Resistance to symptomatic insulin reactions after fasting.

This study was carried out to determine if, in fasting, an adaptation to utilization of ketones could prevent cerebral dysfunction during periods of acute, insulin-induced glucopenia. In the course of standard insulin tolerance tests (0.1-0.2 U/kg), nine obese subjects manifested frank hypoglycemic reactions resulting in an increase in urinary catecholamine excretion from 61 to 113 mug/24 hr (P < 0.01). After fasting 2 months, administration of weight-adjusted doses of insulin produced identical maximum insulin concentrations and disappearance curves. However, no insulin reactions nor significant rises in catecholamine excretion occurred despite equal extent and rate of glucose fall. Glucose concentrations as low as 0.5 mmoles/liter (9 mg/100 ml) failed to precipitate hypoglycemic reactions. During the postfast insulin tolerance tests, mean plasma 2-hydroxybutyrate (beta-OHB) decreased from 8.02 to 6.69 mmoles/liter (P < 0.01). In another five fasting subjects tested, the A-V difference for beta-OHB across brain increased progressively from 0.21 to 0.70 mmoles/liter whereas across the forearm no consistent uptake could be demonstrated. Simultaneously, the A-V difference across the brain for glucose decreased from 0.24 to 0.07 mmoles/liter of plasma. In addition to insulin-induced suppression of hepatic ketogenesis, the augmented cerebral ketone uptake during insulin hypoglycemia contributes to the net fall in plasma beta-OHB. Ketoacids, extracted by the fast-adapted brain, supplant glucose as a metabolic substrate preventing overt hypoglycemic reactions during acute glucopenia.

Therapeutic fasting in morbid obesity.

The weights of 207 morbidly obese patients were reduced via prolonged fasting. Half the patients fasted for close to two months, losing a mean of 28.2 kg; one fourth fasted for less than one month; and the other fourth fasted for more than two months, with a mean 41.4-kg loss. This latter group was heavier initially, and more than 50% attained near-normal weight. Patients with onset of obesity in childhood had the lowest tolerance for fasting and the lowest success rate in attaining normal weight. Over a 7.3-year follow-up period in 121 patients, the reduced weight was maintained for the first 12 to 18 months. Subsequently, regain proceeded equally in all groups irrespective of length of fast, extent of weight loss, or age at onset of obesity. Regain to original weight occurred in 50% within two to three years and only seven patients remained at their reduced weights. Regain to greater than original weight was more common in childhood-onset obesity.

Alterations in basal and TRH-stimulated serum levels of thyrotropin, prolactin, and thyroid hormones in starved obese men.

To investigate further the alterations in pituitary-thyroid function seen during starvation, we have measured basal and TRH-stimulated serum levels of thyrotropin (TSH), prolactin (PRL), growth hormone, thyroxine (T4), triiodothyronine (T3), free T4, free T3, and reverse T3 during prolonged fasting in seven obese men. Fasting was associated with a significant decrease in serum (4, (3, and free T3, while there was an increase in serum reverse T3; these values tended to return toward pre-fast levels as the fast continued beyond 3 weeks. No significant changes were seen in basal serum TSH, PRL, growth hormone, or free T4. Although the TSH response to TRH was diminished during fasting, PRL, T4, and T3 responses were unchanged. In addition to transient alterations in the peripheral metabolism of T4, these findings suggest that alterations in the thyroid hormone binding capacity of serum carrier proteins may occur during fasting. The blunted TSH response to TRH despite reduction of serum T3 concentration suggests that subtle alterations in hypothalamic-pituitary function may also occur.

Loss of body nitrogen on fasting.

An analysis of the change in total body nitrogen during fasting shows that it declines exponentially, a small fraction being lost rapidly (t 1/2 of a few days), and the remainder being lost slowly (t 1/2 of many months). The obese faster loses N, and weight, at a slower relative rate than the nonobese; and the ratio of N loss to weight loss during an extended fast is inversely related to body fat content, being about 20 g/kg in the nonobese and about 10 g/kg in those with body fat burdens of 50 kg or more. The loss of body N on a low protein-calorie adequate diet can also be described in exponential terms, and this function allows an estimate to be made of the N requirement.

Evolution of diabetic ketoacidosis in gross obesity.

Glucose tolerance and insulin responses have been examined over extended periods in severely obese, but otherwise healthy, subjects. Three significant points emerge from this study. First, it was shown that obese, supposedly ketosis resistant, subjects may deteriorate in a brief time span from a state of normal glucose disposal and adequate or increased insulin responses to insulin-deficient diabetes, culminating in ketoacidosis. Unusually high blood glucose levels complicating the ketoacidosis in two patients suggest hyperosmolarity obesity and added risk factor in severely obese diabetics. It appears that, after long-standing obesity and after years of hyperinsulinemia, a large weight gain due to prolonged overeating may impose an excessive challenge to islet cells of marginal competence. Such an event by itself or a superimposed stress or both may then cause acute insulin deficiency and/or insulin resistance leading to diabetic ketoacidosis. Hyperosmolarity may be exacerbated in the obese with cessation of food intake due to large losses of salt and water. Second, many symptoms and manifestations of hyperphagic obesity are similar to the early functional abnormalities of decompensated diabetes. The advent of the critical phase of uncontrolled diabetes, therefore, fails to alarm the obese patient and may escape timely recognition by the physician. Third, technical and mechanical difficulties due to severe obesity are apt to cause critical delays in therapy. These factors, when added to coexisting hyperosmolarity and ketoacidosis, probably account for the high mortality in these patients.

Calcium, magnesium, and phosphate balances during very low calorie diets of soy or collagen protein in obese men: comparison to total fasting.

In 30 obese men, calcium, magnesium, and phosphate balances were measured for 40 days using one of four weight reducing regimens: 1) 400 kcal soy protein; 2) 400 kcal collagen protein; 3) total fasting with potassium; and 4) total fasting without potassium. Relationship of the minerals to each other and to nitrogen and to the QTc interval was also examined. All groups were in negative cumulative calcium balance but the protein-fed groups lost less calcium (soy, -3.0 +/- 2.1 g; collagen -4.9 +/- 3.2 g) than the total fasting groups (with potassium supplement, -9.2 +/- 3.4 g; without potassium supplement, -5.8 +/- 2.1 g) (p less than 0.01). The soy-fed group attained positive cumulative magnesium (0.7 +/- 0.5 g) and phosphate balances (6.9 +/- 3.9 g). The other three groups had significantly more negative magnesium (p less than 0.0005) and phosphate (p less than 0.0005) balances, (collagen, magnesium balance, -1.1 +/- 1.0 g, and phosphate balance, -7.6 +/- 3.7 g; total fasting without potassium, magnesium balance, -1.4 +/- 0.6 g, and phosphate balance, -5.4 +/- 2.7 g). Potassium supplementation during fasting increased urinary losses of calcium and fecal losses of magnesium. High phosphate intake reduced urinary calcium. Nitrogen losses predicted only magnesium losses. Serum mineral levels did not reflect tissue mineral status. Shortening in the QTc interval as an indicator of reduced myocardial instability was related to the increase in serum phosphate in the protein-fed subjects.

Bypass enteropathy: an inflammatory process in the excluded segment with systemic complications.

Evidence is presented that many of the enteric and systemic manifestations after jejunoileal bypass can be related to an inflammatory process within the bypassed small bowel rather than to the surgically induced sequelae of a short bowel syndrome with malabsorption. Invasion of the excluded segment by fecal flora was associated with a histologically demonstrable inflammatory response of the mucosa. The disorder was of variable severity and duration and occurred in the majority of 28 bypass patients. Progression to a clinical syndrome resembling an acute abdomen occurred in about 15% of the patients. Small bowel ileus and, in some patients, obstruction of the colon were suggested by physical signs and x-ray findings. Surgical exploration in such instances demonstrated an inflammaotry process of the excluded small bowel loops with severe distention of this segment and of the colon, but not organic obstruction. Pneumatosis cystoides intestinalis was a sequal in two patients. Exudative protein loss was documented in the severe cases. Most of the systemic sequelae are comparable to those seen with inflammatory diseases of the bowel such as Crohn's disease. Fever, excessive weight and lean tissue loss, and the involvement of skin, blood vessels, joints and possibly, the liver suggest an immune response as a common factor in the pathogenesis. The clinical improvement with antibiotics such as metronidazole or with restitution of normal bowel continuity indicates that the bacterial flora in the excluded small bowel segment or its byproducts are causally related to the systemic complications. Hyperoxaluria may be primarily the sequela of steatorrhea and not of the inflammatory process.

Microbial flora in the bypassed jejunum of patients with biliopancreatic bypass for obesity.

The microbial flora in the bypassed biliopancreatic intestinal segment was studied after obesity surgery. This procedure causes less diarrhea than jejunoileal bypass and appears to avoid extraintestinal complications. This report concerns type and quantity of bacteria colonizing the biliopancreatic segment and changes occurring after oral metronidazole treatment. Twelve specimens were aspirated in 10 patients via catheter inserted percutaneously during surgery. The specimens were plated immediately on selective and nonselective media under aerobic and anaerobic conditions. Essentially equal numbers of aerobes and anaerobes were recovered from the biliopancreatic segment with average counts of 10(4) cfu/mL and median counts of 10(5) cfu/mL. Four patients had counts of 10(7) cfu/mL. The most common aerobes were E. coli, Klebsiella, Gram-positive cocci, and Candida; among anaerobes, Clostridium and the Bacteroides fragilis group were most common. In three patients treated with metronidazole because of diarrhea, anaerobes were eliminated and diarrhea cleared.

Zinc and copper nutriture in obese men receiving very low calorie diets of soy or collagen protein.

Balance studies for Zn and Cu were conducted over 40 days in 10 obese men housed in a metabolic balance unit. Two weight reduction diets providing 400 kcal and 100 g protein daily were administered; to five subjects, a collagen diet which was severely deficient in both Zn and Cu, and to another five subjects, a soy diet which provided a marginal intake of Zn and an adequate intake of Cu. Zn and Cu content of diets, plasma, red blood cells, urine, and feces were determined during eight 5-day periods. Balances were corrected for lean tissue catabolism or deposition. Holter ECG monitoring and measurement of the QTc interval were done on days 0 and 40. Both diets resulted in elevated plasma and red blood cell concentrations of Zn and Cu and in high urinary and fecal losses of Zn. By day 40, 6 of 10 subjects were in negative Zn balance. Urinary Zn was inversely correlated with measures of lean tissue catabolism. During each period, Cu balance was markedly positive in the soy-diet group and negative in the collagen-diet group. Shortening of prolonged QTc intervals was related to the Cu but not Zn status of the individual.

Nitrogen economy during very low calorie reducing diets: quality and quantity of dietary protein.

Controversy exists whether protein quantity or quality affect "nitrogen sparing" or physical health while subsisting on very low calorie diets. Therefore, in 38 obese men, nitrogen economy was evaluated over 2 months periods using one of five regimens: 1) 400 kcal high quality protein: 2) 400 kcal low quality protein; 3) 500 kcal 55 g protein natural food; 4) total fasting with potassium; and 5) total fasting without potassium. Up to the 20- and 40-day intervals, mean cumulative nitrogen deficity for all three diet groups was the same but 60% lower than with total fasting. However, within groups, individual capability to conserve nitrogen varied over as much as 2.8-fold. All 10 subjects of diet groups 1 and 2 had negative nitrogen balances to day 21, and six of these subjects were still negative by day 40. The improvement in nitrogen conservation and the ability to attain nitrogen equilibrium was unrelated to the differences in protein quantity and quality. Intake of essential or branched-chain amino acids was also unrelated to the efficiency of nitrogen conservation, as were insulin, glucagon, and 3-hydroxybutyrate levels. The only indicator correlating positively with nitrogen deficit was a fall in complement C3 (r = 0.87). Despite the extent of overall nitrogen loss, no cardiac arrhythmias were observed with either the high or low quality protein diet.

The role of vasopressin and prolactin in abnormal salt and water metabolism of obese patients before and after fasting and during refeeding.

Arginine vasopressin (AVP) and prolactin (PRL) concentrations were measured in the plasma of grossly obese subjects to determine if abnormalities in salt and water homeostasis could be related to these hormones. Acute oral water loads and hypertonic saline infusions were administered during baseline obesity, after prolonged fasting, and after hypocaloric refeeding. Only 64.7%, 46.1%, and 70.1% of a water load was excreted during the respective three stages. Pre-water load plasma AVP levels were normal, but after the water load the obese failed to suppress AVP secretion in a normal fashion; this defect was corrected after fasting and with refeeding. Salt loading resulted in appropriate osmolality and AVP responses. Serum prolactin levels, normal at baseline during all phases, rose slightly after water loading during fasting. Hypertonic.saline produced no changes in prolactin levels in the obese or in the normal controls. In the disordered salt and water metabolism of the obese, persistently high AVP values during water loading appeared to be a factor in the delay of water excretion. In the observed water retentionduring dietary restriction and refeeding, secretion of AVP and PRL did not appear to have a major regulatory function.

Metabolic and hormonal factors as predictors of nitrogen retention in obese men consuming very low calorie diets.

The ability to conserve body protein during very low calorie diets in ten obese men was observed to correlate with plasma free amino acid concentrations, urinary N tau-methylhistidine: creatinine ratios, resting oxygen consumption, and serum triiodothyronine levels. A diet consisting of only protein, 1.3 g/kg ideal body weight/24 h, was given for 40 days. Cumulative nitrogen deficit ranged from -64 g to -227 g. Nitrogen balance on days 36 to 40 ranged from + 1.37 g/24 h to -3.30 g/24h. Nitrogen balance during this period had a significant direct correlation with pre-diet concentrations of branched-chain amino acids (r = 0.69 to 0.89), methionine (r = 0.85), histidine (r = 0.66), alanine (r = 0.73), arginine (r = 0.70), ornithine (r = 0.66), total essential (r = 0.87, and nonessential (r = 0.68) amino acids, with initial serum levels of triiodothyronine (r = 0.66) and with the fall in triiodothyronine over the 40 days (r = 0.79). Initial resting oxygen consumption was directly correlated (r = 0.78) with final nitrogen balance and inversely with total nitrogen loss (r = -0.81). On day 0, triiodothyronine levels also correlated positively (r ranging from 0.71 to 0.93) with plasma concentrations of several essential and nonessential amino acids. These correlations suggest that individuals who ultimately will or will not achieve nitrogen equilibrium during very low calorie diets can be identified prior to dieting. These data are consistent with the hypothesis that individuals with higher initial protein flux and triiodothyronine levels are better able to adjust the balance between synthesis and degradation to attain nitrogen equilibrium during hypocaloric dieting.

Reoperative surgery for the morbidly obese. A university experience.

Patients who undergo surgery for morbid obesity are often subjected to reoperation for a wide array of indications. To evaluate outcome following revisional procedures, we reviewed the records of 32 such patients treated at UCLA between April 1986 and May 1989. Twenty-five women (78%) and 7 men (22%) with a mean age of 44 years underwent 76 reoperations (2.4 per patient) for complications of prior obesity surgery. Indications for initial surgical revision consisted primarily of metabolic derangements (12 patients) and weight-related problems (11 patients). In contrast, indications for the patients' final surgical procedure were commonly for bowel obstruction (41%), intra-abdominal sepsis (12%), and gastrointestinal bleeding (6%). Following initial revision, 23 patients (71.8%) required further surgery for major complications and four patients died (12.5%). While initial revisions are frequently indicated for metabolic problems, final reoperations are more frequently undertaken for urgent, life-threatening complications. Revisional procedures for morbid obesity should be carefully considered, and the potential for major complications and/or death should be weighted heavily against proposed benefits.

Pelvic lipomatosis: effect of diet.

Pelvic lipomatosis is a disease of dense infiltration of benign fatty tissue within the confines of the deep bony pelvis. A case is reported of an obese, hypertensive, thirty-nine-year-old black man with the typical clinical and radiographic features of pelvic lipomatosis. Prolonged fasting produced an extensive weight loss and profound resolution of his presenting symptoms, signs, and radiologic abnormalities. Subsequent regain of weight resulted in the reappearance of the disorder, confirming that pelvic lipomatosis may be a disease of accelerated and excessive fat deposition which can be reversed by dietary restriction. The literature pertaining to pelvic lipomatosis is reviewed in detail.

Sudden cardiac arrest in morbidly obese surgical patients unexplained after autopsy.

Sixty sudden and unexpected lethal cardiac arrests, with entirely negative findings on autopsy, were reported among 50,314 morbidly obese patients in the care of surgeons performing operations to achieve weight loss. This represented an extrapolated overall annual mortality rate of 65 deaths per 100,000 patients, about 40 times higher than the rate of unexplained cardiac arrests in a matched nonobese population. Eight sudden deaths occurred while waiting for obesity surgery and 22 had cardiac arrest within 10 days after the operation. Late postoperative deaths (more than 4 weeks postoperatively) occurred in 30 instances. A possible marker of a predisposition for sudden, unexpected cardiac arrest was an electrocardiographic abnormality; namely, a Q-Tc interval prolonged to greater than 0.43 seconds. This feature, present in 29 of 38 tracings, denoted increased susceptibility to malignant ventricular arrhythmias. The perioperative clustering of arrests implicated nonspecific stresses incident to otherwise uneventful operations as triggers of lethal dysrhythmias in the absence of organic cardiac disease. Anoxemia after abdominal surgery is an added hazard. Length of postoperative survival among the late deaths was found to be unrelated to degree of initial obesity or to magnitude of weight loss. Patients who died in the late postoperative phase were still grossly obese (mean weight 114.2 kg). Cardiac weights in patients who died within 10 postoperative days (12 patients) or after an average of 103 days (20 patients) were the same (464 and 469 g, respectively), indicating that myocardial mass had remained intact. The data do not suggest nutritional depletion or lean tissue loss as plausible explanations for the cardiac arrests. Screening and postoperative monitoring for Q-T interval prolongation is indicated. Prophylactic beta-blockade in this vulnerable subset of the morbidly obese population may be instituted in anticipation of obesity surgery. The attendant physiologic stresses should be minimized by appropriate measures.