Phillip Gorden

The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man.

In six patients with acanthosis nigricans variable degrees of glucose intolerance, hyperinsulinemia and marked resistance to exogenous insulin were found. Studies of insulin receptors on circulating monocytes suggest that the insulin resistance in these patients was due to a marked decrease in insulin binding to its membrane receptors. When these patients were fasted, there was a fall in plasma insulin but no increase in insulin binding, suggesting that the receptor defect was not secondary to the hyperinsulinemia. The clinical features shared by these cases and several similar ones previously reported may be divided into two unique clinical syndromes: Type A, a syndrome in younger females with signs of virilization or accelerated growth, in whom the receptor defect may be primary, and Type B, a syndrome in older females with signs of an immunologic disease, in whom circulating antibodies to the insulin receptor are found.

Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy

Lipodystrophy is a rare disorder that is characterized by selective loss of subcutaneous and visceral fat and is associated with hypertriglyceridemia, hepatomegaly, and disordered glucose metabolism. It has recently been shown that chronic leptin treatment ameliorates these abnormalities. Here we show that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. This improvement in insulin action was associated with a marked reduction in hepatic and muscle triglyceride content. These data suggest that leptin may represent an important new therapy to reverse the severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy.

Fluctuations in the affinity and concentration of insulin receptors on circulating monocytes of obese patients: effects of starvation, refeeding, and dieting.

The binding of 125I-insulin to insulin receptors on circulating monocytes of obese patients and normal volunteers has been determined under various dietary states. In the basal, fed state the monocytes of obese patients with clinical insulin resistance (n= 6) bound less insulin than normals (n =10) because of a decrease in insulin receptor concentration (obese = 6,000-13,000 sites per monocyte versus normals 15,000-28,000 sites per monocyte). The single obese patient without evidence of clinical insulin resistance demonstrated normal binding of insulin with 16,000 sites per monocyte. In all patients, the total receptor concentration was inversely related to the circulating levels of insulin measured at rest after an overnight fast. For the obese patients with basally depressed insulin binding, a 48-72-h fast lowered circulating insulin and increased binding to normal levels but only at low hormone concentrations; this limited normalization of 125I-insulin binding was associated with increased receptor affinity for insulin without change in receptor concentration. Refeeding after the acute fasting periods resulted in return to the elevated plasma insulin levels, the basal receptor affinity, and the depressed insulin binding observed in the basal, fed state. Chronic diet restored plasma insulin levels, insulin binding, and receptor concentration to normal without change in affinity. When the data from this study are coupled with previous in vivo and in vitro findings they suggest that the insulin receptor of human monocytes is more sensitive to regulation by ambient insulin than the receptors of obese mice and cultured human lymphocytes. The results further indicate than an insulin receptor undergoes in vivo modulation of its interaction with insulin by changing receptor concentration and by altering the affinity of existing receptors.

Localization of Insulinomas to Regions of the Pancreas by Intra-arterial Stimulation with Calcium

Despite the introduction of sophisticated cross-sectional imaging techniquescomputed tomography, magnetic resonance imaging, and ultrasonographythe localization of insulinomas smaller than 2 cm remains a problem. In our previous experience [1], these noninvasive methods of localization had sensitivities of 17% (computed tomography), 25% (magnetic resonance imaging), and 26% (ultrasonography). Our results may have been biased because most patients have negative results on noninvasive imaging studies before referral to the National Institutes of Health. Of the invasive localization techniques, pancreatic arteriography visualized 35% of small (<2 cm) insulinomas. The success of portal venous sampling does not depend on tumor size, and this method localized insulinomas in 77% of patients. However, percutaneous portal venous sampling requires special skills and experience and is associated with slight but significant morbidity [2]. We have developed a technique with which one can localize insulinomas before surgery by stimulating the release of insulin using selective intra-arterial injections of calcium gluconate as a secretagogue and then measuring insulin levels in the right hepatic vein. The results in our first 9 patients were promising [3, 4], and we have since studied an additional 16 patients with surgically proven insulinomas. We present the results of arterial stimulation and venous sampling in these 25 patients studied over the past 4 years. Methods Diagnosis of insulin-secreting islet cell tumor was based on the development of symptomatic hypoglycemia (blood glucose level, <40 mg/100 mL) with inappropriate plasma insulin levels during prolonged fasting. Ten of the patients were men and 15 were women; their average age was 43 years (range, 24 to 72 years). Five patients had had previous unsuccessful explorations of the pancreas, and 3 had had distal pancreatectomy during these explorations. Two patients had multiple endocrine neoplasia type I.1;0 Most of the 25 patients had had computed tomography (n = 23), magnetic resonance imaging (n = 21), and ultrasonography (n = 22) before having arteriography with calcium stimulation. The first 9 patients had portal venous sampling, but this procedure was not done in the other 16 patients because analysis showed that calcium stimulation provided similar information with less morbidity. This decision was supported by the similar sensitivities of portal venous sampling and intra-arterial secretin stimulation in our patients with the Zollinger-Ellison syndrome [5, 6]. Computed tomography (done using a 9800 HiLite, General Electric, Milwaukee, Wisconsin) was done with 5-mm contiguous sections through the pancreas during the bolus injection of 130 mL of iodinated contrast material (iopamidol [Isovue 300, Bristol-Myers Squibb, Princeton, New Jersey]) at 2 mL per second. Magnetic resonance imaging was done using a 0.5-Tesla scanner (Picker, Highland Heights, Ohio) with 10-mm thick axial T1-weighted (repetition time [TR]/echo time [TE] = 300/10) and short inversion time inversion recovery (STIR) (TR/TI [inversion time]/TE = 1800-2200/100/30) sequences. Gadopentetate dimeglumine (Magnevist, Berlex Lab, Wayne, New Jersey) was not given. Ultrasonography was done using a 3.5- or 5-MHz phased-array sector transducer (Acuson, Mountain View, California). Pancreatic arteriography was done by selectively injecting nonionic contrast agent (Isovue 300) into the gastroduodenal, splenic, and superior mesenteric arteries. Care was taken to position the catheter at the origin of these vessels so that major pancreatic arteries originating proximally from these vessels, such as the dorsal pancreatic and pancreatic magna arteries, would be perfused. Selective arteriography of the dorsal pancreatic and pancreatic magna arteries was occasionally done, but we did not infuse calcium into these small pancreatic branches because we feared that doing so might increase the risk for pancreatitis. After each selective arteriogram, calcium gluconate 10% (Lyphomed, Rosemont, Illinois), diluted with saline to a volume of 5 mL, was injected into the selectively catheterized artery at a dose of 0.025 mEq Ca++/kg body weight. Blood samples (5 mL) for insulin determination were obtained from the right (n = 25) and left (n = 17) hepatic veins before and 30, 60, and 120 seconds after calcium infusion. Specimens from the hepatic veins were placed on ice, and plasma was separated in a refrigerated centrifuge and stored at 20C until insulin levels were measured by radioimmunoassay. Samples were obtained from the left as well as the right hepatic vein in the first 17 patients because of concern that an insulinoma in the body or tail of the pancreas might be overlooked if splenic venous effluent streamed into the left hepatic lobe. However, it is more difficult to place and maintain a catheter in the left than in the right hepatic vein. To determine whether diagnostic elevations of insulin levels were ever seen only in the left hepatic vein, we compared insulin levels in the right and left hepatic veins in a subset of 10 patients whose insulinomas were in the pancreatic body and tail. The insulinomas ranged in size from 6 to 25 mm (average, 15 mm). Twelve were located to the right of the superior mesenteric artery (pancreatic head and neck), and 13 were located to the left (pancreatic body and tail). All tumors of the head and neck were enucleated. Tumors of the body and tail were removed by enucleation (n = 5) or distal pancreatectomy (n = 8). Intraoperative ultrasonography (10-MHz transducer, Diasonics, Santa Clara, California) was done in each patient to visualize the tumor, to identify major pancreatic and biliary ducts adjacent to the tumor, and to direct the pancreatic incision for enucleation. All patients were cured. Data Analysis The results of sampling from the right (n = 25) and left (n = 17) hepatic veins were plotted for each patient. Graphs were analyzed by selecting the greatest insulin response in a given vessel in the 30- or 60-second sample after injection. Each patient was coded so that, at the time of analysis, the observers were unaware of the results of any other localizing studies or of the location of the tumor at surgery. A response after calcium infusion into the gastroduodenal or superior mesenteric artery localized the adenoma to the head and neck of the pancreas; a response after splenic artery injection localized the adenoma to the body and tail of the pancreas. A response to calcium stimulation usually involved a single artery (Figure 1). When both the gastroduodenal and superior mesenteric arteries showed a response to calcium stimulation, the insulinoma was presumed to be located to the right of the superior mesenteric artery (pancreatic head and neck) (Figure 2). When no vessel was clearly dominant, the response was considered nonlocalizing (Figure 3). Figure 1. Typical sampling results from a patient with an insulinoma in the pancreatic tail. top bottom Figure 2. In a patient with an insulinoma of the pancreatic head, greater than twofold gradients were seen after calcium injection into both the gastroduodenal and superior mesenteric arteries, with higher elevations in the gastroduodenal artery (top). bottom Figure 3. The only nondiagnostic study in the last 20 cases shows elevated insulin levels in the splenic and gastroduodenal arteries. The sensitivity of calcium stimulation in all 25 patients was calculated and compared with the sensitivity of the noninvasive imaging studies (computed tomography, magnetic resonance imaging, and ultrasonography) and arteriography. Specificity was irrelevant because all patients in the series had proven insulinomas. In the 9 patients who had portal venous sampling, the sensitivity of calcium stimulation was compared with the sensitivity of portal venous sampling. To determine whether it was necessary to sample the left hepatic vein, we compared the maximum insulin levels in the right and the left hepatic veins and the ratio of insulin levels in the hepatic vein with those in the peripheral vein in a subset of 10 patients with insulinomas of the body and tail. Results The results of all localization studies are summarized in Table 1. A response to calcium stimulationthat is, a greater than twofold elevation of insulin levels in the right or left hepatic vein on the 30- or 60-second samplesoccurred in all 25 patients. Calcium stimulation with venous sampling correctly predicted the site of the insulinoma in 22 of 25 patients (sensitivity, 88% [95% CI, 68% to 97%]). In 2 of the 3 patients with false localizations, responses to gastroduodenal and splenic artery injections occurred in the presence of a tumor in the proximal body of the pancreas (Figure 3); in the third patient, a response to a superior mesenteric artery injection occurred in the presence of a tumor in the proximal body. All patients who had a positive response to splenic artery injection only had insulinomas of the body or tail. Two of the three false localizations occurred in our first 5 patients; only one false localization occurred among our last 20 patients. Table 1. Results of Localization Studies in 25 Patients with Surgically Proven Insulinomas In the nine patients who had both portal venous sampling and calcium stimulation, portal venous sampling correctly localized six insulinomas (sensitivity, 67%), and calcium stimulation correctly localized seven insulinomas (sensitivity, 78%). Among 10 patients with surgically proven insulinomas of the body and tail of the pancreas, the maximum insulin levels in response to calcium stimulation were higher in the right than in the left hepatic vein in 8 patients and were equal in the right and left hepatic veins in 1 patient (103 U/mL compared with 107 U/mL [739 pmol/L compared with 768 pmol/L]). Only 1 patient with an insulinoma of the pancreatic body had a higher insulin level in the left than in the right hepatic vein (148 U/L compa

Somatostatin and Somatostatin Analogue (SMS 201-995) in Treatment of Hormone-Secreting Tumors of the Pituitary and Gastrointestinal Tract and Non-Neoplastic Diseases of the Gut

Somatostatin is a peptide synthesized in many tissues that can act as a neurotransmitter, a systemic hormone, or a local hormone, and inhibits the secretion of hormones or other cell products. A long-acting synthetic analogue of somatostatin (SMS 201-995) has been developed which when administered subcutaneously has a biologic half-life of 90 to 120 minutes and can be administered 2 or 3 times per day. SMS 201-995 can lower plasma concentrations of growth hormone and somatomedin-C in patients with pituitary acromegaly, but no controlled trials to assess symptomatic response or change in tumor size have been done. In patients with pituitary thyrotropin-producing pituitary tumors, SMS 201-995 has been remarkably effective in producing biochemical and clinical responses and is the drug of first choice in this syndrome when tumor resection is not possible. In patients with the carcinoid syndrome, SMS 201-995 effectively reduces diarrhea, is the best available drug for treatment of carcinoid flush (effective in approximately 90% of cases), and is useful in treating carcinoid crisis. Eighty-five percent of patients with pancreatic islet cell tumors that produce vasoactive intestinal peptide will respond to SMS 201-995 with a reduction in diarrhea that often has been resistant to all other therapy. SMS 201-995 may also be useful in treating the symptoms in some patients with glucagonomas, growth hormone releasing hormone-producing tumors and insulinomas. Whether SMS 201-995 has a significant effect on gut neuroendocrine tumor growth remains uncertain. Certain nonmalignant diseases of the gut respond to somatostatin, including secretory diarrhea and fistulas of unknown cause. In general, SMS 201-995 has proved safe with few significant side effects, but whether the long-term use of the drug will result in an iatrogenic form of the somatostatinoma syndrome is uncertain.

Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis.

Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.

Intraoperative Ultrasonographic Localization of Islet Cell Tumors: A Prospective Comparison to Palpation

The purpose of the present study was to evaluate prospectively the value of intraoperative ultrasound scanning (IOUS) in localizing islet cell tumors by comparing results of IOUS to those of palpation during 44 consecutive laparotomies for gastrinoma (36) or insulinoma (8). All patients had preoperative radiographic imaging studies and selective venous sampling for hormones, which guided the subsequent laparotomy. Any suspicious finding by palpation and/or IOUS was resected. Pathologic evidence of islet cell neoplasm served as the reference standard. Five patients were excluded from analysis because neither palpation nor IOUS had suspicious findings and no islet cell tumor was found. Seven pancreatic insulinomas were found in seven patients. IOUS was as sensitive as palpation at localizing insulinomas. Twenty-three pancreatic gastrinomas were found in 19 patients. IOUS was equal to palpation in the ability to localize gastrinomas. Gastrinomas that were successfully imaged by IOUS were significantly larger than gastrinomas that were not imaged. Twelve extrapancreatic gastrinomas were found in nine patients, and palpation was more sensitive than IOUS at localizing these small duodenal wall tumors. Five patients (11%) had their surgical management changed by IOUS. Two patients had pancreatic tumors (one gastrinoma and insulinoma) enucleated that would not have been found without IOUS, and three patients had resections of pathologically proven malignant islet cell tumors based on sonographic findings. All five patients were cured with short follow-up. The present results demonstrate that palpation and IOUS are complementary because IOUS can image tumors that are not palpable and IOUS can provide additional information concerning malignant potential not detected by palpation.

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy.

Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation. In the liver, this is associated with steatosis, potentially leading to nonalcoholic steatohepatitis (NASH). We investigated the prevalence of NASH and the effect of leptin replacement in these patients. Ten patients with either generalized lipodystrophy (8 patients) or Dunnigans partial lipodystrophy (2 patients) were included in this analysis. Paired liver biopsy specimens were obtained at baseline and after treatment with recombinant methionyl human leptin (r‐metHuLeptin), mean duration 6.6 months. The extents of portal and parenchymal inflammation, steatosis, ballooning, presence of Mallory bodies, and fibrosis in liver biopsy specimens were scored using a previously validated system developed to assess NASH activity. Histological disease activity was defined as the sum of ballooning, steatosis, and parenchymal inflammation scores. We concurrently tested serum triglycerides and aminotransferases and estimations of liver volume and fat content by magnetic resonance imaging. Eight of 10 patients met histological criteria for NASH at baseline. After treatment with r‐metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P = .006) and ballooning injury (P = .005), with a reduction of mean NASH activity by 60% (P = .002). Fibrosis was unchanged. Significant reductions were seen in mean serum triglycerides (1206→226 mg/dL, P = .002), glucose (220→144 mg/dL, P = .02), insulin (46.4→24.8 μIU/mL, P = .004), ALT (54→24 U/L, P = .02), AST (47→22 U/L, P = .046), liver volume (3209→2391 cm3, P = .007), and liver fat content (31→11%, P = .006). In conclusion, r‐metHuLeptin therapy significantly reduced triglycerides, transaminases, hepatomegaly, and liver fat content. These reductions were associated with significant reductions in steatosis and the hepatocellular ballooning injury seen in NASH. (HEPATOLOGY 2005;41:753–760.)

Defect in insulin binding to receptors in obese man. Amelioration with calorie restriction.

With insulin at 0.1 ng/ml, the binding of (125I)insulin in vitro to circulating lymphocytes from 11 obese patients was less than that observed with cells from 10 thin volunteers. Furthermore, with obese cells, unlabeled insulin was less effective in competing with labeled hormone for binding, both at low and high concentrations of unlabeled insulin. These differences were not accounted for by the high concentrations of insulin in the circulation of the obese patients at the time fthe blood was drawn, or by differences in degradation of hormone, or in the characteristics of the cell population. The decrease in binding appears to be due to a lowering of the receptor concentration, but some loss of affinity has not been excluded. Institution of a calorie restricted diet (nine patients) which ameliorated the hyperinsulinemia, produced an improvement in hormone binding. Since the insulin receptors of lymphocytes in metabolic disorders seem to reflect the state of insulin receptors or target cells such as liver and fat, the lymphocytes or other leukocytes appear to be ideal for studies of impaired cell responsiveness to hormones in man.

Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): A 30-year prospective

Abstract: The interaction of insulin with its cell surface receptor is the first step in insulin action and the first identified target of insulin resistance. The insulin resistance in several syndromic forms of extreme insulin resistance has been shown to be caused by mutations in the receptor gene. We studied 8 female patients with the type A form of extreme insulin resistance and 3 patients (2 male and 1 female) with the Rabson-Mendenhall syndrome and followed the natural history of these patients for up to 30 years. The 11 patients ranged in age from 7 to 32 years at presentation. All 11 patients had extreme insulin resistance, acanthosis nigricans, and hyperandrogenism in the female patients, and all but 1 were of normal body weight. This phenotype strongly predicts mutations in the insulin receptor: of the 8 patients studied, 7 were found to have mutations. Similar results from the literature are found in other patients with type A and Rabson-Mendenhall syndromes and leprechaunism. The hyperandrogenic state resulting from hyperinsulinemia and insulin resistance in these patients was extreme: 6 of 8 patients had ovarian surgery to correct the polycystic ovarian syndrome and elevation of serum testosterone. By contrast, a larger group of insulin-resistant patients who were obese with hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN syndrome) did not have a high probability of mutations in the insulin receptor. The morbidity and mortality of these patients were high: 3 of 11 died, 9 of 11 were diabetic and 1 had impaired glucose tolerance, and 7 of 9 patients had 1 or more severe complication of diabetes. Our literature review revealed that the mortality of leprechaunism is so high that the term leprechaunism should be restricted to infants or young children under 2 years of age. Analogous to patients with the common forms of type 2 diabetes, these patients had a heterogeneous course. In 2 patients who were able to maintain extremely high endogenous insulin production, the fasting blood glucose remained normal even though post-glucose-challenge levels were elevated. Most patients, however, required large doses of exogenous insulin to ameliorate the severe hyperglycemia. Preliminary results of a recent study suggest that recombinant leptin administration may benefit these patients with severe insulin resistance.