摘要:

AbstractGlucose is essential for the energy metabolism of some cells and conservation of glucose is obligatory for survival during starvation. The principal site of this glucose conservation is the mitochondrial pyruvate dehydrogenase (PDH) complex, which is regulated by reversible phosphorylation (phosphorylation is inactivating). In cells in which glucose oxidation is switched off during starvation, fatty acids are used as fuel, and acetyl CoA and NADH formed by β‐oxidation promote phosphorylation of PDH complex by activation of PDH kinase. A longer‐term mechanism further increases PDH kinase activity in response to cAMP and products of β‐oxidation of fatty acids. Coordinated inhibition of glycolytic flux mediated by effects of citrate on PFK1 and PFK2 in muscles and liver results in an associated inhibition of glucose uptake. Similar mechanisms lead to impaired glucose oxidation in diabetes. © 1994 Wiley

ISSN:0730-2312    

DOI:10.1002/jcb.240550002

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe 37‐amino acid amylin, co‐secreted from the pancreatic β cells with insulin in response to nutrient stimuli has actions in a number of tissues of metabolic interest. In muscle it opposes glycogen synthesis and activates glycogenolysis, an action likely to underly its stimulation of lactate flux. Amylin therefore appears to have the effect of transposing carbon from peripheral stores to the liver, where it is made available for hepatic synthesis of glucose, glycogen, and lipid. While amylin induces insulin resistance in skeletal muscle, it does not oppose insulin action in fat and may therefore favor fuel deposition in this tissue. Amylin acts on the β cell to inhibit insulin secretion. Relative impairment of insulin secretion, muscle insulin resistance, relatively preserved insulin sensitivity in fact, increased lactate turnover, and increased hepatic glucose production are features of insulin resistance and early non‐insulin‐dependent diabetes mellitus. Amylin is elevated in these dysfunctional metabolic states and may be involved in their pathogenesis. © 1994 Wiley

ISSN:0730-2312    

DOI:10.1002/jcb.240550003

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractAmylin is a 37‐amino acid peptide first isolated, purified, and characterized from the amyloid deposits in the pancreases of type 2 diabetics. It is synthesized and secreted primarily from pancreatic beta cells along with insulin. The ability of amylin to potently reduce insulin‐stimulated incorporation of glucose into glycogen in skeletal muscle requires both an intact 2Cys–7Cys disulfide bond and a COOH‐terminal amide. Amylin has structural and functional relationships to two other messenger proteins, calcitonin and CGRP. Amylin has relatively potent calcitonin‐like activity on bone metabolism and weaker CGRP‐like activity on the vasculature. CGRP is a slightly weaker agonist than amylin for metabolic responses. Although rat calcitonins are weak, teleost fish calcitonins are very potent agonists for amylin's metabolic effects. This group of peptides appears to act on a family of related G protein‐coupled receptors; several variant calcitonin receptors have recently been cloned and expressed. These receptors appear to be coupled to adenylyl cyclase in many instances; recent evidence supports the view that amylin's effects on skeletal muscle occur, at least in large part, through activation of the cAMP pathway. © 1994 W

ISSN:0730-2312    

DOI:10.1002/jcb.240550004

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractDespite intensive investigation, a clear understanding of the metabolic disturbances in diabetes mellitus and their temporal relationship to each other during disease development has still not emerged. With emphasis on non‐insulin‐dependent diabetes (NIDDM), three possibilities are explored here: (1) that the insulin resistance characteristic of obesity/NIDDM syndromes is the result rather than the cause of hyperinsulinemia, as is widely held, (2) that the linkage between hyperactivity of the pancreatic β‐cell and peripheral insulin resistance is vested in excessive delivery of lipid substrate from liver to the muscle bed, and (3) that conceivably hyperamylinemia works in concert with hyperinsulinemia in promoting overproduction of very‐low‐density lipoproteins by the liver, and thus in the etiology of muscle insulin resistance. © 1994 Wile

ISSN:0730-2312    

DOI:10.1002/jcb.240550005

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractIslet amyloid polypeptide (“amylin”) is the major protein component of amyloid deposits in pancreatic islets of type 2 (non‐insulin‐dependent) diabetic patients. Islet amyloid polypeptide consists of 37 amino acids, is co‐produced and co‐secreted with insulin from islet β‐cells, can act as a hormone in regulation of carbohydrate metabolism, and is implicated in the pathogenesis of islet amyloid formation and of type 2 diabetes mellitus. Rat islet amyloid polypeptide differs from human islet amyloid polypeptide particularly in the region of amino acids 25–28, which is important for amyloid fibril formation. In rat and mouse, diabetes‐associated islet amyloid does not develop. To study the genetic organization and biosynthesis of islet amyloid polypeptide, we have isolated and analyzed the human and rat islet amyloid polypeptide gene and corresponding cDNAs. Both genes contain 3 exons, encoding precursor proteins of 89 amino acids and 93 amino acids, respectively. Apart from a putative signal sequence, these precursors contain amino‐ and carboxy‐terminal flanking peptides in addition to the mature islet amyloid polypeptide. To understand regulation of islet amyloid polypeptide gene expression, we have identified several potentialcis‐acting transcriptional control elements that influence β‐cell‐specific islet amyloid polypeptide gene expression. Using antisera raised against synthetic human islet amyloid polypeptide we developed a specific and sensitive radioimmunoassay to measure levels of islet amyloid polypeptide in plasma and tissue extracts. Also antisera raised against the flanking peptides will be used in studying human islet amyloid polypeptide biosynthesis. Elevated plasma islet amyloid polypeptide levels have been demonstrated in some diabetic, glucose‐intolerant, and obese individuals, as well as in rodent models of diabetes and obesity. To examine the potential role of islet amyloid polypeptide overproduction in the pathogenesis of islet amyloid formation and type 2 diabetes, we generated transgenic mice that overproduce either the amyloidogenic human islet amyloid polypeptide or the nonamyloidogenic rat islet amyloid polypeptide in their islet β‐cells. Despite moderately to highly (up to 15‐fold) elevated plasma islet amyloid polypeptide levels, no marked hyperglycemia, hyperinsulinemia or obesity was observed. This suggests that chronic overproduction of islet amyloid polypeptide “per se” does not cause insulin resistance. No islet amyloid deposits were detected in mice up to 63 weeks of age, but in every mouse producing human islet amyloid polypeptide (as in man), accumulation of islet amyloid polypeptide was observed in β‐cell lysosomal bodies. This may represent an initial phase in intracellular amyloid fibril formation. The human islet amyloid polypeptide overproducing transgenic mice model offers a unique opportunity to study the biosynthesis, intracellular handling, secretion, and extracellular handling of human islet amyloid

ISSN:0730-2312    

DOI:10.1002/jcb.240550006

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractInsulin secretion is triggered by a rise in the intracellular Ca2+concentration that results from the activation of voltage‐gated Ca2+channels in the β‐cell plasma membrane. Multiple types of β‐cell Ca2+channel have been identified in both electrophysiological and molecular biological studies, but it appears that the L‐type Ca2+channel plays a dominant role in regulating Ca2+influx. Activity of this channel is potentiated by protein kinases A and C and is inhibited by GTP‐binding proteins, which may mediate the effects of potentiators and inhibitors of insulin secretion on Ca2+influx, respectively. The mechanism by which elevation of intracellular Ca2+leads to the release of insulin granules is not fully understood but appears to involve activation of Ca2+/calmodulin‐dependent protein kinase. Phosphorylation by either protein kinase A or C, probably at different substrates, potentiates insulin secretion by acting at some late stage in the secretory process. There is also evidence that small GTP‐binding proteins are involved in regulating exocytosis in β cells. The identification and characterisation of the proteins involved in exocytosis in β cells and clarification of the mechanism(s) of action of Ca2+is clearly an important goal for the future. © 19

ISSN:0730-2312    

DOI:10.1002/jcb.240550007

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractChallenge of intact hepatocytes with amylin only succeeded in elevating intracellular cyclic AMP levels and activating phosphorylase in the presence of the cAMP phosphodiesterase inhibitor IBMX. Both amylin and CGRP similarly activated adenylate cyclase, around 5‐fold, although ∼ 400‐fold higher levels of amylin were required to elicit half maximal activation. Amylin activated adenylate cyclase though apparently simple Michaelin kinetics whereas CGRP elicited activation by kinetics indicative of apparent negative co‐operativity. Use of the antagonist CGPP(8–37) showed that both CGRP and amylin activated hepatocyte adenylate cyclase through a common receptor by a mnemonical mechanism where it was proposed that the receptor co‐existed in interconvertible high and low affinity states for CGRP. It is suggested that this model may serve as a paradigm for G‐protein linked receptors in general. Amylin failed to both stimulate inositol phospholipid metabolism in hepatocytes and to elicit the desensitization of glucagon‐stimulated adenylate cyclase. Amylin did, however, elicit the phosphorylation of the inhibitory guanine nucleotide regulatory protein Gi‐2 in hepatocytes and prevented the action of insulin in reducing the level of phosphorylation of this G‐protein. ©

ISSN:0730-2312    

DOI:10.1002/jcb.240550008

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

ISSN:0730-2312    

DOI:10.1002/jcb.240550001

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY