Evidence for Acute Stimulation of Fibrinogen Production by Glucagon in Humans

Abstract

Fibrinogen, an acute-phase protein, and glucagon, a stress hormone, are often elevated in many conditions of physical and metabolic stress, including uncontrolled diabetes. However, the possible mechanisms for this association are poorly known. We have studied the acute effects of selective hyperglucagonemia (raised from -200 to -350 pg/ml for 3 h) on fibrinogen fractional secretion rate (FSR) in eight normal subjects during infusion of somatostatin and replacement doses of insulin, glucagon, and growth hormone. Fibrinogen FSR was evaluated by precursor-product relationships using either Phe (n = 8) or Leu (« = 2) tracers. Hyperglucagonemia did not change either plasma Phe or Tyr specific activity. After hyperglucagonemia, fibrinogen FSR increased by -65% (from 12.9 ± 3.6 to 21.5 ± 6.1% per day, P < 0.025) using plasma Phe specific activity as the precursor pool. FSR increased by -80% (from 16.6 ± 4.8 to 29.4 ± 8.8% per day, P < 0.025) if plasma Phe specific activity was corrected for the ketoisocaproate/Leu enrichment (or specific activity) ratio to obtain an approximate estimate of intrahepatic Phe specific activity. FSR increased by -60% when using plasma Tyr specific activity as precursor pool (n = 8) (P < 0.05), as well as when using the Leu tracer precursorproduct relationship (n = 2). In conclusion, selective hyperglucagonemia for -3 h acutely stimulated fibrinogen FSR using a Phe tracer method. Thus, glucagon may be involved in the increase of fibrinogen concentration and FSR observed under stressed or pathologic conditions. Diabetes 46:1368-1371, 1997 F ibrinogen is an acute-phase protein (1) that is increased in uncontrolled diabetes, vascular disease, and smoking and in many conditions of physical and metabolic stress (2-6). Its plasma concentration has been recognized as a strong and independent cardiovascular risk factor (7). Nevertheless, the mechanisms and the factors that regulate fibrinogen synthesis in vivo are poorly understood. In humans, fibrinogen fractional secretion rate (FSR) was increased by acute insulin deficiency in IDDM (8), while it was decreased by short-term insulin infusion in both normal subjects and subjects with IDDM (8,9). Received for publication 10 December 1996 and accepted in revised form 12 May 1997.FSR, fractional secretion rate; HPLC, high-performance liquid chromatography; KIC, a-ketoisocaproate; MPE, mole percent enrichment.Besides these scarce data, however, the role of other hormonal or metabolic factors in regulating fibrinogen FSR in vivo is largely unknown. In many conditions in which fibrinogen concentration is elevated, including uncontrolled diabetes (10), the concentration of glucagon is also increased. Since glucagon is a stress hormone (11), it might be involved in the synthesis of acute-phase reactants. Thus, it is interesting to investigate whether there is a causal association between increments of glucagon concentrations and fibrinogen FSR in vivo.The aim of this study was therefore to evaluate whether an isolated and acute increase of glucagon concen...

Is Type II diabetes mellitus a disease of the innate immune system?

“…This suggests that insulin resistance can amplify the cytokine effect on the liver. Hyperglucagonaemia can also stimulate the acutephase response [66]. The lack of an increased acutephase response in uncomplicated Type I diabetes indicate that liver insulin resistance is much more prominent in Type II diabetes or that insulin in fact has a relatively minor role in the regulation of the response.…”

Diabetic nephropathy is associated with increased albumin and fibrinogen production in patients with type 2 diabetes

“…The mechanism(s) of such an association in diabetes are not known. Fibrinogen and albumin are two liversynthesised proteins, with different functions and responses to both acute and chronic stimuli [10][11][12][13][14][15][16][17]. In non-diabetic nephrotic syndromes, production of albumin and fibrinogen is increased [18,19], suggesting coordinate changes in hepatic protein production in response to albuminuria.…”

Insulin Acutely Increases Fibrinogen Production in Individuals With Type 2 Diabetes but Not in Individuals Without Diabetes

“…Analytical methods. Fibrinogen was isolated from plasma as previously described (11,21,22). In short, 100 l of a 1 mol/l CaCl 2 solution and 10 IU thrombin in 100 l deionized water were added to 2 ml plasma to activate the reactions leading to the formation of a fibrin clot.…”

“…After 1-h incubation at room temperature, the samples were centrifuged, and the clot was removed from the sample, gently washed on filtered paper with deionized water to remove any plasma residues, and hydrolyzed for 48 h at 110°C in 4 ml 4 N HCl. The fibrinogen-derived free amino acids were then purified through cation exchange AG 50X8 columns (11,21,22). 3 H-leu specific activity in hydrolyzed fibrinogen samples as well as plasma 3 H-␣-ketoisocaproate (KIC) specific activity were measured by HPLC as previously described (20).…”