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At least 523 records · Page 29Linked to original sources
PubMed2000

Mitochondrial signals in glucose-stimulated insulin secretion in the beta cell.

Glucose-induced insulin secretion is determined by signals generated in the mitochondria. The elevation of ATP is necessary for the membrane-dependent increase in cytosolic Ca2+, the main trigger of insulin exocytosis. Beta cells depleted of mitochondrial DNA fail to respond to glucose while still secreting insulin in response to membrane depolarisation. This cell model resembles the situation of defective insulin secretion in patients with mitochondrial diabetes. On the other hand, infants with activating mutations in the mitochondrial enzyme glutamate dehydrogenase are characterised by hyperinsulinism and hypoglycaemia. We have recently proposed that glutamate, generated by this enzyme, participates in insulin secretion as a glucose-derived metabolic messenger. In this model, glutamate acts downstream of the mitochondria by sensitising the exocytotic process to Ca2+. The evidence in favour of such a role for glutamate is discussed in the present review.

Animals↗
PubMed2000

CFTR induces the expression of DRA along with Cl(-)/HCO(3)(-) exchange activity in tracheal epithelial cells.

Thickening of airway mucus and lung dysfunction in cystic fibrosis (CF) results, at least in part, from abnormal secretion of Cl(-) and HCO(3)(-) across the tracheal epithelium. The mechanism of the defect in HCO(3)(-) secretion is ill defined; however, a lack of apical Cl(-)/HCO(3)(-) exchange may exist in CF. To test this hypothesis, we examined the expression of Cl(-)/HCO(3)(-) exchangers in tracheal epithelial cells exhibiting physiological features prototypical of cystic fibrosis [CFT-1 cells, lacking a functional cystic fibrosis transmembrane conductance regulator (CFTR)] or normal trachea (CFT-1 cells transfected with functional wild-type CFTR, termed CFT-WT). Cells were grown on coverslips and were loaded with the pH-sensitive dye 2', 7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, and intracellular pH was monitored. Cl(-)/HCO(3)(-) exchange activity increased by approximately 300% in cells transfected with functional CFTR, with activities increasing from 0.034 pH/min in CFT-1 cells to 0.11 in CFT-WT cells (P < 0.001, n = 8). This activity was significantly inhibited by DIDS. The mRNA expression of the ubiquitous basolateral AE-2 Cl(-)/HCO(3)(-) exchanger remained unchanged. However, mRNA encoding DRA, recently shown to be a Cl(-)/HCO(3)(-) exchanger (Melvin JE, Park K, Richardson L, Schultheis PJ, and Shull GE. J Biol Chem 274: 22855-22861, 1999.) was abundantly expressed in cells expressing functional CFTR but not in cells that lacked CFTR or that expressed mutant CFTR. In conclusion, CFTR induces the mRNA expression of "downregulated in adenoma" (DRA) and, as a result, upregulates the apical Cl(-)/HCO(3)(-) exchanger activity in tracheal cells. We propose that the tracheal HCO(3)(-) secretion defect in patients with CF is partly due to the downregulation of the apical Cl(-)/HCO(3)(-) exchange activity mediated by DRA.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2001

Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: functional and pathological consequences.

Mutations in the human genes encoding the tissue-specific transcription factors hepatocyte nuclear factor (HNF)1alpha, HNF1beta and HNF4alpha are responsible for maturity onset diabetes of the young (MODY), a monogenic dominant inherited form of diabetes mellitus characterized by defective insulin secretion of the pancreatic beta-cells. In addition, the mutated HNF1beta gene causes defective development of the kidney and genital malformation. This review summarizes the main features of these transcription factors and discusses potential events leading to the specific disease phenotypes.

Amino Acid Sequence↗
PubMed1991

Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis.

Hepatic insulin extraction is difficult to measure in humans; as a result, the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001), which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose, the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min), suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients, both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However, with oral glucose the rise in serum C-peptide concentration was relatively delayed, and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1978

Restoration of the acute insulin response by sodium salicylate. A glucose dose-related phenomenon.

Adult-onset diabetics have markedly diminished or absent acute insulin responses to glucose that can be partially restored by sodium salicylate infusion. To determine whether this restoration of the acute insulin response is glucose dose dependent and whether complete restoration can be achieved, adult-onset diabetics with a mean fasting plasma glucose value of 216 +/- 20 mg. per deciliter (x +/- S.E.) were stimulated with various doses of intravenous glucose. Restoration occurred in a glucose dose-dependent manner. Complete restoration could not be achieved with the maximal tolerable glucose dose (80 gm.). Second phase insulin secretion also improved in a glucose dose-dependent manner. These findings are compatible with the hypothesis that defective insulin secretion in adult-onset, hyperglycemic diabetics is not due to absolute deficiency of insulin but may be a result of defective recognition of glucose signals by pancreatic B-cells--a defect that can be partially reversed by sodium salicylate.

Adult↗
PubMed1995

Pharmacologic treatment of abnormal ion transport in the airway epithelium in cystic fibrosis.

Cystic fibrosis (CF) is a recessive genetic disease reflecting mutations in the gene coding for the CF transmembrane regulator (CFTR) protein, which normally functions as a cyclic adenosine monophosphate (cAMP)-regulated chloride (Cl-) channel. Functional abnormalities include thick airway secretions resulting from defective cAMP-mediated Cl- (liquid) secretion and a related defect, excessive sodium (Na+) (liquid) absorption. Novel pharmacologic agents are being tested as therapy for these ion transport defects. Aerosolized amiloride inhibits excessive Na+ absorption, and pilot studies in adult patients with CF show slowing of the disease-associated decline in lung function. Clinical trials of amiloride are currently underway in adults and adolescents, and short-term safety studies have been initiated in children. Aerosolized uridine triphosphate (UTP) induces Cl- (and liquid) secretion in CF airway epithelia via non-CFTR Cl- channels. Short-term aerosolized UTP is well tolerated by normal subjects and patients with CF, and pilot studies in normal subjects show that aerosolized UTP is an effective stimulator of mucociliary clearance. Pharmacotherapy that modifies airway epithelial ion transport may provide new opportunities for treatment of CF lung disease.

Adolescent↗
PubMed1995

Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative.

OBJECTIVE: To test the hypothesis that insulin resistance precedes impaired insulin secretion in individuals genetically predisposed to non-insulin-dependent diabetes mellitus (NIDDM). DESIGN: Case-control study. SETTING: Outpatient facility of clinical research center. PARTICIPANTS: One hundred volunteers of European ancestry having normal glucose tolerance, 50 with and 50 without a first-degree NIDDM relative, matched for age, sex, and degree of obesity. MAIN OUTCOME MEASURES: Insulin secretion and insulin sensitivity assessed by hyperglycemic (N = 100) and euglycemic-hyperinsulinemic (N = 62) clamp experiments. RESULTS: The individuals with a first-degree NIDDM relative had reduced first- and second-phase insulin responses (mean +/- SEM, 939 +/- 68 vs 1209 +/- 82 pmol/L, and 322 +/- 19 vs 407 +/- 24 pmol/L, respectively, P = .001 and .01), but their insulin sensitivity (148 +/- 6 and 92 +/- 6 nmol.kg-1.min-1/pmol.L-1 in hyperglycemic and euglycemic clamp studies) did not differ from that of the control group (126 +/- 5 and 81 +/- 7 nmol.kg-1.min-1/pmol.L-1, in hyperglycemic and euglycemic clamp studies, P = .07 and .24, respectively). In some individuals only first- or only second-phase insulin responses were reduced. CONCLUSION: In this study population, heterogeneous defects in insulin secretion were demonstrated, while defects in insulin sensitivity were not evident. We therefore conclude that since the earliest defects identified in a group genetically at high risk to develop NIDDM are those related to insulin secretion, defects in insulin secretion rather than insulin sensitivity are likely the major genetic factor predisposing to development of NIDDM.

Adult↗
PubMed1999

Recent developments in oral hypoglycemic agents.

Recent large-scale studies in patients with type 2 diabetes have suggested that improved glycemic control will reduce the incidence and severity of chronic complications. However, it is difficult to maintain the blood glucose levels of diabetic patients within a narrow range. Since insulin resistance and impaired insulin secretion cause hyperglycemia in type 2 diabetes, both improvement of insulin resistance and compensation for defective insulin secretion are necessary. Recently, the first insulin sensitizer was released, and a short-acting insulinotropic agent, which should be more convenient for strict glycemic control than sulfonylureas, has also been launched. This review focuses on these two new classes of hypoglycemic agents.

Journal Article↗
PubMed2000

Caenorhabditis elegans beta-G spectrin is dispensable for establishment of epithelial polarity, but essential for muscular and neuronal function.

The Caenorhabditis elegans genome encodes one alpha spectrin subunit, a beta spectrin subunit (beta-G), and a beta-H spectrin subunit. Our experiments show that the phenotype resulting from the loss of the C. elegans alpha spectrin is reproduced by tandem depletion of both beta-G and beta-H spectrins. We propose that alpha spectrin combines with the beta-G and beta-H subunits to form alpha/beta-G and alpha/beta-H heteromers that perform the entire repertoire of spectrin function in the nematode. The expression patterns of nematode beta-G spectrin and vertebrate beta spectrins exhibit three striking parallels including: (1) beta spectrins are associated with the sites of cell-cell contact in epithelial tissues; (2) the highest levels of beta-G spectrin occur in the nervous system; and (3) beta spectrin-G in striated muscle is associated with points of attachment of the myofilament apparatus to adjacent cells. Nematode beta-G spectrin associates with plasma membranes at sites of cell-cell contact, beginning at the two-cell stage, and with a dramatic increase in intensity after gastrulation when most cell proliferation has been completed. Strikingly, depletion of nematode beta-G spectrin by RNA-mediated interference to undetectable levels does not affect the establishment of structural and functional polarity in epidermis and intestine. Contrary to recent speculation, beta-G spectrin is not associated with internal membranes and depletion of beta-G spectrin was not associated with any detectable defects in secretion. Instead beta-G spectrin-deficient nematodes arrest as early larvae with progressive defects in the musculature and nervous system. Therefore, C. elegans beta-G spectrin is required for normal muscle and neuron function, but is dispensable for embryonic elongation and establishment of early epithelial polarity. We hypothesize that heteromeric spectrin evolved in metazoans in response to the needs of cells in the context of mechanically integrated tissues that can withstand the rigors imposed by an active organism.

Amino Acid Sequence↗
PubMed1998

[Chloride secretion in the intestinal epithelium: channels, ions, and intracellular signaling].

Salt and water secretion by epithelial cells is required to hydrate the mucosal surface of both gastrointestinal and respiratory tracts. Intestinal secretion is the result of active transcellular chloride transport by epithelial cells lining the crypts. Defective chloride secretion is responsible for many common disorders such as secretory diarrhea and cystic fibrosis. In this review we deal with the most relevant issues regarding epithelial transcellular chloride secretion. We first consider the principles of membrane transport and transport protein function. Then, we briefly discuss the use of state-of-the-art techniques for electrophysiological studies such as "patch-clamp" and microfluorometry. The epithelial chloride secretion model is described according to observations made in both native tissue and cultured intestinal epithelial cells. Next, we consider the intracellular signaling cascades involved in the regulation of membrane transport systems and transcellular chloride secretion. Finally, the clinical implications of the most recent findings are commented, with emphasis on potential molecular targets for the treatment of cystic fibrosis and secretory diarrhea.

Cell Membrane↗
PubMed1993

Pseudomonas aeruginosa lasB1 mutants produce an elastase, substituted at active-site His-223, that is defective in activity, processing, and secretion.

Pseudomonas aeruginosa secretes elastase in a multistep process which begins with the synthesis of a preproelastase (53.6 kDa) encoded by lasB, is followed by processing to proelastase (51 kDa), and concludes with the rapid accumulation of mature elastase (33 kDa) in the extracellular environment. In this study, mutants of P. aeruginosa were constructed by gene replacement which expressed lasB1, an allele altered in vitro at an active-site His-223-encoding codon. The lasB1 allele was exchanged for chromosomal lasB sequences in two strain backgrounds, FRD2 and PAO1, through a selectable-cassette strategy which placed a downstream Tn501 marker next to lasB1 and provided the selection for homologous recombination with the chromosome. Two lasB1 mutants, FRD720 and PDO220, were characterized, and their culture supernatants contained greatly reduced proteolytic (9-fold) and elastolytic (14- to 20-fold) activities compared with their respective parental lasB+ strains. This was primarily due to the effect of His-223 substitution on substrate binding by elastase and thus its proteolytic activity. However, the concentration of supernatant elastase antigen was also reduced (five- to sevenfold) in the mutant strains compared with the parental strains. An immunoblot analysis of cell extracts showed a large accumulation of 51-kDa proelastase within lasB1 mutant cells which was not seen in wild-type cell extracts. A time course study showed that production of extracellular elastase was inefficient in the lasB1 mutants compared with that of parental strains. This showed that expression of an enzymatically defective elastase inhibits proper processing of proelastase and provides further evidence for autoproteolytic processing of proelastase in P. aeruginosa. Unlike the parental strains, culture supernatants of the lasB1 mutants contained two prominent elastase species that were 33 and 36 kDa in size. Extracellular 51-kDa proelastase was barely detectable, even though it accumulated to high concentrations within the lasB1 mutant cells. These data suggest that production of an enzymatically defective elastase affects proper secretion because autoproteolytic processing of proelastase is necessary for efficient localization to the extracellular milieu. The appearance of reduced amounts of extracellular elastase and their sizes of 33 and 36 kDa suggest that lasB1-encoded elastase was processed by alternate, less-efficient processing mechanisms. Thus, proelastase must be processed by removal of nearly all of the 18-kDa propeptide before elastase is a protein competent for extracellular secretion.

Alleles↗
PubMed1999

[Early changes in the function of pancreatic beta cells and insulin pulsatility as predictors of type 2 diabetes].

Type 2 diabetes mellitus is characterized by a defective insulin secretion and a reduction in insulin action on its targets. These possibly genetically-driven primary defects combine with secondary long term hyperglycemia and metabolic abnormalities. Whereas type 1 diabetes mellitus is clearly linked to a reduction in beta-cell mass, type 2 diabetes mellitus appears as secondary to an hereditary beta-cell dysfunction. Indeed, insulin resistance does not stand as the sole cause for type 2 diabetes, as suggested by cases of severe insulin resistance in diabetes-free, non aged, obese or acromegalic patients, as well as in patients treated with steroids. In fact, type 2 diabetes results from an inappropriate insulin secretion in regards with body needs.

Diabetes Mellitus, Type 2↗
PubMed1982

Intracellular degradation of newly synthesized collagen.

The intracellular degradation of newly synthesized collagen is a cellular pathway that accounts for the destruction of 10-60% of collagen synthesized by a variety of cell types prior to secretion. This pathway can serve in a regulatory role to limit the secretion of defective molecules, and, in response to some extracellular mediators, regulates the amount and type of collagens secreted. In addition, this pathway may contribute to the pathogenesis of a variety of conditions affecting the extracellular matrix including fibrosis, diabetes mellitus, and scurvy.

Animals↗
PubMed1976

A role for alpha-adrenergic receptors in abnormal insulin secretion in diabetes mellitus.

To determine whether endogenous alpha-adrenergic activity contributes to abnormal insulin secretion in nonketotic, hyperglycemic, diabetic patients, alpha-adrenergic blockade was produced in normal and diabetic subjects. The diabetics had a significantly (P less than 0.01) greater increase in circulating insulin 1 h after an intravenous phentolamine infusion than did the normal subjects. During the phentolamine infusion, there was also a significant augmentation of acute insulin responses to intravenous glucose (20 g) pulses in normal subjects (P less than 0.05) and diabetics (P less than 0.02); this augmentation was fivefold greater in the diabetics. Simultaneous treatment with the beta-adrenergic blocking agent, propranolol, did not alter these findings. Thus a role for exaggerated endogenous alpha-adrenergic activity in abnormal insulin secretion of the diabetic subjects is suggested. To determine whether this alpha-adrenergic activity might be related to elevated circulating catecholamines, total plasma-catecholamine levels were compared in normal and nonketotic diabetic subjects given intravenous glucose pulses. These levels were significantly greater (P less than 0.02) in the diabetic compared to the normal group before the glucose pulse, and increased significantly in both groups (P less than 0.02 and less than 0.001, respectively) after the pulse. These data suggest that excessive catecholamine secretion may lead to an abnormal degree of endogenous alpha-adrenergic activity, which contributes to defective insulin secretion in diabetic subjects.

Autonomic Agents↗
PubMed2006

Deletion of nicotinamide nucleotide transhydrogenase: a new quantitive trait locus accounting for glucose intolerance in C57BL/6J mice.

The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion. The genetic locus underlying this phenotype was mapped to nicotinamide nucleotide transhydrogenase (Nnt) on mouse chromosome 13, a nuclear-encoded mitochondrial protein involved in beta-cell mitochondrial metabolism. C57BL/6J mice have a naturally occurring in-frame five-exon deletion in Nnt that removes exons 7-11. This results in a complete absence of Nnt protein in these mice. We show that transgenic expression of the entire Nnt gene in C57BL/6J mice rescues their impaired insulin secretion and glucose-intolerant phenotype. This study provides direct evidence that Nnt deficiency results in defective insulin secretion and inappropriate glucose homeostasis in male C57BL/6J mice.

Animals↗
PubMed1995

Overexpression of choline acetyltransferase reconstitutes discrete acetylcholine release in some but not all synapse formation-defective neuroblastoma cells.

Secretion of acetylcholine (ACh) in neuroblastoma cells overexpressing choline acetyltransferase (ChAT) was examined. With transient transfection of ChAT cDNA, neuroblastoma cells, which have no endogenous ChAT and either adhere to myotubes or not, failed to form functional synapses, and thus no evidence for release of ACh was detected. Stable neuroblastoma cell lines overexpressing ChAT accumulated ACh inside the cell, and slowly released ACh to the outside of the cell in a calcium-independent fashion. However, after co-culturing them with rat muscle cells, these transformed cells adhered to myotubes and ACh was secreted in a discrete fashion into the synaptic cleft efficiently in some neuroblastoma cell lines but rather inefficiently in another cell line. The results show that the latent secretion machinery of ChAT overexpressing neuroblastoma cells either is competent or possess defect(s) in ACh release.

Acetylcholine↗
PubMed2000

Role of insulin in age-related changes in macronutrient metabolism.

Age is associated with an increase in body fat mass and a decrease of protein mass. As body substrate turnover is under insulin control, defects in insulin secretion and/or action may in part account for these changes. As regards secretion, current evidence suggest that no clear defect in insulin secretion is found in the aged. The wide spectrum of glucose tolerance of the elderly may be associated with different patterns of insulin secretion. Insulin sensitivity to glucose metabolism is more or less normal in the aged, despite subtle delays in the onset of its action. Normalization of the data by either body weight or lean body mass is important in defining the insulin sensitivity of the elderly. Increased rates of free fatty acid (FFA) flux and oxidation rates have been found in healthy elderly subjects, both when post-absorptive and during hyperinsulinemia. These differences however disappeared following normalization by fat mass, suggesting that FFA kinetics reflect the established changes in fat mass. Thus, the mechanism(s) leading to an increase in the fat mass in elderly cannot simply be derived from studies of fat kinetics. The operation of the Randle cycle (ie, inverse relationships between fat and glucose oxidation) in the elderly has also been suggested. Finally, the insulin effects on whole-body amino acid and protein metabolism do not seem to be impaired in the aged. However, in the human muscle a decreased synthesis of contractile as well as mitochondrial proteins was found, in association with decreased specific gene expression. The degree of physical activity probably interacts with these changes, possibly playing a causative role. The possible interaction between insulin and exercise in the maintenance of muscle mass in the elderly needs to be studied further.

Aging↗
PubMedDate not supplied

From obesity to diabetes: why, when and who?

Obesity is considered as the most important risk factor for type 2 diabetes. We will briefly discuss why does obesity predispose to diabetes, when does diabetes occur in obese subjects and who among obese individuals is particularly prone to develop diabetes. Obesity, especially intraabdominal adiposity, is associated with increased FFA plasma concentrations which exert a major negative effect on insulin sensitivity at both muscular and hepatic sites. Various metabolic, haemodynamic and hormonal theories have been proposed to explain insulin resistance in obese subjects. A specific role of TNF-alpha has been recently suggested. However, besides insulin resistance, defective insulin secretion is a prerequisie for the development of overt type 2 diabetes. Both lipotoxicity and glucotoxicity may initiate and perpetuate a vicious circle responsible for the metabolic deterioration. Diabetes occurs as a late phenomenon in obesity and is preceded by years of impaired glucose tolerance. The progression to diabetes is heralded by an inability of the B cell to maintain its previously high rate of insulin secretion in response to glucose in face of insulin resistance. This propensity to develop type 2 diabetes may be genetically determined and/or triggered by environmental factors. The evolution from obesity to diabetes represents a continuum that progresses through different phases in which defects in both insulin action and insulin secretion play a critical interaction and must be looked at in concert.

Adipose Tissue↗