Glucose Signaling Pathways Research Articles

Convergence of TOR-nitrogen and Snf1-glucose signaling pathways onto Gln3.

Carbon and nitrogen are two basic nutrient sources for cellular organisms. They supply precursors for energy metabolism and metabolic biosynthesis. In the yeast Saccharomyces cerevisiae, distinct sensing and signaling pathways have been described that regulate gene expression in response to the quality of carbon and nitrogen sources, respectively. Gln3 is a GATA-type transcription factor of nitrogen catabolite-repressible (NCR) genes. Previous observations indicate that the quality of nitrogen sources controls the phosphorylation and cytoplasmic retention of Gln3 via the target of rapamycin (TOR) protein. In this study, we show that glucose also regulates Gln3 phosphorylation and subcellular localization, which is mediated by Snf1, the yeast homolog of AMP-dependent protein kinase and a cytoplasmic glucose sensor. Our data show that glucose and nitrogen signaling pathways converge onto Gln3, which may be critical for both nutrient sensing and starvation responses.

Phosphatidyl-inositol-3 kinase-independent insulin action pathway(s) in the human ovary.

Hyperandrogenism observed in women with a variety of insulin-resistant states is thought to be due to a stimulatory effect of insulin on ovarian steroid hormone production. However, it is not known what mechanisms could allow the ovary to remain sensitive to insulin while classical target organs for insulin action (liver, fat, and muscle) exhibit insulin resistance. One hypothesis proposed to explain this paradox suggests that a postbinding divergence of insulin receptor signaling occurs in the ovary and that signaling pathways for steroid hormone synthesis and other ovarian effects of insulin may be distinct from classical glucose signaling pathways. We now report that activation of phosphatidyl-inositol-3 (PI-3) kinase, which is crucial for glucose transport, is not necessary for the insulin-induced stimulation of progesterone production or for the insulin-induced inhibition of insulin-like growth factor binding protein 1 (IGFBP-1) production in cultured human ovarian cells. Human granulosa cells obtained during in vitro fertilization procedures were cultured with 10, 10(2), 10(3), or 10(4) ng/mL insulin with or without preincubation with 100 nM wortmannin, a specific irreversible inhibitor of PI-3 kinase. IGFBP-1 concentration in the conditioned medium was measured using immunoradiometric assay or by Western blot analysis. Progesterone concentration was measured using RIA. Additional studies were carried out in cultures of human ovarian cells prepared from homogenized whole ovarian tissue of a woman with a family history of breast cancer and a mutation of BRCA-1 gene who underwent bilateral oophorectomy. These cells were cultured with 10(3) ng/mL insulin with or without preincubation with 100 nM wortmannin. Two-way ANOVA was used to compare mean values of IGFBP-1 and progesterone according to insulin dose and the use of wortmannin. In cultured granulosa cell medium, progesterone production was stimulated by insulin in a dose-related manner up to 175% of control (P < 0.0001). In tissue culture medium from ovarian cells obtained from a patient with BRCA-gene mutation, concentration of progesterone in the tissue culture medium increased from 2.5 +/- 0.2 ng/mL for control to 5.4 +/- 0.3 ng/mL for cells incubated with insulin (P < 0.001). IGFBP-1 production in tissue culture medium from human granulosa cells was inhibited by insulin to the nadir of 45% of control (P < 0.0001). Preincubation with wortmannin, despite complete inhibition of PI-3 kinase in both cell systems confirmed by Western blot analysis, failed to significantly alter these results. We conclude that inhibition of PI-3 kinase by wortmannin fails to abolish stimulatory effect of insulin on progesterone production or inhibitory effect of insulin on IGFBP-1 production in cultured human ovarian cells. These findings suggest that activation of PI-3 kinase, an enzyme crucial for insulin-stimulated glucose transport, is not necessary for the above effects of insulin in the ovary. These data provide evidence for the presence of PI-3 kinase-independent insulin signaling pathway(s) in human ovarian cells.

Involvement of a Unique Carbohydrate-responsive Factor in the Glucose Regulation of Rat Liver Fatty-acid Synthase Gene Transcription

Refeeding carbohydrate to fasted rats induces the transcription of genes encoding enzymes of fatty acid biosynthesis, e.g. fatty-acid synthase (FAS). Part of this transcriptional induction is mediated by insulin. An insulin response element has been described for the fatty-acid synthase gene region of -600 to +65, but the 2-3-fold increase in fatty-acid synthase promoter activity attributable to this region is small compared with the 20-30-fold induction in fatty-acid synthase gene transcription observed in fasted rats refed carbohydrate. We have previously reported that the fatty-acid synthase gene region between -7382 and -6970 was essential for achieving high in vivo rates of gene transcription. The studies of the current report demonstrate that the region of -7382 to -6970 of the fatty-acid synthase gene contains a carbohydrate response element (CHO-RE(FAS)) with a palindrome sequence (CATGTGn(5)GGCGTG) that is nearly identical to the CHO-RE of the l-type pyruvate kinase and S(14) genes. The glucose responsiveness imparted by CHO-RE(FAS) was independent of insulin. Moreover, CHO-RE(FAS) conferred glucose responsiveness to a heterologous promoter (i.e. l-type pyruvate kinase). Electrophoretic mobility shift assays demonstrated that CHO-RE(FAS) readily bound a unique hepatic ChoRF and that CHO-RE(FAS) competed with the CHO-RE of the l-type pyruvate kinase and S(14) genes for ChoRF binding. In vivo footprinting revealed that fasting reduced and refeeding increased ChoRF binding to CHO-RE(FAS). Thus, carbohydrate responsiveness of rat liver fatty-acid synthase appears to require both insulin and glucose signaling pathways. More importantly, a unique hepatic ChoRF has now been shown to recognize glucose responsive sequences that are common to three different genes: fatty-acid synthase, l-type pyruvate kinase, and S(14).

Subcellular localization of the Snf1 kinase is regulated by specific beta subunits and a novel glucose signaling mechanism.

The Snf1/AMP-activated protein kinase family has broad roles in transcriptional, metabolic, and developmental regulation in response to stress. In Saccharomyces cerevisiae, Snf1 is required for the response to glucose limitation. Snf1 kinase complexes contain the alpha (catalytic) subunit Snf1, one of the three related beta subunits Gal83, Sip1, or Sip2, and the gamma subunit Snf4. We present evidence that the beta subunits regulate the subcellular localization of the Snf1 kinase. Green fluorescent protein fusions to Gal83, Sip1, and Sip2 show different patterns of localization to the nucleus, vacuole, and/or cytoplasm. We show that Gal83 directs Snf1 to the nucleus in a glucose-regulated manner. We further identify a novel signaling pathway that controls this nuclear localization in response to glucose phosphorylation. This pathway is distinct from the glucose signaling pathway that inhibits Snf1 kinase activity and responds not only to glucose but also to galactose and sucrose. Such independent regulation of the localization and the activity of the Snf1 kinase, combined with the distinct localization of kinases containing different beta subunits, affords versatility in regulating physiological responses.

GLUT2 in pancreatic and extra-pancreatic gluco-detection (review).

Detection of variations in blood glucose concentrations by pancreatic beta-cells and a subsequent appropriate secretion of insulin are key events in the control of glucose homeostasis. Because a decreased capability to sense glycemic changes is a hallmark of type 2 diabetes, the glucose signalling pathway leading to insulin secretion in pancreatic beta-cells has been extensively studied. This signalling mechanism depends on glucose metabolism and requires the presence of specific molecules such as GLUT2, glucokinase and the K(ATP) channel subunits Kir6.2 and SUR1. Other cells are also able to sense variations in glycemia or in local glucose concentrations and to modulate different physiological functions participating in the general control of glucose and energy homeostasis. These include cells forming the hepatoportal vein glucose sensor, which controls glucose storage in the liver, counterregulation, food intake and glucose utilization by peripheral tissues and neurons in the hypothalamus and brainstem whose firing rates are modulated by local variations in glucose concentrations or, when not protected by a blood-brain barrier, directly by changes in blood glucose levels. These glucose-sensing neurons are involved in the control of insulin and glucagon secretion, food intake and energy expenditure. Here, recent physiological studies performed with GLUT2-/- mice will be described, which indicate that this transporter is essential for glucose sensing by pancreatic beta-cells, by the hepatoportal sensor and by sensors, probably located centrally, which control activity of the autonomic nervous system and stimulate glucagon secretion. These studies may pave the way to a fine dissection of the molecular and cellular components of extra-pancreatic glucose sensors involved in the control of glucose and energy homeostasis.

A regulatory shortcut between the Snf1 protein kinase and RNA polymerase II holoenzyme.

RNA polymerase II holoenzymes respond to activators and repressors that are regulated by signaling pathways. Here we present evidence for a "shortcut" mechanism in which the Snf1 protein kinase of the glucose signaling pathway directly regulates transcription by the yeast holoenzyme. In response to glucose limitation, the Snf1 kinase stimulates transcription by holoenzyme that has been artificially recruited to a reporter by a LexA fusion to a holoenzyme component. We show that Snf1 interacts physically with the Srb/mediator proteins of the holoenzyme in both two-hybrid and coimmunoprecipitation assays. We also show that a catalytically hyperactive Snf1, when bound to a promoter as a LexA fusion protein, activates transcription in a glucose-regulated manner; moreover, this activation depends on the integrity of the Srb/mediator complex. These results suggest that direct regulatory interactions between signal transduction pathways and RNA polymerase II holoenzyme provide a mechanism for transcriptional control in response to important signals.

Protein phosphatase type-1 regulatory subunits Reg1p and Reg2p act as signal transducers in the glucose-induced inactivation of maltose permease in Saccharomyces cerevisiae.

The REG1 gene encodes a regulatory subunit of the type-1 protein phosphatase (PP1) G1c7 in Saccharomyces cerevisiae, which directs the catalytic subunit to substrates involved in glucose repression. Loss of REG1 relieves glucose repression of many genes, including the MAL structural genes that encode the maltose fermentation enzymes. In this report, we explore the role of Reglp and its homolog Reg2p in glucose-induced inactivation of maltose permease. Glucose stimulates the proteolysis of maltose permease and very rapid loss of maltose transport activity - more rapid than can be explained by loss of the permease protein alone. In a reg1delta strain we observe a significantly reduced rate of glucose-induced proteolysis of maltose permease, and the rapid loss of maltose transport activity does not occur. Instead, surprisingly, the slow rate of proteolysis of maltose permease is accompanied by an increase in maltose transport activity. Loss of Reg2p modestly reduces the rates of both glucose-induced proteolysis of maltose permease and inactivation of maltose transport activity. Overexpression of Reg2p in a reg1delta strain suppresses the effect on maltose permease proteolysis and partially restores the inactivation of maltose transport activity, but does not affect the insensitivity of MAL gene expression to repression by glucose observed in this strain. Thus, protein phosphatase type-1 (Glc7p-Reglp and Glc7p-Reg2p) plays a role in transduction of the glucose signal during glucose-induced proteolysis of maltose permease, but only Glc7p-Reglp is involved in glucose-induced inactivation of maltose transport activity and glucose repression of MAL gene expression. Overexpression of REG1 partially restores proteolysis of maltose permease in a grr1delta strain, which lacks glucose signaling, but does not rescue rapid inactivation of maltose transport activity or sensitivity to glucose repression. A model for the role of Reglp and Reg2p in glucose signaling pathways is discussed. We also uncovered a previously unrecognized G2/M delay in the grr1delta but not the reg1delta strains, and this delay is suppressed by REG1 overexpression. The G1/S delay seen in grr1delta mutants is slightly suppressed as well, but REG1 overexpression does not suppress other grr1delta phenotypes such as insensitivity to glucose repression.

A PEST-like sequence in the N-terminal cytoplasmic domain of Saccharomyces maltose permease is required for glucose-induced proteolysis and rapid inactivation of transport activity.

Maltose permease is required for maltose transport into Saccharomyces cells. Glucose addition to maltose-fermenting cells causes selective delivery of this integral plasma membrane protein to the yeast vacuole via endocytosis for degradation by resident proteases. This glucose-induced degradation is independent of the proteasome but requires ubiquitin and certain ubiquitin conjugating enzymes. We used mutation analysis to identify target sequences in Mal61/HA maltose permease involved in its selective glucose-induced degradation. A nonsense mutation was introduced at codon 581, creating a truncated functional maltose permease. Additional missense mutations were introduced into the mal61/HA-581NS allele, altering potential phosphorylation and ubiquitination sites. No significant effect was seen on the rate of glucose-induced degradation of these mutant proteins. Deletion mutations were constructed, removing residues 2-30, 31-60, 61-90, and 49-78 of the N-terminal cytoplasmic domain, as well as a missense mutation of a dileucine motif. Results indicate that the proline-, glutamate-, aspartate-, serine-, and threonine-rich (PEST) sequence found in the N-terminal cytoplasmic domain, particularly residues 49-78, is required for glucose-induced degradation of Mal61/HAp and for the rapid glucose-induced inactivation of maltose transport activity. The decreased rate of glucose-induced degradation correlates with a decrease in the level of glucose-induced ubiquitination of the DeltaPEST mutant permease. In addition, newly synthesized mutant permease proteins lacking residues 49-78 or carrying an alteration in the dileucine motif, residues 69 and 70, are resistant to glucose-induced inactivation of maltose transport activity. This N-terminal PEST-like sequence is the target of both the Rgt2p-dependent and the Glc7p-Reg1p-dependent glucose signaling pathways.

The large intracytoplasmic loop of the glucose transporter GLUT2 is involved in glucose signaling in hepatic cells.

The hypothesis that the glucose transporter GLUT2 can function as a protein mediating transcriptional glucose signaling was addressed. To divert the putative interacting proteins from a glucose signaling pathway, two intracytoplasmic domains of GLUT2, the C terminus and the large loop located between transmembrane domains 6 and 7, were transfected into mhAT3F hepatoma cells. Glucose-induced accumulation of two hepatic gene mRNAs (GLUT2 and L-pyruvate kinase) was specifically inhibited in cells transfected with the GLUT2 loop and not with the GLUT2 C terminus. The dual effects of glucose were dissociated in cells expressing the GLUT2 loop; in fact a normal glucose metabolism into glycogen occurred concomitantly with the inhibition of the glucose-induced transcription. This inhibition by the GLUT2 loop could be due to competitive binding of a protein that normally interacts with endogenous GLUT2. In addition, the GLUT2 loop, tagged with green fluorescent protein (GFP), was located within the nucleus, whereas the GFP and GFP-GLUT2 C-terminal proteins remained in the cytoplasm. In living cells, a fraction (50%) of the expressed GFP-GLUT2 loop translocated rapidly from the cytoplasm to the nucleus in response to high glucose concentration and conversely in the absence of glucose. We conclude that, via protein interactions with its large loop, GLUT2 may transduce a glucose signal from the plasma membrane to the nucleus.

Glucose modulates the abscisic acid-inducible Rab16A gene in cereal embryos.

Glucose effects on the expression of the abscisic acid-inducible Rab16A gene were examined in rice and barley embryos. Glucose feeding to rice embryos negatively affects the endogenous abscisic acid content and represses the promoter activity of the Rab16A gene. Glucose repression of the Rab16A gene takes place both at a transcriptional and a post-transcriptional level. Modulation of the abscisic acid content in rice embryos triggered by glucose did not directly influence the expression of the rice alpha-amylase gene RAmy3D, which is known to be under glucose control. The possible interaction between the glucose and abscisic acid signaling pathway is discussed.

Glucose and ethylene signal transduction crosstalk revealed by an Arabidopsis glucose-insensitive mutant.

Glucose is an essential signaling molecule that controls plant development and gene expression through largely unknown mechanisms. To initiate the dissection of the glucose signal transduction pathway in plants by using a genetic approach, we have identified an Arabidopsis mutant, gin1 (glucose-insensitive), in which glucose repression of cotyledon greening and expansion, shoot development, floral transition, and gene expression is impaired. Genetic analysis indicates that GIN1 acts downstream of the sensor hexokinase in the glucose signaling pathway. Surprisingly, gin1 insensitivity to glucose repression of cotyledon and shoot development is phenocopied by ethylene precursor treatment of wild-type plants or by constitutive ethylene biosynthesis and constitutive ethylene signaling mutants. In contrast, the ethylene insensitive mutant etr1-1 exhibits glucose hypersensitivity. Epistasis analysis places GIN1 downstream of the ethylene receptor, ETR1, and defines a new branch of ethylene signaling pathway that is uncoupled from the triple response induced by ethylene. The isolation and characterization of gin1 reveal an unexpected convergence between the glucose and the ethylene signal transduction pathways. GIN1 may function to balance the control of plant development in response to metabolic and hormonal stimuli that act antagonistically.

Glucose-stimulated genes and prospects of gene therapy for type I diabetes.

I. Introduction II. Transcriptional Regulation of Glucose-Responsive Genes A. The insulin gene 1. Glucose-signaling pathway in pancreas β-cells 2. E elements of the insulin gene promoter 3. A elements of the insulin gene promoter 4. Role of the E and A boxes of the insulin gene promoters in glucose-dependent transcriptional regulation 5. Role of the cAMP pathway in glucose responsiveness of the insulin gene promoters B. Transcriptional regulation of glucose-responsive genes in the liver 1. The general outlook for glucose metabolism in the liver 2. Transcriptional glucose signaling mechanisms in the liver 3. Glucose/carbohydrate response elements III. Cell and Gene Therapies for IDDM A. Islet and cell transplantations 1. Transplantation of islets 2. Transplantation of established lines B. Bioartificial pancreas C. Transplantation of genetically engineered cells 1. The “ideal” engineered cell for glucose-dependent insulin secretion 2. Engineering established neuroendocrine cells 3. Engineering endogenous he...

Glucose-Stimulated Genes and Prospects of Gene Therapy for Type I Diabetes

I. Introduction II. Transcriptional Regulation of Glucose-Responsive Genes A. The insulin gene 1. Glucose-signaling pathway in pancreas β-cells 2. E elements of the insulin gene promoter 3. A elements of the insulin gene promoter 4. Role of the E and A boxes of the insulin gene promoters in glucose-dependent transcriptional regulation 5. Role of the cAMP pathway in glucose responsiveness of the insulin gene promoters B. Transcriptional regulation of glucose-responsive genes in the liver 1. The general outlook for glucose metabolism in the liver 2. Transcriptional glucose signaling mechanisms in the liver 3. Glucose/carbohydrate response elements III. Cell and Gene Therapies for IDDM A. Islet and cell transplantations 1. Transplantation of islets 2. Transplantation of established lines B. Bioartificial pancreas C. Transplantation of genetically engineered cells 1. The “ideal” engineered cell for glucose-dependent insulin secretion 2. Engineering established neuroendocrine cells 3. Engineering endogenous he...

Rgt1p of Saccharomyces cerevisiae, a key regulator of glucose-induced genes, is both an activator and a repressor of transcription.

The RGT1 gene of Saccharomyces cerevisiae plays a central role in the glucose-induced expression of hexose transporter (HXT) genes. Genetic evidence suggests that it encodes a repressor of the HXT genes whose function is inhibited by glucose. Here, we report the isolation of RGT1 and demonstrate that it encodes a bifunctional transcription factor. Rgt1p displays three different transcriptional modes in response to glucose: (i) in the absence of glucose, it functions as a transcriptional repressor; (ii) high concentrations of glucose cause it to function as a transcriptional activator; and (iii) in cells growing on low levels of glucose, Rgt1p has a neutral role, neither repressing nor activating transcription. Glucose alters Rgt1p function through a pathway that includes two glucose sensors, Snf3p and Rgt2p, and Grr1p. The glucose transporter Snf3p, which appears to be a low-glucose sensor, is required for inhibition of Rgt1p repressor function by low levels of glucose. Rgt2p, a glucose transporter that functions as a high-glucose sensor, is required for conversion of Rgt1p into an activator by high levels of glucose. Grr1p, a component of the glucose signaling pathway, is required both for inactivation of Rgt1p repressor function by low levels of glucose and for conversion of Rgt1p into an activator at high levels of glucose. Thus, signals generated by two different glucose sensors act through Grr1p to determine Rgt1p function.

The role of islet secretory function in the development of diabetes in the GK Wistar rat

Insulin secretion and glucose metabolism were compared in islets isolated from GK Wistar rats (a non-obese, spontaneous model of non-insulin-dependent diabetes mellitus) and control Wistars aged 8 and 14 weeks. By 8 weeks of age, GK Wistar rats were clearly diabetic as indicated by non-fasting plasma glucose concentrations and impaired glucose tolerance. Islet insulin content was not significantly different to controls at either age. In islets from 14-week-old GK Wistar rats glucose-stimulated insulin release (6-16 mmol/l glucose) was significantly reduced to 25-50% of controls in static incubations (p < 0.001). In perifusion, glucose-stimulated insulin release was reduced by 90% for first phase (p < 0.01) and by 75% for second phase (p < 0.05). The responses to arginine and 2 alpha Ketoisocaproate in islets were similar to those in controls. In contrast, islets isolated from 8-week-old GK Wistar rats exhibited no significant reduction in glucose-stimulated insulin secretion in static incubations. In perifusion, although both first and second phases of glucose-stimulated insulin release were slightly reduced, these were not significantly different to controls. Islets from 8-week-old GK Wistar rats failed however to respond to stimulation by glyceraldehyde. Raising the medium glucose concentration to 16 mmol/l significantly increased rates of glucose utilisation ([3H] H2O production from 5-[3H] glucose) and oxidation ([14C] CO2 production from U-[14C] glucose) in islets isolated from 8-week-old control and GK Wistar rats, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Transcriptional control of yeast plasma membrane H(+)-ATPase by glucose. Cloning and characterization of a new gene involved in this regulation.

The expression of the ATPase gene (PMA1) is regulated by glucose (Rao, R., Drummond-Barbosa, D., and Slayman, C. W. (1993) Yeast 9, 1075-1084) and by the TUF/RAP1/GRF1 transcription factor (Capieaux, E., Vignais, M.-L., Sentenac, A., and Goffeau, A. (1989) J. Biol. Chem. 264, 7437-7446). In this work, we describe the isolation of mutations on seven genes that affect the levels of ATPase. One of these genes (APA1) was cloned by complementation and shown to encode a protein with six putative transmembrane stretches. Expression of APA1 gene is regulated by the carbon source and requires the protein GCR1. Deletion of APA1 causes a defective regulation of the PMA1 expression by glucose but has not noticeable effect on the expression of other TUF-regulated genes. Nevertheless the expression of glucose-repressible HXT3 and SNF3 genes is significantly reduced. These results suggest a model in which APA1 acts on a glucose-signaling pathway that controls the expression of several genes that are transcriptionally regulated by glucose.

Two glucose-signaling pathways in S14 gene transcription in primary hepatocytes: a common role of protein phosphorylation

Two glucose-signaling pathways in S14 gene transcription in primary hepatocytes: a common role of protein phosphorylation

Two glucose-signaling pathways in S14 gene transcription in primary hepatocytes: a common role of protein phosphorylation.

Transcription of the rat S14 gene is induced in response to increased carbohydrate metabolism in the liver. Because carbohydrate-induced changes in lipogenesis are mediated in part by changes in phosphorylation of multiple proteins, we investigated the role of protein phosphorylation on transcriptional regulation of the two carbohydrate response elements, a thyroid hormone receptor-independent carbohydrate response element and a thyroid receptor-dependent glucose response element located up-stream of the S14 gene. S14 reporter constructs were transiently transfected into rat primary hepatocytes and incubated with the protein or phosphatase inhibitor okadaic acid calyculin-A, or one of several protein kinase activators. Low dose okadaic acid blocked glucose induction from both elements without inhibiting glucose metabolism. Calyculin-A, a preferential phosphatase-1 inhibitor, only blocked the glucose response when glucose metabolism was inhibited. The protein kinase-C activator, 12-myristate 13-acetate, did not change the glucose responses, whereas the protein kinase-A activator, 8-(4-chlorophenylthio)cAMP, inhibited S14 transcription by inhibiting glucose metabolism. In contrast, the calcium ionophore A23187, a calmodulin kinase activator, mimicked the effect of low dose okadaic acid, but had no effect on glucose metabolism. We conclude that protein phosphatase-2A and calmodulin kinases may be involved in the glucose signaling pathway of the S14 gene. A similar phosphorylation step may be involved in the two distinct glucose response pathways.

Glucagon-Like Peptide-I and the Control of Insulin Secretion in the Normal State and in NIDDM

Potentiation of glucose-induced insulin secretion by intestinal factors has been described for many years. Today, two major peptides with potent insulinotropic action have been recognized: gastric inhibitory peptide and truncated forms of glucagon-like peptide I, GLP-I(7-37) or the related GLP-I(7-36)amide. These hormones have specific beta-cell receptors that are coupled to production of cAMP and activation of cAMP-dependent protein kinase. Elevation in intracellular cAMP levels is required to mediate the glucoincretin effect of these hormones: the potentiation of insulin secretion in the presence of stimulatory concentrations of glucose. In addition, circulating glucoincretins maintain basal levels of cAMP, which are necessary to keep beta-cells in a glucose-competent state. Interactions between glucoincretin signaling and glucose-induced insulin secretion may result from the phosphorylation of key elements of the glucose signaling pathway by cAMP-dependent protein kinase. These include the ATP-dependent K+ channel, the Ca++ channel, or elements of the secretory machinery itself. In NIDDM, the glucoincretin effect is reduced. However, basal or stimulated gastric inhibitory peptide and glucagon-like peptide I levels are normal or even elevated, suggesting that signals induced by these hormones on the beta-cells are probably altered. At pharmacological doses, infusion of glucagon-like peptide I but not gastric inhibitory peptide, can ameliorate postprandial insulin secretory response in NIDDM patients. Agonists of the glucagon-like peptide I receptor have been proposed as new therapeutic agents in NIDDM.

Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37).

Non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) is a disorder of glucose homeostasis characterized by hyperglycaemia, peripheral insulin resistance, impaired hepatic glucose metabolism, and diminished glucose-dependent secretion of insulin from pancreatic beta-cells. Glucagon-like-peptide-1(7-37) (GLP-1) is an intestinally derived hormone that may be useful for the treatment of NIDDM because it acts in vivo to increase the level of circulating insulin, and thus lower the concentration of blood glucose. This therapeutic effect may result from the ability of GLP-1 to compensate for a defect in the glucose signalling pathway that regulates insulin secretion from beta-cells. In support of this concept we report here that GLP-1 confers glucose sensitivity to glucose-resistant beta-cells, a phenomenon we term glucose competence. Induction of glucose competence by GLP-1 results from its synergistic interaction with glucose to inhibit metabolically regulated potassium channels that are also targeted for inhibition by sulphonylurea drugs commonly used in the treatment of NIDDM. Glucose competence allows membrane depolarization, the generation of action potentials, and Ca2+ influx, events that are known to trigger insulin secretion.