One may carefully evaluate the

One may carefully evaluate the concept ‘pancreas derived GLP-1′ as this may dependent on the specificity of the YT Broth, 2X powder blend used in immunohistochemistry or radiommunoassays. If either a side-viewing antibody or a C-terminal wrapping antibody raised against GLP-1 is applied one may also identify N-terminal elongated isoforms of GLP-1termed GLP-1 1–36 (1–37 in rats). These isoforms are biological inactive and co-secreted with glucagon [36]. Active GLP-1 7–36 measured by a N-terminal specific antibody (or by a sandwich ELISA) targeting the N-terminus (without cross-reaction to N-terminal elongate forms) may therefore more likely reflect biological active forms of GLP-1 and hence contribute to increase glucose-induced insulin secretion. This does not imply that studies reporting expression of active GLP-1 from the pancreatic alpha cells are inaccurate but merely that one may need to be aware that the use of an unspecific GLP-1 antibody may led to inaccurate conclusions and therefore may be viewed as a potential limitation. As an example, we were unable to detect active GLP-1 in pancreatic biopsies from normal mice whereas in mice lacking the glucagon receptor high concentrations of GLP-1 7–36NH2 was found [37]. The same argument may be made for the concept of gut-derived glucagon, why the development of monoclonal C-terminal antibodies by Mercodia and others may be important for determining the molecular structure of glucagon-like immunoreactivity. As such there may exist sufficient evidence to support that a wide range of clinical states induces or at least associates with altered processing of proglucagon as illustrated in Fig. 1B. However, it still needs to be demonstrated if such differential processing of proglucagon actually contribute clinically to parameters such as HbA1c and appetite (body weight). Future studies using specific antibodies and antibody-independent techniques may help determining the actual existence of gut-derived glucagon and pancreatic derived GLP-1.
Antagonizing the glucagon receptor Development of diabetes may depend on the altered glucose-induced glucagon response, termed the glucagonocentric hypothesis, as suggested by Professor Unger and colleagues [5], [38]. Therefore, antagonizing the glucagon receptor has been an appealing strategy [5]. In 1982, diabetic rats treated with a glucagon analog (l-N alpha-trinitrophenylhistidine, 12-homoarginine]-glucagon) possessing antagonistic effects on the glucagon receptor, diminished blood glucose by up to 35 percentages [8]. Subsequently, a range of glucagon receptor antagonists have been developed and tested in animal models [1], [7], [9], [39], [40], [41], [42] however only a few have reached clinical trials [9]. These may chemically be divided into three groups: the small-molecule GRAs (Bay 27–9955, MK-0893 [43], MK-3577, LY-2409021 [9], PF-06291874 [44], LGD-6972 [45]), the monoclonal antibodies against the GCGr (LY2786890 [46], PF-06293620, REMD-477), and thirdly the antisense oligonucleuotides against GCGr mRNA (ISIS-GCGRR and ISIS 325568). These glucagon receptor antagonists have shown to have glucose-regulatory effects however a wide range of side effects including increased liver enzymes, have been challenged their way for clinical application. As recently reviewed, there seem to exist a ‘glucose-lowering’ difference upon glucagon receptor antagonism in animal models of type 1 diabetes and type 2 diabetes [6]. Whereas the animal models of type 1 diabetes obviously lacks insulin the models of type 2 diabetes may not neccesarily reflect individuals with type 2 diabetes as it is multifactorial disease. The most crucial component across the effect of glucagon receptor antagonism in these animal models of diabetes may be insulin and its importance for intra-islet regulation, termed the intra-islet hypothesis [47]. Upon beta cell destruction hyperglycemia is not followed when glucagon receptor signaling is blocked [42]. However, the opposite has also been shown [48]. The reason underlying these differential effects of glucagon receptor antagonism in animal models of type 1 diabetes may be the differences in acute compared chronic studies; In an acute setting lack of glucagon receptor signaling may not save the animal for hyperglycemia whereas long-term treatment with a glucagon receptor antagonist may target different signaling pathways.