How does ethanol interact with insulin?

How does ethanol interact with insulin?

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I know that ethanol increases insulin secretion--could someone explain why?

All I have found till now is experimental data analyses. I am interested in mechanism of alcohol consumption.

Alcoholic beverages, ingested casually, deliver two main nutrients the body will metabolize: sugar and ethanol. The body's natural response to a rise in blood glucose will be stimulated secretion of insulin (from B cells of the pancreatic islets). Alcohol is metabolized primarily by the liver, being first converted to acetaldehyde by alohol dehydrogenase and a coezyme NAD+. Acetaldehyde metabolism quickly converts this to acetate. Acetate is then eventually metabolized elsewhere in the body to carbon dioxide and water. The interesting effects are mediated by acetaldehyde, which can accumulate to toxic levels in some people. This ties into insulin because this article suggests that alcohol consumption changes blood flow from exocrine pancreas (responsible for digestive enzymes) to endocrine pancreas (responsible for secreting homrones, such as glucagon, insulin, somatostatin). Alcohol seems to modulate the late-phase of insulin secretion, increasing secretion, which leads to exaggerated glucose disposal and at least for diabetics causes hypoglycemia.

  1. Huang Z, Sjöholm A. Ethanol acutely stimulates islet blood flow, amplifies insulin secretion, and induces hypoglycemia via nitric oxide and vagally mediated mechanisms. Endocrinology. 2008 Jan;149(1):232-6. Epub 2007 Oct 4.

How Insulin Works in the Body

Elizabeth Woolley is a patient advocate and writer who was diagnosed with type 2 diabetes.

Jay Yepuri, MD, MS, is a board-certified gastroenterologist and a practicing partner at Digestive Health Associates of Texas (DHAT).

Insulin is a hormone produced by the pancreas to help metabolize and use food for energy throughout the body. This is a key biological function, and so a problem with insulin can have a widespread effect on any or all of the tissues, organs, and systems of the body.

Insulin is so important to overall health, and even survival, that when there are problems with insulin production or utilization, as with diabetes, supplemental insulin often is needed throughout the day.

In fact, in the case of type 1 diabetes, an autoimmune disease in which the body produces no insulin, supplemental insulin is vital. Supplemental insulin isn't always necessary for treating type 2 diabetes, the form of diabetes in which insulin production is lower than normal and/or the body isn't able to use it efficiently. This inefficient use of insulin is called insulin resistance.

If you have either type of diabetes, learning how the naturally produced hormone works in the body can help you understand why taking daily insulin shots or wearing an insulin pump or patch may be a key aspect of your treatment plan.

Potential Benefit

Past studies suggested that moderate drinking might reduce insulin resistance and protect against T2DM. More current studies, however, call this into question. A September 2015 "Diabetes Care" article reported on pooled results from 38 studies that evaluated the relationship between alcohol intake and T2DM risk. The researchers found that overall, people who drank 1 standard alcoholic beverage daily were 18 percent less likely to develop T2DM compared to nondrinkers. However, when the researchers analyzed the results further, they found the protective effect was only experienced by certain groups of people.

Insulin Drug Interactions

See references for individual insulin products in

Lexi-Interact [computer program]. Lexi-Comp, Inc. October 30, 2008.

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In total, 4,991 titles were found through the database searches and 24 through additional methods (Supplementary Fig. 1). After screening of titles and abstracts, 46 articles remained eligible and the full text was assessed. Finally, 22 articles met criteria for inclusion in the qualitative synthesis.

Study Characteristics

Descriptive data of the included studies are summarized in Table 1. Of the 22 studies, 15 used a crossover design and 7 a parallel design. The intervention duration of the studies ranged from 2 to 12 weeks, with an average duration of 5.6 weeks for ISI, 4.2 weeks for HOMA-IR, 7.2 weeks for insulin, 5.9 weeks for glucose, and 4.3 weeks for HbA1c. Two studies did not use an alcohol-free control group (14,19). The dosage of alcohol varied from 10 to 70 g/day of which one study used >40 g/day (20). ISI was measured by six studies, of which two used the gold standard HEGC (10,21) and four used indirect measures of insulin sensitivity (based on OGTT, FSIVGTT, or fasting levels) (8,9,22,23). HOMA-IR was measured by four studies (15,24–26). Seven studies were performed by the same institute (10,21–26), but they were treated as independent because they included different subjects.

Characteristics of studies included in this systematic review and meta-analysis on the effect of alcohol consumption on insulin sensitivity

Quality Assessment

The results of the quality assessment are shown in Supplementary Table 1. Of the 22 studies included in the qualitative synthesis, 4 did not report the measurement of compliance to the intervention (9,14,20,27). Blinding of the researcher was not reported or not conducted in any of the studies. Dropout rates were described in 18 studies. The studies scored between 1 and 3 points on the Jadad scale (range 0–5). Of the 22 studies, 2 were excluded from the meta-analysis because they did not include an alcohol-free control group (14,19), and 4 were excluded because they did not have a randomized design (13,28–30). Because only two studies included subjects with type 2 diabetes, these studies were excluded as well (31,32). One study included both healthy and type 2 diabetic subjects, and from this study, only data from healthy subjects were included (15). Overall, 14 studies were included in the meta-analysis (Table 1 and Supplementary Table 1).


The number of included studies in the analysis was 7 for ISI, 5 for HOMA-IR, 9 for insulin, 10 for glucose, and 3 for HbA1c. The forest plots on insulin sensitivity and glycemic status are shown in Figs. 1–3.

Forest plot of meta-analysis of the effect of alcohol consumption on insulin sensitivity. Data are pooled SMDs with 95% CIs and are calculated with exclusion of the results of the two study arms of Chiva-Blanch et al. (15) because they induced heterogeneity.

Forest plots of meta-analysis of the effect of alcohol consumption on fasting insulin (A) and fasting glucose (B). Data are pooled SMDs with 95% CIs. RW, red wine.

Forest plot of meta-analysis of the effect of alcohol consumption on HbA1c. Data are pooled SMDs with 95% CIs.

Pooled analysis showed no difference in ISI after a period of alcohol consumption compared with no alcohol consumption (SMD 0.06 [−0.13 to 0.26], P = 0.53, test for heterogeneity P = 0.76, I 2 = 0%). For HOMA-IR, both the χ 2 (P < 0.01) and I 2 (97%) statistics demonstrated heterogeneity. In a random-effects model, the pooled SMD was 0.35 [−0.90 to 1.59], indicating no effect of alcohol consumption on HOMA-IR (P = 0.59). Similar results were observed when studies measuring ISI and HOMA-IR were combined (SMD −0.12 [−0.61 to 0.39], P = 0.65). A random-effects model was used because heterogeneity was present (P < 0.01, I 2 = 91%). The funnel plot indicated that the results of the intervention arms (i.e., red wine, gin) of Chiva-Blanch et al. (15) were largely responsible for this heterogeneity. Exclusion of this study resulted in an SMD of 0.08 (−0.09 to 0.24, P = 0.35), with no evidence of heterogeneity (P = 0.90, I 2 = 0%). Sex-stratified analysis showed different effects in men and women (Psex = 0.018) (Fig. 1). Alcohol consumption tended to increase insulin sensitivity in women (SMD 0.16 [−0.04 to 0.37], P = 0.12) but not in men (SMD −0.30 [−1.23 to 0.64], P = 0.54). In men, heterogeneity was present (P < 0.01, I 2 = 95%), and exclusion of the study by Chiva-Blanch et al. resulted in a pooled SMD of −0.07 (−0.34 to 0.20, P = 0.61). However, after exclusion of Chiva-Blanch et al., the pooled SMDs in men and women were no longer significantly different (P = 0.18).

Fasting insulin concentrations were lower after alcohol consumption compared with abstinence, as shown by a pooled SMD of −0.19 (−0.35 to −0.02, P = 0.03) and the test for heterogeneity (P = 0.92, I 2 = 0%). Sex-stratified analysis showed that alcohol consumption decreased insulin concentrations in women (SMD −0.23 [−0.41 to −0.04], P = 0.02). Only two studies measured insulin concentrations in men, showing a decrease in insulin levels (SMD −0.13 [−0.62 to 0.36], P = 0.59) (Fig. 2A).

For fasting glucose concentrations, the pooled SMD was 0.07 [−0.11 to 0.24], indicating no effect of alcohol consumption on glucose concentration among individuals without diabetes (P = 0.45, Pheterogeneity = 0.94, I 2 = 0%). Similar results were observed when men and women were analyzed separately (Fig. 2B). In women, the SMD was 0.01 (−0.20 to 0.21, P = 0.94) in men, the SMD was 0.14 (−0.24 to 0.53, P = 0.48).

For HbA1c, a random-effects model was used because the I 2 statistic indicated evidence for some heterogeneity (I 2 = 30%). The pooled SMD was −0.62 (−1.01 to −0.23), showing lower HbA1c concentrations after alcohol consumption compared with no alcohol consumption (P < 0.01) (Fig. 3).

Sensitivity Analyses and Meta-regression

Only the study by Contaldo et al. (20) used a high alcohol dosage (70 g/day) and measured insulin and glucose concentrations. Exclusion of this study from the meta-analysis resulted in generally similar results for insulin (SMD −0.18 [−0.36 to −0.01]) and glucose (SMD 0.06 [−0.12 to 0.23]).

Combining the two intervention arms of the studies by Davies et al. (9) with 15 and 30 g alcohol/day and those of Queipo-Ortuño et al. (33) with red wine and gin resulted in generally similar outcomes. The pooled SMD for insulin sensitivity (ISI and HOMA-IR) was 0.06 (−0.11 to 0.24) overall and 0.15 (−0.08 to 0.38) in women. For insulin, SMD was −0.18 (−0.38 to −0.01) overall and −0.22 (−0.43 to −0.02) in women. Including the nonrandomized crossover study by Cordain et al. (13) resulted in generally similar results for insulin (SMD −0.17 [−0.33 to 0.00]) and glucose (SMD 0.08 [−0.09 to 0.25]).

The meta-regression showed no influence of duration (all Ptrend > 0.60) and/or alcohol dosage (all Ptrend > 0.67) on the pooled SMD of ISI and HOMA-IR and of insulin and glucose. Additionally, the meta-regression showed no differences between results from the studies using the HEGC to measured insulin sensitivity and the other studies (SMD −0.03 for HEGC studies vs. 0.09 for other studies, P = 0.64).

Publication Bias

Results of the Egger and Begg tests showed publication bias for the outcomes of ISI, ISI and HOMA-IR, and glucose (Supplementary Table 2). Visual inspection of the funnel plots showed some asymmetry, which was due to missing results in favor of alcohol treatment from smaller studies (Supplementary Fig. 2). For ISI and HOMA-IR, we calculated an adjusted pooled SMD by using the trim and fill approach by Duval and Tweedie (18). This resulted in four extra study estimates (linear method used) and an adjusted pooled SMD of 0.17 (0.02–0.31, P = 0.03). The trim and fill method shows that without publication bias, the pooled SMD would probably indicate a positive effect of alcohol consumption on insulin sensitivity, whereas the unadjusted SMD did not show an effect (SMD 0.08 [−0.09 to 0.24], P = 0.35). The adjusted results and funnel plot are shown in Supplementary Table 2 and Supplementary Fig. 2.

Production of Ethanol | Microbiology

Microbial production of one of the organic feed stocks from plant substances such as molasses is presently used for ethanol production. This alcohol was produced by fermentation in the early days but for many years by chemical means through the catalytic hydration of ethylene.

In modem era, attention has been paid to the production of ethanol for chemical and fuel purposes by microbial fermentation. Ethanol is now-a-days produced by using sugar beet, potatoes, com, cassava, and sugar cane (Fig. 20.6).

Both yeasts (Saccharomyces cerevisiae, S. uvarum S. carlsbergensis, Candida brassicae, C. utilis, Kluyveromyces fragilis, K. lactis) and bacteria (Zymomonas mobilis) have been employed for ethanol production in industries.

The commercial production is carried out with Saccha­romyces cerevisiae. On the other hand, uvarum has also largely been used. The Candida utilis is used for the fermentation of waste sulphite liquor since it also ferments pentoses.

Recently, experimentation with Schizosaccharomyces has shown promising results. When whey from milk is used, strain of K. fragilis is recommended for the production of ethanol. It is also found that Fusarium, Bacillus and Pachysolen tannophilus (yeast) can transform pentose sugars to ethanol.

Theoretically, it is interesting to note that fermentation process retains most of the energy of the sugar in the form of ethanol. The heat of combustion of solid sucrose is 5.647 MJ mol-1, the heat of combustion of glucose is 2.816 MJ mol -1 but the heat release is 1.371 MJ mol-1.

The equations are given below:

Thus the above reactions show that 97% sugar transforms into ethanol. But in practice, the fermentation yield of ethanol from sugar is about 46% or one hundred grams of pure glucose will yield 48.4 grams of ethanol, 46.6 g of CO2, 3.3 grams of glycerol and 1.2 g of yeast. The biosynthesis of ethanol is given in Fig. 20.6.

It is noteworthy that the ethanol at high concentration inhibits the yeast. Hence, the concentration of ethanol reduces the yeast growth rate which affect the biosynthesis of ethanol.

It can produce about 10-12 % ethanol but the demerit of yeast is that it has limitation of converting whole biomass derived by their ability to convert xylulose into ethanol. The Zymomonas has a merit over yeast that it has osmotic tolerance to higher sugar concentration. It is relatively having high tolerance to ethanol and have more specific growth rate.

1. Preparation of Medium:

Three types of substrates are used for ethanol production:

(a) Starch containing substrate,

(b) Juice from sugarcane or molasses or sugar beet,

(c) Waste products from wood or processed wood. Production of ethanol from whey is not viable.

If yeast strains are to be used, the starch must be hydrolysed as yeast does not contain amylases. After hydrolysis, it is supplemented with celluloses of microbial origin so as to obtain reducing sugars. About 1 ton of starch required 1 litre of amylases and 3.5 litre of glucoamylases. Following steps are involved in conversion of starch into ethanol (Fig. 20.7).

On the other hand, if molasses are used for ethanol produc­tion, the bagasse can also give ethanol after fermentation. Several other non-conventional sources of energy such as aquatic plant biomass, wood after hydrolysis with celluloses gives ethanol. Sulphite waste-liquor, a waste left after production of paper, also contains hexose as well as pentose sugar. The former can be microbially easily converted.

Ethanol is produced by continuous fermentation. Hence, large fermenters are used for continuous manufacturing of ethanol. The process varies from one country to another. India, Brazil, Germany, Denmark have their own technology for ethanol production.

The fermentation conditions are almost similar (pH 5, temperature 35°C) but the cultures and culture conditions are different. The fermentation is normally carried out for several days but within 12h starts production. After the fermentation is over, the cells are separated to get biomass of yeast cells which are used as single cell protein (SCP) for animal’s feed.

The culture medium or supernatant is processed for recovery of ethanol (Fig. 20.6). Ethanol is also produced by batch fermentation as no significant difference is found both in batch and continuous fermentation.

Although as stated earlier within 12h Saccharomyces cerevisiae starts producing ethanol at the rate of 10% (v/v) with 10-20g cells dry weight/lit. The reduction in fermentation time is accomplished use of ceil recycling continuously in fermentation.

Ethanol can be recovered upto 95 percent by successive distillations. To obtain 100 percent, it requires to form an azeotropic mixture containing 5 percent water. Thus 5 percent water is removed from azeotropic mixture of ethanol, water and benzene after distillation. In this procedure, benzene water ethanol and then ethanol-benzene azeotropic mixture are removed so that absolute alcohol is obtained.

Neuberg’s Fermentation:

Yeasts utilize pyruvate during fermentation resulting in the formation of an intermediary product acetaldehyde.

This is trapped by hydrogen sulfite to yield the acetaldehyde in precipitated form and fluid product formation is glycerol as shown below:

Now in place of acetaldehyde, dihydroxyacetone phosphate acts as a hydrogen acceptor which is reduced to glycerol-3-phosphate.

After removal of phosphate i.e. dephosphorylation, it gives glycerol as given below:

Neuberg’s fermentation process is categorized as reward and third fermentation.

The first fermentation equation is given below:

2Glucose + H2O → C2H5OH + acetate + glycerol + 2CO2


All cells in the human body require glucose to survive. However excessive amounts of glucose can also be detrimental to the body. In order to maintain this balance the body uses hormonal regulation. The body will detect high levels of blood glucose and release insulin to allow the sugar into cells. If there is not enough blood glucose, glucagon will be released. This hormone will cause the formation of glucose and the release of glucose stores. If the body is presented with a threat it will initiate the sympathetic nervous system. Part of this response is the release of epinephrine which causes haptic glucose release. If the body can not properly regulate blood glucose levels than it may be a form of diabetes. Diabetes type one stems from an inability to produce insulin. Diabetes type two is due to an insensitivity to insulin. Due to the blood glucose regulatory systems wide reach on the body when alcohol which also has a whole body effect a reaction is bond to occur. Blood glucose levels may initially increase however this is only in the case of high carbohydrate alcoholic beverages, such as beer. Due to the metabolism of alcohol glucose will be turned into pyruvate and blood glucose levels will drop. Alcohol's effects on judgment are also likely to lead to a drop in blood sugar.


Of the 17 men recruited, 16 completed the alcohol intervention component of the study with one drop-out due to a non-study-related issue. Subjects ranged in age from 28 to 65 years (mean 51), were slightly overweight (mean BMI 26.4 ± 0.6 kg/m 2 ), normotensive, euglycemic, and normolipidemic (Table 1). At baseline, 92% of alcohol was derived from beer, a pattern maintained during intervention. The average drinking history at study entry was 21 ± 14 years. Substitution of low-alcohol beer was associated with an average decrease in self-reported alcohol intake of 89%, from a mean of 72 ± 5 to 8 ± 2 g/day (P < 0.001) (Table 1). This is equivalent to a reduction in intake from approximately seven to one standard drink per day (one standard drink = 10 g/day). There was a 24% decrease in the geometric mean of γ-GT in the low compared with the usual alcohol period (18.6 units/l [95% CI 15.5–22.2] vs. 24.4 units/l [19.7–30.2], P < 0.001) and a 17% reduction in HDL cholesterol (1.36 ± 0.07 vs. 1.13 ± 0.07 mmol/l, P < 0.001). Univariate regression showed that the changes in γ-GT and HDL cholesterol were each associated with the self-reported change in alcohol intake (regression coefficient B = 0.006, SE = 0.002, and adjusted R 2 = 0.329) and (B = 0.003, SE = 0.001, and adjusted R 2 = 0.224), respectively, consistent with compliance with restriction of alcohol intake during the low-alcohol period.

Mean weight was 0.9 kg heavier at the end of the usual alcohol period compared with that at the end of the low-alcohol period (Table 1). During the low-alcohol period, the subjects decreased their alcohol-derived energy intake by 485 kcal/day, whereas the frequency of drinking fruit juice and milk increased by 8 vs. 11 times/month (P < 0.05) and 13 vs. 18 times/month (P < 0.05), respectively. Weight was the only variable that had a treatment-order effect (i.e., the weight loss was greater for the group that reduced their alcohol intake in weeks 8–12, P = 0.05). However, with univariate regression the weight change was still associated with change in self-reported alcohol intake (B = 0.02, SE = 0.01, and adjusted R 2 = 0.179).

Baseline ISI (geometric mean 17.7 [95% CI 13.3–23.7]) was within the normal range of 12–32 previously seen in normal glucose-tolerant men (22). At baseline, mean daily alcohol intake was positively correlated (P < 0.05) with fasting insulin (r = 0.55) and HOMA score (r = 0.53), but these associations were no longer significant after controlling for BMI. Of the 16 men who completed the alcohol intervention, 12 underwent the complete set of three LDIGITs. During all of the LDIGITs, blood glucose levels increased during the first 30 min, declining thereafter, regardless of study phase. Insulin levels increased during the test, achieving plateau at 60 min. Table 1 shows details of the results from the LDIGIT with no statistical differences between alcohol intervention with respect to fasting and steady-state glucose and insulin values, fructosamine levels, HOMA score, or ISI.


Diminished tissue sensitivity to insulin is a characteristic of various pathological conditions termed the insulin resistance syndrome, also known as the metabolic syndrome or cardiometabolic syndrome [1]. The metabolic syndrome is not a single disease, but rather a complex cluster of symptoms that include a large waist circumference, hypertension, hyperglycermia, dyslipidemia and insulin resistance, all of which are commonly associated with increased risk of obesity and Type 2 Diabetes [2]. Since patients with metabolic syndrome are commonly afflicted with cardiovascular morbidities, the metabolic syndrome and cardiovascular diseases share common pathways including increased oxidative stress, defective glucose, lipid metabolism, low grade inflammation, hypercoagulability and endothelial damage. Previously, investigators proposed to use the “circulatory syndrome” to refine the metabolic syndrome concept through the addition of markers of cardiovascular diseases such as renal impairment, microalbuminuria, arterial stiffness and left ventricular dysfunction [2]. It has become increasingly obvious that insulin resistance and the efforts made by the insulin-targeted organs to compensate for this defect play a vital role in the pathogenesis and clinical course of the metabolic syndrome [3].

Insulin resistance and hypertension are the components of metabolic syndrome and often coexist [4]. Clinical studies have shown that about 50% of hypertensive individuals have hyperinsulinemia or glucose intolerance, whereas up to 80% of patients with type 2 diabetes have hypertension [4, 5]. In addition to its metabolic effects, insulin induces vasorelaxation by stimulating the production of nitric oxide (NO) in endothelium [6] and regulates sodium homeostasis by enhancing sodium reabsorption in the kidney [7, 8] thereby, contributing to the regulation of blood pressure. Recent studies have demonstrated that insulin resistance can develop not only in the classic insulin-responsive tissues, but also in cardiovascular tissues where insulin participates in the development of cardiovascular diseases and hypertension [1, 9]. Insulin resistance has gained a bad name and is perceived as deleterious: commonly associated with the metabolic syndrome and hypertension that confer an increased risk for type 2 diabetes and cardiovascular diseases [9]. However, in human evolutionary history, insulin resistance may be an essential part of normal homeostasis to facilitate redirection of nutrients to pivotal organs and a physiological adaptive mechanism to promote our ancestor’s survival in times of critical conditions such as, famine, infection, trauma and stress [10, 11]. The same mechanism may be inappropriately activated on a chronic basis on the current obesogenic environment, leading to the manifestation of hypertension, insulin resistance or metabolic syndrome [12]. This article reviews human evolution and the impact of modern environment on hypertension and insulin resistance.

Insulin resistance and elevation of blood pressure as an adaptive mechanism to promote human survival

Human survival has relied upon the ability to withstand starvation through energy storage, the capacity to fight off infection by an immune response, and the ability to cope with physical stresses by an adaptive stress response [11]. The physiological adaptation that is induced by the fasting state includes increased lipolysis, lipid oxidation, ketone body synthesis, endogenous glucose production and uptake and decreased glucose oxidation [13]. These processes are crucial for survival and serve to protect the organism from excessive loss of protein mass. Humans are extremely sensitive to glucose deficits, due to the large energy requirement (glucose) of the brain [11]. The requirement for energy storage is essentially served by the anabolic actions of insulin, during starvation or infection/inflammation it becomes insulin resistant, along with many other adaptations [12]. The way to maintain glucose levels during starvation, pregnancy and infection/inflammation is through insulin resistance in insulin-dependent tissues [12, 14].

Insulin is an anabolic hormone that plays an important role in the regulation of glucose, lipid homeostasis and energy storage through its metabolic effects on classic insulin-responsive tissues [1]. Specifically, insulin promotes the storage of glucose as glycogen in liver and skeletal muscles, and facilitates deposition of fatty acids in the form of triglycerides in adipose tissue [13]. During insulin resistance, insulin-mediated anabolic metabolic effects are inhibited in the classic insulin-responsive tissues. For example, adipose tissue and skeletal muscle reduce the uptake of glucose and storage of glucose as glycogen and triglycerides. Concommintently, there is an increase in the hydrolysis of stored triglycerides and their mobilization as free fatty acids and glycerol, in which the liver increases glucose production via gluconeogenesis and inhibition of glycogen synthesis and storage. Insulin resistance promotes reallocation of energy-rich substrates (glucose to the brain, fetus and immune system fat to the fetus and the organs) and the compensatory hyperinsulinemia [13]. Therefore, negative regulation of insulin signaling could be viewed as a physiologic ‘adaptive mechanism” that is activated in certain conditions such as fasting, inflammation, stress and pregnancy. However, its persistence at a chronic state is the basis of the ultimate changes that we recognize as the symptoms of the metabolic syndrome [11].

Insulin has complex vascular actions that appear as either vascular protective or deleterious effects [1]. Vascular protective effects of insulin, including induction of vasorelaxation, inhibition of vascular smooth muscle cell (VSMC) proliferation and anti-inflammation, are mediated by stimulating nitric oxide-dependent (NO) mechanisms in the endothelium [1]. Vascular deleterious effects of insulin include induction of vasoconstriction, VSMC proliferation and proinflammatory activity. These vascular effects are mediated through the mitogen-activated protein kinase (MAPK) pathway [1]. In addition, insulin increases sodium reabsorption in the kidney and promotes sympathetic nerve activity [8]. Insulin can be both inflammatory and anti-inflammatory [1, 15], in physiological condition insulin stimulates endothelial NO production to exert a vasorelaxation and anti-inflammatory effect. Whereas, in the state of insulin resistance, the insulin-stimulated NO pathway is selectively impaired and the compensatory hyperinsulinemia may activate MAPK pathway, resulting in enhancement of vasoconstriction, proinflammation, increased sodium and water retention and the elevation of blood pressure [15, 16]. The increased blood pressure by insulin resistance may contribute to increased blood perfusion to the brain during starvation and infection, and to the fetus during pregnancy.

Insulin resistance and hypertension are associated with an unhealthy lifestyle and a systemic low grade inflammation

Insulin resistance and hypertension are considered to be Western diseases. It has become clear that most, if not all, typically Western chronic diseases find their primary causes in unhealthy lifestyles and that systemic low grade inflammation is a common denominator [11, 17, 18]. Our ancestors (primitive humans) had to undertake considerable physical activity to gain food and had to adapt to prolonged period of famine [17], which favored fat storage, a trail inherited by modern man. Moreover, our modern lifestyle, characterized by energy- and sodium-rich Western diet, sedentary life and high psychosocial stress, favors positive energy balance. In the long term, this positive energy balance creates the need for surplus fat storage [18]. When the capacity for safe lipid storage in adipose tissue is exceeded lipids overflow to non-adipose tissue, increasing the risk for chronic systemic low grade inflammation and subsequent insulin resistance, hypertension and metabolic syndrome [19].

Obesity in humans may be considered as a symptom of energy imbalance: caloric intake exceeds energy expenditure [11]. The human organism has extensive fuel reserves in the adipose tissue, which may meet energy demands for substantial periods. The adipocyte is thought to be both a static storage depot for calories as triglycerides and an endocrine organ to secret many hormonal factors, including lipid mediators, stress kinases and proinflammatory cytokines and chemokines [11]. These molecules participate in regulating energy metabolism, lipid storage, and inflammatory responses. In addition, excess nutrient intake can induce oxidative stress in the adipose tissue [20]. Oxidative stress conversely exerts significant effects on adipose tissue biology and can lead to dysregulation of adipocyte function, which manifests as inhibited adipocyte differentiation, enhanced immune cell infiltration into adipocytes and increased inflammatory cytokine secretion [21].

Obesity-induced inflammation is associated with increased adipose tissue macrophage (ATM) infiltration [22, 23]. Similar to a pathogenic response to an invading bacterium, excess nutrients found in the obese adipose microenvironment can lead to the pro-inflammatory activation and phenotypic switch (from M2 resident to M1 inflammatory macrophage) of macrophage [24]. One of emerging feature of obesity-associated ATM infiltration is the linkage of the induction of a chronic inflammation in white adipose tissue (WAT) that eventually becomes systemic [22]. Excess WAT is an overactive endocrine organ secreting an array of inflammatory adipokines, such as tumor necrosis factor (TNFα), monocyte attractant protein 1 and interleukin 6(IL6) [24]. These inflammatory cytokines can not only induce a chronic inflammatory process in adipocyte tissue, but also be released into circulatory blood, inhibiting insulin signaling resulting in global insulin resistance [25]. Therefore, chronic inflammation in obesity plays a critical role in pathogenesis of insulin resistance [26]. Ironically, the formation of a systemic and/or local tissue-specific insulin resistance due to inflammatory cell activation may actually be a protective mechanisms that co-evolved with the repartition of energy sources within the body during times of stress and infection [12].

Hypertension is also associated with increased systemic and vascular inflammatory responses and oxidative stress, which may contribute to vascular dysfunction [4, 16]. Although the genetic causes of essential hypertension remain elusive, studies in Dahl salt-sensitive (DS) rat, a paradigm of salt-sensitive hypertension in human, have suggested that chromosome 2 contains quantitative trait loci for blood pressure and genes encoding inflammatory mediators with biological effects on T lymphocytes [27]. DS rats exhibit elevation of blood pressure, vascular inflammation, oxidative stress and endothelial dysfunction. These symptoms are reduced in the SSBN2 rat, a consomic rat, in which chromosome 2 of the DS rat is replaced by that of the normotensive Brown Norway rat [27]. Studies [16, 28] in DS rats have shown that oxidative stress and activated oxdative stress-associated inflammation are linked not only to elevation of blood pressure and vascular dysfunction but also to insulin resistance, Moreover, antioxidant treatment and inhibition of the nuclear factor κ B inflammatory pathway in DS rats reduced blood pressure, vascular inflammation, and improved endothelial function, as well as, systemic and vascular insulin resistance. These studies support the notion that inflammation is a link between hypertension and insulin resistance [26].

Link between insulin resistance and hypertension: what is the evidence from evolutionary biology?

Evolution by natural selection is a central organizing concept in biology. For millions of years, living creatures from lower-level organisms to human beings have been faced with survival stresses, including famine and infection [11]. The survival of multicellular organisms depends on the organism’s ability to store energy for times of low nutrient availability or high energy needs, and the ability to fight infections [29]. To meet the challenges of infection and other environmental stress, an activated immune system has an urgent need for energy-rich substrates that must be allocated from internal and external energy stores (glycogen, proteins, triglycerides, or free fatty acids) [30]. An activated immune system usually requires substantial energy in a quiescent state. This requirement rises into an active phase of inflammation [30]. Therefore, the metabolic and immune systems are among the most basic requirements across the animal kingdom [19, 31]. It is not surprising then that metabolic and immune pathways have evolved to be closely linked and interdependent and that the genes controlling metabolic and pathogen-sensing systems have been highly conserved from lower-level organisms to mammals [32]. In recent years, new insights have been gained through multiple interactions between metabolic and immune system [19, 32]. An increasing body of evidence suggests that energy metabolism is crucial for the maintenance of chronic inflammation, not only in terms of energy supply, but also in the control of the immune response through metabolic signals [11, 33]. It is now apparent that critical proteins are necessary for regulating energy metabolism, such as peroxisome proliferator-activated receptors (PPAR γ), Toll-like receptors, and fatty acid-binding proteins. These critical proteins also act as links between nutrients metabolism and inflammatory pathway activation in immune cells [34, 35]. For example, PPAR-γ a master regulator of adipocyte differentiation, is also a major molecule that drives the accumulation and phenotype of T reg cells in adipose tissue [34] and leptin, an important adipocyte-derived hormone to regulate energy homeostasis, can affect thymic homeostasis and the secretion of acute-phase reactants such as IL-1 and TNF α [36].

Under normal conditions, the integration of the metabolic and immune systems is fundamental for the maintenance of good health. The basic inflammatory response favors a catabolic state and inhibits anabolic pathways, such as the highly conserved insulin signaling pathway, resulting in insulin resistance [37]. As a result of insulin resistance, plasma levels of glucose are elevated to provide energy sources, maintain the function of vital organs, such as, the heart, brain, and immune cells, and combat infection. As the heart, brain and leukocytes are considered as insulin insensitive tissues [14], their energy metabolism is acutely dependent on plasma levels of glucose [18]. Therefore, insulin resistance resulting from acute inflammatory episodes may favor nutrient poor organisms to fight against infection. However, since most aspects in a living body occur with constraints on energy availability, regulation of energy storage and provisions occupy a very high position in the hierarchy of homeosotatic neuroendocrine immune control [38]. Energy regulation operates not only in the cell, but also in coordinating centers of the brain, and in endocrine organs that integrate organismal functions [37].

The time frame of an organism’s response to the acute inflammatory episode may reflect an adaptive natural selection mechanism for the coordination of the immune and energy system to fight against infection [39, 40]. An acute infectious disease can be self-limiting, and may involve an innate immune response of 2-3 days the subsequent phase of the adaptive immune response can last approximately 3 to 4 weeks [40]. Not only does the infection-induced impairment in health and the related anorexia exacerbate a significant reduction in intake of energy-rich substrates but an acute infectious disease can also be very energy consuming. Therefore, organisms must obtain the fuel from energy storage tissues, which primarily occur in fat tissue and skeletal muscle [11, 41]. However, an increase of inflammatory cytokines released from infectious tissue into circulatory blood may result in fat and muscle insulin resistance to reduce energy consumption in these tissues, Additionally, a compensated hyperinsulinemia, high glucose and hyperlipidemia favor the body against infection [11]. While the energy from muscle and fat tissues usually last 3-5 weeks, perfectly matching an adaptive immune response to combat the infection [42]. Unfortunately, if an adaptive immune system cannot appropriately react within this time frame, the affected individual may die from energy exhausted [30].

With the exception of an energy requirement, acute inflammation is often accompanied by local and systemic water loss. Water loss includes local water loss from the exposed surface area of inflamed tissue as well as systemic water loss from insensible perspiration through skin and respiratory tract, and more metabolic water for higher metabolic reaction [40]. To overcome a systemic water loss during acute inflammatory episodes, a water retention system must be activated [40]. The reactive mechanism for water retention includes activation of sympathetic nervous system which subsequently results in activation of renin-angiotensin-aldosterone system, and activation of hypothalamic-pituitary-adrenal (HPA) axis with adrenocorticotropic hormone (ACTH), aldosterone and cortisol [40]. Interestingly, some hormones that mediate water retention such as angiotensin II and aldosterone are also endowed with proinflammatory effects [43], and has an important role in the pathogenesis of hypertensive and metabolic diseases [9].

The water retention system shows important similarities with the energy provision system. The operation of these two interacting systems were likely subject to positive selection and co-evolved to overcome serious and transient inflammatory episodes [40]. Induction of energy storage system and water retention system provides a survival mechanism in response to acute inflammatory episodes. However, prolonged operation of these adaptive programs such as in chronic inflammatory process, which are currently observed in many cardiovascular, hypertensive and metabolic diseases, can become pathogenic because there is no program to counteract continuous water retention and energy appeal actions [10, 11].

Is sodium another link between hypertension and insulin resistance?

Essential hypertension can be classified as salt-sensitive and salt-resistant, according to the blood pressure response to salt loading. Animal and clinical studies suggest that insulin resistance and hypertension are associated with salt-sensitivity [44, 45]. High salt diet impairs insulin sensitivity in hypertensive patients with salt-sensitivity but not in those with salt-resistance [5]. There is a strong clustering of markers of endothelial damage in persons predisposed to salt-sensitive hypertension who concomitantly have insulin resistance and microalbuminuria [45].

Salt sensitivity of blood pressure is an independent risk factor for development of cardiovascular morbidity and mortality [5]. The essential hypertensive patients with salt sensitivity are more insulin resistant than those with salt-resistance. Furthermore, high salt diet impairs insulin sensitivity only in hypertensive patients with salt-sensitivity but not in those with salt-resistance, suggesting that there is a pathogenetic link among hypertension, salt-sensitivity and insulin resistance [4, 28]. A recent clinical study has shown that insulin resistance enhances the blood pressure response to sodium intake 21 . Therefore, reduction in sodium intake may be an especially important component in reducing blood pressure in patients with multiple risk factors for insulin resistance and the metabolic syndrome [46].

The human propensity for hypertension is a product, at least in part, of our evolutionary history [47]. The evolution of hypertension susceptibility has been hypothesized to begin in Africa. With the hot and humid climate, effective heat dissipation is essential in hot environments and is achieved most efficiently through evaporative heat loss [47]. However, sweating due to the hot climate and excessive labor activities can lead to a large loss in the amount of salt and water, and eventually lead to hypovolemia, a threat to human survival. In addition, human and nonhuman primates living in ancient times had very low salt intake available. Low salt intake and large salt losses due to sweating had created robust salt appetite and renal sodium conservation, which were essential to survival. The principle of natural selection may have allowed the ancestral sodium-conserving genotype (thrifty) to persist [48], which may be maladaptive to the modern environment of sodium abundance, resulting in hypertension. An analogous evolutionary framework, sometimes referred to as the sodium-retention hypothesis, was proposed to explain the increased prevalence of essential hypertension in some ethnic groups. Briefly, ancient human populations living in hot, humid areas adapted to the environment by retaining salt. Whereas populations in cooler, temperate climates adapted to conditions of higher sodium levels [47, 48]. Experimental evidence from trials of dietary sodium restriction generally supports the hypothesis of a sodium-hypertension link, particularly among salt-sensitive populations [49]. In support of this hypothesis, a study recently found that African Americans have a higher prevalence of salt sensitivity than White Americans [50].

Evidence suggests that genetic susceptibility to hypertension is ancestral [47]. Ancestral alleles increase the risk of hypertension and the derived protective alleles appear to carry the signature of positive selection at tightly linked neutral sites. For example, chimpanzees and humans share hypertension susceptibility alleles in at least two genes: angiotensinogen (AGT) and the epithelial sodium channel γ subunit (ENaCγ), genes involved in the regulation of sodium and blood pressure homeostasis [39]. AGT carries two variants: a promoter A-6G variant and the T235M variant, which are associated with hypertension [40]. Human genomic studies suggest that the genetic origins of susceptibility to common chronic disease are due to adaptations to ancestral environments [47], these alleles improved survival in ancestral environments characterized by salt scarcity, low-calories diets, and regular physical activity [39]. In the current environment of salt and caloric excesses and infrequent physical activity, these alleles can be detrimental, leading to obesity, type 2 diabetes and hypertension [48].

In salt-sensitive hypertension, the accumulation of sodium in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids. Recent studies [51, 52] suggest that immune cells, such as mononuclear phagocyte system and macrophages, are responsible for interstitial hypertonic sodium retention, resulting from high salt diet intake, and stimulate lymphcapillary network formation via production/release of tonicity-responsive enhancer binding protein and vascular endothelial growth factor C. Notably, vascular endothelial growth factor C may serve as an extra sodium and water storage in skin to buffer extracellular volume expansion and maintain blood pressure homeostasis [51]. Deletion of the mononuclear phagocyte system or inhibiting the interaction of VEGF-C with its receptors (VEGF receptor 3 and/or VEGF receptor 2) blocked the regulatory response of mononuclear phagocyte system to interstitial sodium accumulation and augmented salt-induced hypertension, suggesting that immune system plays the role in the regulation of sodium and water homeostasis.

Interestingly, insulin has been shown to inhibit sodium excretion by increasing sodium reabsorption in the kidney [8]. It is well known that sodium is the main determinant of body fluid distribution. Sodium accumulation causes water retention and often, high blood pressure. Sodium transport through various nephron segments, is quite important in regulating sodium reabsorption and blood pressure [8]. ENaC and sodium proton exchanger type 3 (NHE3) are main mediators to regulate sodium reabsorption in renal tubules. It has been shown that insulin can regulate ENaC and NHE3, therefore increasing renal tubular sodium reabsorption [8, 53]. As mentioned earlier, like energy storage, insulin-mediated sodium preservation may be an adoptive mechanism for human survival during ancient time [7, 54].

Thrifty hypothesis

Natural selection shapes organisms in functioning within a particular set of environmental conditions [55]. Because organisms adapt to the totality of their environment, or ecological niche, it is hypothetically possible that natural selection favors organisms harboring the genotype for a metabolic system (such as the insulin signaling pathway) that has an increased response to inflammation [48]. Since regulation of energy storage and metabolism and the preservation of body fluids are critical for organism’s fight against famine, infection and physical stress, it has also been hypothesized that genes responsible for energy regulation and sodium preservation have been positively selected [48]. These genes were termed thrifty genes. The notion of thrifty genotype was initially proposed by Neel [56], in which he argued that certain genotypes were selected into the human genome because of their selective advantage over the less thrifty genes. Neel [56] defined a thrifty genotype as “being exceptionally efficient in the intake and/or utilization of food”. In ancient time, food supply was never consistent. Thus, it is contended that the ancient hunter-gatherer had cycles of feast and famine, punctuated with obligate periods of famine, and certain genes evolved to regulate efficient intake and utilization of fuel stores [14, 56]. Subsequently, during famines, individuals with the thrifty genotype would have a survival advantage because they relied on larger, previously stored energy to maintain homeostasis [14]. Based on Neel’s thrifty genotype hypothesis, it is proposed that a genetic predisposition in developing diabetes was adaptive to the feast and famine cycles of Paleolithic human existence, allowing humans to fatten rapidly and profoundly during times of feast so that they may have a higher chance of survival during times of famine [55, 56]. This would have been advantageous back then, but not in our current environment, as the current environment provides ready abundant energy rich food. Thus, the preserved thrifty genes that co-regulate energy storage and immune system may actually promote the development of obesity or type 2 diabetic mellitus [55].

Neel’s thrifty gene hypothesis has been challenged many times. One of the most significant problems for the thrifty gene hypothesis is that it predicts that modern hunter-gatherers should get fat in the periods between famines, but data on the body mass index of modern hunter-gatherer does not support this [57]. An alternative hypothesis, called the thrifty phenotype hypothesis, has been proposed. Thrifty phenotype hypothesis emphasizes life-course plasticity in the aetiology of variability in body composition and metabolism, and thrifty factors arising from a direct result of the environment within the womb during development [58]. The development of insulin resistance is theorized to be directly related to the body “predicting” a life starvation for developing fetus [58]. Another theory, thrifty epigenomic hypothesis, argues that an individual’s risk for metabolic diseases is primarily determined by epigenetic events, epigenetic modifications at many genomic loci alter the shape of thrifty genotype in response to environmental influences and thereby establish a predisposition for metabolic syndrome [59].

The concept of thrift has been widely associated with adiposity [14]. Recent studies emphasize that adiposity, like stature, is a polygenic trait, and that population genetic variability primarily comprises different frequencies of particular alleles, rather than major systematic differences [14, 60]. Ethnic differences in body composition, representing different load-capacity ratios, may contribute to ethnic variability in metabolic risk. Lower lean mass and greater adiposity each indicate thrift. It has been proposed that body composition phenotypes, including the fat-lean ratio, the organ-muscle ratio, the central –peripheral ratio and the expandability of adipose tissue, are relevant to variability in the metabolic syndrome [60].

How Does Alcohol Raise and Lower Blood Sugar?

Alcohol and Blood Sugar When You Have Diabetes…

The liver’s functionality is an important part of understanding how alcohol affects blood sugar. Your liver is a key component when it comes to regulating your blood sugar levels throughout the day. When you drink, it impacts the liver and, more specifically, its ability to release glucose into your bloodstream as it’s supposed to. Alcohol impairs liver function and can keep your liver from releasing enough glycogen to keep your blood glucose levels from going too low. So, if you have diabetes, drink alcohol and take insulin as a medicine, you may experience hypoglycemia.

With alcohol and blood sugar, blood sugar can increase, then decrease to a dangerous point. This occurs because alcohol is high in sugar, causing an initial spike. Your body releases insulin to bring this high sugar level down and inhibits the release of more sugar from the liver. This causes your blood sugar to initially spike, then to decrease. This can be especially dangerous if you are using insulin or other diabetes medications because it can lead to hypoglycemia.

Along with the potential for your blood sugar level to go too high or low, many medicines for diabetes aren’t compatible with drinking alcohol. If you do have diabetes and you’re concerned with alcohol and blood sugar interactions, you should plan on checking your levels both before and after drinking. It’s also important to check levels before going to bed to make sure that you don’t enter into a period of hypoglycemia while you’re asleep. Be especially careful about medicating high sugar levels caused by alcohol use, as these can drop suddenly, causing a dangerous episode of hypoglycemia.