REOXIDATION OF NADH AND REDUCTION OF NADPH NADH is generated in the first two reactions of alcohol metabolism as outlined above. It is necessary for NADH to then be reoxidised to NAD+ so that it can be involved in further oxidation reactions in the cytosol:
Reoxidation by the mitochondrial electron transport system ! NAD þ Hþ NADH !
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The cytosolic NADH is reoxidised by the mitochondrial electron transport system, so substrate shuttles need to be used to transport the H atoms to the mitochondria.
Under some conditions, the rate of transfer of H atoms by these shuttles is less than the rate of NADH generation, so that the concentration of NAD+ becomes greatly reduced.
This low concentration of NAD+ also restricts the conversion of lactate to pyruvate in the liver.
This is one element by which alcohol increases the concentration of lactate in the blood.
The low NAD+ level limits the rate of ethanol oxidation by alcohol dehydrogenase (the first step in alcohol metabolism).
Alcohol decreases the ratio of NAD+ to NADH within the hepatocyte while it is being oxidised.
METABOLIC AND CLINICAL EFFECTS OF ALCOHOL CONSUMPTION
Evidence suggests that some of the clinical effects of alcohol ingestion are not due to ethanol itself but to its metabolites NADH and ethanal (acetaldehyde).
The NAD+/NADH concentration ratio in the cytosol is maintained at a value of 1000 (11).
The administration of alcohol can lower this ratio by at least 10- fold (12).
The concentration of all substrates and products which thus use dehydrogenase enzymes will be affected by a change in the NAD+/NADH concentration ratio.
Therefore a reduction of this concentration ratio will lower the concentration of the oxidised reactant and increase that of the reduced reactant.
If either of these reactants has an important metabolic role, marked changes in their concentration could produce abnormal effects.
The increased ethanal levels which are seen after alcohol ingestion are further raised if the activity of aldehyde dehydrogenase is inhibited.
Inhibitors of the enzyme include the higher aliphatic aldehydes which are known to be present in alcoholic beverages.
The following physiological effects can be, in part, explained by the changes in the NAD+/NADH ratio.
FATTY LIVER, HEPATITIS AND CIRRHOSIS Chronic alcohol consumption can cause the deposition of excess triglycerol in the liver leading to a condition known as ‘fatty liver’.
This damage can lead to hepatitis and, if severe enough, to cirrhosis.
The damage is thought to be due to the high concentrations of ethanal within the cell and if severe enough will result in cell death.
Cell damage and death trigger an inflammatory response, i.e. infiltration of lymphocytes and activation of an immune response.
If this is not treated it will lead to the formation of fibrous tissue and a severe reduction in the functioning of the liver.
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HYPOGLYCAEMIA In the fasted state, hepatic gluconeogenesis is essential for the production of glucose and maintenance of the blood sugar level.
Ethanol is a potent inhibitor of gluconeogenesis.
The suppression of gluconeogenesis, even at relatively low alcohol intakes, with low serum insulin and high serum glucagon, results in a decreased ratio of NAD+ to NADH which inhibits the entry of the precursors of gluconeogenesis (i.e. glycerol, lactate, alanine and other amino acids) into the hepatocyte (13).
This can lead to severe and prolonged hypoglycaemia when large volumes of alcohol are ingested rapidly and may occur up to 36 h after alcohol ingestion.
The major problem of alcohol ingestion in the person with diabetes is induction and masking of hypoglycaemia, causing hypogly- caemia unawareness.
Hypoglycaemia most commonly occurs in the fasting state in people with Type 1 and Type 2 diabetes but also in non-diabetics, especially when hepatic glycogen stores are depleted or exhausted.
Alcohol-induced hypoglycaemia may not be effectively treated by glucagon administration because it is related to depleted glycogen stores.
Alcohol consumption leads to delayed glucose recovery from insulin-induced hypoglycaemia in people with Type 1 diabetes, and occurs despite normal adrenalin, nor-adrenalin and glucagon responses, however growth hormone and cortisol are reduced (14).
Hypoglycaemia in alcoholics can be exacerbated by a reduced ability to secrete some of the hormones involved in the control of lipolysis (e.g. cortisol and growth hormone) and results in a decrease in the rate of fatty acid release in starvation.
Alcohol-induced severe hypoglycaemia can also result in irreversible neurological changes by causing irrecoverable damage to neurons and persistent disruption of cerebral functions (15).
Ketoacidosis Alcohol ingestion can cause ketoacidosis in people with diabetes and non- diabetics, as a result of relative insulin deficiency.
Starvation, causing a depletion of glycogen stores and alcohol metabolism, leads to an increase in NADH/NAD+ ratio which inhibits gluconeogenesis.
This is responsible for causing an increased glucagon/insulin ratio, which increases ketogenesis (16,17).
Diabetic ketoacidosis is a potentially life-threatening condition and requires prompt diagnosis and treatment of dehydration and metabolic abnormalities.
Alcohol-induced ketoacidosis can be further complicated by hypoglycaemia (however it more commonly presents with hyperglycaemia).
LACTIC ACIDOSIS The metabolism of alcohol increases the ratio of NADH to NAD+ which inhibits the entry of the precursors of gluconeogenesis, i.e. glycerol, lactate,
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alanine and other amino acids into the hepatocyte (13). The accumulation of lactate increases the risk of lactic acidosis, which is especially serious and potentially life-threatening for those people with diabetes who are treated with a biguanide.
ENDOCRINE DISTURBANCES Chronic alcoholism can also affect gonadal function and lead to testicular atrophy, gynaecomastia (enlargement of male breasts) and sterility.
It is not known what the exact mechanism for these changes is, but it is thought to be a result of reduced liver function.
This reduced liver function decreases the rate of metabolism of female sex hormones, thereby leading to an increased level of circulating oestrogens.
A second mechanism is thought to be that alcohol reduces synthesis of testosterone (18).
Testosterone synthesis involves many steps and some of the intermediates may be dependent on the NAD+/NADH concentration ratio which, as has already been discussed, is affected by alcohol consumption.
HYPERTENSION The UK Prospective Diabetes Study underlined the importance of well- controlled hypertension for people with Type 2 diabetes to reduce the risk of microvascular complications.
There is a direct/empiric relationship between alcohol intake and blood pressure.
Some researchers have found this relationship to be J-shaped (19), others U-shaped, but there is agreement that light to moderate drinkers have lower blood pressure than those who abstain and blood pressure rises steeply with heavier intakes.
In heavy drinkers ingesting 4300 g or 30 units per week there is a four times greater risk of stroke than in non-drinkers (20), whereas moderate alcohol consumption, up to two drinks per day, is protective for ischaemic stroke (21).
Alcohol consumption showed a clear positive correlation with the subsequent development of haemorrhagic stroke but did not show a correlation with the thromboembolic variety (22).
Although blood pressure is important in thrombotic stroke, alcohol’s metabolic effects may exert a counterbalancing protective influence against the occlusive atherosclerotic process, as might be the case for coronary heart disease (19).
So although moderate alcohol intake is cardioprotective, greater alcohol intake can neutralise the effect by having an adverse effect on blood pressure (23).
The INTERSALT and British Heart Study found that the effect on blood pressure from alcohol is similar to that of obesity and greater than that for salt in the populations studied.
A reduction in systolic blood pressure of 5 mmHg achieved by favourable lifestyle changes would reduce coronary mortality by 9%.
Epidemiological evidence suggests that light to moderate drinkers who stop drinking may increase
DIABETES AND ALCOHOL 209
their coronary mortality by up to 10% compared to heavier drinkers who stop drinking, who may experience a 4 mmHg fall in systolic pressure and possibly a 27% reduction in coronary mortality [Klatsky, 1992, cited in Bulpitt (24)].
Studies show a link between increasing alcohol intakes and higher blood pressure.
Klatsky (19) cites the Framingham Study as showing that the prevalence of hypertension (5160 mmHg systolic or 595 mmHg diastolic) was about two times higher among persons drinking 60 ounces or more of alcohol per month (57 g/day) than among those drinking less than 30 ounces per month (28.5 g/day).
Also the Los Angeles Heart Study showed a significant increase in blood pressure for men who drank alcohol three or more times weekly compared to those who drank less than three times weekly or who were non- drinkers.
Blood pressure is acutely affected and hypertension is resolved in those who stop drinking (6).
The ‘Kaiser Permanente’ investigation looked at the effect of ethnicity and found African, American men reached a maximum blood pressure at a lower alcohol intake.
Among women of all races, blood pressure was lower in light to moderate drinkers than non-drinkers (25,26).
All these studies were carried out in the general population not in people with diabetes, however considering the link between diabetes and hypertension and the importance of tight blood pressure control in reducing the risk of complications, recommendations regarding alcohol intakes should be cautious.
CORONARY HEART DISEASE
Light to moderate alcohol consumption is associated with a similar reduction in CHD risk among diabetic and non-diabetic men and women (27,28).
Among the mechanisms accounting for the risk reduction are increased circulating concentrations of HDL cholesterol, inhibition of blood coagulation and the presence of antioxidant substances which reduce oxidative damage (Table 13.2).
However, it is also well established that alcohol increases plasma triglyceride.
Alcoholic hyperlipaemia results primarily from increased hepatic secretion of VLDL and secondarily from impairment in the removal of triglyceride-rich lipoproteins from the plasma.
Raised triglycerides are also a feature of the
Table 13.2 Potential benefits of moderate alcohol intake
Increase in total HDL cholesterol Increased fibrinolytic activity Decreased platelet aggregation Reduced incidence of myocardial infarction Reduced insulin resistance , lower risk of developing Type 2 DM Source: Adapted from Bell (37). Copyright # 1996 American Diabetes Association. From Diabetes Care, Vol. 19, 1996: 509, 513. Reprinted with permission from The American Diabetes Association.