Consensus on Use of Insulins in Gestational Diabetes.

INTRODUCTION: Gestational Diabetes Mellitus (GDM), diabetes diagnosed during pregnancy is associated with maternal (caesarean delivery, hypoglycaemia, hyperbilirubinaemia, shoulder dystocia, pre-term delivery and birth trauma) and fetal (Hyperbilirubinaemia in offspring, Neonatal hypoglycaemia, Macrosomia) complications. Despite, insulin being the standard treatment for GDM cases, there is no existing comprehensive consensus update on use of insulin in Indian patients with GDM. OBJECTIVE: To provide simple and easily implementable guidelines to healthcare physicians on use of insulin in GDM. METHODS: Each consensus based on indications, choice of insulin regimen , titration and insulin therapy during intrapartum and postpartum was presented based on established guidelines and published scientific literature. These evaluations were then factored into the national context based on the expert committee representatives' patient-physician experience in their clinical practice and common therapeutic practices followed in India for successful GDM management. RESULTS: Recommendations based on use of insulin in GDM has been developed. The key recommendations are:to monitor fasting plasma glucose (FPG) and 2-hour post prandial glucose PPG levels and the glycaemic targets are: FPG < 95 mg/dL and 2-hour PPG < 120 mg/dL, short-and intermediate acting human insulin are the first choice of insulin regimens, rapid-acting (Insulin Aspart or Lispro) may be considered, use basal/intermediate acting insulin at bedtime, if FPG>110 mg/dL. During intrapartum, start IV insulin infusion with hourly glucose monitoring. Those women who require insulin < 20 U over 24 hours prior to labor may not need interpartum use of insulin infusion and Insulin dosing is stopped after birth and capillary glucose monitoring for 24-48 hours. CONCLUSIONS: We hope that the consensus based recommendations mentioned in this paper will be a useful reference tool for healthcare practitioners to achieve glycaemic targets in GDM patients.

Consensus recommendations for the management of hyperglycaemia in critically ill patients in the Indian setting.

Hyperglycaemia occurs frequently in critically-ill patients. Not only does it occur among patients with pre-existing diabetes mellitus but elevated blood glucose values during an acute illness can also be seen in previously glucose-tolerant individuals (stress hyperglycaemia). Numerous observational studies have shown an increase in morbidity and mortality in critically ill patients with hyperglycaemia. Interestingly, outcomes in individuals with stress hyperglycaemia are worse than that in critically ill hyperglycaemic patients with pre-existing diabetes. Proper management of hyperglycaemia has been shown to result in improved clinical outcomes. Critically ill patients with hyperglycaemia should primarily be managed with intravenous insulin infusion to allow dynamic adjustment of treatment to suit the rapid changes in blood glucose values in these patients. Currently, there are in existence a fair number of published protocols to administer intensive intravenous insulin therapy that range from the relatively simple to the fairly complex. Different management strategies have been proposed depending upon whether the critically ill hyperglycaemic patient is stationed in the emergency department, the medical intensive care unit (ICU), the surgical ICU or the coronary care unit. Moreover, the ideal target blood glucose value to maintain in this group of patients remains controversial. Keeping these issues in mind, a group of leading experts in the fields of diabetes and critical care extensively reviewed the literature and framed recommendations with special attention to clinical practice in India. The aim was to formulate recommendations which are based on sound evidence and yet are simple and easy to understand and implement across the ICU throughout the country. In the current recommendations, intensive intravenous insulin therapy has been suggested as the preferred mode of managing hyperglycaemia in patients admitted to critical care settings. The current recommendations suggest using a simple and similar protocol for managing hyperglycaemia in critically-ill patients irrespective of their location among the various critical care units in a hospital. Recommendations have also been made for transition from intravenous to subcutaneous administration of insulin when the patient is transferred out of the critical care setting. It is hoped that the current recommendations shall form the basis for the management of hyperglycaemia in critically ill patients across the country.

Time to reposition sulfonylureas in type 2 diabetes management in Indian context: A pragmatic practical approach.

Sulfonylureas (SU) continue to be a vital therapeutic category of oral hypoglycemic agents (OHAs) for the management of type 2 diabetes mellitus (T2DM). Physicians consider modern SU (gliclazide and glimepiride) as "safe and smart" choices for T2DM management. The presence of multiple international guidelines and scarcity of a national guideline may contribute to the challenges faced by few physicians in choosing the right therapeutic strategy. The role of SU in diabetes management is explicit, and the present consensus aims to emphasize the benefits and reposition SU in India. This pragmatic, practical approach aims to define expert recommendations for the physicians to improve caregivers' knowledge of the management of T2DM, leading to superior patient outcomes.

Obstructive sleep apnea presenting as recurrent cardiopulmonary arrest.

A non-obese patient who was admitted initially with hypoglycemia had multiple episodes of cardiopulmonary arrests requiring resuscitations and a short period of mechanical ventilation. A subsequent sleep study confirmed the diagnosis of severe obstructive sleep apnea (OSA) and documented an episode of near-arrest with cerebral hypoxia during rapid eye movement sleep. We suggest that OSA coupled with impairment of arousal response and other apnea termination mechanisms had resulted in prolonged apnea, life-threatening hypoxemia, and cardiopulmonary arrest in this patient. We review the current understanding of the mechanisms of apnea termination in OSA and suggest that further studies are needed to investigate these mechanisms and their roles in sudden death during sleeping hours in patients with OSA.

Unusual presentation of pheochromocytoma with ischemic sigmoid colitis and stenosis.

A 45-year-old woman with poorly controlled hypertension and diabetes mellitus presented with left iliac fossa pain, constipation alternating with diarrhea, and weight loss. She had been diagnosed with idiopathic cardiomyopathy five years previously. Echocardiogram had shown a left ventricular ejection fraction (LVEF) of 35%; coronary angiogram was normal. Colonoscopy revealed sigmoid colitis with stenosis. Abdominal computed tomography revealed a 5 cm right adrenal tumor. Twenty-four hour urinary free catecholamines and fractionated metanephrine excretion values were elevated, confirming pheochromocytoma. Her colitis resolved after one month of adrenergic blockade. Repeat echocardiogram showed improvement of LVEF to 65%. After laparoscopic right adrenalectomy, the patient's hypertension resolved, and diabetic control improved. Timely management avoided further morbidity and potential mortality in our patient.

Recurrent episodes of arthritis in a hyperthyroid patient.

Antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis is a potentially life-threatening adverse effect of antithyroid medications. We present a 22-year-old woman with Graves' disease who developed recurrent episodes of arthritis while on treatment with propylthiouracil. A diagnosis of propylthiouracil-induced ANCA-associated vasculitis was established only after exhaustive rheumatological investigations failed to establish a cause for her arthritis. Anti-myeloperoxidase antibody (anti-MPO) titres were grossly elevated at 172.7 RU/mL (0-20). Her arthritis resolved promptly following the withdrawal of propylthiouracil and the anti-MPO titres declined over 16 months to 66.8 RU/mL. While she did not develop the life-threatening renal or respiratory tract complications, there was a delay in establishing the correct diagnosis with its attendant morbidity. This case highlights the need for greater awareness of this relatively rare adverse effect of antithyroid medications so as to allow its early detection, leading to the prompt cessation of the offending medication.

A hyperthyroid patient with measurable thyroid-stimulating hormone concentration - a trap for the unwary.

INTRODUCTION: In a patient with hyperthyroidism, the detection of elevated thyroid hormone concentration with measurable thyroid-stimulating hormone (TSH) value poses considerable diagnostic difficulties. CLINICAL PICTURE: This 38-year-old lady presented with clinical features of thyrotoxicosis. Her serum free thyroxine concentrations were unequivocally elevated [45 to 82 pmol/L (reference interval, 10 to 20 pmol/L)] but the serum TSH values were persistently within the reference interval [0.49 to 2.48 mIU/L (reference interval, 0.45 to 4.5 mIU/L)]. TREATMENT: Investigations excluded a TSH-secreting pituitary adenoma and a thyroid hormone resistance state and confirmed false elevation in serum TSH concentration due to assay interference from heterophile antibodies. The patient was treated with carbimazole for 18 months. OUTCOME: The heterophile antibody-mediated assay interference disappeared 10 months following the initiation of treatment with carbimazole, but returned when the patient relapsed. It disappeared again 2 months after the initiation of treatment. CONCLUSIONS: Clinicians should be aware of the potential for interference in immunoassays, and suspect it whenever the test results seem inappropriate to the patient's clinical state. Misinterpretation of test values, arising as a result of assay interference, may lead to misdiagnosis, unnecessary and at times expensive investigations, delay in initiation of treatment and worst of all, the initiation of inappropriate treatment.

2-Amino-3-ketobutyrate CoA ligase of Escherichia coli: stoichiometry of pyridoxal phosphate binding and location of the pyridoxyllysine peptide in the primary structure of the enzyme.

Pure 2-amino-3-ketobutyrate CoA ligase from Escherichia coli, which catalyzes the cleavage/condensation reaction between 2-amino-3-ketobutyrate (the presumed product of the L-threonine dehydrogenase-catalyzed reaction) and glycine + acetyl-CoA, is a dimeric enzyme (Mr = 84,000) that requires pyridoxal 5'-phosphate as coenzyme for catalytic activity. Reduction of the hololigase with tritiated NaBH4 yields an inactive, radioactive enzyme adduct; acid hydrolysis of this adduct allowed for the isolation and identification of epsilon-N-pyridoxyllysine. Quantitative determinations established that 2 mol of pyridoxal 5'-phosphate are bound per mol of dimeric enzyme. After the inactive, tritiated enzyme adduct was digested with trypsin, a single radioactive peptide containing 23 amino acids was isolated and found to have the following primary structure: Val-Asp-Ile-Ile-Thr-Gly-Thr-Leu-Gly-Lys*-Ala-Leu-Gly-Gly-Ala-Ser-Gly-Gly -Tyr-Thr-Ala-Ala-Arg (where * = the lysine residue in azomethine linkage with pyridoxal 5'-phosphate). This peptide corresponds to residues 235-257 in the intact protein; 10 residues around the lysine residue have a high level of homology with a segment of the primary structure of 5-aminolevulinate synthase from chicken liver.

Solubilization and modulation of acyl-CoA:1-acyl-glycerophosphocholine acyltransferase activity in rat liver microsomes.

The acylation of 1-acyl-glycerophosphocholine is an important mechanism for the maintenance of the asymmetrical distribution of acyl groups in phosphatidylcholine. The majority of acyl-CoA:1-acyl-glycerophosphocholine acyltransferase is located in the microsomal fraction. In this study, the rat liver microsomes were incubated with various detergents, and the solubilized enzyme was separated from the remainder by centrifugation. Sodium cholate, sodium deoxycholate and octylglucopyranoside caused the solubilization of 14-25% of the enzyme activity. The acyl specificity of the solubilized enzyme was similar to the insoluble enzyme, indicating that there was no selective solubilization of any acyl specific acyltransferase. The solubilized enzyme did not display any lipid requirement, and its activity was inhibited by phosphatidylcholine, phosphatidylethanolamine and 1,2-diacylglycerol. Kinetic studies with varying concentrations of acyl-CoAs revealed that the inhibition by 1,2-diacylglycerol was essentially uncompetitive. The modulation of acyltransferase activity by 1,2-diacylglycerol may be an important mechanism for controlling the acylation of lysophosphatidylcholine.

Placental alkaline phosphatase, insulin, and adenine nucleotides or adenosine synergistically promote long-term survival of serum-starved mouse embryo and human fetus fibroblasts.

Earlier we showed that in serum-starved fibroblasts placental alkaline phosphatase (PALP) can exert growth factor-like effects. Here we report that in mouse embryo (NIH 3T3) and human fetus (HTB-157) fibroblasts, PALP (200 nM) alone provided full protection against serum starvation-induced cell death for 5 days. After 12 days, substantial effects of PALP on cell survival required the copresence of insulin (500 nM) and ATP or adenosine (100 microM). In serum-starved NIH 3T3 cells, PALP induced activating phosphorylation of p42/p44 mitogen-activated protein (MAP) kinases; insulin, but not ATP, had small additional effects. PALP also stimulated the expression of various cyclins; ATP both prolonged and enhanced PALP-induced expression of cyclins A and E. Finally, ATP/adenosine enhanced activation of Akt kinase by insulin. The results suggest that PALP may be a regulator of growth and remodeling of fetal tissues during the second and third trimester of pregnancy when it is expressed.

Expression of human choline kinase in NIH 3T3 fibroblasts increases the mitogenic potential of insulin and insulin-like growth factor I.

In mammalian cells, growth factors, oncogenes, and carcinogens stimulate phosphocholine (PCho) synthesis by choline kinase (CK), suggesting that PCho may regulate cell growth. To validate the role of PCho in mitogenesis, we determined the effects of insulin, insulin-like growth factor I (IGF-I), and other growth factors on DNA synthesis in NIH 3T3 fibroblast sublines highly expressing human choline kinase (CK) without increasing phosphatidylcholine synthesis. In serum-starved CK expressor cells, insulin and IGF-I stimulated DNA synthesis, p70 S6 kinase (p70 S6K) activity, phosphatidylinositol 3-kinase (PI3K) activity, and activating phosphorylation of p42/p44 mitogen-activated protein kinases (MAPK) to greater extents than in the corresponding vector control cells. Furthermore, the CK inhibitor hemicholinium-3 (HC-3) inhibited insulin- and IGF-I-induced DNA synthesis in the CK overexpressors, but not in the vector control cells. The results indicate that high cellular levels of PCho potentiate insulin- and IGF-I-induced DNA synthesis by MAPK- and p70 S6K-regulated mechanisms.

Development of ipsilateral adrenocortical carcinoma sixteen years after resection of an adrenal tumour causing Cushing's syndrome.

INTRODUCTION: At times, it may be difficult to differentiate early stage, low-grade adrenocortical carcinoma from benign adrenal adenoma. CLINICAL PICTURE: A 53-year-old lady underwent right adrenalectomy for a 4-cm adrenocortical tumour causing Cushing's syndrome. Histology revealed an adrenocortical adenoma. Sixteen years later, she presented with a 14-cm adrenal tumour, again on the right side. TREATMENT: She underwent surgical removal of the tumour. Histology confirmed adrenocortical carcinoma. OUTCOME: She died of metastatic disease 17 months later. CONCLUSIONS: This case highlights the importance of long-term, systematic follow-up of patients treated for benign adrenal adenomas, especially if the tumour size exceeds 4 cm.

Clinical, radiological and pathological features of patients with Rathke's cleft cysts: tumors that may recur.

Rathke's cleft cysts are cystic sellar and suprasellar lesions, characteristically lined by a single layer of ciliated cuboidal or columnar epithelium. In contrast, craniopharyngiomass, which are also cystic sellar and suprasellar lesions, are characteristically lined by stratified squamous epithelium with keratinization on a layer of connective tissue. The usual management recommended for Rathke's cleft cysts is simple surgical drainage with partial excision of the cyst wall. Recurrences of these cysts reportedly have been very rare. This retrospective study presents the details of 12 patients (6 females; median age 30 yr, range 21-58 yr) with Rathke's cleft cyst, referred to our department over a 15-yr period (1981-1996), an unusual feature being the recurrence of 4 (33%) of these lesions. Clinical, endocrine, radiological, surgical (10 transsphenoidal; 2 transcranial), and pathological details were recorded. Nine out of 12 patients (75%) were symptomatic; visual symptoms were the commonest, and 8 had visual field defects. The median duration of symptoms was 12 months (range 3-24 months). Three patients (25%) had panhypopituitarism, 2 of whom also had diabetes insipidus (17%). The cysts varied in size from 6 mm to 50 mm, 1 being entirely suprasellar. There were no pathognomonic clinical or radiological features to differentiate them from other pituitary lesions, although the presence of diabetes insipidus in 2 patients suggested that the lesion was not a pituitary adenoma. A definite histological diagnosis was possible in 8 patients; in 4, the diagnosis was presumptive. The median duration of follow-up was 30 months (1-168 months). Four patients (33%) showed reexpansion at 3, 6, 48, and 48 months after initial surgery, 3 of whom were symptomatic and required repeat surgery. Two of these patients were given postoperative external beam pituitary radiotherapy. Apparent recurrence of Rathke's cleft cysts after initially successful surgery in our series was higher than suggested by previous reports, and thus, long-term follow-up with pituitary imaging and neuroophthalmological assessment is essential. There are no specific characteristics of the cyst that predict recurrence. Ideal management of these cysts is unclear, but aspiration, followed by extensive excision of the cyst wall when possible, seems to be the best initial option. For recurrent symptomatic tumors, surgical resection is the treatment of choice. Considering the high recurrence rate with residual structural and functional dysfunction, the role of radiotherapy in preventing recurrence of these cysts needs careful evaluation with a larger study with a longer follow-up period.

Menstrual irregularity in women with acromegaly.

Menstrual irregularity is common in women with acromegaly, occurring in 40-84%. Although it has been attributed to gonadotropin deficiency and/or PRL excess, it has not been evaluated in detail, and its pathogenesis is not well understood. To explore the various possible pathogenic mechanisms, we have analyzed the clinical, endocrinological, and radiological characteristics of 47 women with active acromegaly within the reproductive age range (15-41 yr) with respect to their menstrual pattern; 9 patients (19%) had normal cycles, 7 (15%) had oligomenorrhea, 29 (62%) had amenorrhea, and 2 (4%) had polymenorrhea. Compared to patients with normal cycles (n = 9), patients with menstrual irregularity (oligo/polymenorrhea or amenorrhea; n = 38) were more hirsute, had lower serum estradiol (normal: median, 76.5 pmol/L; range, 20-570; menstrual irregularity: median, 283; range, 140-431; P < 0.01), and sex hormone-binding globulin (SHBG; normal: median, 19.6 nmol/L; range, 5-52; menstrual irregularity: median, 48; range, 18-60; P < 0.01), but similar testosterone levels; in addition, patients with amenorrhea had higher serum GH (normal: median, 100 mU/L; range, 8.8-400; amenorrhea: median, 30; range, 10.7-120; P < 0.05). PRL levels in excess of 1000 mU/L were found in 16 of the 38 patients with menstrual irregularity compared to only 1 of the 9 patients with normal cycles. Patients with menstrual irregularity had a greater impairment of anterior pituitary function than patients with normal cycles. Acromegalic patients who were defined as estrogen sufficient (estradiol, >140 pmol/L) had clinical baseline endocrine profiles and LH responses to GnRH stimulation similar to those in patients with polycystic ovarian disease. There was a positive correlation between GH levels and tumor size (r = 0.35; P < 0.05) and an independent inverse correlation between GH and SHBG levels (r = -0.6; P < 0.01), which persisted even in patients who were estrogen sufficient, but there was no correlation between GH and estradiol levels; in addition, there was a negative correlation between estradiol levels and tumor size (r = -0.42; P < 0.05). Thirty-five of the patients with menstrual irregularity had meso- or macroadenomas and 3 had microadenoma, whereas 6 of the 9 patients with normal cycles had microadenomas. In conclusion, menstrual irregularity is common in women with acromegaly (81% of our patients). Amenorrheic patients have higher GH levels, are mainly estrogen deficient, and tend to have larger tumors than patients with normal cycles. However, the independent negative correlation between GH and SHBG levels suggests that GH may, directly or indirectly, lead to a fall in SHBG, possibly determined by the hyperinsulinemia known to occur in acromegaly. Low SHBG levels may contribute to the menstrual disturbance seen in acromegaly in addition to any gonadotropin deficiency or hyperprolactinemia and may account for hirsutism in the presence of normal testosterone levels.

The role of cytotoxic chemotherapy in the management of aggressive and malignant pituitary tumors.

Pituitary tumors are mostly benign lesions, although 5-35% are locally invasive. A small number exhibit a more aggressive course, infiltrating dura, bone and sinuses, and are designated highly aggressive. However, the presence of metastases separate from the pituitary in the central nervous system or at a distance is necessary to designate pituitary tumors as carcinomas, i.e. truly malignant. When conventional therapeutic modalities fail, systemic chemotherapy remains the last option. We report seven such patients, three with highly aggressive and four with malignant pituitary tumors (n=4) four women; median age, 32 yr; range, 23-48 yr), who received one or more courses of chemotherapy with lomustine and 5-fluorouracil (median, two courses; range, one to six courses). Three patients with systemic metastatic disease had a shorter survival (median, 5 months; range, 1-14 months) than the one patient with central nervous system metastases alone (10 yr). A patient with an aggressive nonmetastatic prolactinoma who initially responded to chemotherapy died from another nondisease-associated cause. Two patients, one with an aggressive and one with a metastatic tumor, achieved symptomatic improvement with a median duration of 6 months. A hormonal reduction greater than 50% was observed in two of seven patients; only one patient who had an aggressive tumor obtained an objective tumor response. The median survival from the time of initiation of chemotherapy in patients with malignant tumors ranged from 3-65 months. Two patients with malignant tumors developed disease progression while receiving chemotherapy; no patient with extracranial metastases showed a response. Treatment was well tolerated, with minimal individual side-effects. Three patients with no response to initial treatment received different chemotherapeutic regimens with no additional response. All patients with metastatic malignant tumors eventually died. Treatment with cytotoxic chemotherapy is noncurative, and current experience is limited. Until another more specific form of treatment is available, chemotherapy may still be of some value in patients with highly aggressive and malignant pituitary tumors, at least in achieving a temporary remission or delay in progression. The combination of lomustine/5-fluorouracil proved easy to administer with minimal toxicity, although the response rate was only 14%. Until a more specific treatment is found, an optimal chemotherapeutic regimen needs to be established.

Comparison of somatostatin analog and meta-iodobenzylguanidine radionuclides in the diagnosis and localization of advanced neuroendocrine tumors.

A comparison has been made of [(123)I]meta-iodobenzylguanidine ([(123)I]MIBG) and [(111)In]pentetreotide scintigraphy in 54 patients with a variety of neuroendocrine tumors of whom 46 patients had metastatic disease. [(111)In]Pentetreotide scintigraphy was more sensitive in detecting metastatic lesions, as demonstrated on computed tomography and/or magnetic resonance scanning, than [(123)I]MIBG: 67% vs. 50% for carcinoid tumors (n = 24), 91% vs. 9% for pancreatic islet cell tumors (n = 12), 100% vs. 60% for medullary thyroid carcinomas (n = 5), and 75% vs. 100% for pheochromocytomas/paragangliomas (n = 4). In only 2 patients were lesions seen with [(123)I]MIBG scanning that were not apparent with [(111)In]pentetreotide. With the exception of pancreatic islet cell tumors, both radionuclides exhibited a similar sensitivity in detecting hepatic metastases, whereas in three patients the two radionuclides exerted a complementary role as different deposits exhibited uptake to only 1 or the other radionuclide. Hepatic metastases were the most important clinical predictor of a positive scan for both radionuclides. Neither elevated 5-hydroxyindoleacetic acid levels nor any other hormonal marker was predictive of a positive scan. In 8 patients with clinical and/or hormonal evidence of a neuroendocrine tumor but negative conventional radiology, [(111)In]pentetreotide scintigraphy was more sensitive than [(123)I]MIBG (37.5% vs. 12.5%) in detecting lesions. In conclusion, scintigraphy with [(111)In]pentetreotide detects more metastatic lesions than [(123)I]MIBG in patients with carcinoid and pancreatic islet cell tumors and medullary thyroid carcinomas; [(123)I]MIBG scintigraphy may be more sensitive for sympathoadrenomedullary tumors. The radionuclides may exert a complementary role in the detection and treatment of neuroendocrine tumors in occasional patients, as areas of different pattern of uptake were identified within the same patient. These data have implications not only for staging such tumors, but also for identifying patients who might benefit from treatment using either [(131)I]MIBG or radioactive somatostatin analogs.

Phosphocholine and sphingosine-1-phosphate synergistically stimulate DNA synthesis by a MAP kinase-dependent mechanism.

We have previously shown that in NIH 3T3 fibroblasts phosphocholine (PCho) potentiates sphingosine-1-phosphate (S1P)-induced mitogenesis. Here we report that PCho and S1P also synergistically stimulate DNA synthesis in mouse Swiss 3T3 fibroblasts and in mouse JB6 epidermal cells. The combined actions of PCho and S1P on DNA synthesis were associated with synergistic activation of the p42/p44 mitogen-activated protein (MAP) kinases. Ethanolamine (50-100 microM) further enhanced the synergistic effects of PCho and SIP on DNA synthesis but not on MAP kinase activity. The results indicate that the synergistic mitogenic effects of PCho and S1P (i) are not restricted to NIH 3T3 fibroblasts, (ii) are predominantly mediated by the MAP kinase-dependent signal transduction pathway, and (iii) are enhanced by ethanolamine via a MAP kinase-independent mechanism.

alpha(1)-antitrypsin can increase insulin-induced mitogenesis in various fibroblast and epithelial cell lines.

alpha(1)-Antitrypsin (AT), the archetypal member of the superfamily of serine proteinase inhibitors, inhibits leukocyte elastase activity and thereby can prevent lung damage. Here we show that in fibroblasts from human fetal lung and mouse embryo as well as in certain epithelial cells AT can also enhance the stimulatory effects of insulin on DNA synthesis and cell proliferation. Warming of AT at a moderate (41 degrees C) temperature for a longer time (21 h) or at a higher (65 degrees C) temperature for 30 min before treatment increased its stimulatory effects on both DNA synthesis and activating phosphorylation of p42/p44 mitogen-activated protein kinases. The results suggest that AT may promote regeneration of damaged tissues under pathophysiological conditions which are associated with fever.

Growth factor-like effects of placental alkaline phosphatase in human fetus and mouse embryo fibroblasts.

Human placental alkaline phosphatase (PALP) is synthesized in the placenta during pregnancy and is also expressed in many cancer patients; however, its physiological role is unknown. Here we show that in human fetus fibroblasts as well as normal and H-ras-transformed mouse embryo fibroblasts PALP stimulates DNA synthesis and cell proliferation in synergism with insulin, zinc and calcium. The mitogenic effects of PALP are associated with the activation of c-Raf-1, p42/p44 mitogen-activated protein kinases, p70 S6 kinase, Akt/PKB kinase and phosphatidylinositol 3'-kinase. The results suggest that in vivo PALP may promote fetus development as well as the growth of cancer cells which express oncogenic Ras.