New technologies for treating obesity.

Obesity has become a national epidemic and a disease of global magnitude. The numbers of patients with obesity have grown exponentially in the last 10 years to the degree that the Centers for Disease Control and Prevention reports that one third of the US population is obese. The prevalence of diabetes has grown by more than 50% in that same time period. Unfortunately, the traditional therapies of diets, exercise, behavioral modification and medications have had little effect, especially in the severely obese. The introduction of bariatric surgery has changed the natural history of the super obese. Operative approaches now provide the most effective treatment of obesity but carry with them possible risks. Only 1% of patients who are estimated to benefit from bariatric surgery have undergone a procedure. The burgeoning field of endoluminal therapy has now allowed us to consider even more minimally invasive procedures to reach a larger patient population. This article will review the most recent advances in innovative technologies to treat the growing numbers of obese patients.

Muscle insulin receptor concentrations in obese patients post bariatric surgery: relationship to hyperinsulinemia.

OBJECTIVE: Obesity results in insulin resistance. Bariatric surgery for obese individuals induces weight loss, improves insulin sensitivity, and lowers insulin levels. We investigated the mechanisms of this improvement. DESIGN: Insulin receptor (IR) content, IR signaling, and adiponectin levels were measured in nine morbidly obese subjects before and after bariatric surgery. SUBJECTS: Seven female and two male, average age 44+/-2y, BMI >40 kg/m(2) and/or at least 100 lbs over ideal body weight, undergoing elective bariatric surgery. MEASUREMENTS: Before surgery BMI, fasting plasma glucose, adiponectin, and insulin levels were measured. A fasting muscle biopsy was obtained from the vastus lateralis for IR concentration and autophosphorylation activity measurements. These procedures were repeated 1 y after surgery. RESULTS: At 1 y after surgery, the subjects had lost an average of 48.3+/-5.6 kg (P<0.001), insulin sensitivity had significantly increased as determined by the minimal model (SI 0.72+/-0.18 vs 3.86+/-1.43, P<0.05), and IR content had increased two-fold in muscle (2.1+/-0.4 vs 4.3+/-0.7 ng/mg protein, P<0.01). The increase in IR content was related to fasting insulin levels. In the subjects with the lowest IR function, there was also an increase in IR function. Plasma adiponectin increased by 40% following weight loss (7.4+/-1.6 pre vs 10.3+/-1.3 mg/ml post, P<0.05). There was no significant change in muscle content of the IR inhibitor, PC-1. CONCLUSION: Increased IR content, most likely regulated by insulin levels, may be one contributor to the increased insulin sensitivity that occurs when morbidly obese patients undergo bariatric surgery.

Neoadjuvant chemoradiation therapy in patients with surgically treated esophageal cancer.

Over the past 10 years, 232 patients were treated at the East Carolina School of Medicine for cancer of the esophagus. Of these, 73 received neoadjuvant chemoradiation therapy and subsequent surgical resection. The results in this group suggest improved cancer control, with 18 patients (25%) remaining free of recurrence 3 years after treatment, compared with 11 out of 159 patients (7%) in the group that was not treated with neoadjuvant therapy (p < 0.0001). The 5-year recurrence-free survival with neoadjuvant chemoradiotherapy and surgery was 16% (12/73) compared with 3% (5/159) with other types of therapy. Two protocols of neoadjuvant chemoradiotherapy with subsequent surgery were compared: I: Split-course, once-a-day radiotherapy and concomitant cisplatinum/5-fluorouracil followed by esophagectomy. II: Accelerated, twice-a-day radiotherapy with concomitant triple chemotherapy using cisplatinum/5-fluorouracil/vinblastine followed by transhiatal extrathoracic esophagectomy. The survival rate was similar in the two groups of patients but the complication rate was higher in group II. Neoadjuvant chemoradiation therapy and the techniques of transhiatal esophagectomy may have contributed to the improved results in the treatment of esophageal carcinoma. Accelerated radiotherapy with triple chemotherapy was more toxic and did not give better survival rates than split-course, once-a-day, conventional, fractionated-protracted radiotherapy combined with two drugs.

Etiology of type II diabetes mellitus: role of the foregut.

The Greenville version of the gastric bypass induced long-term remission of type II diabetes mellitus in 121 of 146 (82.9%) morbidly obese patients. Similarly, the operation returned 150 of 152 (98.7%) morbidly obese patients with impaired glucose tolerance to euglycemia. These outcomes were not merely changes in glucose levels; the operation also reduced the mortality and morbidity of the disease. Diabetic patients submitted to surgery had a 1.0% chance of dying during a 10-year period of follow-up compared to a mortality rate of 4.5% in a matched group (p = 0.0003). These results, the best therapeutic outcomes for type II diabetes ever reported, suggest that the disease is not an untreatable, hopeless illness but one that can be treated successfully with better understanding of the pathophysiology of these surgical remissions. The mechanism of the improvement is not yet clear. The rapidity of the correction to euglycemia, usually a matter of days, suggests that the reason is not the loss of weight (i.e., reduction in fat mass) but, rather, the result of the exclusion of food and a secondary alteration in incretin signals from the antrum, duodenum, and proximal jejunum to the islets.

Increased protein kinase C theta in skeletal muscle of diabetic patients.

In this study we have investigated whether protein kinase C (PKC) protein and activity are increased in skeletal muscle of human diabetic patients. The protein content of different PKC isoforms (beta, Theta, epsilon, delta, mu, and zeta) in the particulate fraction was measured, using Western analysis, in human rectus abdominus skeletal muscle from obese (hyperinsulinemic, normoglycemic) and obese diabetic (hyperinsulinemic, hyperglycemic) subjects. PKC Theta protein content was significantly higher in the particulate fraction of muscle from diabetic patients compared with the nondiabetic controls. PKC Theta was immunoprecipitated and its activity was measured in muscle from diabetic and nondiabetic controls. There was a significant increase in PKC Theta activity in muscle from diabetic patients compared with muscle from nondiabetic controls. Therefore, both PKC Theta protein content and activity were significantly increased in the particulate fraction in muscle from diabetic patients, suggesting the involvement of this isoform in diabetes. Most of the PKC Theta protein was found in the cytosol. There was no change in cytosolic PKC Theta protein content in muscle from diabetic patients compared with muscle from nondiabetic controls. Thus, the increase in particulate-associated PKC Theta was likely due to translocation and activation rather than an increase in protein mass.

Substrate utilization during exercise in formerly morbidly obese women.

The purpose of this study was to compare substrate utilization during fasting and submaximal exercise in morbidly obese women after weight loss (WL) with that in weight-matched controls (C). WL were studied in the weight-stable condition approximately 24 mo after gastric bypass surgery. Energy intake (self-reported) and expenditure ((2)H(2)(18)O) were also compared. The respiratory exchange ratio during exercise at the same absolute (15 W) workload was significantly (P < or = 0.05) elevated in WL vs. C (0.90 +/- 0.02 vs. 0.83 +/- 0.03); this was reflected as lower fat utilization in WL (29.7 +/- 4.8 vs. 53.2 +/- 9.7% of energy from fat). Respiratory exchange ratio during exercise at the same relative (65% of maximal O(2) uptake) intensity was also significantly (P < 0.05) elevated in WL (0.96 +/- 0.01 vs. 0.89 +/- 0.02), and fat use was concomitantly depressed (12.4 +/- 3.0 vs. 34.3 +/- 9.9% of energy from fat). Resting substrate utilization, daily energy expenditure, and self-reported relative macronutrient intake did not differ between groups. These data suggest that lipid oxidation is depressed during physical activity in WL. This defect may, at least in part, contribute to a propensity for the development of morbid obesity.

Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity.

This study was conducted to investigate the possible involvement of protein kinase C (PKC) and serine/threonine phosphorylation of the insulin receptor in insulin resistance and/or obesity. Insulin receptor tyrosine kinase activity was depressed in muscle from obese insulin-resistant patients compared with lean insulin-responsive control subjects. Alkaline phosphatase treatment resulted in a significant 48% increase in in vitro insulin-stimulated receptor tyrosine kinase activity in obese but not lean muscle. To investigate the involvement of PKC in skeletal muscle insulin resistance and/or obesity, membrane-associated PKC activity and the protein content of various PKC isoforms were measured in human skeletal muscle from lean, insulin-responsive, and obese insulin-resistant patients. Membrane-associated PKC activity was not changed; however, PKC-beta protein content, assayed by Western blot analysis, was significantly higher, whereas PKC-theta, -eta, and -mu were significantly lower in muscle from obese patients compared with muscle from lean control subjects. Incubation of muscle strips with insulin significantly increased membrane-associated PKC activity in muscle from obese but not lean subjects. PKC-delta, -beta, and -theta were translocated from the cytosol to the membrane fraction in response to insulin treatment. These results suggest that in skeletal muscle from insulin-resistant obese patients, insulin receptor tyrosine kinase activity was reduced because of hyperphosphorylation on serine/threonine residues. Membrane-associated PKC-beta protein was elevated under basal conditions, and membrane-associated total PKC activity was increased under insulin-stimulated conditions in muscle from obese insulin-resistant patients. Thus, we postulate that the decreased tyrosine kinase activity of the insulin receptor may be caused by serine/threonine phosphorylation by PKC.

Impact of insulin resistance on lipoprotein subpopulation distribution in lean and morbidly obese nondiabetic women.

The purpose of this study was to examine the effects of insulin resistance on the lipoprotein subpopulation distribution of very-low-density, low-density, and high-density lipoproteins (VLDL, LDL, and HDL) in lean and morbidly obese nondiabetic women. Lean women (body mass index [BMI], 20 to 27 kg/m2) stratified by BMI were divided into insulin-sensitive (SL, n = 12) and insulin-resistant (RL, n = 8) groups according to Bergman's minimal model, SI. A group of obese women (BMI, 30 to 53 kg/m2), also stratified by BMI, were divided into insulin-sensitive (SO, n = 10) and insulin-resistant (RO, n = 11) groups in a similar fashion. Resistant groups were similar to sensitive groups (SL v RL and SO vRO) in age, weight, percent body fat, and waist circumference, ie, total and regional adiposity. VLDL, LDL, and HDL subpopulation distributions were determined in fasting plasma samples by nuclear magnetic resonance (NMR) spectroscopy. The average particle sizes of all 3 classes of lipoproteins were similar for the SL and RL groups. In contrast, RO subjects had larger VLDL, smaller LDL, and smaller HDL, than SO subjects (P < .05). Lower concentrations of large LDL and large HDL were found in RO compared with SO subjects (P < .05). In obese women, but not in lean women, VLDL size was associated with plasma insulin (r = .60, P < .005), while LDL size and HDL size were negatively correlated with plasma insulin (r = -.39, P < .05 and r = -.38, P < .05) and positively correlated with SI (r = .54, P < .01 and r = .42, P < .05). These results suggest that in obese women, insulin resistance may be involved in the formation of lipoprotein subpopulation distributions that are associated with vascular disease.

Protein kinase C modulates insulin action in human skeletal muscle.

There is good evidence from cell lines and rodents that elevated protein kinase C (PKC) overexpression/activity causes insulin resistance. Therefore, the present study determined the effects of PKC activation/inhibition on insulin-mediated glucose transport in incubated human skeletal muscle and primary adipocytes to discern a potential role for PKC in insulin action. Rectus abdominus muscle strips or adipocytes from obese, insulin-resistant, and insulin-sensitive patients were incubated in vitro under basal and insulin (100 nM)-stimulated conditions in the presence of GF 109203X (GF), a PKC inhibitor, or 12-deoxyphorbol 13-phenylacetate 20-acetate (dPPA), a PKC activator. PKC inhibition had no effect on basal glucose transport. GF increased (P < 0.05) insulin-stimulated 2-deoxyglucose (2-DOG) transport approximately twofold above basal. GF plus insulin also increased (P < 0.05) insulin receptor tyrosine phosphorylation 48% and phosphatidylinositol 3-kinase (PI 3-kinase) activity approximately 50% (P < 0.05) vs. insulin treatment alone. Similar results for GF on glucose uptake were observed in human primary adipocytes. Further support for the hypothesis that elevated PKC activity is related to insulin resistance comes from the finding that PKC activation by dPPA was associated with a 40% decrease (P < 0.05) in insulin-stimulated 2-DOG transport. Incubation of insulin-sensitive muscles with GF also resulted in enhanced insulin action ( approximately 3-fold above basal). These data demonstrate that certain PKC inhibitors augment insulin-mediated glucose uptake and suggest that PKC may modulate insulin action in human skeletal muscle.

Surgical intervention for the severely obese.

Severe obesity is a grave disease in the U.S. as well as other industrialized nations. This disease has many ramifications on both an individual and social levels. It affects 12.5 million people in the U.S., according to national survey data. The health risks of severe obesity include hypertension, hyperlipidaemia, cardiomyopathy, diabetes, hypoventilation disorders, increased risk of malignancy, cholelithiasis, degenerative arthritis, infertility, and psychosocial impairments. Medical weight reduction programmes have rarely achieved long-term success. Most authorities now agree that bariatric surgery is the treatment of choice for well-informed and motivated obese patients with acceptable operative risks, who strongly desire substantial weight loss or who have severe impairments because of their weight. Surgery is indicated for patients with a BMI greater than 40 kg/m2, or for those with serious medical co-morbidities and a BMI greater than 35 kg/m2. Three procedures, the adjustable silicone gastric banding (ASGB), vertical gastric banding (VBG), and gastric bypass (GB), have produced the best results to date. Each of these procedures is much more effective than dietary therapies. Each has advantages and disadvantages, with GB producing greater sustained weight loss in the long-term, with a slightly higher risk of metabolic complications. All can be done with surprisingly low operative mortality. The pronounced weight loss induced with these operations can relieve and bring co-morbid diseases, such as diabetes and hypertension, once thought to be only barely controllable, into full long-term remission.

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.