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PubMed1999

[Present status in the treatment of type 2 diabetes mellitus. Insulin-secreting agents].

The functional defect of the pancreatic beta cell represents one of the main therapeutic targets in type 2 diabetes mellitus. Among the currently available oral antidiabetic drugs, only hypoglycaemic sulfonylureas exhibit beta cell stimulating properties. However, their use has some limits, particularly those related to the risk of hypoglycaemia and the frequent secondary therapeutic failure. These drugs have largely contributed to the knowledge of the mechanisms of insulin secretion. Besides some galenic modifications of existing sulfonylureas and the development of new drugs of this family with original properties, like glimepiride, the research is essentially focused on drugs derived from the non sulfonylurea moiety of some sulfonylureas, particularly the meglitinide family, which will probably be available for the clinician in the near future. These drugs act however grossly by the same mechanism than sulfonylureas, even if their binding site on a protein coupled with the ATP sensitive K channel appears different. Among the other possible approaches suggested by the theoretical data concerning the mechanisms of insulin secretion, GLP-1 derivatives probably represent good candidates, if stable analogues are developed.

Adenosine Triphosphate↗
PubMed2002

Assessing insulin secretion by modeling in multiple-meal tests: role of potentiation.

We developed a mathematical model of the glucose control of insulin secretion capable of quantifying beta-cell function from a physiological meal test. The model includes a static control, i.e., a secretion component that is a function of plasma glucose concentration (the dose-response function), and a dynamic control, i.e., a secretion component that is proportional to the positive values of the glucose concentration derivative. Furthermore, the dose-response function is assumed to be modulated by a time-varying potentiation factor. To test the model, nine nondiabetic control subjects and nine type 2 diabetic patients received three standardized mixed meals over a period of 14-15 h. Blood samples were drawn for the measurement of glucose, insulin, and C-peptide concentration. The dose-response function, the parameter of the dynamic control, and the potentiation factor were determined by fitting the model to glucose and C-peptide concentrations. In diabetic patients, the dose-response function was shifted to the right (glucose concentration at a reference insulin secretion of 300 pmol.min(-1).m(-2) was 11.7 +/- 1.1 vs. 7.2 +/- 0.7 mmol/l; P < 0.05), and decreased in slope (53 +/- 15 vs. 148 +/- 38 pmol.min(-1).m(-2).mmol(-1).l; P < 0.05) and the parameter of the dynamic control was decreased (220 +/- 67 vs. 908 +/- 276 pmol.m(-2).mmol(-1).l; P < 0.05) compared with the nondiabetic control subjects. Furthermore, potentiation was markedly blunted and delayed: maximum potentiation was observed at the first meal in normal subjects and at the second meal (about 4 h later) in diabetic subjects; the mean time for the potentiation factor was higher (7.1 +/- 0.2 vs. 5.9 +/- 0.2 h; P < 0.01), and the size of potentiation was reduced (2.6 +/- 0.5 vs. 7.2 +/- 1.5 fold increase; P < 0.005). In conclusion, our model of insulin secretion extracts multiple indexes of beta-cell function from a physiological meal test. Use of the model in patients with type 2 diabetes retrieves known defects in insulin secretion but also uncovers new facets of beta-cell dysfunction.

Adult↗
PubMed1983

The anemia of chronic disease.

The anemia of chronic disease (ACD) is defined as a mild anemia associated with a chronic inflammatory, infectious or neoplastic illness and with a characteristic disturbance of iron metabolism. Many of the findings in ACD can be accounted for by release of a monokine called leukocyte endogenous mediator (LEM), endogenous pyrogen, or interleukin-1. This substance is released from "activated" monocytes. Bacterial endotoxins, certain lymphokines and phagocytic challenges are among the factors stimulating its biosynthesis. LEM induces fever, leukocytosis, biosynthesis. LEM induces fever, leukocytosis, and a variety of biochemical changes, including hypoferremia and alterations in plasma protein synthesis, collectively known as the "acute phase response." It is proposed that ACD results from the long-term elaboration of LEM and that release of this material is the common pathogenetic factor found in the illnesses that are associated with ACD. Some suggestions are made for testing the hypothesis. The hypoferremia associated with ACD is probably caused by defective release of iron from cells--particularly from macrophages, but also from hepatocytes and intestinal epithelium. Two possible mechanisms for this abnormality have been proposed: liberation of lactoferrin from neutrophilic leukocytes and induction of apoferritin synthesis. Neither mechanism has been established. Erythrokinetic studies in ACD have detected a modest reduction of erythrocyte survival without an adequate compensatory increase in the rate of red cell production. The reduced erythrocyte survival is probably related to an increase in phagocytic activity by activated macrophages. Impaired bone marrow response is partly related to the restricted iron supply, but there is substantial evidence for an additional defect in erythropoietin secretion. In some malignant diseases, there is evidence of an additional abnormality: impaired marrow response to a normal amount of erythropoietin. The nature of the erythropoietic defects and the relation of LEM to them remain to be established.

Anemia↗
PubMed1977

Glucagon and catecholamine secretion during hypoglycemia in normal and diabetic man.

To examine the role of catecholamines in glucopenia-induced glucagon secretion, urinary epinephrine and norepinephrine and plasma immunoreactive glucagon (IRG) were measured during insulin-induced hypoglycemia in normal and insulin-dependent diabetic-man. Despite equivalent levels of hypoglycemia the mean plasma IRG increment in diabetes was only 15% of normals. The increases in epinephrine and norepinephrine were comparable in diabetics and normals; thus, the blunted response in plasma IRG to the stimulus of low blood sugar in diabetics cannot be explained by a generalized defect in catecholamine secretion. It is suggested that an alpha-cell glucoreceptor defect may account for the abnormal response to glucopenia in diabetics. To evaluate the possibility that impaired sensitivity to circulating catecholamines could explain the alpha cell dysfunction in diabetics, exogenous epinephrine was infused in normals and insulin-dependent diabetics. Elevated plasma IRG during epinephrine infusion was observed in only 50% of normals. The diabetics were hyperresponsive; mean increment in plasma IRG 3 times that of normals. The data demonstrate enhanced rather than impaired sensitivity to catecholamines in diabetes mellitus.

Adolescent↗
PubMedDate not supplied

Development of a chronic skin defect model and a study of cytokine secretion using the model.

In this study, we established a delayed healing chronic type wound model in order to investigate the etiology of chronic wound healing, including wound contraction. Establishment of the model was important for clarification of the mechanism(s) of chronic wound healing and wound contraction and for use in evaluating therapeutic efficacy. A pedicled skin flap was raised beneath the panniculus carnosus membrane on the backs of mice, and after the loose connective tissue at the base of the flap was completely removed surgically, the flap was replaced and sutured. Seven days after surgery, a full-thickness defect measuring 1.5 x 1.5 cm was made in the center of the skin flap. At that time, a defect of the same size, including the panniculus carnosus membrane, was made in another group of mice as controls, and changes with time in wound area were compared between the two groups. The exudate retained on the wound surface was collected, and various cytokines contained in the exudate were measured. In the control group, the wound rapidly contracted and almost completely epithelialized and closed 21 days after surgery. On the other hand, the wound area was significantly larger in the delayed model than in the control animals during the observation period, revealing a delay in wound contraction. Transforming growth factor-beta, interleukin-1beta, and tumor necrosis factor-alpha in the exudates from the wound of the model were significantly higher than in those of the control group, whereas interleukin-6 was low in the model. From these results, it was concluded that this model could be a useful experimental system for studies on wound contraction as well as clarifying the mechanism of so called chronic type wounds.

Animals↗
PubMed2001

Is the defect in pro-hormone processing in Type 2 diabetes mellitus restricted to the beta cell?

AIMS: To investigate whether the defect in pro-hormone processing in people with Type 2 diabetes mellitus is restricted to the pancreatic beta cell or whether there is evidence of a more generalized abnormality. METHODS: Ten Indian subcontinent Asian women with diet-controlled Type 2 diabetes were compared with a control group of nine non-diabetic Asian women who were matched for body mass index. All subjects underwent a standard 75 g oral glucose tolerance test during which plasma glucose, insulin, proinsulin and 32,33 split proinsulin were measured. Subjects in both groups then underwent an intravenous corticotrophin-releasing hormone (CRH) test with 100 microg human CRH. Plasma cortisol, adrenocorticotrophic hormone (ACTH) and ACTH precursors were measured. RESULTS: Basal levels of insulin were lower in diabetic subjects (32.5 (12.5-52) pmol/l) than in the control group (42.2 (21.4-63.0) pmol/l); normalized geometric mean (95% confidence interval), P<0.05; as were the levels at 30 min (29.5 (3.7-55.3) pmol/l) and (34.4 (10.7-58.2) pmol/l), P<0.05. The levels at 60 min were (26.7 (6.4-47.0) pmol/l) in subjects with diabetes and (13.6 (-11.3-38.5) pmol/l) in controls, P<0.05 and at 90 min these were (43.4 (19.4-67.4) pmol/l) and (19.3 (-4.6-43.3) pmol/l), P<0.05, respectively, after the 75-g oral glucose load. The acute insulin response was markedly reduced in the subjects with diabetes (1.8 (0.60-3.1) pmol insulin/ mmol glucose), compared with the control group (31.4 (8.0-54) pmol/l insulin/mmol glucose), P<0.005. Intact proinsulin was much higher in the diabetic subjects (23.9 (10.1-37) pmol/1) than in the control group (7.2 (3.9-10) pmol/1), P<0.002, as was the percentage of proinsulin-like molecules (28 (14-42) and 12 (8-17)%), respectively, P<0.01. There were no differences between basal or stimulated levels of ACTH precursors, ACTH or cortisol between the diabetic subjects and the controls. CONCLUSIONS: The defect in insulin secretion in Indian subcontinent Asian women with Type 2 diabetes is similar to that described in other populations with an increased prevalence of Type 2 diabetes. The absence of any defect in the processing of cortisol precursors in the women with Type 2 diabetes suggests that they do not have a generalized defect of hormone processing.

Adrenocorticotropic Hormone↗
PubMed1996

Alterations in glutathione homeostasis in mutant Eisai hyperbilirubinemic rats.

Eisai hyperbilirubinemic rats (EHBR) are mutant Sprague-Dawley rats that exhibit impaired biliary organic anion and reduced glutathione (GSH) secretion. In addition, liver GSH levels are twice that of age-matched controls. The mechanisms for the defect in biliary GSH secretion and the increase in cell GSH are not fully understood. We previously showed that canalicular membrane-enriched vesicles isolated from EHBR livers exhibited normal GSH transport. In the present study, we examined the steady-state rat canalicular reduced glutathione transporter (RcGshT) messenger RNA (mRNA) and protein levels, as well as the mechanisms for the increase in cell GSH. Both Northern and Western blot analyses of EHBR livers showed nearly identical RcGshT mRNA and polypeptide levels, respectively, as compared with controls. Treatment with phenobarbital, which increased steady-state RcGshT mRNA by five- to sixfold, RcGshT polypeptide, and biliary GSH secretion by onefold in controls, had a smaller effect on steady-state RcGshT-mRNA level in EHBR (by 1.5-fold) and did not increase RcGshT polypeptide or biliary GSH secretion. In examining possible mechanisms for increased liver GSH, both cysteine level and gamma-glutamylcysteine synthetase (GCS) activity were significantly higher than controls, while the activity of GSH synthetase was unchanged. Northern and Western blot analyses also showed increased steady-state GCS heavy subunit (GCS-HS) mRNA and polypeptide levels, respectively. In addition to liver, GSH levels in kidney, duodenal, jejunal, and ileal mucosa of EHBR were 200% to 300% of age-matched control rats. GCS activity was also increased in kidney cytosol of EHBR. Thus, the defect in biliary GSH secretion in EHBR most likely is either at the posttranslational level of RcGshT or in the inhibition exerted by retained endogenous organic anions. In addition, there is a widespread up-regulation of GSH synthesis capacity in the tissues of EHBR.

Analysis of Variance↗
PubMed2003

Insulin granule dynamics in pancreatic beta cells.

Glucose-induced insulin secretion in response to a step increase in blood glucose concentrations follows a biphasic time course consisting of a rapid and transient first phase followed by a slowly developing and sustained second phase. Because Type 2 diabetes involves defects of insulin secretion, manifested as a loss of first phase and a reduction of second phase, it is important to understand the cellular mechanisms underlying biphasic insulin secretion. Insulin release involves the packaging of insulin in small (diameter approximately 0.3 micro m) secretory granules, the trafficking of these granules to the plasma membrane, the exocytotic fusion of the granules with the plasma membrane and eventually the retrieval of the secreted membranes by endocytosis. Until recently, studies on insulin secretion have been confined to the appearance of insulin in the extracellular space and the cellular events preceding exocytosis have been inaccessible to more detailed analysis. Evidence from a variety of secretory tissues, including pancreatic islet cells suggests, however, that the secretory granules can be functionally divided into distinct pools that are distinguished by their release competence and/or proximity to the plasma membrane. The introduction of fluorescent proteins that can be targeted to the secretory granules, in combination with the advent of new techniques that allow real-time imaging of granule trafficking in living cells (granule dynamics), has led to an explosion of our knowledge of the pre-exocytotic and post-exocytotic processes in the beta cell. Here we discuss these observations in relation to previous functional and ultra-structural data as well as the secretory defects of Type 2 diabetes.

Animals↗
PubMed1995

Decreased beta-adrenergic stimulation of glycoprotein secretion in CF mice submandibular glands: reversal by the methylxanthine, IBMX.

beta-adrenergic stimulation of glycoprotein secretion was shown to be decreased in submandibular glands of Cystic Fibrosis (CF) mice. The defective response was partially restored by the methylxanthine, IBMX or cpt-cyclic AMP. Cholinergic stimulation of pancreatic amylase secretion was not affected in CF mice, demonstrating that this is not a generalised depression of protein secretion. The data are the first to show that the CF mouse mimics the protein secretion defect in CF human submandibular cells and that the mechanism of correction of the CF defect is via elevation of cyclic AMP. The results are therefore invaluable towards devising a rational pharmaceutical therapy for CF patients.

1-Methyl-3-isobutylxanthine↗
PubMed2000

Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins.

AIMS/HYPOTHESIS: To estimate the heritability of insulin sensitivity and insulin secretion, both of which are considered to contribute to the development of Type II (non-insulin-dependent) diabetes mellitus. METHODS: Intraclass correlation coefficients and heritability estimates for insulin sensitivity (euglycaemic clamp) as well as first-phase and late-phase insulin secretion (intravenous glucose tolerance test) were calculated in 21 monozygotic and 20 dizygotic twin pairs of the same sex between 54 and 72 years of age. RESULTS: Intrapair correlations for all traits were consistently higher in monozygotic than in dizygotic pairs. Insulin secretion correlated significantly only between monozygotic (first-phase r = 0.55; p = 0.003 and late-phase r = 0.66; p < 0.001) twins giving heritability estimates of 0.55 and 0.58, respectively. Insulin-stimulated glucose uptake showed a more modest correlation between monozygotic twins (r = 0.46; p = 0.015). The heritability estimate was 0.37. The heritability estimate for waist-to-hip ratio was 0.76 in female and 0.70 in male twins. CONCLUSION/INTERPRETATION: Genetic variability seems to contribute to the variance of insulin sensitivity as well as of insulin secretion. In the current study, genetic variance accounted almost 60% for the variance in glucose-stimulated insulin secretion and almost 40% for the variance in insulin-stimulated glucose uptake. Our data is also compatible with findings in monogenic forms of diabetes in which genetic defects in insulin secretion play a predominant part in the pathogenesis of hyperglycaemia.

Aged↗
PubMed2000

Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes.

In light of an occurring growth of elderly people affected by type 2 diabetes and recent observations indicating that type 2 diabetes may be a disease of the innate immune system, we evaluated whether signs of islet cell autoimmunity are associated with an abnormal glucose control, the presence of insulin requirement, or an activation of the acute-phase response in older individuals with type 2 diabetes. GAD65 and IA-2 autoantibodies along with the acute-phase response markers fibrinogen and C-reactive protein were tested in 196 serum samples from patients with type 2 diabetes and in 94 nondiabetic control subjects over the age of 65 years from the Pittsburgh cohort of the Cardiovascular Health Study. Of the diabetic patients, 12% (24 of 196) had autoantibodies against GAD65 and/or IA-2, a prevalence significantly higher than that found in nondiabetic individuals (1 of 94, 1.1%; P = 0.001). Type 2 diabetic patients who were positive for GAD65 and/or IA-2 autoantibodies (Ab+), as compared with those negative for these autoantibodies (Ab-), had an abnormal oral glucose tolerance test (OGTT) (P = 0.03) before and a higher frequency of oral hypoglycemic treatment (P = 0.003) at the time of autoantibody testing. No differences were seen in the percentage of insulin requirement in the two groups. Moreover, a statistically significant increase in fibrinogen (P = 0.005) and C-reactive protein levels (P = 0.025) was found in type 2 diabetic patients with high levels of GAD65 and/or IA-2 autoantibodies as compared with Ab-patients and control subjects. In conclusion, in type 2 diabetic subjects > or =65 years old, the presence of islet cell autoimmunity is associated with an impairment of the acute-phase insulin secretion, as revealed by an OGTT. A pronounced activation of the acute-phase response, found to be associated with islet cell autoimmunity, may in part explain this defect in insulin secretion. These findings not only have direct implications for adequate classification and treatment of diabetes in the elderly, but also for understanding the autoimmune/inflammatory mechanisms involved in the pathogenesis of hyperglycemia.

Aged↗
PubMed2000

Understanding the pathogenesis and treatment of insulin resistance and type 2 diabetes mellitus: what can we learn from transgenic and knockout mice?

The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic B-cells to compensate by adequate insulin secretion. Here, we review studies obtained from genetically engineered mice that have helped dissect the pathophysiology of this disease. Transgenic/knockout models with monogenic impairment in insulin action and insulin secretion have highlighted potential molecular mechanisms for insulin resistance and suggested a mechanism for the development of MODY in humans. Polygenic models have strengthened the idea that minor defects in insulin secretion and insulin action, when combined, can lead to diabetes, pointing out the importance of interactions of different genetic loci in the production of diabetes. Tissue-specific knockouts of the insulin receptor have challenged current concepts on the regulation of glucose homeostasis and have highlighted the importance of insulin action in pancreatic B-cells and brain. The impact of the genetic background on insulin action, insulin secretion and the incidence of diabetes is also evident in these models. These findings highlight potential new therapeutic targets in the treatment of type 2 diabetes.

Animals↗
PubMed1989

Qualitative platelet defects in chronic myeloproliferative disorders: evidence for reduced ATP secretion.

19 consecutive untreated patients with chronic myeloproliferative disorders and thrombocytosis were subjected to comprehensive platelet function tests including platelet aggregometry. 12 patients had essential thrombocythaemia (ET) and 7 patients had polycythaemia vera (PV). Bleeding time was normal. Arachidonic acid, collagen and ristocetin aggregation were abnormal only in a minority of patients, whereas ADP aggregation was impaired in 16 out of 19 patients. The most conspicuous findings were abolished second-wave adrenalin aggregation, increased ADP aggregation threshold, and markedly reduced ATP secretion during collagen-induced aggregation. This triad of qualitative platelet defects seems to be a good diagnostic marker of chronic myeloproliferative disease with thrombocytosis.

Adenosine Diphosphate↗
PubMed1983

Immunoglobulin secretory function of B cells from untreated patients with chronic lymphocytic leukemia and hypogammaglobulinemia: role of T cells.

The mechanism of the hypogammaglobulinemia in patients with chronic lymphocytic leukemia (CLL) was studied by determining the generation of specific immunoglobulin-secreting cells in response to mitogen and antigen stimulation in culture. Normal peripheral blood B lymphocytes from 18 normal subjects cocultured with equal numbers of autologous T cells generated cells secreting 2,542 +/- 695 IgG, 2,153 +/- 615 IgA, and 2,918 +/- 945 IgM. Normal B lymphocytes cocultured with normal allogeneic T cells generated similar numbers. However, B lymphocytes from patients with chronic lymphocytic leukemia cocultured with T cells from the same patient generated only 0.5% as many cells secreting IgG and 11% and 23% as many secreting IgA and IgM, respectively. The reason for this markedly defective generation of immunoglobulin-secreting cells was investigated by evaluating T-helper, T-suppressor, and B-cell function using B cells from tonsil and T and B cells from peripheral blood of normal and leukemic individuals. T cells from patients with chronic lymphocytic leukemia provided somewhat greater help than did normal T cells to normal peripheral blood B cells and normal help to tonsil B cells, whether stimulated with mitogen or antigen. T cells from patients with chronic lymphocytic leukemia did not demonstrate increased suppressor function compared to normals with B cells from normal peripheral blood. The hypogammaglobulinemia in these patients therefore was associated with a markedly defective generation of immunoglobulin secreting cells, and as there was normal or increased T-cell helper activity without excessive suppressor activity, it seems likely that this was due to an intrinsic B-cell defect.

Adult↗
PubMedDate not supplied

The social outcome of adults with constitutional growth delay.

It is well established that children with extreme short stature, secondary to GH deficiency (GHD) or achondroplasia, face a disability that may affect their adult psychosocial outcome, while contrasting data are reported for short normal children. In our hands, adults with GHD have shown an unsatisfactory psychosocial adjustment due to the low adult height and hypothetically to the persistent GHD. This study has been carried out to evaluate the influence of growth in height on the social outcome in 45 adults with constitutional growth delay (CGD). Interviews with subjects and parents were used for assessment. Data obtained were compared with those found in an age, sex and social matched control group of adults with normal height. Some issues were also compared with the data we previously found in adults with GHD. Present mean age of the patients is 24 +/- 2 yr. A high percentage (32.8%) of unemployment or underemployment (part-time work) was found. Four patients (8.8%) were married, while 84.4% lived with their parents or relatives, confirming the notion of prolonged economic dependency on the family. The patients preferred single sporting activities, avoiding team work. Surprisingly, scholastic achievement was in general similar to that observed in controls. Similar findings have been previously observed in patients with GHD. Since no defect in GH secretion has been documented in CGD, the presence of a negative psychosocial outcome more probably seems to be due to the final unsatisfactory height rather than to a GH defect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

The rho-GAP encoded by BEM2 regulates cytoskeletal structure in budding yeast.

Microfilaments are required for polarized growth and morphogenesis in Saccharomyces cerevisiae. To accomplish this, actin cables and patches are redistributed during the cell cycle to direct secretory components to appropriate sites for cell growth. A major component of actin cables is tropomyosin I, encoded by TPM1, that determines or stabilizes these structures. Disruption of TPM1 is not lethal but results in the loss of actin cables and confers a partial defect in polarized secretion. Using a synthetic lethal screen, we have identified seven mutations residing in six genes whose products are required in the absence of Tpm1p. Each mutant exhibited a morphological defect, suggesting a functional link to the actin cytoskeleton. Complementation cloning of one mutation revealed that it lies in BEM2, which encodes a GTPase-activating protein for the RHO1 product. bem2 mutations also show synthetic lethality with rho1 and mutations in certain other cytoskeletal genes (ACT1, MYO1, MYO2, and SAC6) but not with mutations in several noncytoskeletal genes. These data therefore provide a genetic link between the GAP encoded by BEM2 and the functional organization of microfilaments. In addition, we show that bem2 mutations confer benomyl sensitivity and have abnormal microtubule arrays, suggesting that the BEM2 product may also be involved directly or indirectly in regulating microtubule function.

Actin Cytoskeleton↗
PubMed1993

Hereditary renal diseases.

Huge strides have been made in the molecular genetics and clinical investigation of several inherited renal diseases. In autosomal dominant polycystic kidney disease 1) the genetic localization of the defective gene that causes type 1 disease has been narrowed to 500 to 750 kb on chromosome 16; 2) cystogenesis has been associated with increased cell proliferation, continuing cyst secretion, and a defect in cell polarity; however, the mechanisms by which the genetic defects in autosomal dominant polycystic kidney disease translate into cyst formation are unknown; 3) activation of the renin system has been reported as an important potential cause of hypertension; and 4) factors that influence the progression to renal failure have been identified. In Alport's syndrome, mutations in the alpha 5 (IV) collagen gene on the X chromosome have been demonstrated that may induce defective assembly of alpha 3 (IV) chains by an unknown mechanism, which leads to the disruption of the glomerular basement membrane. In diabetic nephropathy, it has been suggested that familial factors, perhaps genetic in origin, may play an important role in its development.

Humans↗
PubMed1999

Defects in inositol 1,4,5-trisphosphate receptor expression, Ca(2+) signaling, and insulin secretion in the anx7(+/-) knockout mouse.

The mammalian anx7 gene codes for a Ca(2+)-activated GTPase, which supports Ca(2+)/GTP-dependent secretion events and Ca(2+) channel activities in vitro and in vivo. To test whether anx7 might be involved in Ca(2+) signaling in secreting pancreatic beta cells, we knocked out the anx7 gene in the mouse and tested the insulin-secretory properties of the beta cells. The nullizygous anx7 (-/-) phenotype is lethal at embryonic day 10 because of cerebral hemorrhage. However, the heterozygous anx7 (+/-) mouse, although expressing only low levels of ANX7 protein, is viable and fertile. The anx7 (+/-) phenotype is associated with a substantial defect in insulin secretion, although the insulin content of the islets, is 8- to 10-fold higher in the mutants than in the normal littermate control. We infer from electrophysiological studies that both glucose-stimulated secretion and voltage-dependent Ca(2+) channel functions are normal. However, electrooptical recordings indicate that the (+/-) mutation has caused a change in the ability of inositol 1,4,5-trisphosphate (IP(3))-generating agonists to release intracellular calcium. The principle molecular consequence of lower anx7 expression is a profound reduction in IP(3) receptor expression and function in pancreatic islets. The profound increase in islets, beta cell number, and size may be a means of compensating for less efficient insulin secretion by individual defective pancreatic beta cells. This is a direct demonstration of a connection between glucose-activated insulin secretion and Ca(2+) signaling through IP(3)-sensitive Ca(2+) stores.

Animals↗