Hisham A. Barakat

Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus.

ObjectiveThis report documents that the gastric bypass operation provides long-term control for obesity and diabetes. Summary Background DataObesity and diabetes, both notoriously resistant to medical therapy, continue to be two of our most common and serious diseases. MethodsOver the last 14 years, 608 morbidly obese patients underwent gastric bypass, an operation that restricts caloric intake by (1) reducing the functional stomach to approximately 30 mL, (2) delaying gastric emptying with a c. 0.8 to 1.0 cm gastric outlet, and (3) excluding foregut with a 40 to 60 cm Roux-en-Y gastrojejunostomy. Even though many of the patients were seriously ill, the operation was performed with a perioperative mortality and complication rate of 1.5% and 8.5%, respectively. Seventeen of the 608 patients (<3%) were lost to follow-up. ResultsGastric bypass provides durable weight control. Weights fell from a preoperative mean of 304.4 lb (range, 198 to 615 lb) to 192.2 lb (range, 104 to 466) by 1 year and were maintained at 205.4 lb (range, 107 to 512 lb) at 5 years, 206.5 lb (130 to 388 lb) at 10 years, and 204.7 lb (158 to 270 lb) at 14 years.The operation provides long-term control of non-insulin-dependent diabetes mellitus (NIDDM). In those patients with adequate follow-up, 121 of 146 patients (82.9%) with NIDDM and 150 of 152 patients (98.7%) with glucose impairment maintained normal levels of plasma glucose, glycosylated hemoglobin, and insulin. These antidiabetic effects appear to be due primarily to a reduction in caloric intake, suggesting that insulin resistance is a secondary protective effect rather than the initial lesion. In addition to the control of weight and NIDDM, gastric bypass also corrected or alleviated a number of other comorbidities of obesity, including hypertension, sleep apnea, cardiopulmonary failure, arthritis, and infertility.

A new paradigm for type 2 diabetes mellitus: could it be a disease of the foregut?

SUMMARY BACKGROUND DATA We previously reported, in a study of 608 patients, that the gastric bypass operation (GB) controls type 2 diabetes mellitus in the morbidly obese patient more effectively than any medical therapy. Further, we showed for the first time that it was possible to reduce the mortality from diabetes; GB reduced the chance of dying from 4.5% per year to 1% per year. This control of diabetes has been ascribed to the weight loss induced by the operation. These studies, in weight-stable women, were designed to determine whether weight loss was really the important factor. METHODS Fasting plasma insulin, fasting plasma glucose, minimal model-derived insulin sensitivity and leptin levels were measured in carefully matched cohorts: six women who had undergone GB and had been stable at their lowered weight 24 to 30 months after surgery versus a control group of six women who did not undergo surgery and were similarly weight-stable. The two groups were matched in age, percentage of fat, body mass index, waist circumference, and aerobic capacity. RESULTS Even though the two groups of patients were closely matched in weight, age, percentage of fat, and even aerobic capacity, and with both groups maintaining stable weights, the surgical group demonstrated significantly lower levels of serum leptin, fasting plasma insulin, and fasting plasma glucose compared to the control group. Similarly, minimal model-derived insulin sensitivity was significantly higher in the surgical group. Finally, self-reported food intake was significantly lower in the surgical group. CONCLUSIONS Weight loss is not the reason why GB controls diabetes mellitus. Instead, bypassing the foregut and reducing food intake produce the profound long-term alterations in glucose metabolism and insulin action. These findings suggest that our current paradigms of type 2 diabetes mellitus deserve review. The critical lesion may lie in abnormal signals from the gut.

Surgical treatment of obesity and its effect on diabetes: 10-y follow-up.

Since 1980 we have performed the identical Greenville gastric bypass (GGB) procedure on 479 morbidly obese patients with an acceptable morbidity and a mortality rate of 1.2%. The weight loss in the series was well maintained over the follow-up period of 10 y. The GGB can control non-insulin-dependent diabetes mellitus (NIDDM) in most patients. The group of 479 patients included 101 (21%) with NIDDM and another 62 (13%) who were glucose impaired. Of these 163 individuals, 141 reverted to normal and only 22 (5%) remained with inadequate control of their carbohydrate metabolism. Those patients who were older or whose diabetes was of longer duration were less likely to revert to normal values. The gastric bypass operation is an effective approach for the treatment of morbid obesity. Along with its control of weight, the operation also controls the hyperglycemia, hyperinsulinemia, and insulin resistance of the majority of patients with either glucose impairment or frank NIDDM.

Influence of Obesity, Impaired Glucose Tolerance, and NIDDM on LDL Structure and Composition: Possible Link Between Hyperinsulinemia and Atherosclerosis

The possible causes of the enhanced risk for coronary heart disease (CHD) were examined in morbidly obese women with normoglycemia, impaired glucose tolerance (IGT), and non-insulin-dependent diabetes mellitus (NIDDM) before and after gastric bypass surgery. Compared with age-matched lean women, plasma lipid and apolipoprotein concentrations of the obese women before surgery favored atherogenesis. The risk for CHD may further be exacerbated in the IGT and NIDDM groups by the prevalence of smaller and denser low-density-lipoprotein (LDL) particles. LDL size correlated negatively with plasma insulin levels independent of triglyceride levels, age, or body mass index (BMI). After surgery, BMI, plasma insulin, and triglyceride levels decreased, but LDL size increased, and LDL density decreased. Neither cholesterol nor LDL cholesterol levels were affected after surgery, but high-density-lipoprotein cholesterol was increased in all patients after surgery. Although the mechanisms underlying the changes in the properties of LDL could not be determined from this study, these changes appear to be of benefit in reducing CHD risk in these patients.

Alterations in low-density lipoproteins in subjects with abdominal adiposity☆☆☆

Abdominal adiposity, as indexed by the waist to hip girth ratio (WHR), has been associated with increased risk and incidence of coronary heart disease (CHD). The purpose of this study was to determine if this enhanced risk is related to alterations in the structure of low density lipoproteins (LDL). LDL were isolated from nine nonobese men with an average WHR of 1.046 and nine nonobese men with a WHR of 0.94, who were matched on age (45.6 +/- 2.7 v 47.7 +/- 2.3 mean +/- SEM) percent body fat (26.5 +/- 0.5 v 26.1 +/- 0.9), and body mass index (27.3 +/- 0.6 v 26.3 +/- 0.6). The average molecular weight of LDL from the subjects with a high WHR was lower than that of subjects with low WHR (2.70 v 3.02 x 10(6) d), the average hydrated density higher (1.050 v 1.040 g/mL), and the mobility (Rf) on 2% to 16% polyacrylamide gradient gel electrophoresis higher. Subfractionation by equilibrium density ultracentrifugation showed that the LDL of subjects with a high WHR was predominantly in the heavy density range (1.038 to 1.048 g/mL) compared with the LDL of subjects with low WHR, which was in the lighter density range (1.030 to 1.040 g/mL). Chemical analysis of the subfractions showed that the peak density fractions of LDL of subjects with a high WHR had a lower cholesterol to protein ratio than the peak density fractions of LDL of subjects with low WHR. Electron microscopy of these peak density fractions showed that LDL of subjects with high WHR was smaller than that of subjects with low WHR. These characteristics of LDL of subjects with abdominal adiposity closely resemble the properties of LDL of patients with documented CHD. It is concluded that the increased risk of CHD associated with abdominal adiposity may be due in part to the alterations in LDL characteristics, and that these alterations in LDL are independent of the degree of obesity.

Cholesteryl Ester Transfer Protein Expression Prevents Diet-Induced Atherosclerotic Lesions in Male db/db Mice

Objective—Accompanying more atherogenic lipoprotein profiles and an increased incidence of atherosclerosis, plasma cholesteryl ester transfer protein (CETP) is depressed in diabetic obese patients compared with nondiabetic obese counterparts. The depressed levels of CETP in the plasma of diabetic obese individuals may contribute to the development of an atherogenic lipoprotein profile and atherogenesis. We have examined the effect of CETP expression on vascular health in the db/db model of diabetic obesity. Methods and Results—Transgenic mice expressing the human CETP minigene were crossed with db/db strain, and 3 groups of offspring (CETP, db, and db/CETP) were placed on an atherogenic diet for 16 weeks. The proximal aorta was then excised and examined for the presence of atherosclerotic plaques. In db mice, 9 of 11 had intimal lesions with a mean area of 26 098±7486 &mgr;m2. No lesions greater than 1000 &mgr;m2 were observed in db/CETP or CETP mice. CETP-expressing mice had lower circulating cholesterol concentrations than db mice. Fractionating plasma lipids by FPLC indicated that the difference in total cholesterol was primarily attributable to differences in VLDL and LDL. Conclusions—The expression of human CETP in db/db mice prevented the formation of diet-induced lesions, suggesting an antiatherogenic effect of CETP in the context of diabetic obesity.

Effect of exercise training on adenyl cyclase and phosphodiesterase in skeletal muscle, heart, and liver

Abstract Adaptive changes in the activities of adenyl cyclase and phosphodiesterase in response to exercise training were studied in muscle, heart, and liver. Basal adenyl cyclase activities were increased in muscle and decreased in heart as a result of training. Epinephrine-stimulated adenyl cyclase activity of heart was depressed by training. Fluoride-stimulated adenyl cyclase activity was not altered by training in any of the tissues studied. Phosphodiesterase activity was depressed in liver of trained rats but unaltered in muscle and heart. These changes in adenyl cyclase and phosphodiesterase activities suggest that the capacity to respond to hormones may be altered by training.

Effects of exercise training on the chemical composition of plasma LDL.

The purpose of the present study was to determine the effects of exercise training on the chemical composition of plasma low-density lipoprotein (LDL). Thirteen men (mean age +/- SE, 47.2 +/- 1.5 years) were examined before and after 14 weeks of endurance-oriented exercise training (3 to 4 d/wk, 30 to 45 min/d). Although calculated plasma LDL concentrations remained unaltered (3.49 +/- 0.24 versus 3.65 +/- 0.23 mmol/L), changes in the chemical composition of LDL (increased LDL free cholesterol, cholesterol ester, and phospholipid content) were associated with a reduction in adiposity, umbilical girth, and basal plasma insulin and glucose concentration with training intervention. Increases in LDL molecular weight and particle diameter were associated with a reduction in fat mass, plasma triglyceride concentration, and basal plasma glucose concentration with physical activity. The LDL lipid-to-protein ratio also increased (P < .01) with training by 7%, primarily due to an increase in LDL free cholesterol content (P < .01). These findings indicate the formation of LDL particles that are more cholesterol enriched and protein poor with exercise training, which provides additional evidence for the cardioprotective effect of long-term physical activity.

Fatty Acid Oxidation by Skeletal Muscle Homogenates From Morbidly Obese Black and White American Women

The purpose of this study was to determine if there were differences in the capacity of skeletal muscle from morbidly obese Black and White American women to oxidize fatty acids. The oxidation rates of (14)C-palmitate, (14)C-palmitoyl-CoA, and (14)C-palmitoyl-carnitine were measured in whole homogenates of rectus abdominus from Black and White women who were similar in age and body mass index (BMI). The activities of muscle citrate synthase (CS), beta-hydroxy acyl-CoA dehydrogenase (beta-HAD), and mitochondrial and microsomal acyl-CoA synthetase (ACS) were measured in the 2 groups. The results showed that the rate of (14)C-palmitate oxidation by muscle of Black women was 25% that of Whites (8.7 +/- 1.5 v 34.4 +/- 6.8 nmol (14)CO(2) produced/gram tissue wet weight/ hour; P <.05), but the rates of (14)C-palmitoyl-CoA and (14)C-palmitoyl-carnitine oxidation were not different in the 2 groups. No differences were found in the activities of CS or beta-HAD. However, the activities of both mitochondrial and microsomal ACS were lower in the Black women than the Whites (mitochondrial ACS 25.1 +/- 3.9 v 36.4 +/- 5.0 nmol/mg protein/min; P <.05; microsomal ACS 6.2 +/- 0.5 v 8.5 +/- 0.5; nmol/mg protein/min; P <.005). The lower rate of palmitate oxidation, and the lack of differences in the rates of palmitoyl-CoA and palmitoyl-carnitine oxidation indicate that there is a defect in the activation of the fatty acid in the muscle of the Black women. This was confirmed by the decrease in mitochondrial ACS activity in the Black women. The decreased fatty acid oxidation by skeletal muscle of obese Black women could result in shunting these fuels from muscle to adipose tissue for storage, which may contribute to the maintenance of obesity in the Black women.

Measurement of in vivo protein synthesis in rats during an exercise bout

Abstract The purpose of the present investigation was twofold: (i) to develop a simple and reliable method for measuring muscle protein synthesis in vivo and (ii) to use the method to study the effect of exercise on muscle protein synthesis. The method that has been developed is based on the principle that [ 3 H]tyrosine is released at a fairly constant rate from a subcutaneously injected emulsion of water and sesame oil. Incorporation of label into muscle protein and [ 3 H]tyrosine specific activity are linear for at least 60 min. Thus, removing muscle samples at two time periods (30 and 60 min) allows the rate of muscle protein synthesis to be determined. In a previous study, we found that swimming rats for 1 hr resulted in an 18% reduction in the rate of protein synthesis. In the present study, 1 hr or running resulted in a 30% depression while running to exhaustion caused a 71% depression in muscle protein synthesis. These results indicate that muscle protein synthesis changes in response to the intensity and the duration of an exercise bout.