Is type II diabetes mellitus (NIDDM) a surgical disease?

Since February 1, 1980, 515 morbidly obese patients have undergone the Greenville gastric bypass (GGB) operation. Of these, 212 (41.2%) were euglycemic, 288 (55.9%) were either diabetic or had glucose intolerance, and 15 (2.9%) were unable to complete the evaluation. After the operation, only 30 (5.8%) patients remained diabetic (and 20 of these improved), 457 (88.7%) became and have remained euglycemic, and inadequate data prevented classification of the other 28 (5.4%). The patients who failed to return to normal glucose values were older and their diabetes was of longer duration than those who did. The effect of the GGB was not only limited to the correction of abnormal glucose levels. The GGB also corrected the abnormal levels of fasting insulin and glycosylated hemoglobin in a cohort of 52 consecutive severely obese patients with non-insulin-dependent diabetes. The GGB effectively controls weight. If morbid obesity is defined as 100 pounds over ideal body weight, 89% of the patients are no longer "morbidly" obese within 2 years. In most patients, the control of the weight has been well maintained during the 11 years of follow-up; most of the upward creep in weight of 20.8% between 24 and 132 months was from the 49 (9.5%) patients who had staple line breakdowns between the large and small gastric pouches. Non-insulin-dependent diabetes, previously considered a chronic unrelenting disease, can be controlled in the severely obese by the gastric bypass. Whether the correction of glucose metabolism affects the complications of diabetes is unknown. Whether the gastric bypass should be considered for patients with advanced non-insulin-dependent diabetes but who are not severely obese deserves consideration. The GGB has an unacceptably high rate of staple line failure. Accordingly, the authors have recently changed their procedure to one that divides the stomach rather than partitions it with staples.

Long-term studies of mental health after the Greenville gastric bypass operation for morbid obesity.

From February 1, 1980, to May 1, 1989, 462 patients underwent the Greenville gastric bypass at the East Carolina University School of Medicine. The operation effectively maintained satisfactory weight loss after 9 years (mean weight preoperatively, 293 lbs; at 24 months, 179 lbs; at 96 months, 194 lbs). The gastric bypass favorably affected non-insulin-dependent diabetes, hypertension, and physical and role functioning. In the most recent 157 patients, our studies were extended to study the effects of the gastric bypass on mental health. The significant improvements in mental health indices that were observed 6 and 12 months after surgery eroded by the end of 2 years. This return of the mental health indices to the preoperative status, plus the late occurrence of 3 suicides and 2 deaths from alcohol abuse among the total 462 patients, suggest that long-term follow-up and continued emotional support are essential ingredients for successful bariatric surgery.

IGF-I--stimulated glucose transport in human skeletal muscle and IGF-I resistance in obesity and NIDDM.

Based on the observation that insulinlike growth factor I (IGF-I) can stimulate glucose utilization in nondiabetic subjects and that the action of the IGF-I receptor is normal in the skeletal muscle of patients with non-insulin-dependent diabetes mellitus (NIDDM), it seems possible that IGF-I might provide an effective acute treatment for the hyperglycemia of NIDDM. Using our recently developed in vitro human muscle preparation, we investigated the hypothesis that IGF-I might be an effective alternative to insulin in stimulating glucose transport in diabetic muscle. Abdominal muscle samples from nonobese nondiabetic, obese nondiabetic, and obese NIDDM patients were obtained during elective abdominal surgery. Plasma levels of IGF-I in diabetic patients were lower than those in either of the nondiabetic groups. Binding studies with wheat-germ-agglutinin-chromatography-purified receptors demonstrated the presence of IGF-I receptors in human muscle, with IGF-I binding being approximately 24% that of insulin. There was no change in IGF-I binding in muscle from obese or diabetic subjects, and the structural characteristics of the IGF-I receptor were not altered, as determined by electrophoretic mobility. IGF-I stimulated glucose transport approximately twofold in incubated muscle from control subjects, but there was no IGF-I stimulation of transport in muscle from obese subjects with or without NIDDM. These results confirm a previous report that human muscle contains receptors for IGF-I and demonstrate for the first time that IGF-I can stimulate glucose transport in human muscle. However, muscle from obese subjects with or without NIDDM is resistant to the action of IGF-I.

Hydrostatic weighing without head submersion in morbidly obese females.

This study tests the validity of hydrostatic weighing without head submersion (HWNS) for determining the body density (Db) of morbidly obese (MO) females. Eighty MO females who were able to perform traditional hydrostatic weighing at residual volume (HW) underwent four counterbalanced trials for each procedure (HW and HWNS) to determine Db. Residual volume was determined by oxygen dilution. Twenty subjects were randomly excluded from the experimental group (EG) and assigned to a cross-validation group (CV). Simple linear regression was performed on EG data (n = 60, means = 36.8 y, means % fat = 50.1) to predict Db from HWNS (Db = 0.569563 [Db HWNS] + 0.408621, SEE = 0.0066). Comparison of the predicted and actual Db for CV group yielded r = 0.69, SEE = 0.0066, E statistic = 0.0067, mean difference = 0.0013 kg/L. The SEE and E statistic for body fat were 3.31 and 3.39, respectively. Mean difference for percent fat was 0.66%. Results indicate that HWNS is a valid technique for assessing body composition in MO females.

Intraoperative video panendoscopy for diagnosing sites of chronic intestinal bleeding.

Intraoperative video panendoscopy was performed in 14 patients with chronic, recurrent gastrointestinal bleeding. All of the study patients had undergone extensive and expensive diagnostic testing including multiple radiographic contrast studies of the gastrointestinal tract, upper and lower endoscopy, nuclear bleeding scans, and selective mesenteric angiography without definition of the bleeding source. Intraoperative video panendoscopy, employing a segmental advance and look technique, allowed visualization and transillumination of the entire gut and identified mucosal disease in 13 patients (93 percent). Angiodysplasia of the colon and small intestine was the most common pathologic finding. Intraoperative video panendoscopy significantly influenced the operation performed in 13 patients (93 percent). Postoperative complications were minimal, with none being directly attributable to intraoperative video panendoscopy. Bleeding was totally controlled in 10 patients (71 percent) during a mean follow-up period of 25 months. Intraoperative video panendoscopy is a valuable technique for assisting in the management of the patient with recurrent gastrointestinal bleeding.

An in vitro human muscle preparation suitable for metabolic studies. Decreased insulin stimulation of glucose transport in muscle from morbidly obese and diabetic subjects.

We have developed an in vitro muscle preparation suitable for metabolic studies with human muscle tissue and have investigated the effects of obesity and non-insulin-dependent diabetes mellitus (NIDDM) on glucose transport. Transport of 3-O-methylglucose and 2-deoxyglucose was stimulated approximately twofold by insulin in muscle from normal nonobese subjects and stimulation occurred in the normal physiological range of insulin concentrations. In contrast to insulin stimulation of 3-O-methylglucose and 2-deoxyglucose transport in muscle from normal, nonobese subjects, tissue from morbidly obese subjects, with or without NIDDM, were not responsive to insulin. Maximal 3-O-methylglucose transport was lower in muscle of obese than nonobese subjects. Morbidly obese patients, with or without NIDDM, have a severe state of insulin resistance in glucose transport. The novel in vitro human skeletal muscle preparation herein described should be useful in investigating the mechanism of this insulin resistance.

Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal rat liver.

Insulin-like growth factor-I (IGF-I) in human hepatoma cells (HEP-G2) has, in addition to its effect on cell growth, short-term metabolic effects acting through its own receptor. We have demonstrated that normal human hepatocytes, compared with HEP-G2 cells, have virtually no IGF-I binding sites. Because the rate of growth is the major difference between the hepatoma and the normal liver, we asked if normal liver might express IGF-I binding sites under physiologic growth conditions. Indeed, whereas adult rat hepatocytes have low IGF-I binding sites similar to those in human liver, hepatocytes from regenerating liver after 3 d subtotal hepatectomy have an approximately sixfold increase (P less than 0.005) and those from fetal rat liver a approximately 12-fold increase (P less than 0.005), to levels comparable to those in the HEP-G2 cells. The specificity of 125I IGF-I binding to its receptor was demonstrated by competition studies with monoclonal antibodies directed toward the IGF-I and the insulin receptors, with unlabeled IGF-I and insulin and by affinity labeling experiments. Thus, if IGF-I has any short-term metabolic functions in the adult human liver, it is not through interaction with its own receptor. Autocrine regulation by IGF-I of liver growth appears possible since IGF-I binding sites are expressed under pathological and physiological conditions of growth. The mechanism that couples these two phenomena remains to be elucidated.

Long-term effect of insulin on glucose transport and insulin binding in cultured adipocytes from normal and obese humans with and without non-insulin-dependent diabetes.

We have tested the hypothesis that in vitro exposure of insulin-resistant adipocytes with insulin results in improved insulin action. A primary culture system of adipocytes from obese subjects with or without non-insulin-dependent diabetes mellitus (NIDDM) and nonobese control subjects has been developed. The adipocytes when cultured in serum-free medium do not lose their original characteristics in regard to insulin binding and glucose transport. The adipocytes from three groups were incubated with insulin (0, 10(-10) M, and 10(-7) M) for 24 h at 37 degrees C, receptor-bound insulin was dissociated, and basal and insulin (1 X 10(-11)-10(-7) M)-stimulated glucose transport and 125I-insulin binding were determined. The 24-h insulin exposure of adipocytes from control subjects decreased basal and insulin-stimulated glucose transport. The effects of 1 X 10(-7) M insulin were more pronounced than 1 X 10(-10) M insulin. Similarly, insulin exposure decreased insulin sensitivity and responsiveness of cultured adipocytes from obese and NIDDM patients. The insulin-induced reduction in insulin sensitivity and responsiveness for glucose transport in three groups were due to alterations at insulin binding and postbinding levels. In conclusion, insulin induces insulin resistance in control adipocytes and further worsens the insulin resistance of adipocytes from obese and NIDDM subjects. For insulin to improve the insulin resistance of adipocytes from NIDDM patients, either more prolonged in vitro insulin exposure and/or other hormonal factors might be required.

The control of diabetes mellitus (NIDDM) in the morbidly obese with the Greenville Gastric Bypass.

Since February 1, 1980, the identical standardized Greenville Gastric Bypass has been performed in 397 morbidly obese patients with an operative mortality rate of 0.8%. The operation effectively controlled weight and maintained satisfactory weight loss even after 6 years (mean weights and ranges: Preoperative: 290 lbs (196-535); 18 months: 175 lbs (110-300); 72 months: 205 lbs (140-320). The gastric bypass favorably affected non-insulin-dependent diabetes (NIDDM), hypertension, physical and role functioning, and several measures of mental health. Rigorous follow-up (97.5% over 6 years) revealed that health problems were common in postoperative patients; there were nine late deaths. Abnormal glucose metabolism was present in 141 (36%) of 397 patients before surgery: NIDDM was present in 88 patients (22%) and 53 patients (14%) were glucose impaired. Of these, all but two became euglycemic within 4 months after surgery without any diabetic medication or special diets. The most recent 42 morbidly obese patients with NIDDM were studied intensively. In that cohort, fasting blood glucose, fasting insulin, and glycosylated hemoglobin returned to normal after surgery; insulin release, insulin resistance, and utilization of glucose improved sharply. The normalization of glucose metabolism after gastric bypass may not be related solely to weight loss and restriction of caloric intake, but may also be due to the bypass of the antrum and duodenum.

Gastric bypass.

The success of gastric bypass probably depends on factors other than merely the restrictive size of the gastric pouch and outlet. Postoperative dumping and a mild degree of malabsorption derived from the redirection of intestinal contents contribute to long-term success. Thus, gastric bypass combines some elements of both malabsorptive and gastric restrictive procedures.

Insulin-receptor kinase activity of adipose tissue from morbidly obese humans with and without NIDDM.

We have determined glucose transport, insulin binding, and insulin-receptor kinase activity in adipose tissue from morbidly obese patients with and without non-insulin-dependent diabetes mellitus (NIDDM). The insulin sensitivity and responsiveness of glucose transport in freshly isolated adipocytes were significantly reduced in NIDDM subjects compared with nondiabetics. This was due in part to decreased insulin binding in adipocytes. Reduced specific 125I-labeled insulin binding was also observed in crude detergent extracts and partially purified insulin receptors from adipose tissue. In addition, the basal and insulin-stimulated tyrosine-specific protein kinase activity per milligram of protein was significantly decreased in NIDDM patients compared with nondiabetics. The differences between maximally insulin-stimulated and basal kinase activities expressed by insulin-binding activity were also significantly reduced in NIDDM subjects. We conclude that insulin resistance in morbidly obese patients with NIDDM is due to both insulin-binding and postbinding defects. One of the postbinding defects in NIDDM appears to be impaired insulin-receptor kinase activity of fat tissue.

Insulin receptor kinase in human skeletal muscle from obese subjects with and without noninsulin dependent diabetes.

We have studied the structure and function of the insulin receptors in obese patients with and without noninsulin dependent diabetes mellitus (NIDDM) and in nonobese controls using partially purified receptors from muscle biopsies. Insulin binding was decreased in obesity due to reduced number of binding sites but no differences were observed in insulin binding between obese subjects with or without NIDDM. The structural characteristics of the receptors, as determined by affinity labeling methods and electrophoretic mobility of the beta-subunit, were not altered in obese or NIDDM compared to normal weight subjects. Furthermore, the ability of insulin to stimulate the autophosphorylation of the beta-subunit and the phosphoamino acid composition of the phosphorylated receptor were the same in all groups. However, insulin receptor kinase activity was decreased in obesity using Glu4:Tyr1 as exogenous phosphoacceptor without any appreciable additional defect when obesity was associated with NIDDM. Thus, our data are supportive of the hypothesis that in muscle of obese humans, insulin resistance is partially due to decreased insulin receptors and insulin receptor kinase activity. In NIDDM the defect(s) in muscle is probably distal to the insulin receptor kinase.

Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity.

We have developed a method to isolate insulin-responsive human hepatocytes from an intraoperative liver biopsy to study insulin action and resistance in man. Hepatocytes from obese patients with noninsulin-dependent diabetes were resistant to maximal insulin concentration, and those from obese controls to submaximal insulin concentration in comparison to nonobese controls. Insulin binding per cell number was similar in all groups. However, insulin binding per surface area was decreased in the two obese groups because their hepatocytes were larger. In addition, the pool of detergent-extractable receptor was further decreased in diabetics. Insulin receptors in all groups were unaltered as determined by affinity-labeling methods. However, insulin-stimulated insulin receptor kinase activity was decreased in diabetics. Thus, in obesity, decreased surface binding could explain resistance to submaximal insulin concentrations. In diabetes, diminished insulin-stimulated protein kinase activity and decreased intracellular pool of receptors could provide an explanation for postinsulin-binding defect(s) of insulin action in human liver.

Retrograde endoscopy of the bypassed stomach segment after gastric bypass surgery: unexpected lesions.

Surgical measures for the treatment of morbid obesity include gastric bypass of the stomach and duodenum. We endoscopically evaluated the bypassed segments in 51 patients three to 24 months after a standard gastric bypass procedure. Retrograde endoscopy was successful in 33 of the patients (65%). There was significantly more gastritis by endoscopic grading in the distal bypassed segment than in the proximal part of the stomach. The gastritis in the bypassed segment was associated with pooled bile in 97% of the patients. The severity of gastritis did not appear to be related to the time after surgery and was as severe three months after surgery as it was at 24 months. Histologically, the gastritis was nonconfluent, and often the histologic and endoscopic findings were at variance. There was intestinal metaplasia in biopsy specimens from the distal pouch in four of the 33 patients. The mechanism for the high incidence of gastritis is unknown, but may be related to decreased antral motility due to distention of the proximal pouch with food. These patients require close observation for changes in the bypassed segment of stomach that may occur as a consequence of chronic inflammation.

The bypassed stomach.

Retrograde duodenogastroscopy solves the problem of postoperative evaluation of the gastric bypass patient. The stomach may be bypassed to treat morbid obesity, but it no longer need be inaccessible. Endoscopic gastritis is rare in the proximal gastric pouch but common in the distal gastric segment and may be related to the presence of bile. Although the gastric mucosa is histologically normal in half of the gastric bypass patients, acute and chronic gastritis, regenerative changes, and intestinal metaplasia may develop in either or both segments. The causes and implications of these endoscopic and histologic findings are unknown.

The Greenville gastric bypass. Progress report at 3 years.

Two hundred and ten morbidly obese patients underwent a standardized gastric bypass procedure between February 1980 and November 1983. We conclude, based on 100% follow-up, that the operation is safe (operative mortality--1%, significant complications--10%) and effective (reoperation rate--4%). Only one patient failed to lose more than 25% of preoperative weight. The operation produced a mean weight loss in the group from 289 pounds (202-505) before surgery to 176 pounds (118-308) at 18 months after surgery. Stated as "per cent of ideal weight," patients lost from a preoperative mean of 214% (153-350) to 130% (88-189) at 18 months. Maximum weight loss was reached by 18 months after the procedure and was maintained during 36 months of observation in over 95% of patients. When patients were divided into four groups according to preoperative weight, weight loss occurred at a roughly similar rate, but heavier patients, although they lost more weight, plateaued at a higher weight than patients originally less obese. Striking and objective benefits were seen in patients with diabetes, hypertension, heart disease, and pulmonary insufficiency.

The effectiveness of gastric bypass over gastric partition in morbid obesity: consequence of distal gastric and duodenal exclusion.

Eighty-seven morbidly obese patients were prospectively randomized to two operations: gastric bypass was performed on 42 and gastric partition on 45. Gastric bypass proved to be more effective; gastric bypass patients lost 15% more of their original weight at 12 months and 21% more at 18 months. There were no failures in the gastric bypass group; 28 of the 45 operations failed in the gastric partition group. An additional 60 patients underwent gastric bypass since the completion of the study. In the total series of 147 patients who underwent gastric bypass or gastric partition, there was no mortality, and the surgical complication rate was 12%. Because the gastric pouches and the anastomoses were similar in the two operations, the superiority of the gastric bypass may well be due to a heretofore unexplained effect of distal gastric and duodenal exclusion.

Colonic displacement. Proposed treatment for gastric remnant volvulus due to eventration of the diaphragm.

Displacement of the gastric remnant in patients with left diaphragmatic eventration may lead to gastric remnant volvulus requiring surgical correction. This results from the strong negative intrathoracic pulling force created by the potential subphrenic space an paradoxical movement of th diaphragm. Unless this strong negative force is first eliminated, gastropexy alone is likely to result in recurrence. Obliteration of the subphrenic space by colonic displacement is an effective and simple way of abolishing this negative subdiaphragmatic pulling force. Once this is achieved, any form of gastropexy will suffice to permanently prevent gastric remnant translocation and volvulus.

"Early-peak" carbon monoxide production in certain erythropoietic disorders.

The "early-labeled" peak (ELP) of 14CO excretion following injection of glycine-2-14C was used to study erythropoiesis in a patient with sideroblastic anemia and in four subjects with myeloproliferative disorders. The ELP was greatly enlarged in all patients, as compared with a normal volunteer. The contour of the peaks from the hematologically abnormal subjects suggested the presence of increased erythroid heme degradation. In the patient with sideroblastic anemia, all hours of the early peak were significantly reduced after transfusion. This was interpreted to mean that even the earliest or "nonerythroid" phase of the peak is influenced by erythropoietic activity, at least under conditions of erythropoietic stress.