American Diabetes Association Guide to Nutrition Therapy for Diabetes. Marion J. Franz

a fuel source. Alcohol is the only nutrient that does not require insulin to be metabolized. The liver is the major organ for alcohol oxidation. The total quantity of alcohol and the rate of ingestion determine its effect. The liver contains three pathways for ethanol metabolism, each located in a different subcellular compartment: 1) the ADH pathway in the cytoplasm; 2) the microsomal ethanol-oxidizing system (MEOS) located in the endoplasmic reticulum; and 3) catalase, located in the peroxisomes. All three pathways result in the production of acetaldehyde, a highly toxic metabolite (Lieber 1976).

      Alcohol is primarily oxidized to acetaldehyde and acetate and then to energy through the ADH pathway (Figure 4.1). Hepatic ADH is the rate-limiting enzyme and determines the action and timing of alcohol metabolism. If the limited number of ADH molecules in hepatocytes are occupied, excess alcohol molecules enter the general circulation and return to the liver when ADH molecules are free to process them. The detoxification rate of ethanol by hepatic ADH is thus limited to a processing rate of ~15 g/h (Goodsell 2006). Thus, longer time periods between ingestion of alcohol are essential so that oxidation can occur in the liver. Additionally, an alcohol-induced increase within the liver cell of the NADH/NAD ratio (NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD) contributes to inhibition of gluconeogenesis. Acetate is released into the bloodstream and completes oxidation in other tissues. Alcohol oxidation is an effective source of energy because it is coupled with the synthesis of adenosine triphosphate.

      Figure 4.1 Alcohol oxidation.

      Alternatively, alcohol may also be metabolized via reactions in the smooth endoplasmic reticulum by the MEOS. The role of the MEOS is small, but may play a more predominant role at intoxicating levels of blood alcohol. Both the MEOS pathway and the smooth endoplasmic reticulum are also involved in the metabolism of many drugs, and this occurrence can potentially lead to adverse drug reactions. Only a small percentage of alcohol is oxidized via the catalase pathway.

      Excessive alcohol that the liver cannot metabolize immediately enters the general circulation, where it becomes a part of all body fluids and enters into cells. Alcohol has a special affinity for the brain and quickly reaches the brain cells. At first, this results in a state of euphoria, often accompanied by release of inhibitions. However, longer-term alcohol use has a depressive effect on mental status.

      In people with no history of chronic exposure to alcohol, it is estimated that ~75% of alcohol is oxidized by the ADH pathway, whereas 25% involves the MEOS. At high alcohol concentrations and longer duration of intake, as much as 80% of alcohol metabolism can proceed via a non-ADH pathway. Therefore, steady and prolonged alcohol consumption allows drinkers to tolerate larger amounts of alcoholic beverages. In addition to the MEOS pathway, there are increases in the ability of the hepatocytes to synthesize ADH to help clear the circulation of alcohol. As a result, the amount of alcohol that can be cleared in 1 h is doubled in an alcoholic (Lieber 1976).

EFFECTS OF ALCOHOL ON GLYCEMIA AND OTHER METABOLIC OUTCOMES

      The 1999 chapter concluded that in short-term studies, in people with type 1 and type 2 diabetes, consumption of moderate amounts of alcohol had no acute postprandial impact on blood glucose and insulin levels in people with either type of diabetes (Franz 1999). However, for individuals with type 1 diabetes, a risk of late-onset hypoglycemia may exist. In individuals with type 2 diabetes, the risk of alcohol-induced acute hypoglycemia was modest (Franz 1999). Table 4.1 summarized studies published after 1999 on alcohol consumption and its effect on glycemia and other metabolic outcomes in people with type 1 and type 2 diabetes.

      Table 4.1 Alcohol Consumption and Its Effect on Glycemia and Other Metabolic Outcomes in Persons with Type 1 and Type 2 Diabetes

      A large cross-sectional study of adults with diabetes (n = 38,564) reported that alcohol consumption was linearly and inversely associated with A1C levels; however, with three or more drinks per day, A1C levels began to increase (Ahmed 2008). Similar findings were reported in NHANES III, in which adults with diabetes who had ≥30 drinks of alcohol per month, compared with nondrinkers, had average A1C levels 1.2% lower than other adults with diabetes (Mackenzie 2006). However, increasing risk for poor adherence to diabetes self-care behaviors with increasing alcohol consumption, starting with individuals who consume one drink per day, has also been reported (Ahmed 2006). Therefore, it is important that health care providers ask people with diabetes about alcohol consumption and encourage moderate and sensible use, shown to have potentially beneficial effects on glycemic control (van de Wiel 2004).

      Type 2 Diabetes

      Two clinical trials examined the effect of alcohol in individuals with type 2 diabetes (Shai 2007; Bantle 2008). Adults with type 2 diabetes (n = 109) who abstained from alcohol were randomly assigned to drink wine (13 g alcohol; ~5 oz) or nonalcoholic beer (controls) each day for 3 months. In individuals drinking wine, fasting plasma glucose (FPG) decreased ~22 mg/dL, but no effect on postprandial glucose levels was observed. In the controls, FPG and postprandial glucose levels did not change. Interestingly, patients in the alcohol group with the higher baseline A1C levels had greater decreases in FPG and reported improvements in their ability to fall asleep (Shai 2007). In the second study, adults with type 2 diabetes drank either wine (24 g alcohol; ~8.5 oz) or grape juice with their evening meal, with no acute effect on glucose or insulin levels. Wine (18 g alcohol; ~6.5 oz) or abstinence was continued for 30 days, with wine having no effect on glucose or lipids but insulin sensitivity improving (Bantle 2008). A systematic review of earlier, small, acute studies also concluded that moderate consumption of alcohol does not acutely impair glycemic control in individuals with type 2 diabetes and may actually result in a small decrease in glucose concentrations (Howard 2004). However, chronic ingestion (>45 g/day) has been shown to cause deterioration in glucose control; the effects from excess alcohol are reversed, however, after abstinence for a number of days.

      In individuals with diet-treated type 2 diabetes, meals with or without alcohol were followed by either rest or 30 min of exercise, and the combination of moderate exercise with or without alcohol did not cause hypoglycemia (Rasmussen 1999). In a second study, in people with diet-treated type 2 diabetes, alcohol or water were ingested before insulin-induced hypoglycemia to determine the influence of alcohol on glucose counterregulation and recovery from insulin-induced hypoglycemia. Alcohol had no effect on recovery from hypoglycemia, although it decreased peak glucagon response (Rasmussen 2001).

      Type 1 Diabetes

      Previous studies reported no acute effect of moderate alcohol intake with a meal on blood glucose levels in people with type 1 diabetes. However, a risk of late-onset hypoglycemia was reported (Franz 1999). Inhibition of gluconeogenesis, reduced hypoglycemia awareness due to cerebral effects of alcohol, and/or impaired counterregulatory responses to hypoglycemia have been reported as possible causes. Five of six men with type 1 diabetes had dinner at 6:00 p.m. followed by drinking wine (70 g alcohol, 20 oz) or water at 9:00 p.m. After drinking wine, treatment for hypoglycemia was required after breakfast; growth hormone was significantly reduced, with no other differences in insulin or other hormone levels (Turner 2001). Similarly, in adults with type 1 diabetes, hypoglycemia (blood glucose 50 mg/dL) resulted in lower peak growth hormone levels compared to placebo; however, this result was also associated with a decrease in insulin sensitivity (Kerr 2007). In a study similar to the Turner study, individuals with type 1 diabetes drank either orange juice or vodka with their evening meal. After drinking alcohol, based on continuous glucose monitoring data, individuals reported more than twice as many