Tissue-Specific Differences in the Levels of Proglucagon-Derived Peptides in Streptozotocin-Induced Diabetes*

Brubaker, Patricia L.; So, Delvin; Drucker, Daniel J.

doi:10.1210/endo-124-6-3003

Cited by 34 publications

(19 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hence, insulin could affect glucagon biosynthesis at multiple levels. Our conclusion is in disagreement with previous results reported using a different experimental model (11). In these studies and despite insulin treatment, hyperglycemia persisted.…”

Section: Discussioncontrasting

confidence: 99%

See 1 more Smart Citation

Insulin, But Not Glucose Lowering Corrects the Hyperglucagonemia and Increased Proglucagon Messenger Ribonucleic Acid Levels Observed in Insulinopenic Diabetes**This work was supported by the Swiss National Fund (Grant 32–46816.96 to J.P. and Grant 32–34086.95 to P.M.), the Institute for Human Genetics and Biochemistry, the Nägeli Wolfermann Foundation, the Horten Foundation, and the Juvenile Diabetes Foundation International (Grant 197124).

et al. 1998

View full text Add to dashboard Cite

The factors that regulate glucagon biosynthesis and proglucagon gene expression are poorly defined. We previously reported that insulin inhibits proglucagon gene expression in vitro. In vivo, however, the effects of insulin on the regulation of the proglucagon gene have been controversial. Furthermore, whether glucose plays any role alone or in conjunction with insulin on proglucagon gene expression is unknown. We investigated the consequences of insulinopenic diabetes on glucagon gene expression in the endocrine pancreas and intestine and whether insulin and/or glucose could correct the observed abnormalities. We show here that in the first 3 days after induction of hyperglycemia by streptozotocin, rats have levels of plasma glucagon and proglucagon messenger RNA comparable to those of normoglycemic controls despite hyperglycemia. With more prolonged diabetes, plasma glucagon and proglucagon messenger RNA levels increase; this increase is corrected by insulin treatment, but not by phloridzin despite normalization of the glycemia by both treatments. Proglucagon gene expression exhibits the same regulatory response to glucose and insulin in both pancreas and ileum. We conclude that insulin tonically inhibits proglucagon gene expression in the pancreas and ileum and that glucose plays a minor, if any, role in this regulation. (Endocrinology 139: 4540 -4546, 1998) T HE ENDOCRINE pancreas plays a central role in the control of glucose homeostasis. Insulin and glucagon are the two major hormones that antagonistically control the balance between glucose storage and consumption and maintain plasma glucose levels within a very narrow range. Plasma insulin and glucagon levels are inversely correlated; insulin is secreted in response to nutrients to promote energy storage, whereas glucagon secretion is increased in the fasting state to activate glycogenolysis and gluconeogenesis.The proglucagon gene is expressed in pancreatic ␣-cells, intestinal L cells, and neurons of hypothalamus and medulla oblongata (1). Glucagon is derived from a larger precursor, proglucagon, which also contains in tandem two glucagonlike peptides, GLP-1 and GLP-2. Posttranslational processing of proglucagon is tissue specific, inasmuch as glucagon is the primary peptide synthesized in the pancreas, whereas glicentin, oxyntomodulin, GLP-1 and GLP-2 are released from the intestine (1).The fact that hyperglycemia is a hallmark of both insulindependent (IDDM) and noninsulin-dependent diabetes mellitus stimulated many studies on the role of the different factors regulating glucagon secretion and biosynthesis (2, 3).However, the precise roles of these factors in pancreatic ␣-cell function are still poorly understood. Control of glucagon secretion is probably mediated by multiple factors, including circulating intermediary metabolites, neurotransmitters, and hormones. However, the plasma glucose concentration, the insulin level, and the activity of the autonomic nervous system appear to be the major determinants (2). Physiologically, glucagon s...

show abstract

Section: Discussioncontrasting

confidence: 99%

“…Although insulin has been suggested to regulate pancreatic proglucagon gene expression in vitro (8,9), conflicting results have appeared in vivo. In the insulinopenic, streptozotocin-induced diabetic rat model, proglucagon messenger RNA (mRNA) levels have been reported to be either elevated (10) or comparable to those in nondiabetic rats (7,11).…”

mentioning

confidence: 99%

Insulin, But Not Glucose Lowering Corrects the Hyperglucagonemia and Increased Proglucagon Messenger Ribonucleic Acid Levels Observed in Insulinopenic Diabetes**This work was supported by the Swiss National Fund (Grant 32–46816.96 to J.P. and Grant 32–34086.95 to P.M.), the Institute for Human Genetics and Biochemistry, the Nägeli Wolfermann Foundation, the Horten Foundation, and the Juvenile Diabetes Foundation International (Grant 197124).

et al. 1998

View full text Add to dashboard Cite

show abstract

“…Pancreatic glucagon-like immunoreactivity showed only a transient rise on day 1 [76]. These differences between normal and diabetic rats were not due to an alteration of post-translational processing of proglucagon [76]. It has been speculated that peptides from proglucagon may exercise a trophic effect upon gastrointestinal mucosa 1781.…”

Section: Glp-1 and Intestinementioning

confidence: 94%

“…A similar increase of glucagon-like immunoreactivity has been shown in hypothermiainduced hyperphagia rats [77], so that the higher concentrations of GLP-1 -like-and glucagon-likeimmunoreactivity in the colon could be a consequence of an increased food intake. In rats with streptozotocin-induced diabetes, plasma levels and ileal peptide concentrations of glucagon-like immunoreactivity were elevated on days 8-22 of diabetes [76]. Pancreatic glucagon-like immunoreactivity showed only a transient rise on day 1 [76].…”

Section: Glp-1 and Intestinementioning

confidence: 94%

“…Investigations on the distribution of GLP-1-like immunoreactivity in the gastrointestinal tract showed highest concentrations in the terminal ileum and colon [16]. The GLP-l(7-36) amide content of the colon is increased in rats with streptozotocin-induced diabetes, which showed an increased food intake [16,76]. A similar increase of glucagon-like immunoreactivity has been shown in hypothermiainduced hyperphagia rats [77], so that the higher concentrations of GLP-1 -like-and glucagon-likeimmunoreactivity in the colon could be a consequence of an increased food intake.…”

Section: Glp-1 and Intestinementioning

confidence: 99%

See 1 more Smart Citation

Glucagon‐like peptide‐1(7–36) amide is a new incretin/enterogastrone candidate

Göke

Fehmann

Göke

1991

Eur J Clin Investigation

View full text Add to dashboard Cite

Molecular and cellular analysis of a neoplastic pancreatic a cell tumor

Drucker

Silverberg

et al. 1990

Cancer

Self Cite

View full text Add to dashboard Cite

Endocrine tumors of the pancreas may produce characteristic syndromes attributable to the increased secretion of one or more hormones. These tumors provide valuable opportunities for the analysis of hormone biosynthesis and secretion in the neoplastic human endocrine cell. The authors studied a pancreatic endocrine tumor obtained from a patient with classical glucagonoma syndrome. Characterization of plasma and tumor glucagon-like immunoreactivity (GLI) by high-performance liquid chromatography and radioimmunoassay for GLI showed different chromatographic profiles, with glucagon the major molecular form in the tumor, and glicentin and oxyntomodulin predominating in plasma. Although immunocytochemical staining of the tumor showed only focal weak positivity for glucagon, tumor extracts contained large amounts of immunoreactive GLI peptide. Northern blot analysis of tumor RNA demonstrated that abundant glucagon mRNA transcripts were present, just slightly larger in size than those detected in normal pancreas and intestine. Electron microscopic analysis of the tumor cellular ultrastructure revealed only occasional small electron dense secretory granules. A large number of complex lysosome-like structures of variable size and electron density were detected throughout the cytoplasm and ringing the nucleus of most cells, a feature atypical of endocrine tumors of the pancreas. Primary cultures of dispersed tumor cells were established and, in contrast to previous results, were obtained using normal or neoplastic islet cell models, GLI secretion was found to be stimulated eightfold by incubation with 5 mM dibutyryl cyclic adenosine monophosphate. Phorbol myristate acetate, the calcium ionophore A23187, and sodium butyrate had no effect on GLI secretion in vitro. These observations indicate that neoplastic human A cells may have abnormalities at different points in the biosynthesis and secretion of glucagon. Cancer 65:1762-1770,1990.EPTIDE HORMONE biosynthesis in normal endocrine P cells occurs as a series of tightly regulated molecular events, from gene transcription to the posttranslational From the

show abstract

Tissue-Specific Differences in the Levels of Proglucagon-Derived Peptides in Streptozotocin-Induced Diabetes*

Cited by 34 publications

References 31 publications

Glucagon‐like peptide‐1(7–36) amide is a new incretin/enterogastrone candidate

Molecular and cellular analysis of a neoplastic pancreatic a cell tumor

Contact Info

Product

Resources

About