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PubMed2005

Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes.

AIMS/HYPOTHESIS: Although insulin resistance induces compensatory increases in beta cell mass and function to maintain normoglycaemia, it is not clear whether insulin resistance can precipitate beta cell dysfunction and hyperglycaemia without a pre-existing beta cell susceptibility. We therefore examined the beta cell phenotype in the MKR mouse, a model in which expression of a dominant-negative IGF 1 receptor (IGF1R) in skeletal muscle leads to systemic insulin resistance and diabetes. MATERIALS AND METHODS: Circulating glucose, insulin and glucagon concentrations were measured. Insulin sensitivity, glucose tolerance and insulin release in vivo were assessed by i.p. insulin and glucose tolerance tests. Beta cell function was assessed via insulin secretion from isolated islets and the glucose gradient in the perfused pancreas. Beta cell morphology was examined via immunohistochemistry. MKR mice were fed a high-fat diet containing sucrose (HFSD) to test metabolic capacity and beta cell function. RESULTS: Insulin-resistant MKR mice developed hyperglycaemia and a loss of insulin responsiveness in vivo. Basal insulin secretion from the perfused pancreas was elevated, with no response to glucose. Despite the demand on insulin secretion, MKR mice had increased pancreatic insulin content and beta cell mass mediated through hyperplasia and hypertrophy. The HFSD worsened hyperglycaemia in MKR mice but, despite increased food intake in these mice, failed to induce the obesity observed in wild-type mice. CONCLUSIONS/INTERPRETATION: Our studies demonstrate that insulin resistance of sufficient severity can impair glucose-stimulated insulin secretion, thereby undermining beta cell compensation and leading to hyperglycaemia. Moreover, because insulin stores were intact, the secretory defects reflect an early stage of beta cell dysfunction.

Animals↗
PubMed1992

Cells and mediators involved in immunoglobulin synthesis by human circulating mononuclear cells. IV. B cells synthesize but do not secrete immunoglobulins because of a defect in the non-T non-B (null) cells.

Null cells (non-T and non-B lymphocytes) have previously been demonstrated to be obligatory participants for immunoglobulin synthesis and secretion by normal B cells in culture. Normal null cells have been demonstrated to secrete a factor, human immunoglobulin synthesis/secretion-facilitating factor (HISFF), which can replace the null cells in the culture. In this investigation, the B cells of an 8-month-old male infant and a 46-year-old male adult who presented with a humoral (antibody) immunodeficiency syndrome synthesized immunoglobulin but did not secrete immunoglobulin after culture with pokeweed mitogen and autologous T cells, monocytes, and null cells. In contrast, the patients' B cells synthesized and secreted immunoglobulin after the addition of allogeneic normal null cells or HISFF to the cultures. The same results were obtained with the cells of the infant and the adult patient tested at monthly intervals for 4 months. The results demonstrate that the patients' T cells, B cells, and monocytes functioned normally and that only the patients' null cells were defective. These findings provide an explanation for the absence of immunoglobulin in the circulation of "non(immunoglobulin)secretors," although they possess normal numbers of circulating immunoglobulin-synthesizing B cells. The defect is in the null cell and not in the B cell and consists of the inability of the null cell to secrete HISFF that facilitates the synthesis and secretion of immunoglobulin by the B cell.

Antigens, CD↗
PubMed2000

The cytosolic termini of the beta- and gamma-ENaC subunits are involved in the functional interactions between cystic fibrosis transmembrane conductance regulator and epithelial sodium channel.

Epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR) are co-localized in the apical membrane of many epithelia. These channels are essential for electrolyte and water secretion and/or reabsorption. In cystic fibrosis airway epithelia, a hyperactivated epithelial Na(+) conductance operates in parallel with defective Cl(-) secretion. Several groups have shown that CFTR down-regulates ENaC activity, but the mechanisms and the regulation of CFTR by ENaC are unknown. To test the hypothesis that ENaC and CFTR regulate each other, and to identify the region(s) of ENaC involved in the interaction between CFTR and ENaC, rENaC and its mutants were co-expressed with CFTR in Xenopus oocytes. Whole cell macroscopic sodium currents revealed that wild type (wt) alphabetagamma-rENaC-induced Na(+) current was inhibited by co-expression of CFTR, and further inhibited when CFTR was activated with a cAMP-raising mixture (CKT). Conversely, alphabetagamma-rENaC stimulated CFTR-mediated Cl(-) currents up to approximately 6-fold. Deletion mutations in the intracellular tails of the three rENaC subunits suggested that the carboxyl terminus of the beta subunit was required both for the down-regulation of ENaC by activated CFTR and the up-regulation of CFTR by ENaC. However, both the carboxyl terminus of the beta subunit and the amino terminus of the gamma subunit were essential for the down-regulation of rENaC by unstimulated CFTR. Interestingly, down-regulation of rENaC by activated CFTR was Cl(-)-dependent, while stimulation of CFTR by rENaC was not dependent on either cytoplasmic Na(+) or a depolarized membrane potential. In summary, there appear to be at least two different sites in ENaC involved in the intermolecular interaction between CFTR and ENaC.

Amiloride↗
PubMed1996

Growth and endocrine function after near total pancreatectomy for hyperinsulinaemic hypoglycaemia.

Seven children, with a mean (SD) age of 4.6 (2.1) years, who as infants (21 (7.5) days) underwent near total (95-98%) pancreatectomy for persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) were studied. At birth all the infants were macrosomic. Four infants had been born after a difficult labour, of whom three had moderate birth asphyxia and respiratory distress. All had normal thyroid function. After surgery transient hyperglycaemia was manifest in six of the children and required insulin treatment for 5.8 (3.8) weeks, and transient hypoglycaemia was encountered in one child and responded well to increased carbohydrate intake and diazoxide for three weeks. Six of the children rapidly crossed down their length and weight centiles during the first year after surgery. At the end of the first year these children were at or below the 5th centile of height and weight for their age and gender. After a period of 4.6 (2.1) years, their mean (SD) height score was -2.57 (0.5), growth velocity 3.9 (0.75) cm/year, and growth velocity SD score -2.1 (0.55)l these were significantly low and denoted significant growth retardation. The growth hormone peak responses to provocation with clonidine were normal (13.5 (2.8) micrograms/l). However, the circulating insulin-like growth factor-I (IGF-I) concentrations were significantly decreased (79 (34) ng/ml). Three of the children developed diabetes at two and a half, five, and seven years after surgery, two others had impaired oral glucose tolerance and six out of the seven children had an impaired C peptide response to glucagon. Defective insulin secretion in these children might directly inhibit IGF-I synthesis in the liver. The body mass index of the pancreatectomised children was 14.9 (0.5) and was normal for age and gender; they had a normal 72 hour faecal fat content and normal serum albumin concentration. These data indicated grossly adequate exocrine pancreatic function. It appears that children requiring near total pancreatectomy for PHHI have normal developmental milestones but defective linear growth with impaired insulin secretion and low IGF-I production despite normal growth hormone response to provocation.

Anthropometry↗
PubMed1995

Regulation of hypothalamic somatostatin by glucocorticoids.

Glucocorticoids (GCs) play a key role in the physiology of the hypothalamic-somatotroph axis, since these steroids enhance growth hormone (GH) gene transcription and increase GHRH receptor synthesis. However, GC excess inhibits normal growth in all species studied. This is mainly due to the impaired GH secretion observed during hypercortisolism, a situation in which GH responses to a number of stimuli, including GHRH, are blunted. The inhibitory effect of GCs on GH secretion seems to be dependent on enhanced hypothalamic SS secretion. Since SS release is stimulated by beta-adrenergic agonism we tested the possibility that GC inhibition of GH secretion would depend on increased beta-adrenoceptor activity in SS-producing neurons. The experimental design consisted in evaluating the GH response to GHRH in normal subjects after having induced hypercortisolism, with DEX, and blocking beta-adrenoceptors with propranolol (PRO). Moreover, to investigate the specificity of this mechanism, GHRH-induced GH release was tested after inducing hypercortisolism and enhancing alpha 2-adrenergic or muscarinic cholinergic tone, by giving clonidine (CLO) or pyridostigmine (PD), respectively. As expected, nocturnal DEX administration inhibited the GH response to GHRH. In this situation of hypercortisolism, both PRO and CLO, but not PD, were able to reverse the inhibitory effect of DEX on GHRH-elicited release. However, the potentiating effect of these drugs on the GHRH-induced GH secretion was only observed for PRO. These data confirm that GC excess inhibits GH release by increasing hypothalamic SS secretion, and that the mechanism is mediated by GC-induced enhanced beta-adrenergic responsiveness. Therefore, the defective GHRH secretion observed in chronic hypercortisolism must be a consequence of the continuous blockade that SS excess exerts on GHRH-producing neurons. Our postulate agrees with other data in the literature showing that GCs modulate the secretion of some hypothalamic peptides by changing the responsiveness of the producing neurons from alpha 2-adrenoceptors to that of beta-adrenoceptors.

Clonidine↗
PubMed2000

CHE-14, a protein with a sterol-sensing domain, is required for apical sorting in C. elegans ectodermal epithelial cells.

BACKGROUND: Polarised trafficking of proteins is critical for normal expression of the epithelial phenotype, but its genetic control is not understood. The regulatory gene lin-26 is essential for normal epithelial differentiation in the nematode Caenorhabditis elegans. To identify potential effectors of lin-26, we characterised mutations that result in lin-26-like phenotypes. Here, we report the phenotypic and molecular analysis of one such mutant line, che-14. RESULTS: Mutations in che-14 resulted in several partially penetrant phenotypes affecting the function of most epithelial or epithelial-like cells of the ectoderm, including the hypodermis, excretory canal, vulva, rectum and several support cells. The defects were generally linked to the accumulation of vesicles or amorphous material near the apical surface, suggesting that secretion was defective. The CHE-14 protein showed similarity to proteins containing sterol-sensing domains, including Dispatched, Patched and NPC1. A fusion protein between full-length CHE-14 and the green fluorescent protein became localised to the apical surface of epithelial cells that require che-14 function. Deletions that removed the predicted transmembrane domains or extracellular loops of CHE-14 abolished apical localisation and function of the protein. CONCLUSIONS: We propose that CHE-14 is involved in a novel secretory pathway dedicated to the exocytosis of lipid-modified proteins at the apical surface of certain epithelial cells. Our data raise the possibility that the primordial function of proteins containing a sterol-sensing domain is to control vesicle trafficking: CHE-14 and Dispatched in exocytosis, Patched and NPC1 in endocytosis.

Amino Acid Motifs↗
PubMed2004

Trophic support delays but does not prevent cell-intrinsic degeneration of neurons deficient for munc18-1.

The stability of neuronal networks is thought to depend on synaptic transmission which provides activity-dependent maintenance signals for both synapses and neurons. Here, we tested the relationship between presynaptic secretion and neuronal maintenance using munc18-1-null mutant mice as a model. These mutants have a specific defect in secretion from synaptic and large dense-cored vesicles [Verhage et al. (2000), Science, 287, 864-869; Voets et al. (2001), Neuron, 31, 581-591]. Neuronal networks in these mutants develop normally up to synapse formation but eventually degenerate. The proposed relationship between secretion and neuronal maintenance was tested in low-density and organotypic cultures and, in vivo, by conditional cell-specific inactivation of the munc18-1 gene. Dissociated munc18-1-deficient neurons died within 4 days in vitro (DIV). Application of trophic factors, insulin or BDNF delayed degeneration up to 7 DIV. In organotypic cultures, munc18-1-deficient neurons survived until 9 DIV. On glial feeders, these neurons survived up to 10 DIV and 14 DIV when insulin was applied. Co-culturing dissociated mutant neurons with wild-type neurons did not prolong survival beyond 4 DIV, but coculturing mutant slices with wild-type slices prolonged survival up to 19 DIV. Cell-specific deletion of munc18-1 expression in cerebellar Purkinje cells in vivo resulted in the specific loss of these neurons without affecting connected or surrounding neurons. Together, these data allow three conclusions. First, the lack of synaptic activity cannot explain the degeneration in munc18-1-null mutants. Second, trophic support delays but cannot prevent degeneration. Third, a cell-intrinsic yet unknown function of munc18-1 is essential for prolonged survival.

Action Potentials↗
PubMed2005

The mass, but not the frequency, of insulin secretory bursts in isolated human islets is entrained by oscillatory glucose exposure.

Insulin is secreted in discrete insulin secretory bursts. Regulation of insulin release is accomplished almost exclusively by modulation of insulin pulse mass, whereas the insulin pulse interval remains stable at approximately 4 min. It has been reported that in vivo insulin pulses can be entrained to a pulse interval of approximately 10 min by infused glucose oscillations. If oscillations in glucose concentration play an important role in the regulation of pulsatile insulin secretion, abnormal or absent glucose oscillations, which have been described in type 2 diabetes, might contribute to the defective insulin secretion. Using perifused human islets exposed to oscillatory vs. constant glucose, we questioned 1) whether the interval of insulin pulses released by human islets is entrained to infused glucose oscillations and 2) whether the exposure of islets to oscillating vs. constant glucose confers an increased signal for insulin secretion. We report that oscillatory glucose exposure does not entrain insulin pulse frequency, but it amplifies the mass of insulin secretory bursts that coincide with glucose oscillations (P < 0.001). Dose-response analyses showed that the mode of glucose drive does not influence total insulin secretion (P = not significant). The apparent entrainment of pulsatile insulin to infused glucose oscillations in nondiabetic humans in vivo might reflect the amplification of underlying insulin secretory bursts that are detected as entrained pulses at the peripheral sampling site, but without changes in the underlying pacemaker activity.

Biological Clocks↗
PubMed2002

Pituitary hypoplasia and lactotroph dysfunction in mice deficient for cyclin-dependent kinase-4.

The lactotroph undergoes dynamic regulation of cell cycle progression during pregnancy, as well as throughout the development of the pituitary. We recently reported that female mice with targeted disruption of Cdk4, one of the G(1)-regulatory cyclin-dependent kinases, are unable to support embryo implantation because of defective progesterone secretion from the corpus luteum. In this study, we demonstrate that this phenotype is not attributable to a primary defect in the corpus luteum but is a consequence of defective prolactin (PRL) production caused by inappropriate development of the pituitary lactotroph population. Specifically, the pituitary of Cdk4-deficient mice is extremely hypoplastic. Lactotrophs and somatotrophs of prepubertal Cdk4-deficient mice were 80% decreased in number, relative to those in wild-type mice, whereas gonadotrophs were unaffected. Lactotrophs of Cdk4-deficient mice did not proliferate in response to estrogen administration, whereas estrogen could induce the expression of galanin, an estrogen-responsive factor required for lactotroph proliferation. The reduction in lactotroph numbers was reflected by markedly diminished serum PRL levels in both prepubertal and postcoital Cdk4-deficient mice. Administration of PRL, after mating, significantly increased serum progesterone levels and restored implantation in Cdk4-deficient female mice. These observations demonstrate that Cdk4 is required for normal proliferation of the lactotroph population.

Animals↗
PubMed1985

A temperature-sensitive Chinese hamster ovary cell mutant pleiotropically defective in protein export.

We have developed a new selection procedure for mammalian cell mutants defective in protein export by the use of diphtheria toxin, and devised a new screening method for defective protein secretion using nitrocellulose membranes. By the combination of these procedures, we have isolated a temperature-sensitive mutant clone of Chinese hamster ovary cells which shows a pleiotropic defect in protein export. This mutant, designated DS28-6, is temperature-sensitive for growth. Secretion of a series of proteins is markedly inhibited at the non-permissive temperature. These proteins seem to be normally synthesized and accumulated within the cell at the non-permissive temperature and secreted upon shift down to the permissive temperature. When this mutant is infected with vesicular stomatitis virus, oligosaccharide processing of G-protein is arrested at an endoglycosidase-H-sensitive stage at the non-permissive temperature. The lesion of this mutant appears to be in the endoplasmic reticulum or the cis Golgi or both.

Animals↗
PubMed1979

Mutations affecting immunoglobulin light chain secretion by myeloma cells. I. Functional analysis by cell fusion.

Two clones of MOPC 315 cells have been selected which synthesize but do not secrete Ig lambda light chains. These clones were analyzed by fusion with a cell line synthesizing and secreting kappa chains. Conditions were established for recovery at high frequency (approximately 10(-3)) of spontaneously fused, viable hybrid cells. The resulting hybrid cell lines synthesized both kappa and lambda chains but secreted only kappa chains. Hybrid cells produced by fusion of a lambda-secreting clone of MOPC 315 with the kappa-secreting cell line were also isolated and shown to synthesize and secrete both kappa and lambda chains. These results suggest that the nonsecretion of lambda chains was not due to a defect the secretion mechanism of the variant cells. A more likely alternative is that the lambda chains in the variant cell lines were structurally altered to a form which could not be secreted.

Animals↗
PubMed2005

[Significance of insulin secretion pattern lectured by "glinides" in the treatment of postprandial hyperglycemia].

The mechanisms by which postprandial hyperglycemia is elicited were discussed through therapies of type 2 diabetes using "glinides". It has been believed that the earliest determinant of progression to type 2 diabetes is a loss of early insulin secretion, a defect which results in postprandial hyperglycemia and is often believed to reflect insulin resistance. To prove that, we improved insulin secretion pattern without increase of total amount of insulin secretion using glinide and assessed glucose response. Glinide which selectively enhances early meal-induced insulin secretion improved postprandial hyperglycemia, could provide a valuable treatment option in the prevention and treatment of type 2 diabetes.

Cyclohexanes↗
PubMed1998

Plasma and fibroblasts of Tangier disease patients are disturbed in transferring phospholipids onto apolipoprotein A-I.

Plasmas of patients with Tangier disease (TD) lack lipid-rich alpha-HDL which, in normal plasma, constitutes the majority of high density lipoprotein (HDL). Residual amounts of apolipoprotein (apo)A-I in TD plasma occur as lipid-poor or even lipid-free prebeta-HDL. By contrast to normal plasma, TD plasma does not convert prebeta-HDL into alpha-HDL. Moreover, fibroblasts of TD patients were found to be defective in secreting cholesterol or phospholipids in the presence of lipid-free apoA-I. We have therefore hypothesized that both defective conversion of prebeta-HDL into alpha-HDL and defective lipid efflux from TD cells onto lipid-free apoA-I result from a disturbance in phospholipid transfer occurring in both cellular and extracellular compartments. To test this hypothesis we established an assay that measures the activity of plasma, cells, and cell culture media to transfer radiolabeled phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI) from vesicles onto apoA-I, apoA-II, albumin, or reconstituted HDL. Plasmas, HDL, and lipoprotein-depleted plasma of normolipidemic probands as well as cell homogenates and culture media of normal fibroblasts were active at 37 degrees C but not at 4 degrees C in transferring radiolabeled PC, PI, and PE dose- and time-dependently onto either lipid-free apoA-I or reconstituted HDL. Transfer of glycerophospholipids onto apoA-II was much lower than onto apoA-I; transfer onto albumin was close to background. Compared to ten normolipidemic plasmas and four apoA-I-deficient plasmas, plasmas of six TD patients were significantly reduced by 40-50% in their glycerophospholipid transfer activities. Compared to eight normal fibroblast cell lines, homogenates and culture media of four TD fibroblast cell lines were reduced by 40-50% and 30-35%, respectively, in their activity to transfer PC, PI, or PE onto apoA-I. Our data suggest that in TD the same mechanism underlies both defective conversion of prebeta-HDL into alpha-HDL and impaired efflux of cellular lipids, namely a defective phospholipid transfer.

Adult↗
PubMed1991

Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man.

We have examined the mechanisms underlying reduced circulating GH concentrations in the obese human. Computer-assisted (deconvolution) analysis was used to determine endogenous GH secretory and clearance rates quantitatively from entire 24-h plasma GH concentration profiles. These analyses revealed that the half-life (t 1/2) of endogenous GH was significantly shorter in obese (11.7 +/- 1.6 min) than in normal weight subjects (15.5 +/- 0.81 min; P less than 0.01). The accelerated blood disposal rate of GH was not due to decreased circulating concentrations of GH-binding protein, since the latter were similar in obese (25 +/- 1.0%) and normal weight (24 +/- 2.3%) men. However, obese men had significantly fewer GH secretory bursts (3.2 +/- 0.53 vs. 9.7 +/- 0.67/day; P less than 0.01). Among the rare GH secretory bursts that occurred in obese subjects, there were significantly prolonged mean intersecretory burst intervals (282 +/- 65 vs. 131 +/- 11 min; P less than 0.05). The resultant daily GH production rate in obese men was reduced to one fourth that in normal weight individuals. Both GH secretion rate and burst frequency were negatively correlated with the degree of obesity (ponderal index). The decreases in GH burst frequency and half-life were specific, since GH secretory pulse amplitude (maximal rate of GH release), the mass of GH released per burst, and the duration of computer-resolved GH secretory bursts were not different in obese and normal weight men. We conclude that obese men harbor a double defect in GH dynamics involving both GH secretion and clearance, and that the severity of the GH secretory deficiency is proportionate to the degree of obesity.

Adult↗
PubMed1989

Serotonergic hypofunction in migraine: a synthesis of evidence based on platelet dense body dysfunction.

We studied the platelet dense body as a model for serotonergic vesicular function. Headache-free migraine sufferers had increased numbers of dense bodies, decreased dense body secretion, a defective link between cytosolic ionized calcium and platelet activation, an abnormal sensitivity to activation by platelet-activating factor and decreased serotonin metabolism in the presence of an unactivated platelet. These findings are interpreted as evidence for low platelet serotonin turnover. Also an abnormality in coupling of secretion to cytosolic ionized calcium caused by a membranal defect results in reduced platelet secretory function. A similar abnormality is postulated for serotonergic vesicles in central neurons. Central serotonergic hypofunction in migraine sufferers may reduce this normally present inhibitory influence on the intrinsic noradrenergic system, the activation of which may initiate the neuronal mechanisms of migraine.

Blood Platelets↗
PubMed1984

Characterization of an amber mutation in the structural gene for ribosomal protein L15, which impairs the expression of the protein export gene, secY, in Escherichia coli.

We have previously described a temperature-sensitive mutant, ts215, which is defective in protein secretion. Complementation studies indicated that the mutation was located at the distal part of the spc ribosomal protein operon and the gene secY is required for efficient protein secretion. We now report a more complete genetic and biochemical analysis of the ts215 mutant. These studies revealed that the ts215 mutant has an amber mutation in the gene rp10 for ribosomal protein L15, which is located upstream and adjacent to secY. The amber mutation exerts a polar effect on secY causing a defect in protein secretion. These conclusions were supported by the following observations. The mutant strain carries a phi 80 prophage containing a temperature-sensitive suppressor, supFts6. The strain contains decreased amounts of L15 and is suppressible by a temperature-independent nonsense suppressor. In addition, L15 contains an extra tyrosine residue when suppressed by supF. DNA sequence analysis revealed the presence of a single base change in rp10 resulting in an amber codon at the 38th codon of L15. The mutant phenotype is complemented by a plasmid carrying only the secY gene under lac promoter control. The mutant cells complemented by secY can grow and synthesize proteins at normal rates and abundances at 42 degrees C, despite the fact that their ribosomes contain barely detectable levels of L15. These results indicate that ribosomal protein L15 is dispensable for protein synthesis and cell growth. In contrast, the decreased level of expression of the secY gene leads to defective protein secretion and defective cell growth.

Electrophoresis, Polyacrylamide Gel↗
PubMed2002

Phasic insulin release and metabolic regulation in type 2 diabetes.

Type 2 diabetes is a heterogeneous disorder due to prevalent insulin resistance associated with deficient insulin secretion or to a prevalent defect of insulin secretion associated with impaired insulin action. The definition is supported by the high frequency at which insulin resistance can be demonstrated in type 2 diabetic patients. Nonetheless, insulin resistance is not a sufficient mechanism to cause diabetes. Impaired beta-cell function is a necessary defect in all conditions of impaired glucose regulation; however, it manifests itself in a different manner in fasting and glucose-stimulated conditions. In the fasting state, the basal insulin secretory rate increases as a function of the progressive decline in insulin action. As such, the fasting plasma insulin concentration is often taken as a marker for insulin sensitivity. After glucose challenge, a specific alteration of acute insulin release is an early and progressive defect. The latter might represent an intrinsic defect, but its continuous decline is affected by glucotoxicity and lipotoxicity. To understand the impact of beta-cell dysfunction in type 2 diabetes on metabolic homeostasis, it is useful to consider the different phases of insulin secretion separately. Insulin secretion can be divided into basal (postabsorptive) and stimulated (postprandial) states. The former prevails during the interprandial phases and plays a major role during the overnight fast; the latter regulates glucose metabolism when carbohydrate is abundant and must be disposed of. Data in animals and humans support a crucial physiological role of first-phase insulin secretion in postprandial glucose homeostasis. This effect is primarily achieved in the liver, allowing prompt inhibition of endogenous glucose production and limiting the postprandial rise in plasma glucose level. In type 2 diabetes, loss of the early surge of insulin release is an early and quite common defect that may have a pathogenetic role in the development of postprandial hyperglycemia, possibly requiring specific therapeutic intervention.

Blood Glucose↗
PubMed2006

The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface.

Autosomal dominant lateral temporal epilepsy (ADTLE) is a partial epilepsy caused by mutations in LGI1, a multidomain protein of unknown function. To begin to understand the biological function of LGI1, we have determined its pattern of glycosylation, subcellular expression and capacity for secretion. LGI1 is expressed as two different isoforms in the brain, and we show that the long isoform is a secreted protein, whereas the short isoform is retained in an intracellular pool. ADLTE-related mutants of the long form are defective for secretion and are retained in the endoplasmic reticulum and Golgi complex. Finally, we show that normal secreted LGI1 specifically binds to the cell surface of differentiated PC12 cells. We propose that LGI1 is a secreted factor important for neuronal development and that ADTLE is a disease that results from the loss of regulation in the protein available either extracellular or intracellularly.

Animals↗