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Biomedical subjects

F Giorgino

Publications and source records attributed to F Giorgino.

At least 19 recordsLinked to original sources
PubMed2005

A six month mitotane course induced sustained correction of hypercortisolism in a young woman with PPNAD and Carney complex.

A low-dose mitotane (MT) regimen was evaluated as a pharmacological approach for correcting the severe hypercortisolism in a young woman affected by Carney complex (CNC) and primary pigmented nodular adrenocortical disease (PPNAD). In the first 12 week period, the MT daily dose was progressively increased from 0.5 to 4.0 g/day. This dosage was maintained for an additional 16 weeks (cumulative dose 602 g, plasma MT maximum level 12 microg/ml), and then stopped because of sustained signs of hypoadrenalism requiring prednisone replacement. Complete regression of seborrhea, acne, and plethora was observed after 8 weeks of treatment (cumulative dose 95 g). Regular menses returned after 13 weeks (cumulative dose 197 g, plasma MT 8 microg/ml). Profound decrease of both serum cortisol (from 615 to 220 nmol/l) and urinary free cortisol (UFC) values (from 1498 to 477 nmol/day) was noted after 16 weeks of treatment (cumulative dose 314 g, plasma MT 8 microg/ml). MT treatment was associated with mild gastric discomfort and reversible increase of cholesterol plasma levels. Low serum cortisol and UFC were still observed 41 weeks after MT was discontinued (plasma MT 0.2 microg/ml). Our report demonstrates that low dose MT treatment may be a safe and effective modality for a sustained correction of hypercortisolism by PPNAD in subjects with CNC waiting for surgery.

Adrenal Cortex Diseases↗
PubMed2005

Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies.

Adipose tissue is now recognized to have a multitude of functions that are of importance in the regulation of energy balance and substrate metabolism. Different hormones, in particular insulin and catecholamines, govern the storage and utilization of energy in the triglyceride depots. In addition, adipocytes produce several different substances with endocrine or paracrine functions, which regulate the overall energetic homeostasis. With excess energy storage, obesity develops, leading to increased risk for type 2 diabetes and cardiovascular disease. The distribution of body fat appears to be even more important than the total amount of fat. Abdominal and, in particular, visceral adiposity is strongly linked to insulin resistance, type 2 diabetes, hypertension and dyslipidaemia, leading to increased risk of cardiovascular disease. The adverse metabolic impact of visceral fat has been attributed to distinct biological properties of adipocytes in this depot compared with other adipose tissue depots. Indeed, regional variations in the metabolic activity of fat cells have been observed. Furthermore, expression studies aiming at defining the unique biological properties of adipose tissues from distinct anatomical sites have identified depot-related differences in the protein content of fat-produced molecules. In this review we wish to summarize important results from the literature and also some recent data from our own work. The main scope is to describe the biological functions of adipose tissue, and to focus on metabolic, hormonal, and signalling differences between fat depots.

Adipocytes↗
PubMed2005

The IGF-I/IGF-I receptor pathway: Implications in the Pathophysiology of Thyroid Cancer.

The biological actions of the insulin-like growth factor(IGF)-I are mediated by its activation of the IGF-I receptor (IGF-I R), a transmembrane tyrosine kinase linked to the Akt and ras-raf-MAPK cascades. A functional IGF-I R is required for the cell to progress through the cell cycle. Most importantly, cells lacking this receptor cannot be transformed by any of a number of dominant oncogenes, a finding that proves that the presence of the IGF-I R is important for the development of a malignant phenotype. Consistent with this role, it has been well established that IGF-I can protect cells from apoptosis under a variety of circumstances. For example, IGF-I prevents apoptosis induced by overexpression of c-myc in fibroblasts, by interleukin-3 withdrawal in interleukin-3-dependent hemopoietic cells, etoposide, a topoisomerase I inhibitor, anti-cancer drugs, UV-B irradiations, and serum deprivation. While the anti-apoptotic effect of IGF-I has been clearly demonstrated, the molecular mechanisms by which IGF-I inhibits apoptosis induced by these various stimuli remain unknown. We have previously documented increased IGF-I and IGF-I receptor immunoreactivity in human thyroid carcinomas with a corresponding up-regulation of IGF-I mRNA. Immunoreactivity for IGF-I and IGF-I receptor positively correlated with tumor diameter, but not with the occurrence of lymph node metastases. Several recent studies have identified new signaling pathways emanating from the IGF-I receptor that affect cancer cell proliferation, adhesion, migration and apoptosis, which represent critical functions for cancer cell survival and metastasizing capacity. In this review, various aspects of the IGF-I/IGF-I R pathway and its relationship to thyroid cancer are discussed.

Gene Expression Regulation, Neoplastic↗
PubMed2005

Associated hormonal declines in aging: DHEAS.

DHEA and its sulfate prohormone DHEAS are the most abundant circulating adrenal steroid hormones in humans. DHEA exerts its actions on peripheral target tissues either indirectly, following its conversion to androgens, estrogens or both, or directly, as a steroid hormone interacting with either a nuclear or a membrane receptor. In humans, DHEA shows a characteristic pattern of secretion throughout life. Serum DHEA concentrations decline with advancing age and vary with gender, ethnicity, and environmental factors. Epidemiological studies show an inverse relationship between plasma DHEA(S) levels in men and age-related illnesses, including cardiovascular and metabolic diseases, immune disorders, malignancies, and neurological dysfunction. This has generated great interest on the putative role of DHEA in age-associated illnesses. Administration of DHEA to rats and mice reduces visceral fat accumulation, and improves insulin resistance in experimental models of diet-induced obesity and/or Type 2 diabetes. In addition, recent studies in vitro have shown that DHEA has the capacity to improve endothelial function by increasing nitric oxide (NO) synthesis. Replacement of DHEA in patients with adrenal insufficiency has been shown to exert beneficial effects on well-being, mood, and sexuality. By contrast, in healthy individuals, the physiological age-associated decline in circulating DHEA(S) per se does not justify DHEA supplementation, since the effects of this hormone on metabolic abnormalities, endothelial function in vivo, and cardiovascular events are contradictory. However, these results do not exclude the possibility that DHEA treatment may prove beneficial in specific subgroups of elderly subjects.

Adrenal Insufficiency↗
PubMed2004

Factors associated with progression to macroalbuminuria in microalbuminuric Type 1 diabetic patients: the EURODIAB Prospective Complications Study.

AIMS/HYPOTHESIS: Type 1 diabetic patients who develop microalbuminuria are clearly disadvantaged in terms of their risk of morbidity and mortality from renal and cardiovascular diseases. It is therefore important to identify potential factors that can predict progression to macroalbuminuria. METHODS: This is a 7-year follow-up study of 352 microalbuminuric Type 1 diabetic patients from 31 European centres. Risk factors at baseline were compared in patients who progressed to macroalbuminuria and in patients who remained microalbuminuric or reverted to normoalbuminuria. Risk factors and albumin excretion rate (AER) were measured centrally. RESULTS: Over 7.3 years, 13.9% of the microalbuminuric patients progressed to macroalbuminuria, 35.5% remained microalbuminuric and 50.6% reverted to normoalbuminuria. Independent baseline risk factors for progression to macroalbuminuria were HbA(1)c (7.9% vs 6.8%, p=0.004), AER (64.4 vs 44.9 microg/min, p=0.0001) and-after adjusting for diabetes duration, HbA(1)c and AER-body weight (72 vs 67 kg, p=0.05). Independent factors associated with regression to normoalbuminuria were diabetes duration (15 vs 18 years, p=0.004), AER (37.2 vs 44.9 microg/min, p=0.0001) and-after adjusting for diabetes duration, HbA(1)c and AER-waist-to-hip ratio (0.83 vs 0.86, p=0.05) and incidence of peripheral neuropathy at baseline (24% vs 38%, p=0.001). Blood pressure and smoking did not emerge as risk factors at baseline for the outcome of microalbuminuria. CONCLUSIONS/INTERPRETATION: A significant fraction of microalbuminuric Type 1 diabetic patients will progress to overt proteinuria. Patients with higher AER values, sub-optimal metabolic control, excess body fat and peripheral neuropathy may carry a particularly high risk of clinical nephropathy requiring aggressive therapeutic intervention.

Adult↗
PubMed2003

The ultrasound assessment of adipose tissue deposition in fetuses of "well controlled" insulin-dependent diabetic pregnancies.

OBJECTIVE: To assess differences in adipose deposition in fetuses from normal pregnancies and women with diabetes. RESEARCH DESIGN AND METHODS: The study group consisted of 15 well controlled insulin-dependent women with diabetes and 16 controls with a normal glucose. Ultrasound measurements were taken of subcuticular tissue thickness at the abdominal and suprascapular level at 31 and 37 weeks gestation. Triceps and subscapular skinfold thickness were also measured at birth. RESULTS: Gestational age at delivery and birthweights were not significantly different. At 31 weeks, fasting glucose levels were 5.0 +/- 1 mmol/l for diabetic vs. 3.3 +/- 0.3 mmol/l for controls (P < 0.01), post-prandial 5.6 +/- 0.4 vs. 5.1 +/- 0.3 mmol/l (P < 0.01). At 37 weeks, they were 4.6 +/- 0.2 mmol/l vs. 3.8 +/- 1.1 mmol/l (P < 0.01) and 6.0 +/- 0.6 mmol/l vs. 5.3 +/- 0.3 mmol/l (P < 0.01). Abdominal and suprascapular subcuticular thickness were 4.4 +/- 0.1 mm vs. 3.7 +/- 0.1 mm (P < 0.05) and 4.3 +/- 0.2 mm vs. 3.5 +/- 0.2 mm (P < 0.05) at 31; 5.6 +/- 0.2 mm vs. 4.8 +/- 0.1 mm (P < 0.05) and 5.4 +/- 0.2 mm vs. 4.4 +/- 0.1 mm (P < 0.05) at 37 weeks. At birth, triceps and suprascapular skinfolds were 4.7 +/- 0.1 mm vs. 4.1 +/- 0.1 mm (P < 0.05) and 4.7 +/- 0.2 mm vs. 3.8 +/- 0.1 mm (P < 0.01). CONCLUSION: Adipose tissue disposition is increased in fetuses of women with well-controlled diabetes. This may be a reflection of higher maternal glucose levels in these women and may explain why even well-controlled diabetic pregnancies are at risk of macrosomia.

Adipose Tissue↗
PubMed2003

Diagnostic utility of thyroglobulin detection in fine-needle aspiration of cervical cystic metastatic lymph nodes from papillary thyroid cancer with negative cytology.

Cystic changes in metastatic cervical lymph nodes (CLN) from papillary thyroid cancer (PTC) may be a diagnostic pitfall in fine-needle aspiration biopsy (FNAB) cytology. We investigated in a series of CLN metastases from thyroid cancers (TC), including cystic PTC, and from a wide spectrum of extrathyroidal malignancies, the diagnostic role for metastatic TC of the rapid detection of thyroglobulin in eluates from FNAB (FNAB-Tg) of CLN. The study was carried out in a group of 79 subjects (22/57 M/F; median age, 56 years; range, 20-86 years) with enlarged CLN and thyroid nodules (TN), examined for potential metastatic TC, and harboring a large spectrum of incidentally diagnosed extrathyroidal malignancies (n = 24, mostly represented by lymphomas, lung, and breast cancers), CLN metastases from thyroid cancers (n = 28, including 6 cystic metastatic PTC), 6 specific lymphadenitis and 21 reactive lymphadenitis mostly detected (n = 16) during follow-up of patients with previously ablated TC. Markedly high FNAB thyroglobulin (Tg) values were found in all metastatic CLN TC. Two of the six cases with cystic metastatic CLN PTC were diagnosed by FNAB-Tg but not by cytology. In conclusion, FNAB-Tg has been confirmed as an easy modality and fast procedure to diagnose CLN metastasis from TC and high FNAB-Tg values with nondiagnostic cystic cytology strongly suggest cystic metastatic PTC.

Adult↗
PubMed2002

A family history of Type 2 diabetes is associated with increased plasma levels of C-reactive protein in non-smoking healthy adult women.

AIMS: The aim of our study was to test whether a family history of Type 2 diabetes (FH) in women is associated with plasma C-reactive protein (CRP). METHODS: CRP plasma levels were measured in 162 women, aged 18-60 years; 95 had a positive family history of Type 2 diabetes in a parent or grandparent (FH+), and 67 gave no family history of this disease (FH-). Other measurements included: central fat accumulation, as evaluated by waist circumference; insulin resistance, as calculated by homeostatic model assessment (HOMAIR); systolic and diastolic blood pressure; and fasting concentrations of glucose, insulin, and lipids. RESULTS: CRP plasma levels were significantly higher in FH+ than in FH- subjects. Moreover, CRP was independently associated with age, body mass index, waist circumference, HOMAIR, and FH. CONCLUSIONS: Our study, performed in a selected population of women free from well-known risk factors for atherothrombosis, demonstrates that subjects with a family history of Type 2 diabetes have higher CRP plasma levels than age- and BMI-matched controls with no family history. Our results show that a family history of Type 2 diabetes is an independent contributor of CRP concentrations, in addition to age, total fatness, central fat accumulation, and insulin resistance.

Adolescent↗
PubMed2002

Obesity.

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Cardiovascular Diseases↗
PubMed2001

High frequency of incidental diagnosis of extrathyroidal neoplastic diseases at the fine-needle aspiration biopsy of laterocervical lymph nodes in patients with thyroid nodules.

This study was undertaken to evaluate the frequency of the incidental diagnosis of extrathyroidal lymph node diseases at ultrasound-guided fine-needle aspiration biopsy/cytology (FNAB/C) being done to check the presence of metastatic thyroid cancer in 30 subjects with thyroid nodule (TN) and enlarged cervical lymph nodes (CLN). The patients in whom cytology suggested the presence of malignancy in the TN or in the CLN underwent surgical removal for histologic diagnosis. The spectrum of diseases revealed by this survey included: (1) 10 benign diseases including 1 case of Piringer-Kuchinka lymphadenitis with benign TN; (2) 10 metastatic thyroid cancers (2 anaplastic and 8 papillary cancers); (3) 3 benign TN associated with metastatic invasion of cervical lymph nodes from lung (2 cases) and breast (1 case) cancer; (4) 1 Hodgkin's lymphoma of the cervical lymph nodes with hyperplastic TN; (5) 3 nodal lymphomas with benign thyroid nodule and 2 cases of thyroid lymphoma with nodal invasion; and (6) 1 nodal sarcoidosis with benign TN. The results of this study demonstrate that important neoplastic and hematologic diseases affecting the cervical lymph nodes may frequently be incidentally detected using ultrasonography (US) and FNAB/C in the diagnostic procedure for thyroid nodule.

Adult↗
PubMed2001

Effects of streptozocin diabetes and diabetes treatment by islet transplantation on in vivo insulin signaling in rat heart.

The insulin signaling cascade was investigated in rat myocardium in vivo in the presence of streptozocin (STZ)-induced diabetes and after diabetes treatment by islet transplantation under the kidney capsule. The levels of insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit, insulin receptor substrate (IRS)-2, and p52(Shc) were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. The amount of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2 were also elevated in diabetes, whereas no changes in IRS-1-associated PI 3-kinase were observed. Insulin-induced phosphorylation of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. In contrast with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate of Akt, was markedly reduced in diabetes. In islet-transplanted rats, the majority of the alterations in insulin-signaling proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association with PI 3-kinase was blunted. In conclusion, in the diabetic heart, 1) IRS-1, IRS-2, and p52(Shc) are differently altered, 2) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3. Islet transplantation under the kidney capsule is a potentially effective therapy to correct several diabetes-induced abnormalities of insulin signaling in cardiac muscle but does not restore the responsiveness of all signaling reactions to insulin.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Relationship between plasma sialic acid concentration and microvascular and macrovascular complications in type 1 diabetes: the EURODIAB Complications Study.

OBJECTIVE: To test the hypothesis that an increased plasma concentration of sialic acid, a marker of the acute-phase response, is related to the presence of diabetic micro- and macrovascular complications in type 1 diabetes. RESEARCH DESIGN AND METHODS: We investigated the relationship between plasma sialic acid concentration and nephropathy, retinopathy, neuropathy, and coronary heart disease (CHD) in a cross-sectional survey of 1,369 people with type 1 diabetes. Subjects were participants in the EURODIAB IDDM Complications Study, which involved 31 centers in 16 European countries. RESULTS: There was a significantly increasing trend of plasma sialic acid with severity of retinopathy (P < 0.001 in men) and with degree of urinary albumin excretion (P < 0.001 men, P < 0.01 women). Plasma sialic acid correlated with increasing plasma creatinine concentration (P < 0.009 men, P < 0.0002 women), and men with neuropathy had a higher plasma sialic acid concentration than those without (P < 0.006). There was no significant correlation between plasma sialic acid and CHD in either sex. Elevated plasma sialic acid concentrations were also associated with several risk factors for diabetic vascular disease: diabetes duration, HbA1c, plasma triglyceride and cholesterol concentrations, waist-to-hip ratio, hypertension and smoking (in men), and low physical exercise (in women). In multiple logistic regression analysis, plasma sialic acid was independently related to proliferative retinopathy and urinary albumin excretion rate in men. CONCLUSIONS: We conclude that an elevated plasma sialic concentration is strongly related to the presence of microvascular complications in type 1 diabetes, especially retinopathy and nephropathy. Further study of acute-phase response markers and mediators as indicators or predictors of diabetic microvascular complications is therefore justified.

Adult↗
PubMed2000

The sentrin-conjugating enzyme mUbc9 interacts with GLUT4 and GLUT1 glucose transporters and regulates transporter levels in skeletal muscle cells.

Glucose transport in insulin-regulated tissues is mediated by the GLUT4 and GLUT1 transporters. Using the yeast two-hybrid system, we have cloned the sentrin-conjugating enzyme mUbc9 as a protein that interacts with the GLUT4 COOH-terminal intracellular domain. The mUbc9 enzyme was found to bind directly to GLUT4 and GLUT1 through an 11-aa sequence common to the two transporters and to modify both transporters covalently by conjugation with the mUbc9 substrate, sentrin. Overexpression of mUbc9 in L6 skeletal muscle cells decreased GLUT1 transporter abundance 65%, resulting in decreased basal glucose transport. By contrast, mUbc9 overexpression increased GLUT4 abundance 8-fold, leading to enhanced transport stimulation by insulin. A dominant-negative mUbc9 mutant lacking catalytic activity had effects opposite to those of wild-type mUbc9. The regulation of GLUT4 and GLUT1 was specific, as evidenced by an absence of mUbc9 interaction with or regulation of the GLUT3 transporter isoform in L6 skeletal muscle cells. The mUbc9 sentrin-conjugating enzyme represents a novel regulator of GLUT1 and GLUT4 protein levels with potential importance as a determinant of basal and insulin-stimulated glucose uptake in normal and pathophysiological states.

3T3 Cells↗
PubMed2000

Reversal of foetal hydrops and foetal tachyarrhythmia associated with maternal diabetic coma.

Foetal hydrops is always a challenge for the clinician. We report a case of tachycardia associated with hydrops and hydramnios in a pregnancy complicated with diabetic coma at 28 weeks gestation. Normal foetal heart rate was recorded immediately after correction of maternal acidotic status and hydrops eventually disappeared. The woman was delivered at 32 weeks and the baby had an uncomplicated postnatal course. We hypothesise that maternal ketoacidosis has been the precipitating factor of tachycardia and congestive heart failure and that this case is conceptually similar to the "late death" phenomenon, reported in cases of poorly controlled maternal diabetes.

Adult↗
PubMed2000

[Fetal growth restriction and insulin-like growth factors].

The insulin-like growth factors (IGFs) and their receptors are implicated in pre- and postnatal growth and development. It is believed that the alteration in their activity may contribute to intrauterine growth restriction (IUGR). The aim of this experimental study was to relate some metabolic alterations, involving insulin-like growth factor pathway, in the placenta of pregnancies complicated by intrauterine growth restriction. Placental samples were obtained from six uncomplicated pregnancies and four pregnancies complicated by IUGR. These samples were then stained by immunohistochemical technique, using monoclonal antibodies. Our data have not shown a significant difference in the IR, the Shc isoforms and Akt levels between normal and IUGR placentas. The IUGR placentas had significantly lower levels of IRS-2 expression and higher levels of p85 transcription. IGF-I receptor binds to its ligand and activates two intracellular processes mainly a Shc-mediated pro-mitotic pathway and an anti-apoptotic pathway mediated by IRS and Akt. The diminished activity of one of the two pathways may alter the mitosis/apoptosis balance. Because of the low number of samples and the knowledge about the enzymatic pathways, we have not been able to associate our data to any biological consequence. We can only demonstrate that the enzymatic differences between IUGR and controls tend to the pro-apoptotic processes. It seems to be an other in vivo aspect in favour of the placental role in the IUGR pathogenesis.

Female↗
PubMed1999

In vivo insulin signaling in the myocardium of streptozotocin-diabetic rats: opposite effects of diabetes on insulin stimulation of glycogen synthase and c-Fos.

Diabetes induced by streptozotocin (STZ) in laboratory rats leads to impaired glucose metabolism in the heart and changes in myocardial contractile protein isoform expression and cardiac function. The purpose of this study was to investigate in vivo insulin signaling responses in the myocardium of STZ-diabetic rats. Insulin rapidly stimulated tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1 (IRS-1) and, to a lesser extent, IRS-2 in normal and diabetic myocardium. In diabetic rats, there was 2-fold higher insulin receptor content and insulin-stimulated receptor tyrosine phosphorylation in comparison with control rats. IRS-1 tyrosine phosphorylation also increased in STZ diabetes in spite of a decrease in IRS-1 content, resulting in a 4-fold higher ratio of phosphorylated to total IRS-1. This was associated with 2-fold higher IRS-1 precipitable phosphatidylinositide 3-kinase activity in diabetic animals. Insulin stimulation of glycogen synthase activity was significantly diminished in STZ diabetes, consistent with resistance to insulin in a step downstream from phosphatidylinositide 3-kinase activation. Under the same experimental conditions, there was a marked increase in insulin stimulation of myocardial c-fos messenger RNA content in diabetic animals in comparison with controls. These data demonstrate altered early steps in insulin signaling in STZ-diabetic rat myocardium. Consequent oppositely directed disturbances in growth regulatory and glucose regulatory responses to insulin may contribute to the development of myocardial functional abnormalities in this model of diabetes.

Animals↗
PubMed1999

Islet transplantation restores normal levels of insulin receptor and substrate tyrosine phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle and myocardium of streptozocin-induced diabetic rats.

Insulin-dependent diabetes in rats is characterized by abnormalities of post-binding insulin signaling reactions that are not fully corrected by exogenous insulin therapy. The aim of this study was to investigate the effects of islet transplantation on insulin signaling in skeletal muscle and myocardium of streptozocin (STZ)-induced diabetic rats. Control rats, untreated diabetic rats, and diabetic rats transplanted with syngeneic islets under the kidney capsule were studied. Compared with controls, diabetic rats were characterized by multiple insulin signaling abnormalities in skeletal muscle, which included 1) increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrates IRS-1 and IRS-2, 2) increased substrate tyrosine phosphorylation in the basal state, 3) a decreased amount of IRS-1 protein, 4) markedly elevated basal and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in anti-IRS-1 immunoprecipitates from total tissue extracts, and 5) increased PI 3-kinase activity in low-density microsomes. A similar augmentation of insulin receptor and substrate tyrosine phosphorylation in response to STZ-diabetes was also found in myocardium, although with lower magnitude than that found in skeletal muscle. In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. Islet transplantation fully corrected the diabetes-induced changes in protein tyrosine phosphorylation and PI 3-kinase activity and normalized IRS-1 and IRS-2 protein content in both skeletal muscle and myocardium. Thus, insulin delivered into the systemic circulation by pancreatic islets transplanted under the kidney capsule can adequately correct altered insulin signaling mechanisms in insulinopenic diabetes.

Animals↗