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Although type 2 diabetes mellitus (T2DM) is a poorly managed disease, the armamentarium of medicines available to provide optimal care is growing.Two of the latest antihyperglycemic drugs, pramlintide and exenatide, not only improve glycemic control, but also promote weight loss--a benefit not available with most of the other oral agents for the treatment of T2DM.The current and primary treatment goal for T2DM is to achieve target glycosylated hemoglobin A1C levels to minimize diabetes-related complications.Combination therapy is indicated whenever current efforts to reach target goals fail.Newer insulin analogs provider greater flexibility to patients as to when they administer their medications and eat. [ABSTRACT FROM AUTHOR]

The glycosylated hemoglobin (HbA1C) level is the best available indicator of blood glucose control in patients with diabetes.Target goals for HbA1C range from 6.5% to 7.0%, and as low as 6.0% in individual patients.Reducing elevated HbA1 C levels has a positive impact on risk of microvascular diabetes complications and may also reduce the risk of cardiovascular events and mortality from cardiovascular disease.Only about 37% of people with diagnosed diabetes have an HbA1C level less than 7.0%.Glycemic goals in diabetes are not pursued aggressively enough by physicians or patients.A team approach to diabetes management works best; diet and nutritional counseling are essential for achieving glycemic goals.Aggressive prescribing of oral medications or insulin for type 2 diabetes should begin before the HbA1C rises above recommended levels. [ABSTRACT FROM AUTHOR]

Key aspects of managing this family of syndromes are awareness of the varied presentations of nerve dysfunction, simple tests for detecting early signs of sensory loss, and drugs for relieving neuropathic pain. [ABSTRACT FROM AUTHOR]

The most important preventive strategy for the major complications of diabetes is good glycemic control. Aggressive BP managemnt nad use of new treatment modalities, such as growth factors, nephroprotective agents, and anticonvulsants, can help slow disease progression. [ABSTRACT FROM AUTHOR]

Diabetes and thyroid disorders are common in older persons. Who are appropriate candidates for screening? How should these diseases be treated in this population? Standard therapeutic regimens may require adjustment for use in elderly patients. [ABSTRACT FROM AUTHOR]

Medications in this class are now recommended for patients with diabetes and hypertension, microalbuminuria, or diabetic nephropathy. ACE inhibitors have been proven to limit cardiovascular disease and nephropathy. [ABSTRACT FROM AUTHOR]

Used alone or in combination, oral antidiabetic drugs target specific defects to reduce hyperglycemia and, sometimes, improve dyslipidemia. Together with insulin, some can prevent the weight gain and hypoglycemia associated with insulin monotherapy. [ABSTRACT FROM AUTHOR]

Medications in this class are now recommended for patients with diabetes and hypertension, microalbuminuria, or diabetic nephropathy. CE inhibitors have been proven to limit cardiovascular disease and nephropathy. [ABSTRACT FROM AUTHOR]

The pat answer is, 'The lower the better,' when it comes to decreasing the risk of diabetes complications. With so many patients failing to achieve their glycemic goals, are you doing all you can to help keep them on track? [ABSTRACT FROM AUTHOR]

The lower the better when it comes to HbA1C levels in diabetes and their association with disease complications. Yet since too few patients are achieving glycemic goals, more aggressive therapeutic strategies are needed. [ABSTRACT FROM AUTHOR]

The most important preventive strategy for the major microvascular complications of diabetes is good glycemic control. Aggressive BP management and use of new treatment modalities, such as growth factors, nephroprotective agents, and anticonvulsants, can help slow disease progression. [ABSTRACT FROM AUTHOR]

Discusses the case of a 17-year-old male presenting with Rathke's cleft cyst as a secondary cause of headache. Clinical signs and symptoms; Severity and duration of attacks; Treatment regimen; Magnetic resonance imaging of the lesion; Disease background.

Objective: Managing type 1 diabetes is stressful. Stress physiology influences glucose metabolism. Continuous glucose monitors allow us to track glucose variability in the real-world environment. Managing stress and cultivating resiliency should improve diabetes management and reduce glucose variability., Research Design and Methods: The study was designed as a randomized prospective cohort pre-post study with wait time control. Participants were adult type 1 diabetes patients who used a continuous glucose monitor and recruited from an academic endocrinology practice. The intervention was the Stress Management and Resiliency Training (SMART) program conducted over 8 sessions over web-based video conference software. The main outcome measures were Glucose variability, the Diabetes Self-Management questionnaire (DSMQ),Short-Form Six-Dimension (SF-6D), and the Connor-Davidson Resiliency (CD-RSIC) instrument., Results: There was statistically significant improvement in participants DSMQ and CD RISC scores though the SF-6D did not change. Participants under age 50 years-old showed a statistically significant reduction in average glucose (p = .03) and Glucose Management Index (GMI) (p = .02). Participants also had reduced percentage of time high and increased time in range though this did not reach statistical significance. The participants found doing the intervention online acceptable if not always ideal., Conclusions: An 8-session stress management and resiliency training program reduced diabetes related stress and improved resiliency and reduced average blood glucose and GMI in those under 50 years-old., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT04944264., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Stahl, Ammana, Kwak and Comi.)

Objectives: To our knowledge, no prior research has explored the prevalence of wearing continuous glucose monitors (CGMs) and/or insulin pumps among in-training fellows and their perception of doing so as part of their education. Our objectives therefore were to estimate the frequency with which wearing a CGM and/or insulin pump is used as a learning opportunity and explore the main motivators and perception on its value. Methods: A multiple-choice survey that addressed each fellow's level of training, type of fellowship training program, and use of CGM and/or insulin pump was sent to all Accreditation Council for Graduate Medical Education endocrinology, diabetes, and metabolism program coordinators or program directors. We asked them to forward this survey to their graduating fellows. Their perception on the value of wearing these devices was addressed. Results: Fifty-one graduating fellows responded to the survey; 78.43% and 62.5% of them wore a CGM and insulin pump, respectively. A total of 89.48% and 90% of those who wore a CGM and insulin pump, respectively, thought it was above-average value for their education, and the most common reasons were to learn the technical aspects and understand what patients with diabetes go through. Conclusion: Wearing a CGM and/or insulin pump is perceived by endocrinology graduating fellows as valuable to their education, specifically, to learn the technical aspects, understand the patient's experience, and develop empathy. Abbreviations: ACGME = Accreditation Council for Graduate Medical Education; CGM = continuous glucose monitor.

Objective: An individualized approach is recommended by guidelines when establishing hemoglobin A1c (HbA1c) goals. Setting a goal requires experience and awareness; it is time consuming and not always trivial. A previous study proposed an algorithm for assessing the recommended HbA1c target according to individual patient characteristics. Few investigations have explored the variation of HbA1c goals recommended among different types of providers., Methods: We conducted a survey regarding practice settings, practices related to diabetes mellitus type 2, and HbA1c targets recommended to patients. Our objective was to compare HbA1c goals between Dartmouth Hitchcock Healthcare System providers (including endocrinology department, general internal medicine, and family medicine providers) and a previously validated algorithm. The clinical cases presented were those used in the previously published study., Results: The survey was sent to 228 healthcare providers of whom 81 (35.5%) responded. As recommended by the guidelines, healthcare providers individualize their patients' glycemic goals. The glycemic goals proposed by the providers in our institution were similar to those proposed by the international diabetologists and by the algorithm., Conclusion: Our results further validate the proposed algorithm within a heterogeneous population of healthcare providers. The algorithm could help establish glycemic goals and assist healthcare systems in providing more standardized care., Abbreviations: ADA = American Diabetes Association; APRN = advanced practice registered nurse; DH = Dartmouth Hitchcock Healthcare System; FM = family medicine; GIM = general internal medicine; HbA1c = hemoglobin A1c; PA-C = certified physician assistant.

Content: Management of primary hyperparathyroidism has evolved over the past two decades, yet impaired renal function has consistently been a surgical indication. This recommendation has been based upon the historical association between primary hyperparathyroidism and renal impairment, and a review of the literature is needed to determine whether such a recommendation is warranted., Evidence Acquisition and Synthesis: PubMed was utilized to identify English-language articles published between January 1990 and February 2014 using keywords related to hyperparathyroidism and renal function. The keywords were "primary hyperparathyroidism," "surgery," "parathyroidectomy," "kidney," "renal," "glomerular filtration rate," and "creatinine." Of the 1926 articles obtained with this search, all articles germane to the topic that quantified the relationship between primary hyperparathyroidism and renal function were included. All references within these articles were investigated for inclusion. When helpful, data tables were constructed to summarize the results succinctly., Conclusions: A secondary elevation of PTH levels has not been consistently shown to occur at the threshold currently indicated for surgical intervention. While renal impairment is seen with more significant disease, mild asymptomatic primary hyperparathyroidism has not been conclusively associated with renal impairment. Furthermore, there is no evidence to suggest that surgically curing primary hyperparathyroidism via a parathyroidectomy has any impact upon renal function.

Electron paramagnetic resonance (EPR) spectroscopy has been well established as a viable technique for measurement of free radicals and oxygen in biological systems, from in vitro cellular systems to in vivo small animal models of disease. However, the use of EPR in human subjects in the clinical setting, although attractive for a variety of important applications such as oxygen measurement, is challenged with several factors including the need for instrumentation customized for human subjects, probe, and regulatory constraints. This article describes the rationale and development of the first clinical EPR systems for two important clinical applications, namely, measurement of tissue oxygen (oximetry) and radiation dose (dosimetry) in humans. The clinical spectrometers operate at 1.2 GHz frequency and use surface-loop resonators capable of providing topical measurements up to 1 cm depth in tissues. Tissue pO2 measurements can be carried out noninvasively and repeatedly after placement of an oxygen-sensitive paramagnetic material (currently India ink) at the site of interest. Our EPR dosimetry system is capable of measuring radiation-induced free radicals in the tooth of irradiated human subjects to determine the exposure dose. These developments offer potential opportunities for clinical dosimetry and oximetry, which include guiding therapy for individual patients with tumors or vascular disease by monitoring of tissue oxygenation. Further work is in progress to translate this unique technology to routine clinical practice., (Copyright © 2014 AUR. Published by Elsevier Inc. All rights reserved.)

Objective: To describe our clinical experience with U500 insulin in insulin-resistant patients, including change in glucose control, body weight, insulin dose, and hypoglycemic episodes., Methods: In September 2010, we undertook a retrospective chart review of patients who had U500 insulin in their medication list in the preceding 2 years who were treated in the endocrinology section at Dartmouth Hitchcock Medical Center. Glycosylated hemoglobin (A1C), body weight, and insulin dosage were documented before U500 insulin introduction, after 6 months of U500 insulin use, and at the last clinic visit when the patient was still taking U500 insulin. Hypoglycemic episodes and number of daily injections were recorded., Results: Records of 53 patients were analyzed, one of the largest reports of U500 insulin use published to date. The mean A1C level decreased from 10.1% before U500 insulin was initiated to 9.1% after 6 months of U500 use to 8.6% at the last follow-up visit (mean follow-up was 36.6 ± 24 months). At the last charted visit, body weight increased by a mean of 6.8 kg and insulin dosage increased by a mean of 0.44 units/kg. We observed a significant increase in the number of nonsevere hypoglycemic episodes and a decrease in the number of daily injections., Conclusion: Patients with uncontrolled, severely insulin-resistant diabetes can be satisfactorily treated with U500 insulin with the potential to improve glycemic control. An increase in body weight, insulin dosage, and the number of nonsevere hypoglycemic episodes was observed.

Objective: To investigate the impact of sociocultural workplace attributes on participation in employer sponsored health assessments., Methods: Medical center employees were encouraged to participate in free, voluntary, and confidential biometric screening and on-line health risk appraisal. A job satisfaction database, aggregated by job type and work area, was used to identify workplace sociocultural attributes correlated with participation., Results: : Thirty-seven percent of the population engaged in the health assessments; however, participation varied widely by work area (10% to 83%) and by job type (17% to 56%). Participation was significantly correlated with selected aspects of job satisfaction., Conclusions: Overall participation rates in employee population health assessments can disguise large variation in employee engagement. This variation is associated with work sociocultural characteristics. Attention to these attributes may be essential to improving involvement in employer sponsored health promotion.

Many studies of tight control of blood glucose in critically ill patients are associated with poor outcomes. However, randomized studies of tight glucose control in patients admitted to coronary care or surgical intensive care units showed a reduction in mortality rates; supported by recommendations from professional organizations, many intensive care units implemented protocols for tight glucose control. More recent studies in medical intensive care units did not confirm the benefits of tight control, however, and the most recent study suggests that tight control increases mortality rates. Furthermore, tight control significantly increases episodes of hypoglycemia. The sum of the recent literature suggests that a degree of glucose control lies between the extremes of the adverse outcomes related to poor glucose control and those related to overly aggressive glucose control.

For worksite biometric screening, we shortened traditional fasting instructions to 4h. The positive predictive value (PPV) of elevated capillary glucose test results (> or =100mg/dL) for predicting elevated values obtained on repeat testing after an 8h fast was 57%, which rivals the PPV of an 8h fasting glucose.

EPR oximetry is a technique that can make repeated non-invasive measurements of the PO2 in tissues. To extend the application of EPR oximetry to humans, India ink is the probe of choice because appropriate India inks have EPR signals whose line widths are sensitive to changes in oxygen concentrations, and, most importantly, India ink already has been used extensively in humans as a marker in the skin, lymphatics, various organs during surgery, tumors, and for decoration as tattoos. We have developed an India ink that has good sensitivity to oxygen, high stability in tissues, good signal intensity, and minimal toxicity. In this article we describe the various properties of this India ink, results obtained from our animal experiments, and our first preliminary clinical results, which are part of the first systematic clinical use of EPR oximetry. The clinical results indicate that it is possible to do repeated measurements over several months and probably years after the injection of the ink, indicating that long-term follow-up studies are feasible. We are very encouraged with these results and are confident that EPR oximetry using India ink will be a non-invasive, fast, and reliable technique for pO2 measurements in clinical studies.

Objective: To investigate, in a clinical setting, the effect of implementation of continuous subcutaneous insulin infusion (CSII) on control of plasma glucose and to identify factors associated with improved glycemic control in patients with type 1 diabetes mellitus., Methods: Nineteen patients (16 women and 3 men) with type 1 diabetes were studied retrospectively. Their mean age was 42.6 years (range, 30 to 58), and the mean duration of diabetes was 21 years. The subjects underwent follow-up for a mean of 14 months after conversion to CSII therapy. With use of paired t tests, pre-CSII and follow-up data were evaluated relative to changes in weight, insulin dosing, and glycosylated hemoglobin (HbA(1c))., Results: At follow-up, the total daily dose of insulin had decreased by 18%, from a baseline mean value of 45.2 IU to 37.1 IU (P = 0.02). HbA(1c) was reduced from 8.4% to 7.7% (P<0.01). The total daily insulin-to-weight ratio also significantly decreased from 0.66 IU/kg to 0.53 IU/kg (P<0.05). Before insulin pump use, the regular/NPH insulin ratio was 0.5 IU; at follow-up, the pump bolus/basal insulin ratio was 1.0 IU (P = 0.02). No weight gain was observed; the mean weight of the study patients decreased 0.2 kg, from 69.4 kg at baseline to 69.2 kg at follow-up (not significantly different)., Conclusion: In a clinical setting, CSII therapy in patients with type 1 diabetes improves glycemic control and lowers the total daily basal insulin dose without affecting weight. Improved glycemic control was associated with a shift in insulin therapy from a high percentage of intermediate-acting insulin to a greater percentage of insulin administered in a meal-associated bolus form. This study emphasizes the importance of mealtime insulin adjustment for tight glycemic control in patients using CSII therapy. Future studies evaluating the benefits of decreased total insulin and an increased bolus/basal insulin ratio may be important in helping to understand how to avoid long-term complications of diabetes.

Background: The morbidity of hypercortisolemia due to ectopic production of ACTH by various tumors may be greater than the morbidity of the tumor itself., Methods: We report three cases of long-term treatment of ectopic ACTH syndrome due to metastatic bronchial carcinoid, islet cell carcinoma, and malignant thymoma tumors. Clinical and biochemical eucortisolemia was achieved in each case and was sustained from 24 to 55 months. We review the therapeutic options and their reported efficacy., Results: Cessation of therapy resulted in recurrence of hypercortisolemia in each case, showing the effectiveness of therapy., Conclusion: Long-term treatment of ectopic ACTH-induced hypercortisolemia by blocking adrenal steroidogenesis is clinically effective and well tolerated.

We assessed the association between cigarette smoking and basal levels of adrenal cortical hormones in 11 postmenopausal smokers and 11 postmenopausal nonsmokers and measured the acute adrenal effects of cigarettes in the smokers. After an overnight food, alcohol and tobacco fast, participants smoked or sham-smoked every hr for 8 hr and provided serum samples for hormone assay before and after every other cigarette/sham, as well as before and after a corticotropin stimulation test. The postmenopausal smokers had substantially higher basal levels of androstenedione (4.60 +/- 0.42 vs. 2.70 +/- 0.36 nmol/l, P < .05) and dihydroepiandrosterone sulfate (2.88 +/- 0.36 vs. 1.91 +/- 0.16 mumol/l, P < .05) and higher average levels of cortisol and androstenedione from 0800 to 1300 hr (351.0 +/- 17.5 vs. 295.5 +/- 17.1, nmol/l and 3.58 +/- 0.42 vs. 2.51 +/- 0.19 nmol/l, P = .03, and P < .05, respectively). There were small acute effects of individual cigarettes on the hormones, but the response to corticotropin was similar in smokers and nonsmokers. Our results indicate that cigarette smoking causes a generalized disturbance in adrenal cortical hormone levels. There is no evidence for acute tolerance to the adrenocortical affects of the hourly smoking of medium-nicotine cigarettes, but these acute effects do not explain the higher hormone levels in smokers. There is no evidence for a partial block in the cortisol synthesis pathway to explain the increased adrenal androgen levels in smokers.

The function of the red blood cell glucose transporter was compared in samples from subjects with and without diabetes. Activity of the glucose transporting protein (GLUT-1) was measured by determining the first order rate constant for uptake of sorbose, a sugar transported by GLUT-1. Red cells were isolated from 13 patients with diabetes and 9 patients without diabetes and were washed free of intracellular glucose. The uptake rate constant was calculated from measurements of sorbose uptake at 0, 1, 2, 5 and 90 minutes at 37 degrees C. The rate constant was significantly decreased in cells isolated from patients with diabetes (0.242 vs 0.303 min-1 in non-diabetic subjects, p < 0.005). The number of GLUT-1 present per mg of membrane protein and clinical parameters such as weight, age, serum cholesterol and urea nitrogen were not significantly different between the groups. The rate constant per pmol of GLUT-1 was significantly decreased in the diabetic subjects. The relationship between diabetes control and the rate constant was not linear and there was no relationship between the calculated intrinsic activity and the HA1c. Because red cell GLUT-1 are not translocated and red cells do not synthesize new proteins, these data suggest that the intrinsic function of the glucose transporter from red cells of patients with diabetes is diminished. This may be due to alterations in the transporter or its membrane environment.

Hypoglycemia is a common clinical disorder with a large number of possible causes. Hypoglycemia is defined for the clinician as a diagnosis rather than a symptom complex. Hypoglycemic states can be characterized initially as medication associated, fasting, or postprandial. An approach based on the physiologic mechanisms that support euglycemia is useful to sort through the differential diagnosis of hypoglycemia for both adults and children.

Objective: We wished to determine the effects of octreotide acetate, a somatostatin analogue, on gall-bladder function during treatment of acromegaly., Design: We used a prospective, open label trial of somatostatin analogue., Patients: Seventeen patients with acromegaly took part., Measurements: Ultrasonographic evaluation of gall-bladder contents were performed pretreatment, after 1 month, and subsequently at intervals of 3-6 months., Results: Non-shadowing floating echogenic particles were observed in the gall-bladder in 12 of 17 patients after (mean +/- SEM) 2.5 +/- 0.6 months of treatment. During long-term treatment (mean 20.8 +/- 4.3, median 13, range 1-59 months), ultrasound evidence for cholelithiasis was observed in four patients after 20 +/- 4 months (range 4.2-43) months of octreotide therapy. No symptoms of biliary tract disease have been observed. Duration of acromegaly, average GH, average IGF-I, gender, age at entry, dose of analogue, and concurrent use of non-steroidal anti-inflammatory drugs did not affect the occurrence of sludge or gallstones., Conclusions: Formation of non-shadowing, floating echogenic particles occurs commonly during the first 6 months of treatment with octreotide acetate. Cholelithiasis is a risk of long-term treatment.

The DCNH is a unique collaborative venture in outpatient diabetes education. We believe it can serve as a model for rapidly developing standardized diabetes education in geographically dispersed communities. The heart of the organization is the educators' meeting, which enables an extensive sharing of ideas and information that benefit all patients in the region. The features crucial to our success have been (1) administrative leadership with a nursing management or educator background, (2) data collection and analysis, (3) local development of an educational curriculum based on ADA standards, and (4) centralized medical and administrative directors who are available to meet individual program needs. However, we are most indebted to the farsighted and strong commitment of our member hospitals to diabetes care in their communities.

Octreotide is a new agent with many documented useful applications and a huge number of possible applications. Each documented therapeutic effect will require careful analysis. Particular care must be taken to design controls, use double-blind tests for objective study of subjective benefits, and frame questions to elicit precise answers. The most important guide is to keep an open mind when attempting to discern a mechanism of action.

We compared insulin receptors obtained from cells widely used in human studies, the circulating monocytes and erythrocytes. Biochemically, these receptors possess both binding (alpha-subunit) and tyrosine kinase (beta-subunit) activities similar to insulin receptors from other sources. Subtle differences in molecular weight, however, were detected between the alpha-subunits of these two cell types when analyzed by NaDodSO4-PAGE. Crosslinked [125I]insulin-labeled alpha-subunit of the monocyte insulin receptor was of higher apparent molecular weight than the alpha-subunit derived from red cells. Neuraminidase treatment of the alpha-subunits from each cell type indicated more sialic acid residues were present on the monocyte than the red cell alpha-subunit. The structural properties of the insulin receptors of human circulating cells are similar but not identical to insulin receptors of other characterized systems.

Synthetic copolymers containing tyrosine residues were used to characterize the substrate specificity of the insulin receptor kinase and compare it to tyrosine kinases stimulated by epidermal growth factor, insulin-like growth factor-1 and phorbol ester. In partially purified receptor preparations from eight different tissues insulin best stimulated (highest V) phosphorylation of a random copolymer composed of glutamic and tyrosine residues at a 4:1 ratio (Glu/Tyr, 4:1). The insulin-stimulated phosphorylation of this polymer was highly significant also in receptor preparations from fresh human monocytes, where insulin binding and autophosphorylation were difficult to detect. Other tyrosine-containing polymers Ala/Glu/Lys/Tyr (6:2:5:1) and Glu/Ala/Tyr (6:3:1) were also phosphorylated by the insulin-stimulated kinase but to a lower extent. A tyrosine kinase stimulated by insulin-like growth factor-1, and one stimulated by phorbol ester also best phosphorylated the polymer Glu/Tyr (4:1). The three kinases differed only in their capability to phosphorylate Glu/Ala/Tyr (6:3:1) or Ala/Glu/Lys/Tyr (6:2:5:1). Glu/Tyr (4:1) was a poor substrate for the epidermal growth factor receptor kinase which best phosphorylated the polymer Glu/Ala/Tyr (6:3:1). Three additional polymers: Glu/Tyr (1:1), Glu/Ala/Tyr (1:1:1), and Lys/Tyr (1:1) failed to serve as substrates for all four tyrosine kinases tested. Taken together these findings suggest that. Hormone-sensitive tyrosine kinases have similar yet distinct substrate specificity and are likely to phosphorylate their native substrates on tyrosines adjacent to acidic (glutamic) residues. Tyrosine-containing polymer substrates are highly sensitive and convenient tools to study (hormone-sensitive) tyrosine kinases whose native substrates are unknown or present at low concentrations.

SMS 201-995 (SMS) is a long-acting analog of somatostatin. We studied the effect of SMS (50-100 micrograms, sc, every 8 h) on serum GH in five patients with acromegaly. Serum GH decreased significantly in four of the five patients 4 h after SMS treatment. In two of the four patients, this reduction was not sustained for 7 h, but sustained reduction to normal GH concentrations did occur in the two patients who had basal serum GH levels below 15 ng/ml. In the two patients whose responses were not sustained for 7 h, a higher dose of SMS did not cause sustained reduction in GH. SMS was well tolerated, except for one episode of elevated serum aminotransferase levels. These results indicate that SMS-induced reductions in serum GH in patients with acromegaly are often not sustained despite SMS administration every 8 h and indicate that the insufficient duration of effect may limit its therapeutic efficacy.

The function of the insulin receptor subunits isolated from cells of a patient with the type A syndrome of insulin resistance was examined. Iodine 125-labeled insulin binding, insulin-stimulated phosphorylation of both endogenous and exogenous substrates, and internalization of 125I-insulin were evaluated. 125I-insulin binding to intact peripheral monocytes and erythrocytes, cultured skin fibroblasts, and cultured Epstein-Barr virus-transformed lymphocytes, as well as to partially purified receptor preparations from these cells, was entirely normal. In contrast, the insulin-stimulated receptor autophosphorylation and tyrosine kinase activity of the partially purified monocyte, erythrocyte, and fibroblast receptor preparations were markedly diminished. Solubilized, lectin-purified receptors from virally transformed cultured lymphocytes, however, demonstrated normal insulin-sensitive kinase activity. The patient's peripheral monocytes did not internalize 125I-insulin at 37 degrees C, but her transformed lymphocytes internalized it normally, as assessed by electron microscopic autoradiography. Our findings suggest that the discordance between the functions of the alpha-subunits and beta-subunits of the insulin receptor from monocytes of this insulin-resistant patient (Science 1984;223:932-4) extends to other freshly isolated cell types and persists in her cultured cells. Viral transformation of her cells results directly or indirectly in normal expression of the receptor kinase activity. Whether the defective kinase activity of the insulin receptor and the impaired receptor internalization exhibited by her monocytes ultimately cause the patient's insulin resistance awaits further studies.

Thyrotropin-secreting pituitary adenomas are aggressive, invasive tumors that respond poorly to available surgical and medical treatments. Inappropriate release of thyrotropin by these tumors can result in hyperthyroidism. We treated five patients who had thyrotropin-secreting pituitary adenomas with the long-acting somatostatin analogue SMS 201-995, which was administered by subcutaneous injection in doses of 50 to 100 micrograms every 8 to 12 hours. Serum levels of thyrotropin were dramatically reduced by treatment in four of the five patients, and levels of another tumor marker, the alpha-subunit of thyrotropin, were reduced in all five. In two patients with hyperthyroidism due to production of excess thyrotropin by the tumor, treatment with the somatostatin analogue resulted in a sustained euthyroid state. One patient who was treated for more than 16 months had a persistent reduction in serum levels of thyrotropin and iodothyronines. We conclude that SMS 201-995 is an effective means of controlling hypersecretion of thyrotropin and the associated hyperthyroidism due to thyrotropin-secreting pituitary tumors.

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.

The insulin receptor contains an alpha subunit with insulin binding properties and a beta subunit with insulin-stimulated tyrosine kinase function. Preparations containing insulin and insulinlike growth factor I (IGF-I) receptors were obtained from solubilized human red cell membranes by affinity chromatography. After separate assays for insulin binding and insulin-stimulated tyrosine kinase activities, a high degree of correlation was found between these activities in preparations from normals and diabetics. Identical studies using IGF-I as the ligand showed a lesser degree of correlation. We compared 24 normal subjects and 14 untreated type II diabetics and found significant diminution in the slope of the line coupling insulin binding and insulin-stimulated kinase activities in the diabetics. This difference was not observed in a similar study of IGF-I-related activities. Compared to normal controls, untreated type II diabetics have reduced tyrosine kinase activity stimulated per unit insulin binding.