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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. [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: 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.

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.

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.

The syndrome of type A insulin resistance in nonobese women is characterized by hyperinsulinemia, resistance to exogenous insulin, acanthosis nigricans, polycystic ovaries, and masculinization. Insulin binding to intact circulating monocytes and cultured Epstein-Barr virus-transformed B-lymphocytes derived from these patients is decreased in some patients but normal in others. Insulin receptors consist of two subunits; the alpha-subunit contains the insulin-binding site, and the beta-subunit possesses an insulin-sensitive tyrosine-specific protein kinase activity. Insulin binding to circulating monocytes was decreased in five patients, suggesting a decreased number of alpha-subunits on the surface of cells from the patients with type A insulin resistance. In the present work, we demonstrated that there is a proportional decrease in the function of the beta-subunit (i.e. tyrosine kinase activity) in cells from these subjects. In one patient, insulin binding to circulating monocytes was normal, and the insulin-stimulated tyrosine kinase activity of the receptors was normal as well. In separate studies, using cultured Epstein-Barr virus-transformed lymphocytes from the same six patients with type A extreme insulin resistance, the results were similar, in that the functions of the alpha- and beta-subunits of the receptor from these cells correlated. Though heterogeneity among the six patients with type A extreme insulin resistance at the level of the kinase activity of their insulin receptors was demonstrated, it does not appear that a selective defect in beta-subunit phosphorylation per se can be implicated in the mechanisms of insulin resistance of these patients. These findings are distinct from our previously reported patient with normal binding and very low insulin-stimulated phosphorylation of the beta-subunit of the receptor of circulating monocytes, in whom it was speculated that selective reduction in beta-subunit phosphorylation was responsible for insulin resistance.

The insulin receptor is synthesized as a single chain, 190 kDa glycoprotein precursor, which undergoes proteolytic cleavage, carbohydrate processing, and fatty acylation to generate the mature receptor on the plasma membrane. The relationship of these post-translational modifications to the acquisition of receptor function, i.e. ligand binding and phosphokinase activity, is not fully understood. Therefore, the 190 kDa proreceptor and mature receptor kinase activities were separately examined in vitro, and their phosphorylation properties compared. The solubilized receptor precursor from IM-9 lymphocytes was purified by sequential lectin chromatography and, following site specific anti-receptor antibody immunoprecipitation, phosphokinase studies performed. The isolated proreceptor was activated by insulin and phosphorylated exogenous substrate alpha-casein, as similarly observed for the mature receptor. Structurally, the phosphorylated proreceptor was identified as a 360 kDa homodimer under non-reducing condition.