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Alcohol and other endocrine tissues.

In addition to the brain areas and organs involved in the main hormone axes in the body that are discussed in this article, several other tissues also produce and secrete hormones that regulate crucial body functions, including the pancreas and fat (i.e., adipose) tissue. Alcohol exposure also can interfere with diese hormonal systems.

The Endocrine Pancreas

The pancreas, which lies behind the stomach, serves two major functions. First, acinar cells secrete digestive enzymes into the small intestine, thereby supporting digestion. Second, islet cells dispersed throughout the whole pancreas have an endocrine activity by producing hormones (i.e., insulin and glucagon) that regulate blood glucose levels. These islet cells can be further subdivided into [alpha]- and [beta]-cells. The [alpha]-cells produce glucagon, which raises blood glucose levels by stimulating the liver to metabolize glycogen into glucose molecules and to release the glucose into the blood. In addition, glucagon stimulates the adipose tissue to metabolize triglycerides into glucose, which then is released into the blood. Conversely, the [beta]-cells of the pancreas produce insulin, which lowers blood glucose levels after a meal by stimulating the absorption of glucose by liver, muscle, and adipose tissues and promoting the storage of glucose in the form of glycogen in these tissues. The endocrine function of the pancreas primarily is controlled by both the sympathetic and the parasympathetic divisions of the autonomic nervous system.

Alcohol's Effects on the Endocrine Pancreas

Heavy alcohol drinking can induce the development of inflammation of the pancreas (i.e., pancreatitis), most commonly in acinar cells. However, the inflammatory aspect of this disease also can damage islet cells and, therefore, the endocrine pancreas (Apte et al. 1997). Chronic alcohol consumption also is a risk factor for the development of pancreatic cancer, with moderate to heavy consumption increasing the risk both alone and in combination with other risk factors, such as tobacco and obesity (de Menezes et al. 2013; Haas et al. 2012). One type of pancreatic cancer called ductal adenocarcinoma has a very aggressive behavior with a 5-year survival rate of less than 4 percent (Welsch et al. 2006).

Chronic alcohol consumption also is a known independent risk factor for the development of type 2 diabetes (Hodge et al. 1993; Holbrook et al. 1990; Wei et al. 2000). This syndrome is characterized by impaired glucose metabolism with high blood glucose levels (i.e., hyperglycemia) and peripheral insulin resistance. The relationship between alcohol consumption and the risk of type 2 diabetes is "U" shaped--that is, risk is lower with moderate alcohol consumption than with either abstention or high alcohol consumption. Thus, the risk was reduced by 30 percent in moderate drinkers compared with abstainers, whereas no risk reduction was observed in heavy drinkers consuming 48 grams of ethanol (i.e., 3 to 4 drinks) per day or more (Koppes et al. 2005). Moderate alcohol use may have protective effects by enhancing peripheral insulin sensitivity (Conigrave et al. 2001; Tomie Furuya et al. 2005).

Some studies have shown that moderate alcohol consumption improves peripheral insulin sensitivity without affecting insulin secretion from pancreatic [beta]-cells (Avogaro et al. 2004), whereas others determined a reduced basal insulin secretion rate associated with a lower fasting plasma glucagon concentration (Bonnet et al. 2012). The beneficial metabolic effects of moderate alcohol use on insulin sensitivity and glucose homeostasis therefore might explain the significant reduction in the risk of development of type 2 diabetes and of cardiovascular disorders (Avogaro et al. 2004; Bande et al. 2008).

Heavy alcohol consumption, in contrast, has several detrimental effects resulting in impaired control of blood glucose levels. In addition to its effects on peripheral tissues, such as adipose tissue and the liver, where it induces insulin resistance, heavy drinking also negatively affects pancreatic [beta]-cell function. In a study by Patto and colleagues (1993), chronic drinkers exhibited a decreased insulin-secretion response to glucose compared with the control group. When the investigators measured the total integrated response values for secreted insulin and for C-peptide (1) following oral or intravenous glucose administration in diese two groups, both values were significantly lower in the chronic drinkers compared with the control group. Moreover, in both groups the total integrated response value for insulin was significantly higher after oral glucose administration than after intravenous administration, suggesting a potentiating incretin (2) effect on insulin secretion. These findings clearly indicate that chronic alcohol exposure induces a [beta]-cell dysfunction and not an enteroinsular incretin dysfunction, because the decrease in insulin response compared with the control group also was observed when glucose was administered intravenously.

Animal studies demonstrated that mice exposed to chronic alcohol for 8 to 10 weeks developed impairments in fasting glucose levels and exhibited an increase in [beta]-cell apoptosis, which were associated with diminished insulin secretion (Kim et al. 2010). The investigators suggested that alcohol exposure led to a down-regulation and inactivation of the enzyme glucokinase, which acts as a [beta]-cell sensor for blood glucose levels. Glucokinase is involved in glucose metabolism that leads to increased production of adenosine-triphosphate, a necessary step in insulin secretion by [beta]-cells. The researchers also detected a decrease in the glucose transporter Glut2 in [beta]-cells as well as a decrease in insulin synthesis, further exacerbating the effects of chronic alcohol exposure.

More recendy, Wang and colleagues (2014) reported that intraperitoneal administration of ethanol (3g/kg body weight) to mice resulted in an impaired glucose metabolism, which was associated with decreased expression of two subunits (i.e., [alpha]1 and [delta]-subunits) of the type A gamma-aminobutyric acid (GABA) receptors on pancreatic [beta]-cells. This could account at least for part of the alcohol-induced impairment in [beta]-cell function, because activation of GABA receptors in pancreatic [beta]-cells increases insulin secretion (Bansal et al. 2011), has a protective and regenerative effect on [beta]-cells, and decreases cell apoptosis in cultured islet cells (Dong et al. 2006). The investigators further showed that acute treatment of cultured rat [beta]-cells (i.e., the INS-1 cell line) with 60 mM ethanol interfered with GABA-mediated cell activation as well as insulin secretion and that these effects could be prevented by pretreating the cultured cells with GABA (100 mM), further supporting the theory that alcohol's effects on [beta]-cells and insulin production are mediated at least in part by GABA signaling (Wang et al. 2014). In addition, experiments in another cultured [beta]-cell line indicated that heavy alcohol consumption may induce [beta]-cell dysfunction in type 2 diabetes by increasing the production of reactive oxygen species and inducing apoptosis in the cells (Dembele et al. 2009). All of these studies clearly show that heavy alcohol consumption has deleterious effects on pancreatic [beta]-cell function and glucose homeostasis. However, more studies are needed to specify the mechanisms by which chronic alcohol affects [beta]-cell function.

Endocrine Adipose Tissue

There are two types of adipose tissue--white adipose tissue (WAT) and brown adipose tissue (BAT)--that differ in their morphology and function. For a long time, WAT had been considered a passive reservoir for energy storage. Over the last decade, however, numerous studies have demonstrated that WAT is a dynamically active endocrine organ that can produce and secrete biologically active peptides and proteins called adipokines, which have autocrine, paracrine, and endocrine actions. In fact, WAT may be the largest endocrine organ in mammals and can be found in individual pads in different locations throughout the body, both near other organs (i.e., viscerally) and under the skin (i.e., subcutaneously). Depending on its location, WAT synthesizes and secretes different sets of adipokines (Coelho et al. 2013). Since the discovery of leptin (Zhang et al. 1994), multiple adipokines released by WAT have been identified, including hormones, growth factors, and cytokines (Coelho et al. 2013).

WAT also expresses several receptors that allow it to respond to signals from other hormone systems and from the central nervous system. Through these different communication pathways, WAT can influence the function of many tissues, such as hypothalamus, pancreas, skeletal muscle, and immune system. In addition, WAT can coordinate numerous important biological processes through its various adipokines, such as food intake and body weight (leptin), glucose homeostasis (adiponectin and resistin), lipid metabolism, pro- and anti-inflammatory functions (tumor necrosis factor alpha [TNF[alpha]] and interleukin-6 [IL-6]), as well as reproductive functions (Campfield et al. 1996; Coelho et al. 2013).

BAT, on the other hand, is present at birth but is almost absent in adult mammals. Brown adipocytes are smaller than white adipocytes, have numerous mitochondria, and specialize in heat production through oxidation of fatty acids (i.e., thermogenesis). However, recent direct and indirect evidence also suggests a potential endocrine role for BAT (Villarroya et al. 2013). Thus, BAT was shown to release factors such as IGF-1, fibroblast growth factor-2, IL-1[alpha], IL-6, bone morphogenetic protein-8b, and lipocalin prostaglandin D synthase that primarily have autocrine or paracrine actions (Villarroya et al. 2013). The only known endocrine factor released by BAT is the active thyroid hormone T3. Upon thermogenic activation, the type II thyroxine 5'-deiodinase enzyme, which is expressed specifically in BAT, converts T4 into T3 (de Jesus et al. 2001).

Alcohol's Effects on Endocrine Adipose Tissue

Although the results have not been consistent, numerous studies have shown that alcohol consumption can change adipokine levels. For example, studies found that leptin levels were increased (Nicolas et al. 2001; Obradovic and Meadows 2002), decreased (Calissendorff et al. 2004), or remained unchanged (Beulens et al. 2008; Strbak et al. 1998) by alcohol exposure. Another adipokine is adiponectin, which is produced and secreted exclusively by WAT and has antidiabetogenic and anti-inflammatory effects. Its production and actions are regulated by TNF[alpha], with the two compounds suppressing each other's production and antagonizing each other's actions in target tissues (Maeda et al. 2002). Moderate alcohol consumption can increase adiponectin plasma levels, which is associated with a significant increase in insulin sensitivity (Sierksma et al. 2004; Thamer et al. 2004); the extent of this effect, however, depends on the frequency of alcohol administration. In a study comparing the effects of exposure of high-fat--fed rats to 5 g/kg body weight ethanol per day delivered either by twice-daily administration via a gastric tube or through free-access drinking, Feng and colleagues (2012) demonstrated greater improvement of insulin sensitivity with twice-daily ethanol administration. Accordingly, adiponectin plasma levels were significantly increased in the twice-daily administration group compared with the free-access group. The researchers suggested that ethanol concentrations in the blood might be an important factor influencing adiponectin secretion and, consequendy, insulin sensitivity.

One proposed mechanism for the adiponectin-mediated improvement in insulin sensitivity is that the increase in adiponectin causes a decrease in plasma levels of TNF[alpha] (Ouchi et al. 2000; Yokota et al. 2000). Conversely, decreasing adiponectin levels would be expected to result in increasing TNF[alpha] levels. High circulating TNF[alpha] levels, in turn, have been implicated in the development of peripheral insulin resistance (Hotamisligil et al. 1995). Chronic alcohol consumption can significantly decrease adiponectin levels (Xu et al. 2003). (3) Thus, male rats that had received ethanol for 4 weeks exhibited significantly decreased mRNA levels of adiponectin and retinol binding protein 4 but increased mRNA levels of monocyte chemo-attractant protein 1, TNF[alpha], and IL-6 in epididymal adipose tissue. These changes were associated with increased macrophage infiltration into adipose tissue and the development of insulin resistance (see figure) (Kang et al. 2007).

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In addition, studies have suggested that reduced adiponectin expression could play an important role in the development of alcohol-induced liver damage (Xu et al. 2003). Alcoholic fatty liver (i.e., steatosis) is one of the most prevalent forms of chronic liver diseases caused by alcohol abuse; it is characterized by the excessive accumulation of fat in the liver and can progress to more severe forms of liver injury, such as steatohepatitis, fibrosis, and cirrhosis. Adiponectin's protective effects on the liver are believed to be mediated through its actions on hepatic signaling molecules involved in enhanced fat oxidation and reduced lipid synthesis (Rogers et al. 2008; Xu et al. 2003). A recent study assessed the serum concentrations of total adiponectin, leptin, and resistin in male and female patients with chronic alcohol abuse and different degrees of liver dysfunction (Kasztelan-Szczerbinska et al. 2013). The analyses found elevated total levels of adiponectin and resistin in patients with alcoholic liver disease (ALD) compared with control subjects. Also, women with ALD had lower leptin levels than did control subjects, whereas there were no significant differences in leptin concentrations in males with and without ALD. Gender-related differences in serum leptin concentrations may influence the clinical course of ALD, which differs in males and females. It is possible that metabolic alterations caused by ethanol in the course of ALD, by differentially modulating leptin secretion, may be responsible for different clinical presentations of the disease in females and males (Kasztelan-Szczerbinska et al. 2013). However, more studies are needed to help with our understanding of the adipose tissue pathology associated with alcohol abuse.

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(1) C-peptide is a chain of 31 amino acids that during insulin synthesis connects the two parts, or chains, of the insulin molecule in a precursor molecule. During final processing of the insulin molecule, the C-peptide is removed to yield the functional insulin molecule with its two chains.

(2) Incretin is a hormone secreted by the wall of the intestine that acts on the pancreas to regulate insulin production after glucose administration. This so-called enteroinsular signaling pathway can therefore only occur after oral glucose administration, which results in increased glucose levels in the intestine, but not after intravenous administration, which bypasses the intestine.

(3) The increased TNF[alpha] levels associated with decreased adiponectin also may play a role in the development of liver disease. TNF[alpha] production was increased in adipose tissue at early stages of alcoholic fatty liver, resulting in increases in both circulating and local TNF[alpha] levels (Lin et al. 1998).
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Publication:Alcohol Research: Current Reviews
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Date:Mar 22, 2017
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