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Glycotoxins in diet and tobacco smoking: The new faces of an old enemy, atherosclerosis
Post-congress, Kos Mediterranean diet MEDITERRANEAN WAY OF EATING: FROM EPIDEMIOLOGY TO CLINICAL CARE M. Mancini. Department of Clinical and Experimental Medicine II University Medical School, Naples. Italy
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Federico
The famous epidemiological studies of Ancel Keys have indicated that CHD incidence and mortality is much lower in Mediterranean Countries than in Northern Europe and United States. Diet has been identified as the main environmental factor playing an important etiological role in the different CHD incidence rates in these areas. Olive oil, a constant ingredient of the Mediterranean Diet (M.D.), particularly rich in monounsaturated oleic acid and antioxidants, could play a beneficial role in CHD prevention as indicated by the Italian Nine Communities Study, carried out on the early 80 s in about 5000 healthy men and women. Consumption of olive oil was inversely associated with serum glucose, blood pressure and serum cholesterol. The M.D., particularly rich in complex carbohydrates, fibers, monounsaturated fatty acids and antioxidants is very useful in the treatment of diabetes mellitus through a positive influence both on glucose and lipid metabolism. The M.D. has also shown useful effects in the regulation of blood pressure in arterial hypertension and in normalizing plasma lipid profile in hyperlipidemia. These clinical findings in the management of the most important pathological conditions predisposing to atherosclerosis reinforce the concept that the M.D. represents a useful and effective non pharmacological tool in the management of various chronic degenerative diseases and in preventive cardiology. DIETARY THERAPY OF THE METABOLIC SYNDROME AND TYPE I! DIABETES S.M. Grundy. UniuersiO' of Texas Southwestern Medical Center at Dallas,
USA
171
substances, referred to as glycotoxins. The kidney has been identified as a key regulator of AGE metabolism and clearance, but also as a principal target for AGE toxicity. At the tissue level, a cell-associated AGE-specific receptor (AGE-R) system, found on numerous cell types, including vascular, renal and neruonal/glial cells regulates AGE uptake and removal. AGE-R also modulates growth-related mediators, protein synthesis and cell proliferation, consequently influencing organ structure/function. In susceptible individuals, the AGE-receptor expression/function is subject to environment- and/or gene-related alterations which, together with metabolic/hormonal factors coexisting with diabetes, may influence renal cell and matrix regulatory gene functions. Recent finding suggest altered expression and activity of AGE-R in diabetic mice (NOD), which are prone to diabetic complications as well in IDDM patients with established complications. Several effective strategies are available or are under development for the amelioration of AGEs as causative factors in diabetic complications: 1. Limiting the synthesis of endogenous AGEs by optimal glucose control; 2. Pharmacologic inhibition o f glycoxidation pathways, eg. by aminoguanidine; 3. Pharmacologic disruption of pre-existing AGE-crosslinks via agents known as AGEbreakers; 4. Dietary-AGE restriction. Clinical trials to determine whether aminoguanidine will prevent complications are nearing completion, while Phase 1 trials for AGE-breakers have just begun.
OXIDATION OF DIETARY FAT IS DECREASED ON AN ISOCALORIC SATURATED FAT DIET COMPARED WITH A MONOUNSATURATED FAT DIET A.E. Jones 1, R.D. Smith 2, C. Kelly2, C.M. Williams 2, S.A. Wootton1.
The metabolic syndrome is characterized by four cardiovascular risk factors: a therogenic dyslyidemia (high triglycerides, small LDL, and low HDL), hypertension, a prothrombotic state, and glucose intolerance. Many investigators believe that insulin resistance lies at the heart of the metabolic syndrome. However, the particular expression of this syndrome depends on the interaction of insulin resistance with factors affecting the response elements of the syndrome, whether regulation of blood pressure, synthesis and catabolism of lipoproteins, synthesis of coagulation factors, and secretion of insulin by pancreatic beta cells. Abnormalities in the regulation of any of these elements combined with insulin resistance can produce categorical risk factors. When insulin secretion, the result is type 2 diabetes. The major causes of insulin resistance are obesity, physical inactivity, and heredity. The former two predominate in most patients. Therefore, the first step in treatment of the metabolic syndrome is to reduce insulin resistance. This is best carried out by weight reduction and increased physical activity. This diet composition has a greater effect on the response elements of the metabolic syndrome than an insulin resistance. In particular a diet high in carbohydrates can accumulate a therogenic dyslipidemia and entrance a hyperglycemic resonse. For this reason, a diet higher in fat and lower in carbohydrates has been recommended for patients having insulin resistance and the metabolic syndrome. Since saturated fatty acid raise LDL-cholesterol levels, higher intakes of fat must contain mainly in saturated fatty acid. Although previous investigators proposed that polyunsaturated acids are preferable, recent studies suggest that monounsaturated fatty acids may be even better. Thus, a diet high in monounsaturated fatty acids, such as commonly consumed in the Mediterranean region, apprears to be the preferable diet for patients with the metabolic syndrome. GLYCOTOXINS IN DIET AND TOBACCO SMOKING: THE NEW FACES OF AN OLD ENEMY, ATHEROSCLEROSIS H. Vlassara. Mount Sinai School of Medicine, New York. USA Substantial evidence suggests that genetic factors may predispose patients to diabetic complications shown to be exacerbated by hyperglycemia (HG). Glucose-derived Advanced Glycation Endproducts (AGE) accumulate in vascular, renal and neuronal tissues in both IDDM and NIDDM, and contribute to organ damage. Recent studies have revealed a major environmental risk factor that exacerbates diabetic complications, beyond glycemia: diet-, and smoking associated AGEs, that are absorbed via the digestive or the respiratory tract and are carried into the circulation. It is estimated that twothirds of these exogenous AGEs are deposited permanently in vascular and renal tissues. Glycation derivatives include a number of chemically reactive
t lnstitute of Human Nutrition, Unioersi~ of Southampton, Southampton; 2Hugh Sinclair Unit of Human Nutrition, UniuersiO, of Reading. Reading, UK Stable isotope tracer methodologies in combination with indirect calorimetry were used to determine the oxidation of dietary fat in subjects fed a monounsaturated fat (MUFA) diet and a saturated fat (SFA) diet. Nine normal, healthy adults (4 males, 5 females, 18-23 years; BMI 23.3+3.9 kg/m 2) were fed a MUFA diet for 4 weeks (36.0% energy from fat: 12.9% cis-MUFA; 12.3% SFA; 4.9% cis-PUFA) followed by an isocaloric SFA diet for 4 weeks (36.4% energy from fat; I 1.7% cis-MUFA; 14.4% SFA; 5.0% cis-PUFA). Postprandial lipid metabolism was measured in all subjects at the end o f each diet. Oxidation o f exogenous fat was determined by measuring the excretion of |3CO2 on the breath following the consumption of either [ l, 1, I - 13C]tripalmitin or [ l, I, I -13C]triolein ( l 0 mg/kg body weight) ingested as a casein-glucose-sucrose-lipid emulsion and as part of a test meal. The test meal was identical for both diets and provided 3.7 MJ energy; 46 g fat (45.0% energy; 12.1% cis-MUFA; 21.9% SFA; 6.5% cis-PUFA); 93 g CHO (39.9% energy) and 33 g protein (l 5.1% energy). Measurements of gaseous exchange from indirect calorimetry were used to determine net fat oxidation (Frayn, 1983). Endogenous fat oxidation was determined as the difference between net and exogenous fat oxidation. There was no difference in excretion o f 13CO2 on breath in subjects who consumed [ l,l,l-13C]tripalmitin compared with [ l,l,l-13C]triolein on either diet. Combining the results for [1,1,1-L3C]tripalmitin and triolein excretion of 13CO2 on breath was greater on the MUFA diet ( 16.9+4.0% administered dose/8 h) compared with the SFA diet (14.4+ 3.4% administered dose/8 h; P < 0.05) with 8 of the 9 subjects showing a decrease in breath 13CO2 excretion on the SFA diet. As net fat oxidation did not differ between the diets (23.8 5= I 1.5 g/8 h vs 24.7+7.8 g/8 h; NS) the decrease in exogenous fat oxidation (40.3% of net fat oxidation vs 29.7% of net fat oxidation) was compensated for by an increase in endogenous fat oxidation (59.7% of net fat oxidation vs 70.3% o f net fat oxidation). These results suggest that the fatty acid composition of background diet may influence the relative proportion of fat oxidation that is attributed to exogenous (ie dietary) and endogenous fat oxidation. It would appear that even a relatively small increase in the SFA content of a diet for only a short period (4 weeks) can decrease exogenous fat oxidation. The support of The Ministry of Agriculture Fisheries and Food is acknowledged. References
[I] Frayn K 0983)J Appl. Physiol. 55: E628-634.
71st EAS Congress and Satellite Symposia
C o
-
Federico
The famous epidemiological studies of Ancel Keys have indicated that CHD incidence and mortality is much lower in Mediterranean Countries than in Northern Europe and United States. Diet has been identified as the main environmental factor playing an important etiological role in the different CHD incidence rates in these areas. Olive oil, a constant ingredient of the Mediterranean Diet (M.D.), particularly rich in monounsaturated oleic acid and antioxidants, could play a beneficial role in CHD prevention as indicated by the Italian Nine Communities Study, carried out on the early 80 s in about 5000 healthy men and women. Consumption of olive oil was inversely associated with serum glucose, blood pressure and serum cholesterol. The M.D., particularly rich in complex carbohydrates, fibers, monounsaturated fatty acids and antioxidants is very useful in the treatment of diabetes mellitus through a positive influence both on glucose and lipid metabolism. The M.D. has also shown useful effects in the regulation of blood pressure in arterial hypertension and in normalizing plasma lipid profile in hyperlipidemia. These clinical findings in the management of the most important pathological conditions predisposing to atherosclerosis reinforce the concept that the M.D. represents a useful and effective non pharmacological tool in the management of various chronic degenerative diseases and in preventive cardiology. DIETARY THERAPY OF THE METABOLIC SYNDROME AND TYPE I! DIABETES S.M. Grundy. UniuersiO' of Texas Southwestern Medical Center at Dallas,
USA
171
substances, referred to as glycotoxins. The kidney has been identified as a key regulator of AGE metabolism and clearance, but also as a principal target for AGE toxicity. At the tissue level, a cell-associated AGE-specific receptor (AGE-R) system, found on numerous cell types, including vascular, renal and neruonal/glial cells regulates AGE uptake and removal. AGE-R also modulates growth-related mediators, protein synthesis and cell proliferation, consequently influencing organ structure/function. In susceptible individuals, the AGE-receptor expression/function is subject to environment- and/or gene-related alterations which, together with metabolic/hormonal factors coexisting with diabetes, may influence renal cell and matrix regulatory gene functions. Recent finding suggest altered expression and activity of AGE-R in diabetic mice (NOD), which are prone to diabetic complications as well in IDDM patients with established complications. Several effective strategies are available or are under development for the amelioration of AGEs as causative factors in diabetic complications: 1. Limiting the synthesis of endogenous AGEs by optimal glucose control; 2. Pharmacologic inhibition o f glycoxidation pathways, eg. by aminoguanidine; 3. Pharmacologic disruption of pre-existing AGE-crosslinks via agents known as AGEbreakers; 4. Dietary-AGE restriction. Clinical trials to determine whether aminoguanidine will prevent complications are nearing completion, while Phase 1 trials for AGE-breakers have just begun.
OXIDATION OF DIETARY FAT IS DECREASED ON AN ISOCALORIC SATURATED FAT DIET COMPARED WITH A MONOUNSATURATED FAT DIET A.E. Jones 1, R.D. Smith 2, C. Kelly2, C.M. Williams 2, S.A. Wootton1.
The metabolic syndrome is characterized by four cardiovascular risk factors: a therogenic dyslyidemia (high triglycerides, small LDL, and low HDL), hypertension, a prothrombotic state, and glucose intolerance. Many investigators believe that insulin resistance lies at the heart of the metabolic syndrome. However, the particular expression of this syndrome depends on the interaction of insulin resistance with factors affecting the response elements of the syndrome, whether regulation of blood pressure, synthesis and catabolism of lipoproteins, synthesis of coagulation factors, and secretion of insulin by pancreatic beta cells. Abnormalities in the regulation of any of these elements combined with insulin resistance can produce categorical risk factors. When insulin secretion, the result is type 2 diabetes. The major causes of insulin resistance are obesity, physical inactivity, and heredity. The former two predominate in most patients. Therefore, the first step in treatment of the metabolic syndrome is to reduce insulin resistance. This is best carried out by weight reduction and increased physical activity. This diet composition has a greater effect on the response elements of the metabolic syndrome than an insulin resistance. In particular a diet high in carbohydrates can accumulate a therogenic dyslipidemia and entrance a hyperglycemic resonse. For this reason, a diet higher in fat and lower in carbohydrates has been recommended for patients having insulin resistance and the metabolic syndrome. Since saturated fatty acid raise LDL-cholesterol levels, higher intakes of fat must contain mainly in saturated fatty acid. Although previous investigators proposed that polyunsaturated acids are preferable, recent studies suggest that monounsaturated fatty acids may be even better. Thus, a diet high in monounsaturated fatty acids, such as commonly consumed in the Mediterranean region, apprears to be the preferable diet for patients with the metabolic syndrome. GLYCOTOXINS IN DIET AND TOBACCO SMOKING: THE NEW FACES OF AN OLD ENEMY, ATHEROSCLEROSIS H. Vlassara. Mount Sinai School of Medicine, New York. USA Substantial evidence suggests that genetic factors may predispose patients to diabetic complications shown to be exacerbated by hyperglycemia (HG). Glucose-derived Advanced Glycation Endproducts (AGE) accumulate in vascular, renal and neuronal tissues in both IDDM and NIDDM, and contribute to organ damage. Recent studies have revealed a major environmental risk factor that exacerbates diabetic complications, beyond glycemia: diet-, and smoking associated AGEs, that are absorbed via the digestive or the respiratory tract and are carried into the circulation. It is estimated that twothirds of these exogenous AGEs are deposited permanently in vascular and renal tissues. Glycation derivatives include a number of chemically reactive
t lnstitute of Human Nutrition, Unioersi~ of Southampton, Southampton; 2Hugh Sinclair Unit of Human Nutrition, UniuersiO, of Reading. Reading, UK Stable isotope tracer methodologies in combination with indirect calorimetry were used to determine the oxidation of dietary fat in subjects fed a monounsaturated fat (MUFA) diet and a saturated fat (SFA) diet. Nine normal, healthy adults (4 males, 5 females, 18-23 years; BMI 23.3+3.9 kg/m 2) were fed a MUFA diet for 4 weeks (36.0% energy from fat: 12.9% cis-MUFA; 12.3% SFA; 4.9% cis-PUFA) followed by an isocaloric SFA diet for 4 weeks (36.4% energy from fat; I 1.7% cis-MUFA; 14.4% SFA; 5.0% cis-PUFA). Postprandial lipid metabolism was measured in all subjects at the end o f each diet. Oxidation o f exogenous fat was determined by measuring the excretion of |3CO2 on the breath following the consumption of either [ l, 1, I - 13C]tripalmitin or [ l, I, I -13C]triolein ( l 0 mg/kg body weight) ingested as a casein-glucose-sucrose-lipid emulsion and as part of a test meal. The test meal was identical for both diets and provided 3.7 MJ energy; 46 g fat (45.0% energy; 12.1% cis-MUFA; 21.9% SFA; 6.5% cis-PUFA); 93 g CHO (39.9% energy) and 33 g protein (l 5.1% energy). Measurements of gaseous exchange from indirect calorimetry were used to determine net fat oxidation (Frayn, 1983). Endogenous fat oxidation was determined as the difference between net and exogenous fat oxidation. There was no difference in excretion o f 13CO2 on breath in subjects who consumed [ l,l,l-13C]tripalmitin compared with [ l,l,l-13C]triolein on either diet. Combining the results for [1,1,1-L3C]tripalmitin and triolein excretion of 13CO2 on breath was greater on the MUFA diet ( 16.9+4.0% administered dose/8 h) compared with the SFA diet (14.4+ 3.4% administered dose/8 h; P < 0.05) with 8 of the 9 subjects showing a decrease in breath 13CO2 excretion on the SFA diet. As net fat oxidation did not differ between the diets (23.8 5= I 1.5 g/8 h vs 24.7+7.8 g/8 h; NS) the decrease in exogenous fat oxidation (40.3% of net fat oxidation vs 29.7% of net fat oxidation) was compensated for by an increase in endogenous fat oxidation (59.7% of net fat oxidation vs 70.3% o f net fat oxidation). These results suggest that the fatty acid composition of background diet may influence the relative proportion of fat oxidation that is attributed to exogenous (ie dietary) and endogenous fat oxidation. It would appear that even a relatively small increase in the SFA content of a diet for only a short period (4 weeks) can decrease exogenous fat oxidation. The support of The Ministry of Agriculture Fisheries and Food is acknowledged. References
[I] Frayn K 0983)J Appl. Physiol. 55: E628-634.
71st EAS Congress and Satellite Symposia
C o