Zhou YP, Grill VE.Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. Journ. 1994 93 2 870 6
Glucose-induced preproinsulin gene expression is inhibited by the free fatty acid palmitate. Journ. Ritz-Laser B. Meda P. Constant I. Klages N. Charollais A. Morales A. et al. 1999 140 9 4005 14
Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. Journ. Kelpe C. L. Moore P. C. Parazzoli S. D. Wicksteed B. Rhodes C. J. Poitout V. 2003 278 32 30015 21
Glucolipotoxicity of the pancreatic beta-cell: myth or reality? Journ. Poitout V. 2008Pt 5):901-4.
Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation. Journ. Cnop M. Hannaert J. C. Hoorens A. Eizirik D. L. Pipeleers D. G. 2001 50 8 1771 7
Inhibition of insulin gene expression by long-term exposure of pancreatic beta cells to palmitate is dependent on the presence of a stimulatory glucose concentration. Journ. Jacqueminet S. Briaud I. Rouault C. Reach G. Poitout V. 2000 49 4 532 6
Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Journ. Briaud I. Harmon J. S. Kelpe C. L. Segu V. B. Poitout V. 2001 50 2 315 21
Targeting beta-cell mass in type 2 diabetes: promise and limitations of new drugs based on incretins. Journ. Salehi M. BA Aulinger D’Alessio. D. A. 2008 29 3 367 79
Kao WH, Puddey IB, Boland LL, Watson RL, Brancati FL.Alcohol consumption and the risk of type 2 diabetes mellitus: atherosclerosis risk in communities study. Journ. 2001 154 8 748 57
Wannamethee SG, Shaper AG, Perry IJ, Alberti KG.Alcohol consumption and the incidence of type II diabetes. Journ. 2002 56 7 542 8
Alcohol intake and incidence of type 2 diabetes in men. Journ. Wei M. Gibbons L. W. Mitchell T. L. Kampert J. B. Blair S. N. 2000 23 1 18 22
Ethanol feeding induces insulin resistance with enhanced PI 3-kinase activation. Journ. Onishi Y. Honda M. Ogihara T. Sakoda H. Anai M. Fujishiro M. et al. 2003 303 3 788 94
Ethanol feeding impairs insulin-stimulated glucose uptake in isolated rat skeletal muscle: role of Gs alpha and cAMP. Journ. Wan Q. Liu Y. Guan Q. Gao L. Lee K. O. Zhao J. 2005 29 8 1450 6
Carbohydrate intolerance associated with reduced hepatic glucose phosphorylating and releasing enzyme activities and peripheral insulin resistance in alcoholics with liver cirrhosis. Journ. Sotaniemi E. A. Keinanen K. Lahtela J. T. Arranto A. J. Kairaluoma M. 1985 1 3 277 90
Phillips GB, Safrit HF. Alcoholic diabetes.Induction of glucose intolerance with alcohol. Journ. 1971 217 11 1513 9
Study on background factors associated with impaired glucose tolerance and/or diabetes mellitus. Journ. Umeki S. Hisamoto N. Hara Y. 1989 120 6 729 34
Environmental and behavioral determinants of fasting plasma glucose in women. A matched co-twin analysis. Journ. Selby J. V. Newman B. King M. C. Friedman G. D. 1987 125 6 979 88
Journ. Holbrook T. L. Barrett-Connor E. Wingard D. L. A. prospective population-based. study of. alcohol use. non-insulin-dependent diabetes. mellitus 1990 132 5 902 9
Journ. MJ Stampfer Colditz. G. A. Willett W. C. Manson J. E. Arky R. A. Hennekens C. H. et al. A. prospective study. of moderate. alcohol drinking. risk of. diabetes in. women 1988 128 3 549 58
Wannamethee SG, Camargo CA, Jr., Manson JE, Willett WC, Rimm EB.Alcohol drinking patterns and risk of type 2 diabetes mellitus among younger women. Journ. 2003 163 11 1329 36
Prospective study of cigarette smoking, alcohol use, and the risk of diabetes in men. Journ. Rimm E. B. Chan J. MJ Stampfer Colditz. G. A. Willett W. C. 1995 310 6979 555 9
Alcohol consumption and type 2 diabetes among older adults: the Cardiovascular Health Study. Journ. Djousse L. Biggs M. L. Mukamal K. J. DS Siscovick 2007 15 7 1758 65
Hodge AM, Dowse GK, Collins VR, Zimmet PZ.Abnormal glucose tolerance and alcohol consumption in three populations at high risk of non-insulin-dependent diabetes mellitus. Journ. 1993 137 2 178 89
Journ. Hodge A. M. English D. R. O’Dea K. Giles G. G. Alcohol intake. consumption pattern. beverage type. the risk. of Type. . diabetes 2006 23 6 690 7
Journ. Conigrave K. M. Hu B. F. CA Camargo Jr MJ Stampfer Willett. W. C. Rimm E. B. A. prospective study. of drinking. patterns in. relation to. risk of. type . diabetes among. men 2001 50 10 2390 5
Journ. Goldberg D. M. Soleas G. J. Levesque M. Moderate alcohol. consumption the. gentle face. of Janus. 1999 32 7 505 18
Alcohol consumption and risk of type 2 diabetes mellitus in Japanese: a systematic review. Journ. Seike N. Noda M. Kadowaki T. 2008 17 4 545 51
Relationship between moderate alcohol consumption and adiponectin and insulin sensitivity in a large heterogeneous population. Journ. Thamer C. Haap M. Fritsche A. Haering H. Stumvoll M. 2004 1240 EOF 1240 EOF
Alcohol consumption in relation to metabolic regulation, inflammation, and adiponectin in 64-year-old Caucasian women: a population-based study with a focus on impaired glucose regulation. Journ. Englund Ogge. L. Brohall G. Behre C. J. Schmidt C. Fagerberg B. 2006 29 4 908 13
Alcohol consumption and type 2 diabetes Meta-analysis of epidemiological studies indicates a U-shaped relationship. Journ. Carlsson S. Hammar N. Grill V. 2005 48 6 1051 4
Koppes LL, Dekker JM, Hendriks HF, Bouter LM, Heine RJ.Moderate alcohol consumption lowers the risk of type 2 diabetes: a meta-analysis of prospective observational studies. Journ. 2005 28 3 719 25
Alcohol as a risk factor for type 2 diabetes: A systematic review and meta-analysis. Journ. DO Baliunas Taylor. B. J. Irving H. Roerecke M. Patra J. Mohapatra S. et al. 2009 32 11 2123 32
Sjoberg RJ, Kidd GS. Pancreatic diabetes mellitus.Journ. 1989 12 10 715 24
Separate and combined effects of smoking and alcohol abuse in middle-aged men. Journ. Rosengren A. Wilhelmsen L. Wedel H. 1988 223 2 111 8
Hurt RD, Patten CA.Treatment of tobacco dependence in alcoholics. Journ. 2003 16 335 59
Understanding the pathogenesis and treatment of insulin resistance and type 2 diabetes mellitus: what can we learn from transgenic and knockout mice? Journ. Mauvais-Jarvis F. Kahn C. R. 2000 26 6 433 48
Pathophysiology of insulin resistance. Journ. Sesti G. 2006 20 4 665 79
atherosclerosis. Journ.; Gustafson B. Adipose tissue. inflammation 17 4 332 41
Alcohol suppresses meal-induced insulin sensitization. Journ. Lautt W. W. Legare D. J. MA Reid Sadri. P. Ting J. W. Prieditis H. 2005 3 1 51 9
Insulin sensitivity and regular alcohol consumption: large, prospective, cross sectional population study (Bruneck study). Journ. Kiechl S. Willeit J. Poewe W. Egger G. Oberhollenzer F. Muggeo M. et al. 1996 313 7064 1040 4
Hepatic glutathione and nitric oxide are critical for hepatic insulin-sensitizing substance action. Journ. Guarino M. P. Afonso R. A. Raimundo N. Raposo J. F. Macedo M. P. 2003G 588 94
Depressed hepatic glutathione and increased diene conjugates in alcoholic liver disease. Evidence of lipid peroxidation. Journ. Shaw S. Rubin K. P. Lieber C. S. 1983 28 7 585 9
Alcohol consumption and insulin concentrations. Role of insulin in associations of alcohol intake with high-density lipoprotein cholesterol and triglycerides. Journ. Mayer E. J. Newman B. CP Quesenberry Jr Friedman G. D. Selby J. V. 1993Pt 1): 2190 EOF 7 EOF
Flanagan DE, Moore VM, Godsland IF, Cockington RA, Robinson JS, Phillips DI.Alcohol consumption and insulin resistance in young adults. Journ. 2000 30 4 297 301
Journ. Goude D. Fagerberg B. Hulthe J. Alcohol consumption. the metabolic. syndrome insulin resistance. in 58-year-old. clinically healthy. men . A. I. R. study 2002 102 3 345 52
Davies MJ, Baer DJ, Judd JT, Brown ED, Campbell WS, Taylor PR.Effects of moderate alcohol intake on fasting insulin and glucose concentrations and insulin sensitivity in postmenopausal women: a randomized controlled trial. Journ. 2002 287 19 2559 62
Bell DS.Alcohol and the NIDDM patient. Journ. 1996 19 5 509 13
Influence of moderate chronic wine consumption on insulin sensitivity and other correlates of syndrome X in moderately obese women. Journ. Cordain L. Melby C. L. Hamamoto A. E. DS O’Neill Cornier. MA Barakat H. A. et al. 2000 49 11 1473 8
Alcohol consumption alters insulin secretion and cardiac autonomic activity. Journ. Flanagan D. E. Pratt E. Murphy J. Vaile J. C. Petley G. W. Godsland I. F. et al. 2002 32 3 187 92
Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM.Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Journ. 1994 91 11 4854 8
Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver. Journ. Yeon J. E. Califano S. Xu J. Wands J. R. De La Monte S. M. 2003 38 3 703 14
Chronic ethanol consumption lessens the gain of body weight, liver triglycerides, and diabetes in obese ob/ob mice. Journ. Fromenty B. Vadrot N. Massart J. Turlin B. Barri-Ova N. Letteron P. et al. 2009 331 1 23 34
Serum immunoreactive-leptin concentrations in normal-weight and obese humans. Journ. Considine R. V. Sinha M. K. Heiman M. L. Kriauciunas A. Stephens T. W. Nyce M. R. et al. 1996 334 5 292 5
Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Journ. Frederich R. C. Hamann A. Anderson S. Lollmann B. Lowell B. B. Flier J. S. 1995 1 12 1311 4
Relationship of plasma leptin to plasma insulin and adiposity in normal weight and overweight women: effects of dietary fat content and sustained weight loss. Journ. Havel P. J. Kasim-Karakas S. Mueller W. Johnson P. R. Gingerich R. L. Stern J. S. 1996 81 12 4406 13
Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Journ. Segal K. R. Landt M. Klein S. 1996 45 7 988 91
Modulation of insulin activities by leptin. Journ. Cohen B. Novick D. Rubinstein M. 1996 274 5290 1185 8
Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus. Journ. Seufert J. Kieffer T. J. CA Leech Holz. G. G. Moritz W. Ricordi C. et al. 1999 84 2 670 6
Journ. Widjaja A. Stratton I. M. Horn R. Holman R. R. Turner R. Brabant G. U. K. P. D. S. 2. plasma leptin. obesity plasma insulin. in type. . diabetic subjects. 1997 82 2 654 7
The influence of insulin on circulating ghrelin. Journ. Flanagan D. E. Evans M. L. Monsod T. P. Rife F. Heptulla R. A. Tamborlane W. V. et al. 2003E 313 6
Insulin regulates plasma ghrelin concentration. Journ. Saad M. F. Bernaba B. Hwu C. M. Jinagouda S. Fahmi S. Kogosov E. et al. 2002 87 8 3997 4000
Patterns of alcohol consumption and alcohol-related morbidity and mortality. Journ. Berkelman R. L. Ralston M. Herndon J. Gwinn M. Bertolucci D. Dufour M. 1986 1SS EOF 5SS EOF
Magis DC, Jandrain BJ, Scheen AJ. [Alcohol, insulin sensitivity and diabetes].Journ. 2003 501 EOF 7 EOF
Diabetes mellitus and alcohol. Journ. van de Wiel A. 2004 20 4 263 7
Leptin is associated with craving in females with alcoholism. Journ. Kraus T. Reulbach U. Bayerlein K. Mugele B. Hillemacher T. Sperling W. et al. 2004 213 EOF 219 EOF
Relationship between ghrelin levels, alcohol craving, and nutritional status in current alcoholic patients. Journ. Addolorato G. Capristo E. Leggio L. Ferrulli A. Abenavoli L. Malandrino N. et al. 2006 30 11 1933 7
Leptin as a possible modulator of craving for alcohol. Journ. Kiefer F. Jahn H. Kellner M. Naber D. Wiedemann K. 2001 58 5 509 10
Increased fasting plasma ghrelin levels during alcohol abstinence. Journ. Kim D. J. Yoon S. J. Choi B. Kim T. S. Woo Y. S. Kim W. et al. 2005 40 1 76 9
Weigle DS, Cummings DE, Newby PD, Breen PA, Frayo RS, Matthys CC, et al.Roles of leptin and ghrelin in the loss of body weight caused by a low fat, high carbohydrate diet. Journ. 2003 88 4 1577 86
Hyperleptinemia prevents increased plasma ghrelin concentration during short-term moderate caloric restriction in rats. Journ. Barazzoni R. Zanetti M. Stebel M. Biolo G. Cattin L. Guarnieri G. 2003 124 5 1188 92
Ghrelin and leptin pulse discharge in fed and fasted rats. Journ. Bagnasco M. Kalra P. S. Kalra S. P. 2002 143 2 726 9
Direct effect of leptin on gastric ghrelin secretion. Journ. Lippl F. Erdmann J. Atmatzidis S. Schusdziarra V. 2005 37 2 123 5
Aas AM, Hanssen KF, Berg JP, Thorsby PM, Birkeland KI.Insulin-stimulated increase in serum leptin levels precedes and correlates with weight gain during insulin therapy in type 2 diabetes. Journ. 2009 94 8 2900 6
High leptin levels acutely inhibit insulin-stimulated glucose uptake without affecting glucose transporter 4 translocation in l6 rat skeletal muscle cells. Journ. Sweeney G. Keen J. Somwar R. Konrad D. Garg R. Klip A. 2001 142 11 4806 12
Journ. Poirier L. A. Rachdaoui N. Nagy L. E. G. L. U. T. vesicle trafficking. in rat. adipocytes after. ethanol feeding. regulation by. heterotrimeric G-proteins. 2001Pt 2): 323 EOF 30 EOF
Sebastian BM, Nagy LE.Decreased insulin-dependent glucose transport by chronic ethanol feeding is associated with dysregulation of the Cbl/TC10 pathway in rat adipocytes. Journ. 2005E 1077 84
Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Journ. Kojima M. Hosoda H. Date Y. Nakazato M. Matsuo H. Kangawa K. 1999 402 6762 656 60
Journ. Date Y. Kojima M. Hosoda H. Sawaguchi A. MS Mondal Suganuma. T. et al. Ghrelin a. novel growth. hormone-releasing acylated. peptide is. synthesized in. a. distinct endocrine. cell type. in the. gastrointestinal tracts. of rats. humans 2000 141 11 4255 61
Journ. Tortorella C. Macchi C. Spinazzi R. Malendowicz L. K. Trejter M. Nussdorfer G. G. Ghrelin an. endogenous ligand. for the. growth hormone-secretagogue. receptor is. expressed in. the human. adrenal cortex. 2003 12 2 213 7
Journ. Horvath T. L. Diano S. Sotonyi P. Heiman M. Tschop M. Minireview ghrelin. the regulation. of energy. balance--a hypothalamic. perspective 2001 142 10 4163 9
The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Journ. MD Klok Jakobsdottir. S. Drent M. L. 2007 8 1 21 34
Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women. Journ. Tolle V. Kadem M. Bluet-Pajot M. T. Frere D. Foulon C. Bossu C. et al. 2003 88 1 109 16
Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans. Journ. Tong J. Prigeon R. L. Davis H. W. Bidlingmaier M. Kahn S. E. Cummings D. E. et al. 2010 59 9 2145 51
Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats. Journ. Irako T. Akamizu T. Hosoda H. Iwakura H. Ariyasu H. Tojo K. et al. 2006 49 6 1264 73
Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients. Journ. Anderwald C. Brabant G. Bernroider E. Horn R. Brehm A. Waldhausl W. et al. 2003 52 7 1792 8
Ghrelin regulates insulin release and glycemia: physiological role and therapeutic potential. Journ. Yada T. Dezaki K. Sone H. Koizumi M. Damdindorj B. Nakata M. et al. 2008 4 1 18 23
Vaccination against weight gain. Journ. Zorrilla E. P. Iwasaki S. Moss J. A. Chang J. Otsuji J. Inoue K. et al. 2006 103 35 13226 31
Journ. Penicaud L. Leloup C. Fioramonti X. Lorsignol A. Benani A. Brain glucose. sensing a. subtle mechanism. 2006 9 4 458 62
Effects of ghrelin on glucose-sensing and gastric distension sensitive neurons in rat dorsal vagal complex. Journ. Wang W. G. Chen X. Jiang H. Jiang Z. Y. 2008 169 EOF 175 EOF
Central and peripheral roles of ghrelin on glucose homeostasis. Journ. Sun Y. Asnicar M. Smith R. G. 2007 86 3 215 28
Relationships between desacylated and acylated ghrelin and insulin sensitivity in the metabolic syndrome. Journ. Barazzoni R. Zanetti M. Ferreira C. Vinci P. Pirulli A. Mucci M. et al. 2007 92 10 3935 40
Serum ghrelin and the prediction of the development of impaired glucose regulation and Type 2 diabetes in middle-aged subjects. Journ. Vartiainen J. Rajala U. Jokelainen J. Keinanen-Kiukaanniemi S. Kesaniemi Y. A. Ukkola O. 2010 33 7 496 500
Circulating ghrelin levels in patients with polycystic ovary syndrome. Journ. Schofl C. Horn R. Schill T. Schlosser H. W. MJ Muller Brabant. G. 2002 87 10 4607 10
Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells. Journ. Murata M. Okimura Y. Iida K. Matsumoto M. Sowa H. Kaji H. et al. 2002 277 7 5667 74
Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis. Journ. Dezaki K. Sone H. Yada T. 2008 118 2 239 49
Journ. Broglio F. Arvat E. Benso A. Gottero C. Muccioli G. Papotti M. et al. Ghrelin a. natural G. H. secretagogue produced. by the. stomach induces. hyperglycemia reduces insulin. secretion in. humans 2001 86 10 5083 6
Journ. Kojima M. Hosoda H. Matsuo H. Kangawa K. Ghrelin discovery. of the. natural endogenous. ligand for. the growth. hormone secretagogue. receptor 2001 12 3 118 22
Ghrelin induces adiposity in rodents. Journ. Tschop M. Smiley D. L. Heiman M. L. 2000 407 6806 908 13
Journ. Gauna C. Delhanty P. J. Hofland L. J. Janssen J. A. Broglio F. Ross R. J. et al. Ghrelin stimulates. whereas des-octanoyl. ghrelin inhibits. glucose output. by primary. hepatocytes 2005 90 2 1055 60
Plasticity of central autonomic neural circuits in diabetes. Journ. Zsombok A. Smith B. N. 2009 1792 5 423 31
German JP, Thaler JP, Wisse BE, Oh IS, Sarruf DA, Matsen ME, et al.Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Journ. 2010 152 2 394 404
Effect of intrahypothalamic injection of neostigmine on the secretion of epinephrine and norepinephrine and on plasma glucose level. Journ. Honmura A. Yanase M. Saito H. Iguchi A. 1992 130 5 2997 3002
Decrease in plasma glucose concentration after microinjection of insulin into VMN. Journ. Iguchi A. Burleson P. D. Szabo A. J. 1981E 95 100
Trayhurn P. Hoggard N. Mercer J. G. Rayner D. V. Leptin fundamental. aspects Journ. 1999Suppl 1 22 8
Ruhl CE, Everhart JE.Leptin concentrations in the United States: relations with demographic and anthropometric measures. Journ. 2001 74 3 295 301
Journ. de Lecea L. Kilduff T. S. Peyron C. Gao X. Foye P. E. Danielson P. E. et al. The hypocretins. hypothalamus-specific peptides. with neuroexcitatory. activity 1998 95 1 322 7
Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Journ. Sakurai T. Amemiya A. Ishii M. Matsuzaki I. Chemelli R. M. Tanaka H. et al. 1998page following 696.
The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization. Journ. Bittencourt J. C. Presse F. Arias C. Peto C. Vaughan J. Nahon J. L. et al. 1992 319 2 218 45
Journ. Date Y. Nakazato M. Matsukura S. [. A. role for. orexins melanin-concentrating hormone. in the. central regulation. of feeding. behavior] 2001 59 3 427 30
Dynamic regulation of leptin entry into brain by the blood-brain barrier. Journ. Kastin A. J. Pan W. 2000 37 EOF 43 EOF
Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Journ. Schwartz M. W. Peskind E. Raskind M. Boyko E. J. Porte D. Jr 1996 2 5 589 93
Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Journ. Caro J. F. Kolaczynski J. W. Nyce M. R. Ohannesian J. P. Opentanova I. Goldman W. H. et al. 1996 348 9021 159 61
Kolaczynski JW, Ohannesian JP, Considine RV, Marco CC, Caro JF.Response of leptin to short-term and prolonged overfeeding in humans. Journ. 1996 81 11 4162 5
Kieffer TJ, Heller RS, Habener JF.Leptin receptors expressed on pancreatic beta-cells. Journ. 1996 224 2 522 7
Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Journ. Emilsson V. Liu Y. L. MA Cawthorne Morton. N. M. Davenport M. 1997 46 2 313 6
Leptin levels in type 2 diabetes: associations with measures of insulin resistance and insulin secretion. Journ. Wauters M. Considine R. V. Yudkin J. S. Peiffer F. De Leeuw I. Van Gaal L. F. 2003 35 2 92 6
Glucose metabolism rather than insulin is a main determinant of leptin secretion in humans. Journ. Wellhoener P. Fruehwald-Schultes B. Kern W. Dantz D. Kerner W. Born J. et al. 2000 85 3 1267 71
Sonnenberg GE, Krakower GR, Hoffmann RG, Maas DL, Hennes MM, Kissebah AH.Plasma leptin concentrations during extended fasting and graded glucose infusions: relationships with changes in glucose, insulin, and FFA. Journ. 2001 86 10 4895 900
Leptin effects on pancreatic beta-cell gene expression and function. Journ. Seufert J. 2004Suppl 1:S 152 8
Acute stimulation of glucose metabolism in mice by leptin treatment. Journ. Kamohara S. Burcelin R. Halaas J. L. Friedman J. M. MJ Charron 1997 389 6649 374 7
Alcohol intake modifies leptin, adiponectin and resistin serum levels and their mRNA expressions in adipose tissue of rats. Journ. Pravdova E. Macho L. Fickova M. 2009 43 3 117 25
Animal models in type 2 diabetes research: an overview. Journ. Srinivasan K. Ramarao P. 2007 125 3 451 72
Recombinant methionyl human leptin administration activates signal transducer and activator of transcription 3 signaling in peripheral blood mononuclear cells in vivo and regulates soluble tumor necrosis factor-alpha receptor levels in humans with relative leptin deficiency. Journ. Chan J. L. Moschos S. J. Bullen J. Heist K. Li X. Kim Y. B. et al. 2005 90 3 1625 31
Journ. Higgins S. C. Gueorguiev M. Korbonits M. Ghrelin the. peripheral hunger. hormone 2007 39 2 116 36
Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Journ. Kalra S. P. Dube M. G. Pu S. Xu B. Horvath T. L. Kalra P. S. 1999 20 1 68 100
Bowers CY.Unnatural growth hormone-releasing peptide begets natural ghrelin. Journ. 2001 86 4 1464 9
Journ. Shintani M. Ogawa Y. Ebihara K. Aizawa-Abe M. Miyanaga F. Takaya K. et al. Ghrelin an. endogenous growth. hormone secretagogue. is a. novel orexigenic. peptide that. antagonizes leptin. action through. the activation. of hypothalamic. neuropeptide Y. Y. receptor pathway. 2001 50 2 227 32
Ghrelin--a hormone with multiple functions. Journ. Korbonits M. Goldstone A. P. Gueorguiev M. Grossman A. B. 2004 25 1 27 68
Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. Journ. Banks W. A. Tschop M. Robinson S. M. Heiman M. L. 2002 302 2 822 7
Journ. Ueno H. Yamaguchi H. Kangawa K. Nakazato M. Ghrelin a. gastric peptide. that regulates. food intake. energy homeostasis. 2005 11 EOF 9 EOF
The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Journ. MA Cowley Smith. R. G. Diano S. Tschop M. Pronchuk N. Grove K. L. et al. 2003 37 4 649 61
Journ. Nakazato M. Murakami N. Date Y. Kojima M. Matsuo H. Kangawa K. et al. A. role for. ghrelin in. the central. regulation of. feeding 2001 409 6817 194 8
Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Journ. Kamegai J. Tamura H. Shimizu T. Ishii S. Sugihara H. Wakabayashi I. 2001 50 11 2438 43
Ghrelin-induced food intake is mediated via the orexin pathway. Journ. Toshinai K. Date Y. Murakami N. Shimada M. MS Mondal Shimbara. T. et al. 2003 144 4 1506 12