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Proglucagon Products in Plasma of Noninsulin-Dependent Diabetics and Nondiabetic Controls in the Fasting State and After Oral Glucose and Intravenous Arginine

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Proglucagon Products in Plasma of Noninsulin-Dependent Diabetics and Nondiabetic Controls in the Fasting State and After Oral Glucose and Intravenous Arginine Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine. C Orskov, … , S Madsbad, J J Holst J Clin Invest. 1991;87(2):415-423. https://doi.org/10.1172/JCI115012. Research Article We investigated the major products of proglucagon (PG) processing in plasma in the fasting state, after intravenous arginine and after an oral glucose load in noninsulin-dependent diabetics (NIDDM) and in weight matched controls using specific radioimmunoassays and analytical gel filtration. In the fasting state the glucagonlike peptide-1 (GLP-1) immunoreactivity was significantly elevated in the NIDDM group compared with the control group. Both after intravenous arginine and after an oral glucose load a rise in the plasma concentrations of all immunoreactive moieties measured was seen. All integrated incremental responses after intravenous arginine were identical in the two groups. After oral glucose the insulin concentrations in plasma were lower and the concentrations of all proglucagon products were higher in the NIDDM group compared to the control group. The gel filtration analysis showed that arginine stimulated the secretion of pancreatic glucagon (PG 33-61), major proglucagon fragment (PG 72-158) and probably GLP-1 (PG 72-107 amide) in both groups, whereas oral glucose stimulated the secretion of glicentin (PG 1-69) and intestinal GLP-1 (PG 78-107 amide), an insulinotropic hormone. The elevated levels of immunoreactive GLP-1 in diabetics in the fasting state were mainly due to an increased concentration of major proglucagon fragment. Find the latest version: https://jci.me/115012/pdf Proglucagon Products in Plasma of Noninsulin-dependent Diabetics and Nondiabetic Controls in the Fasting State and after Oral Glucose and Intravenous Arginine Cathrine 0rskov,* Jorgen Jeppesen,t Sten Madsbad,t and Jens J. HoisP *Department of Clinical Biochemistry, Rigshospitalet, and OInstitute ofMedical Physiology C, Panum Institute, University of Copenhagen, Copenhagen; and tDepartment ofMedicine F, Herlev Hospital, Herlev, Denmark Abstract composition of rat MPGF, which was determined by Patzelt et al., is compared with the rat proglucagon sequence it is most We investigated the major products of proglucagon (PG) pro- likely that MPGF corresponds to PG 72-158 in the rat (4). The cessing in plasma in the fasting state, after intravenous arginine only proglucagon derived pancreatic peptide with known bio- and after an oral glucose load in noninsulin-dependent diabetics logical activity is glucagon. (NIDDM) and in weight matched controls using specific radio- In the small intestine the main products of proglucagon are immunoassays and analytical gel filtration. In the fasting state enteroglucagon (named glicentin in the pig [51) which corre- the glucagonlike peptide-1 (GLP-1) immunoreactivity was sig- sponds to PG 1-69 and thus includes the glucagon sequence, nificantly elevated in the NIDDM group compared with the and two separate peptides, both showing great homology with control group. Both after intravenous arginine and after an oral glucagon: glucagonlike peptide- 1 (GLP-1) which corresponds glucose load a rise in the plasma concentrations of all immuno- to PG 78-107 amide and glucagonlike peptide-2 (GLP-2) reactive moieties measured was seen. All integrated incremen- which corresponds to PG 126-158 (5-7). The major intestinal tal responses after intravenous arginine were identical in the proglucagon product with known biological effect is GLP- 1, two groups. After oral glucose the insulin concentrations in which has been shown to be both potently insulinotropic and plasma were lower and the concentrations of all proglucagon glucagonostatic (8-12). products were higher in the NIDDM group compared to the Though much is known about the structure ofthe progluca- control group. The gel filtration analysis showed that arginine gon products that can be extracted from pancreatic and intes- stimulated the secretion of pancreatic glucagon (PG 33-61), tinal tissues, little is known about the secreted proglucagon major proglucagon fragment (PG 72-158) and probably GLP-1 products in man and about stimuli for the secretion of these (PG 72-107 amide) in both groups, whereas oral glucose stimu- peptides. lated the secretion of glicentin (PG 1-69) and intestinal GLP-1 To elucidate these questions, we studied the proglucagon (PG 78-107 amide), an insulinotropic hormone. The elevated products in plasma under three conditions: in the fasting state, levels of immunoreactive GLP-1 in diabetics in the fasting state after an oral glucose load, and after an intravenous arginine were mainly due to an increased concentration of major proglu- infusion (the glucose and the arginine load being known to cagon fragment. (J. Clin. Invest. 1991. 87:415-423.) Key stimulate the secretion of intestinal and pancreatic progluca- words: glucagon - glucagonlike * peptide-1 * glicentin * oxynto- gon products, respectively, in pigs) (12). Furthermore, the modulin * enteroglucagon study was carried out both in noninsulin-dependent diabetics and in weight-matched controls to investigate whether distur- Introduction bances in the glucose metabolism might influence the secretion of proglucagon products in man. In 1983 the structure of human proglucagon was deduced by To be able to identify the proglucagon products in plasma Bell and co-workers from the nucleotide sequence ofthe gluca- we used two methods: (a) radioimmunoassays, using both an gon gene (1). The 160-amino acid prohormone, proglucagon antiserum directed against the carboxy-terminus of pancreatic (PG)', has been shown to be processed differentially in the pan- glucagon (4305) and an antiserum which cross-reacts with creas and the small intestine in man (2). In the pancreas the equal strength with all peptides containing the glucagon se- main products produced are (a) glucagon, (b) a 30-amino acid quence regardless of NH2- or COOH-terminal extensions peptide glicentin-related pancreatic peptide (GRPP), and (c) a (4304) (a so-called processing-independent antiserum) for glu- large peptide-designated major proglucagon fragment (MPGF) cagon measurements, and using an antiserum for GLP- 1 mea- that contains two glucagonlike sequences (3, 4) (Fig. 1). The surements which cross-reacts with equal strength with all pep- exact structure of MPGF is not known, but if the amino acid tides containing the GLP- 1 sequence regardless of NH2- or COOH-terminal extensions; and (b) gel filtration analysis. Be- cause processing-independent antisera have the virtue as well Address correspondence to Dr. Cathrine Orskov, Dept. of Clinical Bio- as the disadvantage of measuring all molecular forms contain- chemistry KK 3011, Rigshospitalet, Blegdamsvej 9, DK-2 100 Copen- the amino acid sequence against which the antiserum was hagen 0, Denmark. ing Receivedfor publication 26 February 1990 and in revised form 30 raised, gel filtration was a necessary supplement to determine August 1990. the molecular nature of the peptides measured. J. Clin. Invest. 1. Abbreviations used in this paper: GLP-1, glucagonlike peptide-l; © The American Society for Clinical Investigation, Inc. GRPP, glicentin-related pancreatic peptide; MPGF, major progluca- 0021-9738/91/02/0415/09 $2.00 gon fragment; NIDDM, noninsulin-dependent diabetic; PG, progluca- Volume 87, February 1991, 415-423 gon. Proglucagon Products in Plasma 415 1 3132 6263 78 109 110 160 I HII I I 70 71 124 125 -. Figure 1. Proglucagon processing in human pancreas and PancreascPGGRPP1-3099% IGlucagon9gIG33-61 . MPGFPG 72-158?65% small intestine. Solid boxes indicate known structures; peptides with incompletely characterized structures are * GLP-1-lR 35% * GLP-2-IR 35% * * PG 72107 ? i* PG 111-158 ? indicated as hatched boxes. The relative amount of a given peptide sequence occurring in each organ is indicated in percent of the total amount of proglucagon processed. In the pancreas the main products are 1 3132 6263 78 109110 160 glucagon, GRPP, and MPGF. Smaller amounts of not I fully characterized glucagonlike peptide- I and -2 (GLP- I H II1 H H I and GLP-2) immunoreactivities are found. *Very small 70 71 124 125 amounts ( l%) of PG 1-61 and PG 1-69 are formed in Enteroglucagon, 60% GLP-1 90% GLP-2 90% the pancreas. In the small intestine the main products Gut 1 PG 1-69 PG 78-107 PG126-158 1 are GLP- 1, GLP-2, glicentin, oxyntomodulin, and GRPP, 40% Oxyntomodulin GRPP. *A small amount (< 10%) of the total GLP-I-like PG 1-30 40% PG 33-691 immunoreactivity probably corresponds to MPGF. For the two additional intestinal products of proglucagon, porcine glucagon (Novo Research Institute) as described (14, 15). Anti- intervening peptide-2 and glucagonlike peptide-2 no biological serum 4305 recognizes the COOH-terminus of glucagon and thus activity has been discovered so far (7) and none of the peptides cross-reacts with all peptides with the same COOH-terminus as pancre- influence the secretion from the endocrine pancreas (unpub- atic glucagon. The experimental detection limit was below 2 pmol/ lished studies). Analyses for these peptides were therefore not liter. Total glucagon immunoreactivity (IR) was measured using the antiserum 4304, monoiodinated '25I-labeled glucagon and highly puri- included in the present study. fied porcine glucagon as described (14, 15). Antiserum 4304 cross- reacts with equal strength with all peptides that contain the glucagon Methods sequence, regardless of the presence or absence of COOH- or NH2-ter- minal extensions. The experimental detection limit was < 2 pmol/liter. Eight noninsulin-dependent diabetics (NIDDM) and eight weight- None of the glucagon antisera cross-reacted with GLP- 1 or any other matched nondiabetic controls were studied. The diagnosis NIDDM members of the glucagon/secretin family of peptides. The intraassay was based on World Health Organization criteria: venous fasting blood coefficient of variation in plasma was < 6%, and the interassay coeffi- glucose > 6.7 mmol/liter and/or venous blood glucose 120 min after a cient of variation was < 15% for both glucagon assays. 75-g oral glucose load at or above 10.0 mmol/liter.
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