Monica C. Skarulis

Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling

Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-β/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3-deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3(-)(/-) white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3(-/-) adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1α expression. We observe significant correlation between TGF-β1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-β signaling protects mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-β signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-β activity might be an effective treatment strategy for obesity and diabetes.

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

Genetic and Clinical Features of 42 Kindreds with Resistance to Thyroid Hormone: The National Institutes of Health Prospective Study

Resistance to thyroid hormone, first described by Refetoff and coworkers in 1967 [1], is characterized by decreased pituitary and tissue responsiveness to thyroid hormone. Patients typically have elevated serum free and total triiodothyronine (T3) and thyroxine (T4) levels and inappropriately normal or elevated thyroid-stimulating hormone (TSH) levels. The phenotype is heterogeneous; classic features include attention-deficit hyperactivity disorder, growth delay, and tachycardia [2, 3]. Resistance to thyroid hormone is usually transmitted in an autosomal dominant manner, but sporadic de novo cases are common, and recessive inheritance is rare [1, 4]. Linkage between resistance to thyroid hormone and the thyroid hormone receptor (TR ) gene was shown in 1988 [5]. Since then, about 100 mutations have been found in that gene [6], clustered primarily in two hot spots in the T3-binding domain (exons 9 and 10), respecting the integrity of the dimerization domain [7]. Mutant receptors have normal DNA binding, but T3 binding and transactivation are impaired to varying degrees [8, 9]. Moreover, the abnormal receptors antagonize the function of normal receptors in a dominant negative manner [10, 11]. Thyroid hormone action is mediated through two types of nuclear receptors, (TR ) and TR [12, 13], which have different organ distributions. Thus, resistance to thyroid hormone provides an exciting opportunity to study the in vivo, tissue-specific action of thyroid hormone. The prevalence of resistance to thyroid hormone is unknown but is thought to be low. The phenotype is heterogeneous and ranges from highly symptomatic to subclinical [2, 3, 14]. Resistance to thyroid hormone is traditionally defined as generalized resistance and, more rarely, as pituitary resistance [15]. In generalized resistance, pituitary and peripheral tissues are not always involved to the same degree, and this creates a mosaic of hypothyroid and hyperthyroid symptoms in the patient. If the degree of resistance is similar in pituitary and peripheral tissues, high levels of thyroid hormone result in compensation, and patients are euthyroid. Patients with pituitary resistance are predominantly hyperthyroid and have hypermetabolism and tachycardia [16]. A single case of isolated peripheral resistance has been reported [17]. Since 1976, 104 patients with resistance to thyroid hormone from 42 unrelated kindreds have been studied prospectively at the National Institutes of Health (NIH), along with 114 of their unaffected relatives, who serve as a control group with environmental and genetic back-grounds similar to those of the patients. Here, we report the results of their initial evaluation. Our goals were to analyze the resistance-to-thyroid-hormone phenotype, including its newly recognized features; to assess the organ specificity of resistance to thyroid hormone; and to define factors contributing to the heterogeneity of the phenotype. Methods Patients and Controls Data collected at the time of initial hospitalization at the NIH were analyzed for 218 persons (104 with and 114 without resistance to thyroid hormone, including 29 persons who had married into families that had resistance to thyroid hormone) from 42 unrelated families. Patients were referred to the NIH for the evaluation of inappropriate TSH secretion. Appropriate informed consent was obtained as approved by the National Institute of Diabetes and Digestive and Kidney Diseases institutional review board. Participants younger than 16 years of age were considered to be children. A full personal and family history was taken from each participant, and specific information about goiter; cardiac symptoms; speech; ear, nose, and throat infections; and hearing problems was collected through interviews. Resting pulse (taken while participants were sleeping or after at least 10 minutes of rest) and goiter were recorded from physical examination, and height (an average of 10 measurements with a stadiometer), weight, and weight-for-height were plotted using charts adapted from Hamill and colleagues [18]. Diagnostic Criteria Resistance to thyroid hormone was diagnosed on the basis of elevated free and total thyroid hormone levels in the presence of normal or elevated TSH levels. Blood was analyzed for levels of T3 (Quanticoat TM, Kallesad Diagnostic, Chasco, Minnesota), T4 (fluorescein polarization immunoassay, Abbott TDx, Abbott Park, Illinois), free T4 (Gammacoat TM two-step RIA, INC-STAR, Stillwater, Minnesota), free T3 (RIA, Becton Dickinson kit, SmithKline Beecham Laboratories, Van Nuys, California), TSH (MAIAclone, Serono Diagnostics, Walpole, Massachusetts), -subunit of TSH (RIA, Hazelton-Washington, Vienna, Virginia), prolactin (TOSOH AIA-1200, Hazelton), and thyroxine-binding globulin (TBG) (Cornings Immunophase, TBG125 I, Corning Medical, Norwood, Massachusetts). Thyroid uptake of 123I was measured at 24 hours. Diagnosis was confirmed by DNA analysis using traditional methods in 14 families [7] or using a new strategy, a modification of single-stranded conformational polymorphism, to screen [19] and identify the other mutations [20]. We used the new consensus [6] for exon, codon, and nucleotide designation. Parents of affected persons were screened if possible; if both parents tested negative, patients were considered to have sporadic cases. Magnetic resonance imaging (MRI) of the pituitary gland was done to rule out a TSH-secreting pituitary adenoma. Parameters of Thyroid Hormone Action Assessment of Pituitary Resistance In patients with no history of thyroidectomy who were not receiving thyroid medication (untreated patients), TSH-releasing hormone tests (Relefact, Ferring Laboratory, Suffern, New York) were done. Levels of TSH, -subunit of TSH, and prolactin were measured 0 and 30 minutes after intravenous injection of 500 g (for adults) or 7 g/kg body weight (for children) of TSH-releasing hormone. Assessment of Peripheral Resistance Attention-deficit hyperactivity disorder and IQ were assessed using previously described methods [21, 22]. Briefly, a neuropsychologist, blinded to the diagnosis of resistance to thyroid hormone assessed IQ by using age-appropriate Wechsler intelligence tests. Attention-deficit hyperactivity disorder was diagnosed by psychiatrists, also blinded to the diagnosis of resistance to thyroid hormone, using appropriate structured psychiatric interviews. Right-ankle reflex was measured with an achillometer (Polymed GmbH, Polymed Medical Center, Medizintechnik, Glattbugg ZH, Switzerland) connected to a 1511B electrocardiograph (Hewlett-Packard, Waltram, Massachusetts) in untreated persons. Results given are each an average of three measurements. Audiologic evaluation included threshold tests of pure tones and speech stimuli and biochemical studies of middle-ear function (tympanometry and acoustic reflexes). Significant hearing loss was defined as a speech threshold greater than 20 decibels. Bone age was determined in children by using a hand-wrist radiograph according to the method of Greulich and Pyle [23]. Standard deviations were calculated using the Brush foundation table [23]. Basal metabolic rate was measured at Georgetown University Hospital in Washington, D.C., in untreated persons by using a Sensor Medics 2900 metabolic cart (Sensor Medics Corp., Yorba Linda, California). Results are expressed as a ratio between observed and theoretical basal metabolic rate adjusted for age, sex, height, and weight. Pulsed and continuous echocardiography assessed cardiac dimension and cardiac cycle intervals in 36 untreated adults with resistance to thyroid hormone and 15 untreated adults without resistance. Indices of thyroid hormone actionlevels of cholesterol, ferritin (Abbott Diagnostics), testosterone-binding globulin (TeBG) (Hazelton, Washington, Virginia), and carotene (SmithKline Beecham Clinical Laboratories)were measured [24-27] in fasting, untreated patients. Levels of IgG, IgA, and IgM were also measured. Criteria for Organ Assessment of Thyroid Hormone Action Table 1 shows the variables that were selected to assess end-organ action of thyroid hormone, and it defines the hypothyroid, euthyroid, and hyperthyroid ranges. For basal metabolic rate and for cholesterol, ferritin, and TeBG levels, normal ranges were those validated at our center; for resting pulse, normal values were adapted from Cole [28]; for bone and brain, ranges were based on clinical observation in persons with congenital hypothyroidism. Table 1. Criteria for Tissue Assessment of Thyroid Hormone Action Statistical Analysis Continuous variables are expressed as mean SE, and binary variables are expressed as proportion SE. We estimated SE for all variables (continuous and binary) using a bootstrap approach [29] by resampling the 42 families (not the individual persons) with replacement 1000 times and estimating the distribution of means or proportions from the 1000 replicates. Specifically, we estimated the mean (or proportion) in each replicate and estimated the SE from the sample of 1000 means (or proportions). This procedure allowed us to take into account correlations among persons within families, because we used families rather than individual persons as resampling units. Similarly, we did statistical tests that took correlations within families into account and yielded P values that discriminated between the factor being studied [such as whether a person had resistance to thyroid hormone] and familial traits. We did four sets of statistical tests that compared 1) persons who had resistance to thyroid hormone with persons who did not; 2) persons with resistance to thyroid hormone who had exon 9 mutations with persons with resistance to thyroid hormone who had exon 10 mutations; 3) persons with resistance to thyroid hormone who had an affected mother with persons with resistance who did not have an affected mother, separately in children and in adults; and 4) children with adults, separately acco

Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds.

Familial hyperparathyroidism (HPT) encompasses a clinically and genetically heterogeneous group of disorders. Syndromes with familial HPT include multiple endocrine neoplasia type 1 (MEN1) (Mendelian Inheritance in Man [MIM] 1311001) (63, 87), multiple endocrine neoplasia type 2A (MEN2A) (MIM 171400)(42, 79, 86), familial hypocalciuric hypercalcemia (FHH) (MIM 145980, 145981, 600740) also known as familial benign hypercalcemia (38, 64), and the hyperparathyroidism-jaw tumor syndrome (HPT-JT; HRPT2) (MIM 145001) (45). Familial isolated hyperparathyroidism2 (FIH; HRPT1) (MIM 145000) is a subgroup of familial HPT that can result from the incomplete expression of a syndromic form of familial HPT or from full expression of other entities (Figure 1). It is unknown how many as yet unrecognized clinical entities, including mutant genotypes, can also present as FIH. MEN1 is an autosomal dominant disorder characterized by endocrine and nonendocrine tumors, most strikingly involving the parathyroids, enteropancreatic endocrine system, and pituitary. Because FIH is seen less frequently than full expressions of MEN1, because HPT is the earliest and most frequent endocrinopathy in MEN1, and because even some large families with an apparent phenotype of FIH ultimately express MEN1, we (59, 67) and others (2, 61) previously speculated that most kindreds with FIH were occult expressions of MEN1. The gene responsible for MEN1 has been cloned (15), leading to powerful gene sequencing methods applicable to MEN1, FIH, and other conditions (63). MEN2A, unlike MEN1, is not typically a consideration in the differential diagnosis of FIH, because the higher penetrance of medullary thyroid carcinoma and pheochromocytoma than of HPT in MEN2A dominates the clinical presentation in a family (42, 79, 86). FHH is an autosomal dominant trait usually causing mild HPT (62) with relative hypocalciuria; hypercalcemia in FHH is highly penetrant at all ages, even in the perinatal period (64). Mild hypermagnesemia is sometimes seen in FHH but is unusual in other forms of primary HPT (53, 64). FHH cases almost always remain hypercalcemic following standard subtotal parathyroidectomy (PTX) (64). FHH always presents 0025-7974/02/8101-0001/0 MEDICINE® 81: 1-26, 2002 Vol. 81, No. 1 Copyright

A prospective trial evaluating a standard approach to reoperation for missed parathyroid adenoma.

OBJECTIVES The authors evaluate the results of preoperative imaging protocols and surgical re-exploration in a series of patients with missed parathyroid adenomas after failed procedures for primary hyperparathyroidism. BACKGROUND The success rate is lower and the complication rate is increased in patients undergoing reoperation for primary hyperparathyroidism compared with initial procedures. Scarring and distortion of tissue planes plus the potential for ectopic gland location leads to this worsened outcome. METHODS Two hundred eighty-eight consecutive patients with persistent/recurrent hyperparathyroidism were treated at a single institution after a failed procedure or procedures at outside institutions. Two hundred twenty-two of these patients (77%) were believed to have a missed single adenoma, and these patients underwent 228 operations and 227 preoperative work-ups. Preoperative evaluation consisted of a combination of four noninvasive imaging studies--neck ultrasound, nuclear medicine scan, neck and mediastinal computed tomography scan, and neck and mediastinal magnetic resonance imaging. Based on the noninvasive testing alone, 27% patients underwent surgery whereas the other patients underwent invasive studies, including selective angiography (58%), selective venous sampling for parathyroid hormone (43%), or percutaneous aspiration of suspicious lesions (15%). RESULTS Abnormal parathyroid adenomas were found in 209 of 222 initial procedures and 6 of 6 second procedures, with an overall success rate in terms of resolution of hypercalcemia in 97% (215/222) of patients. The single most common site of missed adenoma glands was in the tracheal-esophageal groove in the posterior superior mediastinum (27%). The most common ectopic sites for parathyroid adenomas are thymus (17%), intrathyroidal (10%), undescended glands (8.6%), carotid sheath (3.6%), and the retroesophageal space (3.2%). The most sensitive and specific noninvasive imaging test is the sestamibi subtraction scan, with 67% true-positive and no false-positive results. The rate of true-positive and false-positive results for ultrasound, computed tomography, magnetic resonance imaging, and technetium thallium scans were 48%/21%, 52%/16%, 48%/14% and 42%/8%, respectively. The incidence of injury to the recurrent laryngeal nerve was 1.3%. CONCLUSIONS A single missed parathyroid adenoma is the most common cause for a failed initial parathyroid operation. Appropriate use of preoperative imaging tests and knowledge of the potential location or parathyroid adenomas can lead to very high cure rates with minimal morbidity.

Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes

Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB1Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB1R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB1R-deficient (Cnr1−/−) or Nlrp3−/− mice, with the endocannabinoid anandamide. Peripheral CB1R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB1R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB1R as a therapeutic target in T2DM.

Multiple endocrine neoplasia type 1: new clinical and basic findings

Multiple endocrine neoplasia type 1 (MEN1) provides a prime example of how a rare disease can advance our understanding of basic cell biology, neoplasia and common endocrine tumors. MEN1 is expressed mainly as parathyroid, enteropancreatic neuroendocrine, anterior pituitary and foregut carcinoid tumors. It is an autosomal dominant disease caused by mutation of the MEN1 gene. Since its identification, the MEN1 gene has been implicated in many common endocrine and non-endocrine tumors. This is a brief overview of recent scientific advances relating to MEN1, including newly recognized clinical features that are now better characterized by genetic analysis, insights into the function of the MEN1-encoded protein menin, and refined recommendations for mutation testing and tumor screening, which highlight our increasing understanding of this complex syndrome.

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.

Molecular Pathology of the MEN1 Gene

Abstract: Multiple endocrine neoplasia type 1 (MEN1), among all syndromes, causes tumors in the highest number of tissue types. Most of the tumors are hormone producing (e.g., parathyroid, enteropancreatic endocrine, anterior pituitary) but some are not (e.g., angiofibroma). MEN1 tumors are multiple for organ type, for regions of a discontinuous organ, and for subregions of a continuous organ. Cancer contributes to late mortality; there is no effective prevention or cure for MEN1 cancers. Morbidities are more frequent from benign than malignant tumor, and both are indicators for screening. Onset age is usually earlier in a tumor type of MEN1 than of nonhereditary cases. Broad trends contrast with those in nonneoplastic excess of hormones (e.g., persistent hyperinsulinemic hypoglycemia of infancy). Most germline or somatic mutations in the MEN1 gene predict truncation or absence of encoded menin. Similarly, 11q13 loss of heterozygosity in tumors predicts inactivation of the other MEN1 copy. MEN1 somatic mutation is prevalent in nonhereditary, MEN1‐like tumor types. Compiled germline and somatic mutations show almost no genotype/phenotype relation. Normal menin is 67 kDa, widespread, and mainly nuclear. It may partner with junD, NF‐kB, PEM, SMAD3, RPA2, FANCD2, NM23β, nonmuscle myosin heavy chain II‐A, GFAP, and/or vimentin. These partners have not clarified menins pathways in normal or tumor tissues. Animal models have opened approaches to menin pathways. Local overexpression of menin in Drosophila reveals its interaction with the jun‐kinase pathway. The Men1+/− mouse has robust MEN1; its most important difference from human MEN1 is marked hyperplasia of pancreatic islets, a tumor precursor stage.

Recurrence after treatment of micropapillary thyroid cancer.

BACKGROUND Despite very low mortality associated with micropapillary thyroid cancer, locoregional recurrence is common and controversy exists regarding optimal surgical treatment and the role of adjunctive radioiodine. METHODS The National Thyroid Cancer Treatment Cooperative Study Group Registry was analyzed for recurrences in patients with unifocal versus multifocal micropapillary cancer, with or without nodal disease, depending upon the extent of surgery and the use of adjunctive radioiodine. Six hundred eleven patients considered disease-free after initial therapy were followed for 2572 person-years. RESULTS Thirty patients (6.2%) had recurrences detected at a mean 2.8 years after primary treatment. Recurrences did not differ between patients with unifocal and multifocal disease overall; however, among patients who received less than a near-total thyroidectomy (NTT), those with multifocal disease had more recurrences than those with unifocal disease (18% vs. 4%, p = 0.01). Patients with multifocal disease who had a total (T) or NTT trended toward fewer recurrences than those undergoing less than an NTT (6% vs. 18%, p = 0.058). In patients who did not receive radioiodine therapy, recurrence was more common in patients with multifocal disease versus unifocal disease (7% vs. 2%, p = 0.02). However, radioiodine did not reduce recurrences in patients with multifocal disease or patients with positive nodes. Patients with positive nodes had more recurrences than node-negative patients regardless of surgical extent or use of radioiodine. CONCLUSIONS Patients with micropapillary multifocal disease have a reduced risk of recurrence after a T/NTT compared with less surgery. A randomized, controlled trial is necessary and feasible to determine if radioiodine ablation of thyroid remnants is advantageous in patients with intrathyroidal micropapillary cancer.