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PubMed2002

Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities.

Defects in insulin action and insulin secretion are both present in type 2 diabetes, and both are believed to be genetically predetermined. In the absence of a defect in beta-cell function, individuals can compensate indefinitely for insulin resistance with appropriate hyperinsulinemia, as observed even in obese populations such as the Pima Indians of Arizona. However, loss of beta-cell function leads eventually to the postprandial and fasting hyperglycemia that characterizes type 2 diabetes. This progression occurs despite initially effective antidiabetic therapies, a situation clearly demonstrated by the United Kingdom Prospective Diabetes Study (UKPDS). External factors (access to high-calorie foods, lack of exercise, weight gain), the increased insulin requirements imposed by insulin resistance, and toxicities from hyperglycemia and elevated free fatty acids may all contribute to beta-cell deterioration. Free fatty acids, resistin, and tumor necrosis factor (TNF)-alpha potentially worsen the insulin resistance. beta-Cell dysfunction resulting from glucose toxicity and lipotoxicity is potentially reversible with restoration of metabolic control. Therefore, attention to these toxicities may delay the deterioration of beta-cell function and suggest new approaches to the management of type 2 diabetes.

Adipose Tissue↗
PubMed1996

Molecular basis of T cell dysfunction in cancer is influenced by the paracrine secretion of tumor-derived IL-2.

Previously we reported that T cells from mice bearing parental tumors have a variety of functional and biochemical defects when compared with T cells from mice bearing IL-2-secreting tumors. The biochemical defects included reduced levels of several cytoplasmic proteins such as p56lck, p59fyn, and zeta, all of which are known to be critical for signal transduction through the TCR. Based upon these results, we determined the consequences of these alterations on downstream signaling events. First, we showed that T cells of parental tumor-bearing mice have a reduction of total in vitro kinase activity associated with the TCR/CD3 compared with T cells from mice with IL-2-secreting tumors. Second, we observed that following activation, only T cells from IL-2-secreting tumor-bearing mice had completely phosphorylated CD3-associated zeta-chains and recruited ZAP-70 to cell surface-associated TCR. In contrast, T cells from mice with parental tumors contained incompletely phosphorylated CD3-associated zeta-chains with little or no TCR-associated ZAP-70. Third, the recruitment of ZAP-70 to the TCR/CD3 complex was seen only in animals with an increase in in vitro p56lck kinase activity after T cell activation. Finally, we report that these defects in T cell signaling were associated with generalized anergy in vivo. Our findings provide a molecular basis to explain T cell suppression of mice with parental tumors and offer a hypothesis to explain the protective effect of tumor-derived IL-2.

Animals↗
PubMed1979

A variant of S49 mouse lymphoma cells with enhanced secretion of cyclic AMP.

A novel variant of S49 mouse lymphoma cells is described which is resistant to growth arrest and cytolysis by dibutyryl cyclic AMP but, in contrast to previously described variants, has normal cyclic AMP-dependent protein kinase. The variant is also resistant to N6-monobutyryl cAMP but is sensitive to killing by 8-bromo cAMP and cholera toxin. Extracts of the variant appear to contain wild type levels of both O2'-butyrylesterase and cyclic AMP phosphodiesterase activities. Accumulation of exogenous [3H]dibutyryl cyclic AMP is reduced in the variant suggesting a defect in either uptake or secretion of the analog or its metabolic products. Accumulation of cyclic AMP in variant cells after stimulation of adenylate cyclase with either isoproterenol or cholera toxin is also reduced compared with wild type cells, although cyclase activity of membranes prepared from the variant cells is normal. Extracellular accumulation of cyclic AMP after stimulation of variant cells with isoproterenol is greater than that found with wild type cells. It is concluded that the variant has an alteration in its cyclic AMP secretion mechanism resulting in more efficient extrusion of cyclic AMP than in wild type cells.

Animals↗
PubMed1996

Pretransplant CD4 helper function and interleukin 10 response predict risk of acute kidney graft rejection.

In a prospective study of 80 patients, we investigated the association of acute kidney graft rejection with pretransplant T helper/suppressor activity, B-cell responses, and in vitro cytokine secretion. Patients' CD4+ or CD8+ T cells were cocultured with control B cells and pokeweed mitogen for 6 days. SAC I was used for T cell- and monocyte-independent B-cell stimulation and pokeweed mitogen was used for T cell-dependent B-cell stimulation. B-cell differentiation was assessed in a reverse hemolytic plaque assay. Cytokine responses of T cells (interleukin [IL]-2, IL-10, gamma-interferon) and B cells/monocytes (IL-6, IL-8, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor) were determined in culture supernatants using ELISA. Subsets of CD4+ T cells, CD8+ T cells, and B cells were assessed by flow cytometry. None of 12 patients with pretransplant CD4 helper defects (CD4 helper activity < 10%) had acute rejection episodes, in contrast to 32 of 68 (47%) patients with normal pretransplant CD4 helper function (P = 0.001). Patients with pretransplant CD4 helper defects also had better 1-year graft function than patients without CD4 helper defects (serum creatinine 1.2 +/- 0.1 mg/dl and 1.7 +/- 0.1 mg/dl, respectively, P < 0.05). Pretransplant IL-10 responses were significantly associated with the occurrence of acute rejection episodes (P = 0.001) and impaired 1-year graft function (P < 0.001). All 14 patients with low pretransplant IL-10 responses (< 100 pg/ml) had 1-year serum creatinine values of < 1.5 mg/dl. Pretransplant B-cell defects and B cell/monocyte-derived cytokine secretion were not related to the incidence of graft rejection or infectious complications. Pretransplant CD8 suppressor-effector (CD11b+), cell counts were significantly associated with the occurrence of infections (P < 0.05). These results show that pretransplant CD4 helper defects and low IL-10 responses predict a low risk of graft rejection, whereas Th1 (IL-2, gamma-interferon) and B-cell/monocyte responses are not of predictive value.

Acute Disease↗
PubMed1992

Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.

Abetalipoproteinemia is a human genetic disease that is characterized by a defect in the assembly or secretion of plasma very low density lipoproteins and chylomicrons. The microsomal triglyceride transfer protein (MTP), which is located in the lumen of microsomes isolated from the liver and intestine, has been proposed to function in lipoprotein assembly. MTP activity and the 88-kilodalton component of MTP were present in intestinal biopsy samples from eight control individuals but were absent in four abetalipoproteinemic subjects. This finding suggests that a defect in MTP is the basis for abetalipoproteinemia and that MTP is indeed required for lipoprotein assembly.

Abetalipoproteinemia↗
PubMed1994

Hyper IgM syndrome associated with defective CD40-mediated B cell activation.

Recent studies show that most patients with X-linked hyper IgM syndrome have defects in the gene for CD40 ligand. We evaluated 17 unrelated males suspected of having X-linked hyper IgM syndrome. Activated T cells from 13 of the 17 patients failed to bind a soluble CD40 construct. In these patients, the sequence of CD40 ligand demonstrated mutations. By contrast, T cells from the remaining four patients exhibited normal binding to the CD40 construct. Sequencing of the cDNA for CD40 ligand from these patients did not show mutations. The possibility that hyper IgM syndrome in these four patients was due to abnormalities in the B cell response to CD40-mediated signals was examined. Peripheral blood lymphocytes were stimulated with anti-CD40 alone, IL4 alone or anti-CD40 plus IL4. In comparison with B cells from controls or patients with hyper IgM syndrome and mutant CD40 ligand, B cells from the patients with hyper IgM syndrome and normal CD40 ligand were defective in their ability to secrete IgE (P < 0.02) or express activation markers, CD25 and CD23 (P < 0.02) in response to stimulation with anti-CD40. The failure of these B cells to respond to CD40-mediated activation could not be attributed to a generalized deficiency in B cell activation because IL4 induced normal up-regulation of CD23 and CD25 expression. These findings indicate that hyper IgM syndrome may result from defects in expression of CD40 ligand by activated T cells or defects in CD40-mediated signal transduction in B cells.

Antigens, CD↗
PubMed1988

Three predominant proteins secreted by the human prostate gland.

Analyses of the proteins of azoospermic ejaculates from subjects with defective seminal vesicles demonstrated that three prostatic-secreted proteins were predominant. Prostatic acid phosphatase (PAP), prostate-specific antigen (PSA; or gamma-seminoprotein), and beta-microseminoprotein (beta-MSP; or beta-inhibin), were identified as the three predominant proteins secreted by the normal human prostate gland. Immunohistochemical localization of these proteins, in the epithelium of normal prostatic acini and ducts, with the avidin-biotin complex procedure demonstrated that each PAP-immunoreactive cell was invariably immunoreactive both with PSA-and beta-MSP-monospecific antisera as well.

Acid Phosphatase↗
PubMed2003

Cytokine immuno-gene therapy for treatment of brain tumors.

The prognosis for patients with an intracerebral (i.c.) neoplasm is poor. Conventional treatments such as surgery, radiation therapy and chemotherapy have done little to affect long-term survival, and new methods of treatment are urgently needed. In this report approaches involving cytokine gene therapy in treatment of malignant brain tumors are reviewed and contrasted to a strategy developed in this laboratory involving the use of allogeneic cells genetically modified to secrete cytokines. In our studies, mice with an i.c. glioma, melanoma or breast carcinoma treated solely by intratumoral injections with allogeneic cells genetically modified to secrete interleukin-2 (IL-2) were found to survive significantly longer than mice in various control groups. The anti-tumor response was mediated predominantly by T-cell subsets (CD8+ and NK/LAK cells). The injections resulted in the killing of only the neoplastic cells; non-neoplastic cells were unaffected. Experiments involving treatment of animals with i.c. tumor using subcutaneous injections of cytokine-secreting allogeneic cells in the presence of tumor antigens demonstrated no effect in prolonging survival in spite of the development of a vigorous systemic anti-tumor immune response. Of special interest, mice injected intracerebrally with the cytokine-secreting allogeneic cells alone exhibited no neurologic defect and there were no adverse effects on survival. The injection of cytokine-secreting allogeneic cells into the microenvironment of an i.c. tumor is hypothesized to induce an anti-tumor immune response capable of prolonging survival. This pre-clinical animal data directly translates into clinical treatments for patients with a malignant i.c. tumor.

Animals↗
PubMed1997

Genes encoding farnesyl cysteine carboxyl methyltransferase in Schizosaccharomyces pombe and Xenopus laevis.

The mam4 mutation of Schizosaccharomyces pombe causes mating deficiency in h- cells but not in h+ cells. h- cells defective in mam4 do not secrete active mating pheromone M-factor. We cloned mam4 by complementation. The mam4 gene encodes a protein of 236 amino acids, with several potential membrane-spanning domains, which is 44% identical with farnesyl cysteine carboxyl methyltransferase encoded by STE14 and required for the modification of a-factor in Saccharomyces cerevisiae. Analysis of membrane fractions revealed that mam4 is responsible for the methyltransferase activity in S. pombe. Cells defective in mam4 produced farnesylated but unmethylated cysteine and small peptides but no intact M-factor. These observations strongly suggest that the mam4 gene product is farnesyl cysteine carboxyl methyltransferase that modifies M-factor. Furthermore, transcomplementation of S. pombe mam4 allowed us to isolate an apparent homolog of mam4 from Xenopus laevis (Xmam4). In addition to its sequence similarity to S. pombe mam4, the product of Xmam4 was shown to have a farnesyl cysteine carboxyl methyltransferase activity in S. pombe cells. The isolation of a vertebrate gene encoding farnesyl cysteine carboxyl methyltransferase opens the way to in-depth studies of the role of methylation in a large body of proteins, including Ras superfamily proteins.

Amino Acid Sequence↗
PubMed1996

[The role of Ca2+ in the pathogenesis of human pituitary GH-secreting adenomas].

Effects of Ca2+ channel blockers (nicardipin and nifedipin) and Ca2+ ionophore A23187 on the basal secretion and on the secretion stimulated by GRH or inhibited by SMS, a SRIF analogne of GH were investigated in monolayer cell cultures of 23 cases of human pituitary GH-secreting adenomas. The roles of GRH and SMS in 45Ca influx were investigated also. The GH secretion of most GH adenomas was depended on Ca2+, but the abnormality in different link of GH secretion mediated by Ca2+ was observed. The defects of receptor and post-receptor including Ca2+ channel and Ca(2+)-GH secretion couple regulated by GRH and SRIF were found in 66.7% and 55.6% of GH adenomas respectively. These abnormalities may contribute to GH hypersecretion in GH adenomas.

Adenoma↗
PubMed2000

Antiangiogenic gene therapy for cancer via systemic administration of adenoviral vectors expressing secretable endostatin.

A growing number of antiangiogenesis strategies have been investigated for the treatment of cancer and other angiogenesis-dependent diseases. One of the most promising strategies is to systemically administer one or more antiangiogenic proteins frequently enough to achieve a sufficient long-term steady state level of the protein(s) to achieve the maximum beneficial effect. However, the utility of this strategy is limited because of many technical difficulties, including obtaining both the quantity and quality of the protein(s) necessary for optimal therapeutic benefit. To overcome these difficulties, we hypothesized that a single administration of a replication-defective adenoviral vector expressing a secretable antiangiogenic protein could achieve an optimal long-term systemic concentration. We constructed a recombinant adenoviral vector, Av3mEndo, which encodes a secretable form of murine endostatin. We demonstrated secretion of endostatin from several cell lines transduced with Av3mEndo. Partially purified endostatin secreted from Av3mEndo-transduced mammalian cells was shown to potently inhibit endothelial cell migration in vitro. A single intravenous administration of Av3mEndo in mice was shown to result in (1) prolonged and elevated levels of circulating endostatin, (2) partial inhibition of VEGF-induced angiogenesis in a VEGF implant angiogenesis model, and (3) prolonged survival and in 25% of mice the complete prevention of tumor growth in a prophylactic human colon/liver metastasis xenograft murine model. These results support our contention that adenoviral vector-mediated expression of an antiangiogenic protein(s) represents an attractive therapeutic approach to cancer and other angiogenesis-dependent diseases.

Adenoviridae↗
PubMed2002

Brazilian individuals with impaired glucose tolerance are characterized by impaired insulin secretion.

BACKGROUND: To better understand the pathogenesis of type 2 diabetes mellitus, insulin secretion and insulin sensitivity (IS) were evaluated in white Brazilians with impaired glucose tolerance (IGT), using the oral glucose tolerance test (OGTT) and the hyperglycemic clamp technique. METHODS: Twenty-five IGT subjects were individually matched with normal glucose-tolerant (NGT) subjects for demographic characteristics. At first, they were submitted to the OGTT and plasma glucose and insulin were measured. Of the 25 pairs, 20 could participate in the hyperglycemic clamp procedures, at a second visit. All participants had their plasma glucose levels equally increased to 180 mg/dl; this was maintained for three hours by variable glucose infusion. During the procedure, plasma glucose and insulin were measured at established intervals. RESULTS: In the postabsorptive state, the IGT subjects presented higher levels of plasma glucose, blood HbA1, and serum triglycerides, but similar plasma insulin levels. After the oral glucose load, early and total insulin release, in relation to glucose levels, were respectively, 43 and 67% lower in the IGT individuals. The index of whole-body IS was increased in the IGT individuals (4.36 +/- 1.71 vs 3.61 +/- 1.28 mg(-1). micro U(-1).100.ml2; p<0.05). By the hyperglycemic clamp technique first- (82 +/- 26 vs 215 +/- 88 micro U/ml; p<0.001) and second- (36 +/- 19 vs 73 +/- 44 micro U/ml; p<0.05) phases of insulin secretion was decreased in the IGT individuals, especially the first one. However, the groups did not differ in relation to the IS: IGT=13.52 +/- 7.27 and NGT=9.96 +/- 6.70 mg.ml/kg. micro U.min(-1); p > 0.05. Functional relationship of IS (y) on first-phase insulin release (x) showed a smaller (p<0.05) regression coefficient for the IGT group. CONCLUSION: Brazilians with IGT well-matched with NGT ones were characterized by impaired first- and second-phase insulin secretion (mainly the former), while defects in IS were not evident.

Adult↗
PubMed1986

Gestational hyperglycaemia and insulin release by the fetal rat pancreas in vitro: effect of amino acids and glyceraldehyde.

Unrestrained pregnant rats were infused with glucose during the last week of pregnancy to produce slight or high gestational hyperglycaemia. Control rats were infused with distilled water. Insulin secretion of the fetuses at term was studied in vitro using a perifusion system. Compared with controls, perifused pancreases of slightly hyperglycaemic fetuses showed a similar pattern of insulin secretion in response to 10 mmol/l leucine. Arginine-induced insulin secretion at 20 mmol/l was higher than in controls. In both groups, 10 mmol/l alpha-ketoisocaproate had a poor stimulatory effect on insulin release, and 5 mmol/l D-glyceraldehyde was ineffective in eliciting insulin secretion. In highly hyperglycaemic fetuses all the secretagogues, with the exception of arginine, which induced a sustained monophasic insulin secretory response, had no effect on insulin release. These data show that long-term exposure of fetal B cells to high plasma glucose levels in utero suppresses or alters further insulin secretory response not only to glucose but also to other nutrient secretagogues. The partially spared insulin secretory response to arginine suggests that the defect may concern stimulus-secretion coupling rather than insulin releasing machinery.

Amino Acids↗
PubMed1981

Selected aspects of the pathophysiology of metabolic acidosis in diabetes mellitus.

Metabolic acidosis with a normal anion gap results from either bicarbonate loss or a urine acidification defect. The bicarbonate loss may be via the gastrointestinal tract or the urine, or may be indirect due to excretion of the sodium and potassium as opposed to the ammonium salts of ketone body anions. Defects in urine acidification in the diabetic have several etiologies: first, hydrogen ion secretion may be decreased because of an intrinsic defect in the hydrogen ion pump (i.e., diseases of the renal medulla); second, there may be a failure to augment hydrogen ion secretion by a favorable electrical gradient (e.g., reduced mineralocorticoids); and third, there may be a failure to generate a favorable chemical gradient to augment hydrogen ion secretion (e.g., reduced urine ammonia). Reduced levels of aldosterone associated with hyporeninemia has been termed type IV RTA, and these patients have specific therapeutic needs.

Anions↗
PubMed2002

Effect of withdrawal of somatostatin plus GH-releasing hormone as a stimulus of GH secretion in obesity.

OBJECTIVES: Somatostatin (SS) may not merely be inhibitory to GH secretion but, under appropriate temporal conditions, may act in a paradoxically positive manner to sensitize somatotroph responsiveness to GH-releasing hormone (GHRH). SS infusion withdrawal (SSIW) produces a rebound GH rise in humans and increases GHRH-induced GH release. Theoretically, SSIW leaves the somatotroph cell in a situation of low endogenous SS. In obesity, there is markedly decreased GH secretion. In both children and adults, the greater the body mass index (BMI), the lower the GH response to provocative stimuli. It has been postulated that increased hypothalamic somatostatin secretion is the main mechanism responsible for the blunted GH secretion of obesity. There are no data evaluating GH responsiveness to SSIW plus GHRH in obese adults. The aim of the present study was to evaluate the GH response to SSIW plus GHRH in a group of control subjects and a group of obese patients. PATIENTS AND MEASUREMENTS: Seven obese patients (six female, one male) with a BMI of 36.1 +/- 7.7 kg/m2 were studied. As a control group, seven normal subjects (six female, one male) with a BMI of 20.3 +/- 0.9 kg/m2 were also studied. Two tests were performed. On one day, somatostatin (SS) i.v. infusion (500 microg from 0-90 min) was performed followed by a placebo i.v. bolus 90 min after SS withdrawal (SSIW). On another day, SS i.v. infusion (500 microg from 0-90 min) was performed followed by a GHRH (100 microg) i.v. bolus 90 min after SS withdrawal. A second group of seven obese patients (six female, one male) with a BMI of 32.2 +/- 2.3 kg/m2 were studied. As a second control group, seven normal healthy subjects (six female, one male) with a BMI of 20.1 +/- 0.6 kg/m2 were also studied. On one day, saline infusion was performed followed by a placebo i.v. bolus at 90 min. On another day, saline infusion was performed followed by a GHRH (100 microg) i.v. bolus at 90 min. Blood samples were taken at appropriate intervals for determination of GH. Serum GH was measured by chemiluminescent immunometric assay. Statistical analysis was performed by Wilcoxon and Mann-Whitney tests. RESULTS: GHRH-induced GH secretion in normal subjects showed a mean peak of 15.8 +/- 2.1 microg/l. Normal control subjects had a mean peak of 3.1 +/- 1.5 microg/l after SSIW-induced GH secretion. When GHRH was administered after SSIW there was an increased GH secretion with a mean peak of 23.3 +/- 4.4 microg/l, significantly greater than the response after SSIW alone (P < 0.05) and GHRH alone (P < 0.05). GHRH-induced GH secretion in obese patients was decreased with a mean peak of 3.9 +/- 1.5 microg/l. In obese patients, GH secretion after SSIW was markedly decreased with a mean peak of 1.0 +/- 0.4 microg/l. When GHRH was administered after SSIW, an increase in GH secretion was observed with a mean peak of 4.3 +/- 0.9 microg/l, significantly greater than SSIW alone (P < 0.05) but not GHRH alone (P = NS), and significantly less than in normal subjects (P < 0.05). CONCLUSIONS: This study demonstrates a significantly blunted peak GH response to somatostatin infusion withdrawal plus GHRH in obese patients compared to normal subjects. In this theoretical situation of decreased somatostatinergic tone, there is persistence of GH hyposecretion in obesity, suggesting the existence of multiple defects responsible for decreased GH secretion in obesity. We also found that in obese patients, in contrast to normal subjects, SSIW did not increase GHRH-induced GH secretion.

Adult↗
PubMed1997

Signal transduction in pancreatic beta-cells: regulation of insulin secretion by information flow in the phospholipase C/protein kinase C pathway.

The physiologic regulation of glucose-induced insulin secretion is dependent upon the activation of information flow in the phospholipase C (PLC)/protein kinase C (PKC) signal transduction system. In both rat and human pancreatic beta-cells, glucose has several time-dependent effects on secretory responsiveness including the regulation of biphasic insulin secretion, time-dependent potentiation and time-dependent suppression. PLC/PKC activation has been implicated in all three response patterns. Islets of Langerhans contain the three major PLC isozyme classes (beta1, gamma1 and delta1) and the available evidence suggests that one class is activated by fuel secretagogues and another by neurohumoral agonists. The expression and activation of PLC is labile. When rat islet are cultured for short periods, the content and activation of PLC in response to glucose decreases and this biochemical defect in signal transduction is paralleled by significant reductions in glucose-induced insulin secretion. Similar defects are observed when human islets are cultured as well. Mouse islet responses to glucose stimulation differ in several major and dramatic ways from rat and human islet responses. When stimulated by 15mM glucose, mouse islets fail to develop a rising second phase secretory response, they fail to exhibit either time-dependent potentiation or time-dependent suppression to the hexose. Biphasic insulin secretion can be evoked and time-dependent potentiation can be induced in mouse islets by carbachol, an agonist that activates an isozyme of PLC distinct from that activated by glucose. These divergent response patterns are attributable to the underexpression in mouse islets, when compared to rat islets, of a fuel-sensitive PLC isozyme. When taken in their entirety, the experimental evidence suggests that the activation of PLC is an essential component in the physiologic regulation of insulin secretion and that disordered activation of the enzyme culminates in disordered insulin release.

Animals↗
PubMed1995

Genetics of a-agglutunin function in Saccharomyces cerevisiae.

The Saccharomyces cerevisiae cell adhesion protein a-agglutinin is composed of an anchorage subunit (Aga1p) and an adhesion subunit (Aga2p). Although functional a-agglutinin is expressed only by a cells, previous results indicated that AGA1 RNA is expressed in both a and alpha cells after pheromone induction. Expression of the Aga2p adhesion subunit in alpha cells allowed a-agglutinability, indicating that alpha cells express the a-agglutinin anchorage subunit, although no role for Aga1p in alpha cells has been identified. Most of the a-specific agglutination-defective mutants isolated previously were defective in AGA1; a single mutant (La199) was a candidate for an aga2 mutant. Expression of AGA2 under PGK control allowed secretion of active Aga2p from control strains but did not complement the La199 agglutination defect or allow secretion of Aga2p from La199, suggesting that the La199 mutation might identify a new gene required for a-agglutinin function. However, the La199 agglutination defect showed tight linkage to aga2::URA3 and did not complement aga2::URA3 in a/a diploids. The aga2 gene cloned from La199 was nonfunctional and contained an ochre mutation. The inability of pPGK-AGA2 to express functional Aga2p in La199 was shown to result from an additional mutation(s) that reduces expression of plasmid-borne genes. AGA2 was mapped to the left arm of chromosome VII approximately 28 cM from the centromere.

Base Sequence↗
PubMed1997

Leptin: a potent inhibitor of insulin secretion.

The hormone leptin is expressed and secreted by the adipose tissue and impacts on the central nervous system. Leptin is involved in the regulation of energy balance, satiety, and body composition. The lack of active leptin results in obesity, high food intake, hyperglycemia, and hyperinsulinemia. We present data supporting effects of leptin on the endocrine pancreas. We found the leptin receptor to be expressed in insulin- and glucagon-secretin cells derived from mouse, hamster, and rat pancreas. In the isolated perfused rat pancreas leptin is a potent inhibitor of basal and glucose-induced insulin secretion, especially during the first phase of the insulin response. At isolated mouse islets and insulin-secreting INS-1 cells leptin reduced promptly and persistently the intracellular Ca2+ levels. Cytoplasmic Ca2+ oscillation amplitude was decreased and the oscillation frequency increased. These findings suggest functional active receptors for leptin on insulin-secreting B-cells. Therefore, leptin is a metabolic hormone and not only a signal to the brain indicating filled fat stores. Our data suggest that leptin is also a signal back to the endocrine pancreas that no more insulin is required to replenish fat stores. Thus, an "adipo-insular axis" operating with two arms exists: insulin and glucagon are signals to the adipocyte. This releases leptin, which could be the mediator of the respective feedback to the pancreas. A defective leptin suppression of insulin secretion could contribute to hyperinsulinemia and disturbances of glucose metabolism.

Animals↗