Studies of the human liver insulin receptor in noninsulin-dependent diabetes mellitus.

The insulin binding characteristics and the structural components of the insulin receptor were studied in the purified liver plasma membranes from seven patients with noninsulin-dependent diabetes (NIDDM) and seven control subjects. In comparison to the controls, diabetic subjects had a 65% reduction in plasma insulin levels in response to an oral glucose load. Specific insulin binding by liver membranes from diabetic patients was, however, twofold greater than the binding activity by membranes from control subjects. This alteration resulted largely from an increase in the number of insulin receptors and a modest increase in receptor binding affinity. Holo (nonreduced) receptor species of similar molecular weights were detected by an affinity labeling technique in the two membrane preparations and sulfhydryl reduction demonstrated an insulin binding subunit of 125,000 mol wt. Overall, these results show that the hepatic insulin resistance of NIDDM cannot be explained by a deficiency in insulin binding.

Hepatic uptake of bile acids in man. Fasting and postprandial concentrations of individual bile acids in portal venous and systemic blood serum.

This investigation was undertaken in order to (a) characterize the postprandial inflow of individual bile acids to the liver and (b) determine if peripheral venous bile acid levels always adequately reflect the portal venous concentration, or if saturation of hepatic bile acid uptake can occur under physiological conditions. In five patients with uncomplicated cholesterol gallstone disease, the umbilical cord was cannulated during cholecystectomy, and a catheter was left in the left portal branch for 5 to 7 d. The serum concentrations of cholic acid, chenodeoxycholic acid, and deoxycholic acid in portal venous and systemic circulation were then determined at intervals of 15 to 30 min before and after a standardized meal. A highly accurate and specific gas chromatographic/mass spectrometric technique was used. The sum of the fasting concentrations of the three bile acids averaged 14.04+/-4.13 mumol/liter in portal venous serum, and 2.44+/-0.31 mumol/liter in peripheral venous serum. The estimated hepatic fractional uptake of cholic acid was approximately 90%, and those of chenodeoxycholic acid and deoxycholic acid were 70-80%. This resulted in an enrichment of systemic bile acids in the dihydroxy bile acid species. In response to a standardized meal, portal venous bile acid concentrations increased two- to sixfold, with a peak seen 15-60 min after the meal. The maximum postprandial portal venous bile acid concentration averaged 43.04+/-6.12 mumol/liter, and the corresponding concentration in peripheral serum was 5.22+/-0.74 mumol/liter. The estimated fractional uptakes of the individual bile acids were not affected by the increased inflow to the liver. The peripheral venous concentrations of individual as well as total bile acids were well correlated with those in portal venous serum. The results (a) give a quantitation of postprandial bile acid inflow to the liver and (b) indicate that the hepatic uptake system for bile acids in healthy man cannot be saturated during maximal inflow of endogenous bile acids. Measurement of peripheral serum bile acids can thus give important information on the status of the enterohepatic circulation.

Glucagon receptor of human liver. Studies of its molecular weight and binding properties, and its ability to activate hepatic adenylyl cyclase of non-obese and obese subjects.

The glucagon receptor and the adenylyl cyclase system of human liver membranes were studied in six non-obese and six obese subjects who had elevated insulin and plasma glucagon levels. Analysis of specific glucagon binding by the method of Scatchard demonstrated a linear (monocomponent) plot with a dissociation constant of 2-3 nM, and the binding at low hormone concentrations was sensitive to guanosine triphosphate (GTP). The molecular weight of the glucagon receptor was 63,000 D as determined by an affinity labeling procedure and sodium dodecyl sulfate gel electrophoresis. Affinity labeling of this structure was specific for glucagon and inhibited by GTP. Glucagon stimulated the production of cyclic adenosine monophosphate (cAMP) by human membranes with half-maximal activation elicited by 6 nM hormone. The human cyclase system required GTP to facilitate an optimal glucagon response. NaF (10 mM) also activated the cyclase system and produced the same magnitude of response as maximum glucagon activation. A comparison of the liver adenylyl cyclase system of non-obese and obese subjects was made using glucagon (5 nM and 1 microM) and NaF (10 mM). No significant differences in cAMP production were noted between the two groups, regardless of the agent used to activate the enzyme. These findings agree with the glucagon binding studies that showed similar amounts of binding activity in the membranes from the two groups. Also, there was no influence of either age or sex of the subjects on the adenylyl cyclase response. In conclusion, human liver membranes contain a glucagon receptor and an adenylyl cyclase system that correspond closely to the well-studied system in animal liver. This system in human obesity is not altered by the approximately twofold elevation in plasma glucagon that occurs in this metabolic disorder.

Different dose regimens of the mouse monoclonal-antibody 17-1a for therapy of patients with metastatic colorectal-carcinoma.

Seventy-one patients with metastatic colorectal carcinoma(CRC) were treated with varying doses of the mouse monoclonal antibody (MAb) 17-1A. One patient achieved a partial remission (PR) (1%) with a survival duration of 114+ months. Further 10 patients showed a minor response (MR) or stable disease > 3 months (SD) (14%). In patients receiving a total dose of MAb17-1A < 2 g the overall response rate was 22% (10/45) (1 PR, 2 MR, 7 SD) while patients treated with a total dose > 2 g had a corresponding figure of 4% (1/26) (1 MR) (p < 0.05). Responding patients (n = 11) survived significantly longer than non-responding patients (n = 60) (median: 20 vs 10 months) (p < 0.0027). In the most intensive treatment group (total 12 g), 14 patients received 500 mg of MAb17-1A tiw for 8 weeks. The frequency and intensity of side-effects were mild and did not cause withdrawal or dose reduction of MAb17-1A, even in the 12 g dose schedule. Patients with a pretreatment ADCC (antibody dependent cellular cytotoxicity) activity above the median of all patients, survived significantly longer than those with a low value (p < 0.05).

Metabolic effects of four intravenous nutritional regimens after elective surgery. I. Clinical data and biochemistry.

Biochemical variables have been determined in 28 patients before and after resection of carcinoma of colon or rectum. A synthetic oral diet was given for four days before operation, (0.1 gN.kg/day and 165 kJ.kg/day) and four isocaloric intravenous regimens with different amounts and proportions of amino acids were given for six days after operation. During the preoperative diet the serum urea, glucose, urate, inorganic phosphate and cholesterol concentration decreased while those of triglyceride, iron and alanine amino-transferase increased. After operation the serum triglyceride, protein, albumin, iron, TIBC and urate concentrations decreased. The serum calcium fell in all groups receiving amino acids after operation while magnesium increased in all groups except the one receiving the highest amount of amino acids. The urea concentration decreased when no amino acids were given but increased when amino acids were administered whereas the reverse situation occurred with cholesterol. The highest increase in glucose level was observed when the highest amount of amino acids were given.

Postprandial serum concentration of individual bile acids in man. Influence of ileal resection.

For the purpose of characterizing the importance of intestinal function in the maintenance of the enterohepatic circulation of individual bile acids, the serum concentrations of cholic acid (C), chenodeoxycholic acid (CD), and deoxycholic acid (D) were determined after a standardized meal. Two groups of subjects were included: 10 healthy controls and 7 patients with ileal resections 20-80 cm long. The bile acid concentrations were determined using a highly specific and accurate gas chromatographic-mass spectrometric technique with the aid of deuterium-labelled internal standards. In patients with ileal resections, only a moderate and early increase was seen in C concentration after a meal, whereas the CD elevation was more pronounced and prolonged. The D concentrations were reduced both after fasting and postprandially. The data indicate that ileal resection results in essentially complete absence of active bile acid resorption and that intestinal uptake via nonionic diffusion is probably dominant, resulting in postprandial rise of mainly CD in serum.

On the enterohepatic circulation of bile acids in man.

1. Fasting concentrations of C, CD and D were determined in systemic and portal venous serum in gallstone patients and controls (patients with adenomyoma of the gallbladder) undergoing cholecystectomy. No differences were observed between the two groups either in systemic or portal serum concentrations of the bile acids or in their hepatic uptake. Ketonic bile acid concentrations amounted to 9% and 8% of the non-oxidized bile acids in the systemic and portal circulation, respectively. 2. Fasting systemic and portal venous serum concentrations of bile acids were measured in gallstone patients fed with C and CD prior to cholecystectomy. Treatment with CD increased the total portal inflow of bile acids by 60%, whereas C treatment did not alter this total inflow compared with controls. This difference may partly explain why hepatic bile is unsaturated during treatment with CD, but not with C. 3. The postprandial concentrations of bile acids were determined in the systemic and portal venous circulation in cholecystectomized patients. The systemic venous bile acid level reflected the portal venous level. The estimated hepatic uptake of the individual bile acids was highly efficient and could not be saturated during maximal physiological portal inflow to the liver. The existence of a lymphatic transport of bile acids, calculated to correspond to about 0.2% of the portal transport, was demonstrated in four patients undergoing renal transplantation. 4. Cholestyramine treatment was shown to reduce the plasma cholesterol level in patients with familial hypercholesterolaemia without lowering the fasting systemic level of total bile acids. Nor did this treatment reduce the fasting portal inflow of total bile acids. The total bile acid concentration in healthy volunteers during treatment showed a 40% reduction postprandially, but not in the fasting state, indicating that the effect of cholestyramine on hepatic cholesterol metabolism is the consequence of a reduced postprandial inflow of portal bile acids. The effects of the loss of the active site of bile acid absorption on the postprandial serum bile acid pattern were studied in patients with ileal resections. In general, the postprandial response of C was reduced whereas that of CD remained less affected.

Cannulation of the umbilical vein in adult man. A review of surgical techniques, possible complications and clinical applications.

A short description is given of relevant anatomy and surgical techniques for transumbilical portal venous catheterisation in adults. Possible complications and applications of the procedure are discussed.

The acid secretory response to betazole and insulin hypoglycemia after selective proximal vagotomy for duodenal ulcer.

In order to assess the result of vagotomy an insulin test is usually performed postoperatively. The insulin test, however, is associated with troublesome side-effects and potentially dangerous. Also its prognostic value as regards ulcer recurrence is doubtful. In this follow-up study of 118 patients, who had selective proximal vagotomy (SPV) performed for duodenal ulcer between 1968 and 1971, the insulin test is compared with a postoperative betazole (Histalog) test. Both tests were carried out 1-3 months after SPV. The insulin tests were classified according to Hollander. For the betazole tests the following criteria were used: the test was classified as negative if the reduction in peak acid output (PAOB) exceeded 50% or if the postoperative PAOB-value was lower than 15 mmol/h irrespective of the preoperative value. Values outside these were considered positive. At the follow-up 5-9 years after surgery, a total of 17 recurrent ulcers were diagnosed. The sensitivity and the specificity - i.e. the percentage of patients with recurrent ulceration and positive criteria respectively patients without recurrent ulcer and negative criteria - were calculated for the tests. Thus, the sensitivity and specificity for the insulin tests were found to be 53% and 84% respectively and for the betazole tests 59% and 91% respectively. The difference is thus very small and it seems that a postoperative test with a non-vagal gastric stimulant gives as good prognostic information as an insulin test after selective proximal vagotomy. However, both tests give a low sensitivity (53% resp. 59%) and therefore the prognostic value regarding ulcer recurrence is doubtful.

Roux-en-Y loop reconstruction as remedial operation for reflux gastritis after gastric resection.

Reflux gastritis is a symptom-complex consisting of antacid-resistent epigastric pain, nausea and frequent vomiting, weight loss and anaemia, sometimes with evident gastrointestinal haemorrhage. Gastric secretory studies usually show achlorhydria. The onset of symptoms is usually abrupt in previously healthy subjects. From 1973 to 1977, eleven patients with the established diagnosis of reflux gastritis have been treated with a Roux-en-Y reconstruction, as a remedial operation. There was no mortality in the series. At follow-up after a mean time of two years, the result was graded as excellent in ten patients and as fair in one. It is concluded that the Roux-en-Y procedure can be recommended in patients with reflux gastritis.

Ursodeoxycholic acid treatment in cholesterol gallstone disease: effects on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, biliary lipid composition, and plasma lipid levels.

The present study was undertaken to characterize the effects of ursodeoxycholic acid on biliary lipid metabolism in man. Fifteen gallstone patients were treated with ursodeoxycholic acid at a daily dosage of 15 mg per kg body weight for about 4 weeks before cholecystectomy. At operation a liver biopsy, together with gallbladder and hepatic bile, were obtained. Eighteen untreated gallstone patients undergoing cholecystectomy served as controls. During treatment with ursodeoxycholic acid, hepatic bile became unsaturated with cholesterol in all patients investigated. The total biliary lipid concentration remained unchanged. The hepatic cholesterol concentration decreased by about 20%. No significant change in the microsomal HMG CoA reductase activity was observed (38.5 +/- 6.7 pmol . min-1 . mg protein-1 vs 38.3 +/- 4.7 pmol . min-1 . mg protein-1 in the controls; means +/- SEM). Plasma concentrations of total cholesterol were reduced by about 10%, and those of high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol by about 15%. Plasma triglyceride levels remained essentially unchanged during treatment. We conclude that, similar to chenodeoxycholic acid therapy, ursodeoxycholic acid treatment results in unsaturation of fasting hepatic bile. In contrast to the changes seen during chenodeoxycholic acid feeding, however, the unsaturation of hepatic bile during ursodeoxycholic acid treatment is not primarily related to a decreased hepatic HMG CoA reductase activity. Furthermore, while chenodeoxycholic acid tends to increase plasma LDL levels, such changes are not seen during ursodeoxycholic acid treatment.

The incidence of fecal fistula following exploratory laparotomy and appendicectomy in patients with ileocolic Crohn's disease.

The aim of this study was to investigate if appendicectomy en passant in connection with exploratory laparotomy for ileocolic Crohn's disease increases the risk for development of postoperative fecal fistula. This was studied among 105 patients, 65 of whom had an additional appendicectomy and 40 who had not. The postoperative frequency of fecal fistula was 18.5 versus 15% in the two groups. The difference is not significant. On balance, appendicectomy is advised under these circumstances.

Intestinal metaplasia in the gastric remnant following resection for benign ulcer disease: a comparison between morphology and histochemistry.

A follow-up study including endoscopic examinations was performed on patients previously (23--27 years earlier) treated with partial gastrectomies for benign ulcer disease. From 106 patients satisfactory biopsy specimens were obtained. Intestinal metaplasia was diagnosed on pure morphologic findings and on histochemical findings (alcian blue at pH 2,5). The histochemical method was shown to be more sensitive. The significance of intestinal metaplasia in the carcinogenesis is briefly discussed.

Altered action of glucagon on human liver in type 2 (non-insulin-dependent) diabetes mellitus.

Glucagon may play a role in the metabolic derangements of overt Type 2 (non-insulin-dependent) diabetes mellitus. We therefore have evaluated the early steps in glucagon action by investigating the hormone-sensitive adenylyl cyclase system in liver membranes from seven Type 2 diabetic patients with fasting hyperglycaemia and two-fold elevations in plasma glucagon. The comparison was made with seven control subjects matched for age, sex and body weight. Glucagon receptor binding was almost identical in the two groups. There were, however, marked alterations in the adenylyl cyclase activity in membranes from the diabetic patients. This activity was reduced by 35-50% when compared to control activity. Basal cyclase activity, as well as the activity after stimulation with glucagon or with agents (i.e., sodium fluoride and forskolin) that act beyond the glucagon receptor, was significantly decreased (p less than 0.05, p less than 0.001 respectively). In conclusion, uncontrolled Type 2 diabetes in associated with an over-all loss of responsiveness of the hormone-sensitive adenylyl cyclase in human liver, which apparently results from post-receptor alterations. This change may provide a mechanism for reducing the effect of hyperglycagonaemia in Type 2 diabetes mellitus.

Biliary lipid composition in patients with porta cirrhosis of the liver.

Fasting duodenal bile was collected under standardized conditions in 10 male patients with stable portal cirrhosis of the liver and in 12 healthy male controls matched for age, body weight, and serum lipid levels. The proportion of cholesterol, expressed as molar percentage of total biliary lipids, was lower in patients with cirrhosis than in controls (4.6 +/- 0.6 versus 6.4 +/- 0.4 molar %, mean +/- S.E.M.; P less than 0.025), whereas the proportions of bile acids and phospholipids were similar in the two groups. The cholesterol saturation of bile was lower in cirrhotic patients (68 +/- 8%) than in controls (94 +/- 7%; P less than 0.025). The contribution of deoxycholic acid to total bile acids was diminished in cirrhosis and that of chenodeoxycholic acid slightly increased. The results suggest that, in spite of the disturbances of bile acid metabolism generally seen in cirrhosis, such patients are not prone to develop cholesterol gallstones.

Occurrence and outcome after primary treatment of anal fistulae in Crohn's disease.

During the period 1955 to 1974 inclusive, 826 patients developed Crohn's disease and were registered citizens of Stockholm County at the time of definite diagnosis. These patients were followed up and investigated with reference to the occurrence of and outcome after treatment for anal fistulae. These fistulae were recorded in 184 patients (23%). The incidence of anal fistulae increased the further distally the intestinal lesion was located. Healing followed local operation for anal fistula before curative intestinal resection in approximately 60% of the patients with small intestinal and combined ileocolic disease. However, patients with colonic Crohn's disease did not heal after such treatment. When curative intestinal resection was the primary procedure, 47% of the patients healed spontaneously. Small intestinal and combined ileocolic disease was associated with a good prognosis--90% were healed at follow-up, while patients with colonic disease had a poor prognosis. The combination of rectal Crohn's disease and anal fistula invariably led to proctocolectomy.

Carcinoma of Meckel's diverticulum.

Acute intestinal obstruction in a women, aged 56, was caused by a highly malignant adenocarcinoma arising in a Meckel's diverticulum. Despite radical surgery, the tumour recurred after four months, and the patient died nine months after her first operation. This confirms the general bad prognosis associated with carcimomas of Meckel's diverticulum.