what are the consequences of ethanol metabolism to the maintenance of blood glucose levels?

Abstruse

Background

Ingestion of the calorically dense compound booze may cause metabolic disturbances including hypoglycaemia, hepatic steatosis and insulin resistance, but the underlying mechanisms are uncertain. The gastrointestinal tract is well recognised every bit a major influencer on glucose, protein and lipid metabolism, but its role in alcohol metabolism remains unclear.

Objective

To examine the effects of oral and intravenous alcohol, respectively, on plasma concentrations of several gluco-regulatory hormones including serum/plasma insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-one) and fibroblast growth factor 21 (FGF21).

Design and methods

In a double-blinded, randomised, crossover design, we subjected 12 healthy men to intragastric ethanol infusion (IGEI) and an isoethanolaemic intravenous ethanol infusion (IVEI) (0.7 grand booze per kg body weight), respectively, on 2 separate experimental days.

Results

Isoethanolaemia during the two booze administration forms was obtained (P = 0.38). During both interventions, plasma glucose peaked after ~30 min and thereafter roughshod below baseline concentrations. GIP and GLP-i concentrations were unaffected by the two interventions. Insulin concentrations were unaffected by IGEI just decreased during IVEI. C-peptide, insulin secretion rate and glucagon concentrations were lowered similarly during IGEI and IVEI. FGF21 concentrations increased dramatically (ix-fold) and similarly during IGEI and IVEI.

Conclusions

Alcohol does not seem to affect the secretion of incretin hormones but decreased insulin and glucagon secretion independently of gut-derived factors. IGEI also as IVEI potently stimulate FGF21 secretion indicating a gut-independent effect of alcohol on FGF21 secretion in humans.

Introduction

The majority of the world's population consumes booze occasionally and alcohol-related diseases correspond a major healthcare burden worldwide (i). Consumption of alcohol is related to several metabolic processes affecting glucose metabolism (2). It is well known that astute booze ingestion increases the risk of hypoglycaemia; most likely due to inhibitory effects of booze on hepatic gluconeogenesis (iii). In add-on, it is well known that chronic alcohol consumption may crusade hepatic steatosis which in some individuals leads to insulin resistance and impaired glucose tolerance (4, five). However, the exact mechanisms underlying these pathophysiological processes accept not been identified. Alcohol has been found both to increase and subtract serum insulin concentrations under various conditions and assistants forms (6, 7, 8), and results from studies investigating the effect of alcohol on plasma glucagon concentrations are ambiguous as well (9, 10). Besides, the effect of alcohol on the secretion of the gut-derived insulinotropic incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide ane (GLP-one) remains unclear (half-dozen, eleven, 12). Recently, alcohol was shown to institute a strong stimulator of the liver-derived hormone fibroblast growth cistron 21 (FGF21) in humans (13, xiv). In rodents, FGF21 has been shown to increase insulin sensitivity (xv) and decrease hepatic glucose production, and thus, play an important role in the regulation of plasma glucose concentrations. In humans, FGF21 is mainly secreted from the liver in response to fructose (sixteen), high-saccharide diet (17) and oral alcohol ingestion (13, xiv). It is not known how alcohol mediates FGF21 secretion and information technology remains obscure whether pancreatic or gut-derived hormones are involved in alcohol-induced secretion of FGF21.

The gastrointestinal tract plays a major part in glucose, poly peptide and lipid metabolism; and energy-rich macronutrients, that is, carbohydrate, protein and lipid, stimulate insulin secretion to a larger extent when administered orally compared to intravenously (18, nineteen, 20, 21). This miracle is called the incretin upshot and is due to nutrient-induced secretion of GIP and GLP-1 from enteroendocrine Chiliad and L cells, respectively. It remains unknown whether the calorically dense compound alcohol, which can be considered a macronutrient, induces an incretin effect, and the furnishings of intragastric ethanol infusion (IGEI) and isoethanolaemic intravenous ethanol infusion (IVEI), respectively, have never been evaluated.

In this study we investigated (1) if alcohol elicits an incretin effect, (2) the potential function of the gut in alcohol metabolism and (3) alcohol'southward effect on glucose metabolism.

Materials and methods

Approval and ethics

The study was approved by the Scientific-Ethical Committee of the Capital Region of Denmark (identification no. H-16026085) and the Danish Data Protection Agency and registered on Clinicaltrials.gov (clinical trial Identifier: NCT03348371). The study was conducted co-ordinate to the Helsinki Declaration Ii and written informed consent was obtained from all participants.

Subjects

We included 12 healthy Caucasian men between 20 and l years of age (characteristics in Tabular array 1). Key inclusion criteria were body mass index (BMI) between 19 and 25 kg/thou², weekly alcohol intake of less than fourteen units of booze (1 unit = 12 k alcohol), fasting plasma glucose <6 mmol/L, haemoglobin A1c <vi% (<42 mmol/mol), normal haemoglobin and written informed consent. Key exclusion criteria were liver disease or other alcohol-related disease and nephropathy and beginning-degree relatives with blazon ane diabetes, type ii diabetes and/or liver affliction.

Table 1

Characteristics of participants.

Participants (n = 12)	Mean ±south.d.
Sex (male/female)	12/0
Historic period (years)	25 ± iii.9
Body weight (kg)	77 ± 7.9
Meridian (m)	ane.85 ± 0.1
Body mass alphabetize (kg/g²)	23 ± 2.6
Fasting plasma glucose (mmol/L)	5.2 ± 0.four
Haemoglobin A1c (%)	five.3 ± 0.iv
Haemoglobin A1c (mmol/mol)	30 ± 2.8
HOMA2-IR	0.7 ± 0.two
ALAT (U/L)	28 ± eleven
Creatinine (μmol/L)	87 ± 12

ALAT, alanine aminotransferase; HOMAR2-IR, homeostasis model assessment 2 of insulin resistance (44); south.d., standard departure.

Experimental procedures

The report comprised ii split up experimental days performed in randomised order (using a randomisation list generated from www.random.org). On the experimental days, the participants received an infusion of alcohol either via an intravenous catheter or intragastrically through a nasogastric tube (to ensure blinding and avoid the initial metabolism of alcohol in the mucosa of the mouth (22)). The alcohol infusions were designed (see below) to obtain isoethanolaemia on the two written report days. The road of alcohol assistants was double-blinded using similarly looking saline infusions administered simultaneously via the opposite route of administration, that is, intravenous placebo was given on the day of intragastric alcohol administration and vice versa. A laboratory technician was responsible for preparing the infusions; this person was otherwise not involved in the study. The participants abstained from alcohol intake for five days prior to each of the experimental days and met after an overnight fast (10 h). An intravenous catheter was inserted into an antecubital vein in each arm; one for infusion (alcohol or placebo) and one for blood sample collection, and a nasogastric tube was inserted. The hand of the forearm, from which blood samples were drawn, was wrapped in a heating pad (~42ºC) throughout the experiment for arterialisation of the blood. At time signal 0 min, the participants received alcohol (0.70 one thousand booze per kg trunk weight (xx% alcohol solution (v/w)) mixed in isotonic saline water, equivalent to 20.3 kJ per kg body weight) or placebo (saline) via the gastric tube for five min or alcohol (same amount) was infused for 45 min through the intravenous catheter. The time for the intravenous infusion was based on a report made by Christiansen et al. (viii) in which a bolus of 0.66 g alcohol/kg was given orally and peaked after 45–60 min. Claret samples were sampled at time points −30, −15, 0, fifteen, thirty, 45, 60, 90, 120, 180 and 240 min. For bedside measurement of plasma glucose, claret was collected in sodium-fluoride tubes and centrifuged (7400 grand ) immediately for xxx s. For the analyses of insulin and C-peptide in serum, blood was sampled in obviously tubes and left to coalesce for 20 min. For analyses of FGF21, GIP, GLP-1 and glucagon in plasma, blood was nerveless in chilled EDTA tubes containing EDTA and a specific dipeptidyl peptidase 4 (DPP-4) inhibitor (valine pyrrolidide, 0.01 mmol/Fifty, Novo Nordisk). For the analysis of alcohol, claret was collected in lithium-heparin tubes. All tubes were centrifuged for 15 min at 2000 g and 4°C. Plasma and serum samples were stored at −xx and −80°C, respectively, until analyses.

Analyses

Glucose was analysed on a glucose analyzer (YSI 2300 STAT glucose analyzer, Xylem Inc., Xanthous Springs, OH, USA). Plasma alcohol was analysed past reflectance photometry at 340 nm (Vitros, Ortho-Clinical Diagnostics). Serum insulin and C-peptide were analysed with two-sided electrochemiluminescence assays (Roche/Hitachi Modular Analytics; Roche Diagnostics). Total plasma GLP-1 (23), full plasma GIP (21) and glucagon (24) were measured by RIAs as previously described. Intact (i.east. full-length and active) plasma FGF21 was analysed by ELISA using detection and capture antibodies targeted to the North and C-termini of the full-length human being poly peptide (EagleBiosciences, Nashua NH, USA True cat#: F21K31-K01) (13).

Calculations and statistical analysis

Baseline values for each endpoint were calculated as a mean of time points −30, −15 and 0 min for the plasma/serum samples. Area nether the curve (AUC) was calculated by the trapezoid rule and compared with paired t tests. Changes over time were calculated using two-way repeated-measures ANOVA and Tukey's multiple comparison was used to examination for differences over time, betwixt booze administration forms and for the interaction between intervention and time. Differences resulting in P values <0.05 were accepted as statistically significant. Statistical analyses and graphs were made using GraphPad Prism 7.02 (GraphPad Software, Inc.). Data are presented as hateful ±s.d. unless otherwise stated.

Insulin secretion rates (ISRs) were calculated using EasyISEC 1.01 software based on C-peptide concentrations, age, height, weight and population-based variables for C-peptide kinetics as previously described (25). Insulin/glucose ratio was calculated for each data point. Insulinogenic index was calculated as the insulin delta value from baseline to 30 min divided by the glucose delta value from baseline to 30 min (Δinsulin_{0–30 min}/Δglucose_{0–thirty min}) (26). The presented gluco-metabolic results represent a sub-written report of an investigation of hepatic inflammation (unpublished). Therefore, the sample size was calculated to discover a minimal divergence of 15% in the inflammation marker CD163.

Results

Characteristics of participants are shown in Table 1. During the experiments, none of the participants reported unpleasant symptoms of intoxication like nausea, headache or vomiting. Three of the participants developed self-limiting superficial phlebitis afterward the alcohol infusion. Ane of the participants experienced symptomatic hypoglycaemia (plasma glucose 2.nine mmol/L) 180 min after receiving IVEI after which the participant received a cup of juice to prevent further drop in plasma glucose. Therefore, just 11 participants are included in the ii-way repeated-measurement ANOVA.

Alcohol

All participants started with a plasma ethanol concentration of 0 g/L on both days. Plasma concentrations increased immediately, rapidly and similarly afterward the 2 alcohol administration forms (Fig. 1A, Table ii). At that place were no significant differences in plasma alcohol concentrations between the two assistants forms; therefore, isoethanolaemia was obtained (P = 0.38) (Fig. 1A and B, Table 2).

Table ii

Alcohol, glucose, insulin, C-peptide, glucagon, GIP, GLP-1 and FGF21.

Assistants form:	IGEI	IVEI	T test (P values)
Alcohol
Baseline (g/50)	0 ± 0	0 ± 0
AUC_{0–240 min} (g/L × min)	251 ± 26	256 ± 30	0.38
Peak plasma concentration (g/L)	ane.7 ± 0.3	1.8 ± 0.3	0.22
Fourth dimension to peak (min)	38 ± 18	44 ± four.3	0.24
Glucose
Baseline (mmol/50)	four.ix ± 0.iii	iv.9 ± 0.two	0.54
AUC_{0-240 min} (mmol/Fifty × min)	1177 ± 65	1127 ± 186	0.30
Peak plasma concentration (mmol/50)	5.three ± 0.4	5.3 ± 0.3	0.34
Fourth dimension to superlative (min)	36 ± 53	54 ± 60	0.65
Insulin
Baseline (pmol/L)	53 ± 19	50 ± xviii	0.67
AUC_{0-240 min} (pmol/L × min)	12 ± four.0	11 ± 3.7	0.18
Nadir (pmol/L)	36 ± xiv	27 ± 12	0.04
Time to nadir (min)	86 ± 98	55 ± 40	0.23
C-peptide
Baseline (pmol/L)	321 ± 72	325 ± 87	0.82
AUC_{0-240 min} (pmol/L × min)	69 ± 17	69 ± 21	0.95
Nadir (pmol/L)	242 ± 58	235 ± 74	0.77
Time to nadir (min)	151 ± 106	105 ± 91	0.08
Insulin secretion rate
Baseline (pmol/kg/min)	i.one ± 0.three	1.1 ± 0.three	0.98
AUC_0-240 (pmol/kg/min × min)	220 ± 56	219 ± 53	0.97
Nadir (pmol/kg/min)	0.6 ± 0.2	0.7 ± 0.2	0.94
Time to nadir (min)	93 ± 104	86 ± 89	0.88
Insulin/glucose ratio
Baseline (pmol/mmol)	11 ± ii.7	10 ± 2.5	0.lx
AUC_0-240 (pmol/mmol × min)	2504 ± 786	2153 ± 687	0.20
Nadir (pmol/mmol)	7.0 ± ii.5	5.3 ± 1.8	0.04
Time to nadir (min)	61 ± 88	44 ± 4.1	0.52
Beta cells
Insulinogenic alphabetize	−29 ± 88	−127 ± 152	0.05
Glucagon
Baseline (pmol/L)	6.0 ± 3.viii	v.1 ± 1.7	0.45
AUC_{0-240 min} (pmol/L × min)	1013 ± 678	1227 ± 552	0.20
Nadir (pmol/L)	2.2 ± 1.5	2.5 ± 1.6	0.37
Time to nadir (min)	41 ± 34	40 ± 27	0.91
GIP
Baseline (pmol/L)	17 ± 7.7	15 ± 4.6	0.fourteen
AUC_{0-240 min} (pmol/L × min)	2479 ± 1071	2496 ± 1240	0.96
Peak plasma concentration (pmol/50)	xviii ± five.6	xviii ± 7.eight	0.89
Time to peak (min)	70 ± 81	160 ± 73	0.01
GLP-1
Baseline (pmol/L)	19 ± 7.9	21 ± 9.4	0.52
AUC_{0-240 min} (pmol/L × min)	5093 ± 2103	4266 ± 1707	0.24
Peak plasma concentration (pmol/Fifty)	30 ± ix.two	30 ± 7.9	0.67
Time to peak (min)	44 ± 34	65 ± 113	0.56
FGF21
Baseline (pg/mL)	31 ± 35	30 ± 35	0.89
AUC_{0-240 min} (pg/mL × min)	37,738 ± 27,855	32,592 ± 20,728	0.21

Glucose

Baseline plasma glucose concentrations were similar before IGEI and IVEI, respectively (P = 0.54) (Tabular array 2). Plasma glucose concentrations showed significant changes over fourth dimension (P < 0.0001) merely not betwixt interventions (P = 0.66) or for time × intervention (P = 0.21). During both alcohol administration forms, plasma glucose concentrations increased by ~0.iv mmol/L and hereafter slowly decreased to reach significantly lower concentrations compared to baseline afterwards 240 min (iv.5 ± 0.4 mmol/Fifty (P = 0.009) and 4.six ± 0.2 mmol/L (P = 0.002) after IGEI and IVEI, respectively) (Fig. 1C). AUCs for plasma glucose were like during IGEI and IVEI (P = 0.20) (Fig. 1D, Table 2).

Insulin and C-peptide

We observed no meaning differences between serum insulin concentrations at baseline or between AUCs during the two administration forms (Fig. 2A and B, Table two). Serum insulin concentrations were unaffected by IGEI, whereas the concentrations declined to a mean nadir of 27 ± 12 pmol/L (P < 0.0001 and P = 0.04 compared to baseline and nadir of IGEI, respectively) at 55 ± 40 min during IVEI later which concentrations increased towards baseline (Fig. 2A). A pregnant difference was seen over time (P < 0.0001) and for time × intervention (P = 0.0064), but non for intervention (P = 0.18) evaluated using 2-fashion repeated-measures ANOVA. Pregnant differences betwixt serum insulin concentrations during IGEI and IVEI were observed for time points fifteen, 30 and 45 min (P = 0.013, P = 0.004 and P = 0.001, respectively) (Fig. 2A). Insulin/glucose ratio fell significantly afterward booze assistants compared to baseline (P < 0.0001 after both IGEI and IVEI); even so, nadir afterwards IVEI was significantly lower compared to IGEI (P = 0.04) (Fig. 3C and D, Table 2). Serum C-peptide concentrations were like at baseline and decreased similarly afterwards both alcohol administration forms to reach concentrations below normal range for good for you individuals (27) and significantly below baseline concentrations (P < 0.0001 for both IGEI and IVEI) (Fig. 2C and D, Tabular array ii). At that place was no divergence between baseline values and AUCs for ISR during the ii administration forms (Fig. 3A and B, Tabular array 2). ISR barbarous similarly and significantly after both alcohol administration forms compared to baseline (P < 0.0001 later both IGEI and IVEI). Beta cell function evaluated by insulinogenic index was more reduced later on IVEI compared to IGEI (P = 0.05) (Table two).

Glucagon

Baseline plasma glucagon concentrations were like on the two experimental days and decreased significantly (P = 0.0004 and P < 0.0001 for IGEI and IVEI, respectively) and similarly compared to baseline subsequently both forms of alcohol administration, reaching mean nadirs at time point 40 ± 27 min (IVEI) and time betoken 41 ± 34 min (IGEI), respectively, afterwards which glucagon concentrations returned towards baseline concentrations (Fig. 4A and B, Table ii).

GIP and GLP-1

Baseline plasma concentrations of GIP and GLP-1, respectively, were similar on both experimental days and no meaning differences in GIP or GLP-one responses (every bit assessed by AUCs) were observed between IGEI and IVEI (Fig. 5A and B, Table 2). Similar tiptop plasma GLP-1 (P = 0.67) and GIP (P = 0.89) concentrations, respectively, were observed during IGEI and IVEI. We observed a minor merely significant variation over time in both plasma GIP (P < 0.0001) and plasma GLP-1 (P = 0.01) concentrations during the two experimental days. For plasma GIP a significant difference was seen for fourth dimension × intervention (P = 0.0001), merely non for intervention (P = 0.10) evaluated using 2-way repeated-measures ANOVA. A difference was observed between IGEI and IVEI at the fourth dimension points 15, 30 and 60 min (P = 0.005, P = 0.005 and P = 0.0004, respectively) (Fig. 5A and B).

FGF21

There was no pregnant difference between baseline plasma FGF21 concentrations during the two experimental days (Table two). Plasma FGF21 concentrations started to increase lx min subsequently ethanol assistants (~twenty min after serum ethanol had peaked) and afterward 240 min FGF21 had increased approximately nine-fold from 31 ± 35 to 270 ± 215 pg/mL for IGEI and from 30 ± 35 to 268 ± 217 pg/mL for IVEI (without signs of peaking and with no difference between the two administration forms (P = 0.97)) (Fig. 6A and B, Tabular array two).

Discussion

In this report we provide a detailed description of how acute alcohol (administered intragastrically also as intravenously) affects circulating concentrations of insulin, glucagon, GIP, GLP-1 and the liver-derived hormone FGF21. Overall, alcohol seems to (1) inhibit the secretion of both insulin and glucagon (independently of administration form), (two) accept petty or no effect on the secretion of the incretin hormones GIP and GLP-1 and (3) dramatically increase the secretion of FGF21 during both IGEI and IVEI.

Alcohol lowers glucose concentrations regardless of administration form

Alcohol consumption is associated with increased risk of hypoglycaemia (3). Still, the mechanism(s) behind this is unclear. Nosotros observed an initial increase in plasma glucose concentration ~thirty–35 min after alcohol administration and a reject to below baseline values after ~3.five h. The decline could be due to the continued fasting of the participants and not the incretin hormones, insulin or the alcohol infusion itself. Nosotros did not include a placebo intervention (intragastric and intravenous placebo administration) which is a limitation of our report. Nonetheless, previous studies of saline infusions (intraduodenally and intravenous) in healthy subjects observed no changes in the secretion of pancreatic or incretin hormones (28, 29). In addition to the reduced glucagon concentrations we observed afterwards ethanol assistants (discussed below), hepatic metabolism of ethanol may contribute to the risk of hypoglycaemia. Booze is metabolised in the liver past alcohol dehydrogenase to acetaldehyde and subsequently to acetate. These reactions reduce nicotinamide adenine dinucleotide (NAD⁺) to NADH and thus facilitate a decline in the NAD⁺/NADH ratio, which inhibits several dehydrogenases essential for gluconeogenesis (ii, 3).

Alcohol reduces insulin secretion after IGEI too as IVEI

High alcohol consumption may cause insulin resistance (30, 31). Traditionally, the machinery is believed to involve booze-induced increase in NADH inhibiting fat acid oxidation, promoting steatosis and inducing liver inflammation (32, 33). The directly effect of booze on insulin secretion has been investigated with ambiguous results (half-dozen, 7, x). Insulin concentrations decreased later on intravenous booze administration in good for you individuals (7). In dissimilarity, pre-treatment with oral alcohol increased AUCs of insulin and C-peptide during an intravenous glucose tolerance test in good for you individuals (6). Also, glucose and insulin concentrations increased after oral booze administration and subsequent continuous intravenous alcohol infusion maintaining constant alcohol concentration of nearly ii mmol/L in healthy subjects (10). In the present report, we observed no stimulating consequence of alcohol on insulin concentrations after IGEI just a pocket-sized decrease during IVEI. In line with this, insulin/glucose ratios decreased after booze administration reaching a lower nadir after IVEI. This could exist due to the relatively higher portal alcohol concentrations after IGEI reducing hepatic insulin extraction more than isoethanolaemic IVEI. In contrast, C-peptide undergoes negligible hepatic extraction which is why circulating C-peptide constitutes a more precise measure out of pancreatic insulin secretion than circulating insulin (34). Interestingly, we observed a decline in C-peptide and ISR after both administration forms, which suggests that booze suppresses insulin secretion independently of alcohol's potential effects in the gut. Also, beta cell function evaluated past insulinogenic index appeared to be impaired later IVEI compared to IGEI. Nevertheless, the insulinogenic index was negative subsequently both administration forms, which may indicate an impaired beta cell function after astute alcohol intake. The insulinogenic index is a validated measure out of beta cell function after an oral glucose tolerance test and its apply during the conditions investigated in the present study may be questioned. Moreover, nosotros used only a single dose of alcohol; repeated dosing may show different results.

Booze decreases glucagon concentrations regardless of abdominal stimulation

The effect of booze on glucagon secretion has been studied with inconsistent results (9, 10). Intravenous administration of alcohol enhanced alanine-stimulated glucagon release (9), whereas the counter-regulatory glucagon response to insulin-induced hypoglycaemia in immature healthy men was delayed and macerated after oral and subsequent maintenance by intravenous alcohol assistants (x). In the latter study, alcohol assistants had no effect on fasting glucagon concentrations (ten) which contrasts to our findings. A directly inhibitory effect of booze on the alpha cells or the initially increased glucose concentrations may explain the decline in glucagon concentrations during both administration forms in the present study. Yet, the present results demonstrate that the effect of alcohol on glucagon secretion is not due to mechanisms derived from an intestinal stimulus.

Alcohol does non arm-twist an incretin consequence

The incretin outcome is defined as the relative increment in insulin response to oral vs intravenous administration of glucose during like plasma glucose concentrations (due to insulinotropic actions of the gut-derived incretin hormones) (35). The incretin result of alcohol has never been investigated properly (comparing incretin concentrations after IGEI vs IVEI). Still, the upshot of alcohol on circulating concentrations of incretin hormones has previously been studied under diverse conditions and with inconsistent results (6, eleven, 12). Oral alcohol did not take a significant effect on GLP-1 secretion earlier an intravenous glucose tolerance exam in healthy participants (6). In addition, orally administered alcohol did non bear on GLP-1 secretion in fasting good for you individuals (11). However, oral alcohol administered during a fat-rich mixed meal suppressed the early postprandial GIP and GLP-1 responses in patients with type two diabetes (12). In the nowadays report, we did not observe any physiologically relevant changes in GLP-1 or GIP concentrations during IGEI or IVEI. This suggests that alcohol – unlike other macronutrients – does not stimulate GIP or GLP-1 after intragastric administration, and, combined with the lack of whatsoever stimulatory event of alcohol on insulin secretion (see above), that alcohol intake does non elicit an incretin effect.

Booze increases circulating FGF21 concentrations dramatically regardless of assistants route

Studies in rodents have shown that exogenous FGF21 decreases the gustation preference for sweets and alcohol (14, 36). Also, contempo human testify supports the notion that the FGF21 cistron plays a office in taste preference for sweets and booze consumption (37, 38, 39, xl) positioning FGF21 as a potential negative regulator of alcohol consumption. Furthermore, FGF21 has been shown to increase insulin sensitivity and decrease hepatic glucose production in mice (15) and an FGF21 analogue has been shown to exert insulinotropic actions in patients with type two diabetes (41). In the present report, FGF21 concentrations increased dramatically, which is consistent with previous studies (thirteen, 14). This could signal towards FGF21 equally a gene linking alcohol intake and glucose metabolism and supports the existence of a liver-brain feedback loop; ingestion of alcohol increases FGF21 secretion which in turn may decrease alcohol intake via the primal nervous organisation (39, 40). Therefore, FGF21 may non only constitute a potential future antidiabetic agent only maybe likewise a potential target for patients diagnosed with alcohol use disorder. Interestingly, the temporal secretion of FGF21 was not parallel to the plasma booze concentrations. As previously described (xiv), we observed plasma alcohol to peak ~40 min later alcohol administration, whereas plasma FGF21 rose after ~60 min and kept ascension throughout the study period (240 min). Samms et al. (42) institute FGF21 secretion to exist stimulated by increased insulin concentrations, and others have plant acute glucagon assistants to cause an increase in FGF21 concentrations in humans (43). However, in the present written report we saw no increases in insulin or glucagon; precluding that elevations in insulin and/or glucagon are required for FGF21 secretion. Rather, FGF21 may be secreted as a direct response to booze exposure and FGF21 actions could issue in the reduced insulin secretion after alcohol administration seen in this study. However, the mechanisms underlying booze-induced FGF21 secretion and actions related to insulin secretion remain to be established.

Conclusion

Alcohol – unlike other macronutrients (i.eastward. saccharide, lipid and protein) – does not seem to stimulate GIP or GLP-i after intragastric administration. Moreover, alcohol appears to subtract the secretion of both glucagon and insulin from the pancreas independently of the route of administration (intragastrically vs intravenously). The higher concentrations of circulating FGF21 observed after both alcohol administration forms, suggest alcohol to be a stimulator of FGF21 secretion acting independently of the gut (and gut-derived factors), glucagon and insulin.

Declaration of interest

A R 50, 50 Southward G, Northward C B, S B, Yard Yard H, M P M, B H and T V take nothing to declare. J J H has served on advisory boards, served every bit a consultant and/or received inquiry support from AstraZeneca, Hanmi, Intarcia, Merck, MSD, NovoNordisk and Zealand Pharma. F K Thousand has served on scientific advisory panels and/or been office of speaker'southward bureaus for, served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi and Zealand Pharma.

Funding

This work was supported by Herlev-Gentofte'southward Research Foundation (2016), Brødrene Hartmann'south Foundation (2016) and the A. P. Møller Foundation (2016).

Acknowledgments

The authors are thankful to all study subjects for their participation and lab technicians Sisse M Schmidt and Inass Al-Nachar (Center for Clinical Metabolic Research, Gentofte Hospital) for their invaluable help with experimental procedures. In add-on, they want to give thanks Lene Albæk (Department for Biomedical Sciences, University of Copenhagen) for GIP, GLP-1 and glucagon measurements.

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Source: https://ec.bioscientifica.com/view/journals/ec/8/10/EC-19-0317.xml

what are the consequences of ethanol metabolism to the maintenance of blood glucose levels?

Abstruse

Background

Objective

Design and methods

Results

Conclusions

Introduction

Materials and methods

Approval and ethics

Subjects

Experimental procedures

Analyses

Calculations and statistical analysis

Results

Alcohol

Glucose

Insulin and C-peptide

Glucagon

GIP and GLP-1

FGF21

Discussion

Alcohol lowers glucose concentrations regardless of administration form

Alcohol reduces insulin secretion after IGEI too as IVEI

Booze decreases glucagon concentrations regardless of abdominal stimulation

Alcohol does non arm-twist an incretin consequence

Booze increases circulating FGF21 concentrations dramatically regardless of assistants route

Conclusion

Declaration of interest

Funding

Acknowledgments

References

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