- Email: [email protected]
Diabetes mellitus and weight control
Nutrition Volume 19, Number 2, 2003
Diabetes Mellitus and Weight Control: Differences of Respiratory Quotient in Type 2 Diabetic Obese Subjects Receiving Sulfonylureas and Non-Diabetic Obese Controls INTRODUCTION At diagnosis of disease, most patients with type 2 diabetes are overweight to obese.1 Thus, weight reduction is the primary target of intervention in these subjects before or in addition to pharmacologic treatment. The benefit of weight loss in type 2 diabetes has been recognized since the early 1940s.2 A significant reduction in morbidity and mortality was found after moderate weight loss in these patients.3 Most medium- to long-term studies aiming to induce weight loss in obese type 2 diabetic patients have failed to achieve an acceptable maintenance of weight reduction.4,5 Further, significant weight gains were found in type 2 diabetic patients receiving insulinotropic medications such as sulfonylureas, as demonstrated by the United Kingdom Prospective Diabetes Study.6 The mechanism is still a subject of debate, but the most prominent explanation is the lipogenic effect of insulin. Moreover, the antilipolytic effect of insulin may contribute to weight gain by reducing levels of free fatty acids and their availability for oxidation.7 Therefore, we investigated possible differences of respiratory quotient (RQ) between obese, type 2 diabetic subjects receiving sulfonylureas and obese, non-diabetic control subjects.
MATERIALS AND METHODS Patients Twelve (four male, eight female) obese patients with type 2 diabetes and 12 (four male, eight female) non-diabetic obese control subjects were randomly recruited from the outpatient clinic for diabetes and metabolic diseases at the Department of Internal Medicine, Karl Franzens University, Graz, Austria. All patients gave informed consent before participating in the study. All subjects were moderately sedentary and not participating in any physical fitness training program. Table I summarizes the characteristics of all subjects. All subjects who showed no alteration greater than 1 kg of body weight during the 3 mo before recruitment were elligible because it suggested an equilibrium in energy balance. All diabetic patients were on oral antidiabetic treatment with sulfonylureas (80 mg of gliclazide, three times daily); controls were free of any acute or chronic medication. Subjects taking drugs that could influence fat oxidation, e.g., -blockers, thyroid hormones, psychoactive medication, hormone replacement therapy, and corticosteroids, were excluded. Methods RQ is defined as the quotient of CO2 production and O2 consumption. At 8.00 AM, after a 12-h overnight fast, O2 and CO2 consumption values were measured continuously for 30 min under controlled conditions with the use of open-circuit indirect calorim-
Correspondence to: B. Bahadori, MD, Federal Hospital Muerzzuschlag, Grazerstrasse 63-65, A-8680 Muerzzuschlag, Austria. E-mail: babak. [email protected]
Diabetes Mellitus and Weight Control
159
TABLE I. CHARACTERISTICS OF THE SUBJECTS PARTICIPATING IN THE STUDY*
n Male/female Age (y) Fasting glucose (mg/dL) HbA1c (%)† BMI (kg/m2) Fat mass (kg) Lean body mass (kg) Total body water (%) REE (kcal/d) REE/lean body mass (kcal 䡠 kg⫺1 䡠 d⫺1)
Type 2 diabetics
Controls
12 4/8 54.08 ⫾ 7.8 189.5 ⫾ 62.7 8.10 ⫾ 1.53 32.0 ⫾ 4.9 28.0 ⫾ 8.6 58.0 ⫾ 11.3 46.2 ⫾ 2.4 1574 ⫾ 308 27.5 ⫾ 4.8
12 4/8 50.42 ⫾ 11.1 95.8 ⫾ 11.8 5.27 ⫾ 0.83 34.5 ⫾ 6.2 32.9 ⫾ 13.2 63.3 ⫾ 12.9 43.4 ⫾ 3.9 1693 ⫾ 256 27.2 ⫾ 4.3
* Values are mean ⫾ standard deviation. † P ⬍ 0.001. BMI, body mass index; HbA1c, hemoglobin A1c; REE, resting energy expenditure
etry (Deltatrac Datex, Helsinki, Finland), which includes a differential parametric O2 sensor and an infrared CO2 analyzer. Exhaled air was collected with a canopy. Resting energy expenditure was calculated from the 30-min period of measurement by using Weir’s equation. An internal calibration procedure was performed before starting each measurement. All subjects received a standard meal containing 600 kcal of energy, 30% fat, 15% protein, and 55% carbohydrates 12 h before RQ measurement. Weight and height were measured in the fasting state before the RQ measurement, with subjects lightly dressed; the weight of the clothes they had been wearing was subsequently subtracted. Total body water was measured by bioelectrical impedance (AKERNRJL BIA 101/S, Frankfurt, Germany). Fat mass and fat-free mass were calculated according to the method of Kushner et al.8 All laboratory parameters were measured by routine laboratory methods. Hemoglobin A1c was assessed by HPLC (Bio-Rad, Germany). Statistics Statistical analysis was performed with StatView 5.0 on an Apple Macintosh. Intergroup comparisons were performed by unpaired Student’s t test; the level of significance was set to P ⬍ 0.05. All data are presented as mean ⫾ standard deviation, unless otherwise indicated.
RESULTS The characteristics of both groups are summarized in Table I. Both groups were similar with regard to age, sex, body weight, and body composition. As to be expected, fasting blood glucose (diabetics, 189.5 ⫾ 62.7; controls, 95.8 ⫾ 11.8; P ⬍ 0.001) and hemoglobin A1c (diabetics, 8.10 ⫾ 1.53; controls, 5.27 ⫾ 0.8; P ⬍ 0.001) were significantly higher in diabetic than in non-diabetic subjects. In the diabetic population, RQ was significantly (P ⬍ 0.005) elevated in comparison with the non-diabetic control group (0.84 ⫾ 0.07 versus 0.77 ⫾ 0.04; Fig. 1). In diabetic patients, no correlation between RQ and body mass index, blood glucose, or hemoglobin A1c was observed (data not shown). We also investigated a possible correlation of RQ and waist circumference, but
160
Bahadori et al.
Nutrition Volume 19, Number 2, 2003
CONCLUSION We can state that weight gain in patients with type 2 diabetes treated with sulfonylureas is at least partly due to a reduced lipolytic effect caused by anabolic effects of insulin. In these patients new therapeutic strategies, such as reinforcement of a low-fat diet and physical exercise to increase fat oxidation, should be considered to offset this side effect of sulfonylureas.
B. Bahadori, MD M. Trinker S. J. Wallner B. Yazdani-Biuki T. C. Wascher Department of Internal Medicine Kar Franzens University Graz. Austria
FIG 1. Respiratory quotient in diabetic and control subjects. *P ⬍ 0.005.
Federal Hospital of Muerzzuschlag Muerzzuschlag, Austria the results were negative in both groups (diabetics, r ⫽ 0.027; controls, r ⫽ 0.44). In contrast, resting energy expenditure was comparable between groups by means of absolute values and when lean body mass was expressed as kilograms (Table I). In our study RQ was measured in the fasting state 12 h after a standardized dinner. Thus, a low RQ (⬍0.8) was indicative of a shift from carbohydrate oxidation to fat oxidation.9 Our study provides clear evidence that RQ in obese patients with type 2 diabetes treated with sulfonylureas is higher than that in nondiabetic obese subjects.
DISCUSSION Kelley et al. reported no differences in systemic RQ between obese diabetic and non-diabetic patients.10 Our diabetic patients were receiving sulfonylureas. Sulfonylureas alone were found to increase RQ in diabetic patients.11 This effect may be induced by increased insulin secretion, leading to the following metabolic changes in addition to lipogenic effect: 1) inhibition of the hormone-sensitive lipase, followed by reduction of lipolysis; 2) increased re-esterification of free fatty acid, leading to an increased level of intracellular triacylglycerols; and 3) decreased oxidation of free fatty acids in the mitochondria through the metabolic effects of insulin.
REFERENCES 1. Albu J, Pi-Sunyer F. Obesity and diabetes. In: Bray G, Bouchard C, James W, eds. Handbook of obesity. New York: Marcel Dekker, 1998:697 2. Newburgh LH. Control of hyperglycemia of obese “diabetics” by weight reduction. Ann Intern Med 1942;17:935 3. Lean MEJ, Powrie JK, Anderson AS, Garthwaite PH. Obesity, weight loss and prognosis in type 2 diabetes. Diabet Med 1990;7:228 4. Franz MJ, Monk A, Barry B, et al. Effectiveness of medical nutrition therapy provided by dietitians in the management of non–insulin-dependent diabetes mellitus: a randomized, controlled clinical trial. J Am Diet Assoc 1995;95:1009 5. Laitinen JH, Ahola IE, Sarkkinen ES, et al. Impact of intensified dietary therapy on energy and nutrient intakes and fatty acid composition of serum lipids in patients with recently diagnosed non–insulin-dependent diabetes mellitus. J Am Diet Assoc 1993;93:276 6. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837 7. McGarry DJ. Glucose–fatty acid interaction in health and disease. Am J Clin Nutr 1998;67:500S 8. Kushner R, Schoeller D. Estimation of total body water by bioelectrical impedance analysis. Am J Clin Nutr 1986;44:417 9. Ferrannini E. The theoretical bases of indirect calorimetry: a review. Metabolism 1988;37:287 10. Kelly DE, Simoneau J-A. Impaired free fatty acid utilization by skeletal muscle in non–insulin-dependent diabetes mellitus. J Clin Invest 1994;94:2349 11. Avignon A, Lapinski H, Rabasa-Lhoret R, et al. Energy metabolism and substrates oxidative patterns type 2 diabetic patients treated with sulphonylurea alone or in combination with metformin. Diabetes Obes Metab 2000;2(4):229
PII S0899-9007(02)01063-8
Diabetes Mellitus and Weight Control: Differences of Respiratory Quotient in Type 2 Diabetic Obese Subjects Receiving Sulfonylureas and Non-Diabetic Obese Controls INTRODUCTION At diagnosis of disease, most patients with type 2 diabetes are overweight to obese.1 Thus, weight reduction is the primary target of intervention in these subjects before or in addition to pharmacologic treatment. The benefit of weight loss in type 2 diabetes has been recognized since the early 1940s.2 A significant reduction in morbidity and mortality was found after moderate weight loss in these patients.3 Most medium- to long-term studies aiming to induce weight loss in obese type 2 diabetic patients have failed to achieve an acceptable maintenance of weight reduction.4,5 Further, significant weight gains were found in type 2 diabetic patients receiving insulinotropic medications such as sulfonylureas, as demonstrated by the United Kingdom Prospective Diabetes Study.6 The mechanism is still a subject of debate, but the most prominent explanation is the lipogenic effect of insulin. Moreover, the antilipolytic effect of insulin may contribute to weight gain by reducing levels of free fatty acids and their availability for oxidation.7 Therefore, we investigated possible differences of respiratory quotient (RQ) between obese, type 2 diabetic subjects receiving sulfonylureas and obese, non-diabetic control subjects.
MATERIALS AND METHODS Patients Twelve (four male, eight female) obese patients with type 2 diabetes and 12 (four male, eight female) non-diabetic obese control subjects were randomly recruited from the outpatient clinic for diabetes and metabolic diseases at the Department of Internal Medicine, Karl Franzens University, Graz, Austria. All patients gave informed consent before participating in the study. All subjects were moderately sedentary and not participating in any physical fitness training program. Table I summarizes the characteristics of all subjects. All subjects who showed no alteration greater than 1 kg of body weight during the 3 mo before recruitment were elligible because it suggested an equilibrium in energy balance. All diabetic patients were on oral antidiabetic treatment with sulfonylureas (80 mg of gliclazide, three times daily); controls were free of any acute or chronic medication. Subjects taking drugs that could influence fat oxidation, e.g., -blockers, thyroid hormones, psychoactive medication, hormone replacement therapy, and corticosteroids, were excluded. Methods RQ is defined as the quotient of CO2 production and O2 consumption. At 8.00 AM, after a 12-h overnight fast, O2 and CO2 consumption values were measured continuously for 30 min under controlled conditions with the use of open-circuit indirect calorim-
Correspondence to: B. Bahadori, MD, Federal Hospital Muerzzuschlag, Grazerstrasse 63-65, A-8680 Muerzzuschlag, Austria. E-mail: babak. [email protected]
Diabetes Mellitus and Weight Control
159
TABLE I. CHARACTERISTICS OF THE SUBJECTS PARTICIPATING IN THE STUDY*
n Male/female Age (y) Fasting glucose (mg/dL) HbA1c (%)† BMI (kg/m2) Fat mass (kg) Lean body mass (kg) Total body water (%) REE (kcal/d) REE/lean body mass (kcal 䡠 kg⫺1 䡠 d⫺1)
Type 2 diabetics
Controls
12 4/8 54.08 ⫾ 7.8 189.5 ⫾ 62.7 8.10 ⫾ 1.53 32.0 ⫾ 4.9 28.0 ⫾ 8.6 58.0 ⫾ 11.3 46.2 ⫾ 2.4 1574 ⫾ 308 27.5 ⫾ 4.8
12 4/8 50.42 ⫾ 11.1 95.8 ⫾ 11.8 5.27 ⫾ 0.83 34.5 ⫾ 6.2 32.9 ⫾ 13.2 63.3 ⫾ 12.9 43.4 ⫾ 3.9 1693 ⫾ 256 27.2 ⫾ 4.3
* Values are mean ⫾ standard deviation. † P ⬍ 0.001. BMI, body mass index; HbA1c, hemoglobin A1c; REE, resting energy expenditure
etry (Deltatrac Datex, Helsinki, Finland), which includes a differential parametric O2 sensor and an infrared CO2 analyzer. Exhaled air was collected with a canopy. Resting energy expenditure was calculated from the 30-min period of measurement by using Weir’s equation. An internal calibration procedure was performed before starting each measurement. All subjects received a standard meal containing 600 kcal of energy, 30% fat, 15% protein, and 55% carbohydrates 12 h before RQ measurement. Weight and height were measured in the fasting state before the RQ measurement, with subjects lightly dressed; the weight of the clothes they had been wearing was subsequently subtracted. Total body water was measured by bioelectrical impedance (AKERNRJL BIA 101/S, Frankfurt, Germany). Fat mass and fat-free mass were calculated according to the method of Kushner et al.8 All laboratory parameters were measured by routine laboratory methods. Hemoglobin A1c was assessed by HPLC (Bio-Rad, Germany). Statistics Statistical analysis was performed with StatView 5.0 on an Apple Macintosh. Intergroup comparisons were performed by unpaired Student’s t test; the level of significance was set to P ⬍ 0.05. All data are presented as mean ⫾ standard deviation, unless otherwise indicated.
RESULTS The characteristics of both groups are summarized in Table I. Both groups were similar with regard to age, sex, body weight, and body composition. As to be expected, fasting blood glucose (diabetics, 189.5 ⫾ 62.7; controls, 95.8 ⫾ 11.8; P ⬍ 0.001) and hemoglobin A1c (diabetics, 8.10 ⫾ 1.53; controls, 5.27 ⫾ 0.8; P ⬍ 0.001) were significantly higher in diabetic than in non-diabetic subjects. In the diabetic population, RQ was significantly (P ⬍ 0.005) elevated in comparison with the non-diabetic control group (0.84 ⫾ 0.07 versus 0.77 ⫾ 0.04; Fig. 1). In diabetic patients, no correlation between RQ and body mass index, blood glucose, or hemoglobin A1c was observed (data not shown). We also investigated a possible correlation of RQ and waist circumference, but
160
Bahadori et al.
Nutrition Volume 19, Number 2, 2003
CONCLUSION We can state that weight gain in patients with type 2 diabetes treated with sulfonylureas is at least partly due to a reduced lipolytic effect caused by anabolic effects of insulin. In these patients new therapeutic strategies, such as reinforcement of a low-fat diet and physical exercise to increase fat oxidation, should be considered to offset this side effect of sulfonylureas.
B. Bahadori, MD M. Trinker S. J. Wallner B. Yazdani-Biuki T. C. Wascher Department of Internal Medicine Kar Franzens University Graz. Austria
FIG 1. Respiratory quotient in diabetic and control subjects. *P ⬍ 0.005.
Federal Hospital of Muerzzuschlag Muerzzuschlag, Austria the results were negative in both groups (diabetics, r ⫽ 0.027; controls, r ⫽ 0.44). In contrast, resting energy expenditure was comparable between groups by means of absolute values and when lean body mass was expressed as kilograms (Table I). In our study RQ was measured in the fasting state 12 h after a standardized dinner. Thus, a low RQ (⬍0.8) was indicative of a shift from carbohydrate oxidation to fat oxidation.9 Our study provides clear evidence that RQ in obese patients with type 2 diabetes treated with sulfonylureas is higher than that in nondiabetic obese subjects.
DISCUSSION Kelley et al. reported no differences in systemic RQ between obese diabetic and non-diabetic patients.10 Our diabetic patients were receiving sulfonylureas. Sulfonylureas alone were found to increase RQ in diabetic patients.11 This effect may be induced by increased insulin secretion, leading to the following metabolic changes in addition to lipogenic effect: 1) inhibition of the hormone-sensitive lipase, followed by reduction of lipolysis; 2) increased re-esterification of free fatty acid, leading to an increased level of intracellular triacylglycerols; and 3) decreased oxidation of free fatty acids in the mitochondria through the metabolic effects of insulin.
REFERENCES 1. Albu J, Pi-Sunyer F. Obesity and diabetes. In: Bray G, Bouchard C, James W, eds. Handbook of obesity. New York: Marcel Dekker, 1998:697 2. Newburgh LH. Control of hyperglycemia of obese “diabetics” by weight reduction. Ann Intern Med 1942;17:935 3. Lean MEJ, Powrie JK, Anderson AS, Garthwaite PH. Obesity, weight loss and prognosis in type 2 diabetes. Diabet Med 1990;7:228 4. Franz MJ, Monk A, Barry B, et al. Effectiveness of medical nutrition therapy provided by dietitians in the management of non–insulin-dependent diabetes mellitus: a randomized, controlled clinical trial. J Am Diet Assoc 1995;95:1009 5. Laitinen JH, Ahola IE, Sarkkinen ES, et al. Impact of intensified dietary therapy on energy and nutrient intakes and fatty acid composition of serum lipids in patients with recently diagnosed non–insulin-dependent diabetes mellitus. J Am Diet Assoc 1993;93:276 6. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837 7. McGarry DJ. Glucose–fatty acid interaction in health and disease. Am J Clin Nutr 1998;67:500S 8. Kushner R, Schoeller D. Estimation of total body water by bioelectrical impedance analysis. Am J Clin Nutr 1986;44:417 9. Ferrannini E. The theoretical bases of indirect calorimetry: a review. Metabolism 1988;37:287 10. Kelly DE, Simoneau J-A. Impaired free fatty acid utilization by skeletal muscle in non–insulin-dependent diabetes mellitus. J Clin Invest 1994;94:2349 11. Avignon A, Lapinski H, Rabasa-Lhoret R, et al. Energy metabolism and substrates oxidative patterns type 2 diabetic patients treated with sulphonylurea alone or in combination with metformin. Diabetes Obes Metab 2000;2(4):229
PII S0899-9007(02)01063-8