The Glucagon Receptor Antagonist LY2409021 has No Effect on Postprandial Glucose in Type 2 Diabetes

Objective: Type 2 diabetes (T2D) pathophysiology includes fasting and postprandial hyperglucagonemia, which has been linked to hyperglycemia via increased endogenous glucose production (EGP). We used a glucagon receptor antagonist (LY2409021) and stable isotope tracer infusions to investigate consequences of hyperglucagonemia in type 2 diabetes. Design: A double-blinded, randomized, placebo-controlled crossover study was conducted. Methods: Ten patients with T2D and ten matched non-diabetic controls underwent two liquid mixed meal tests preceded by single-dose administration of LY2409021 (100 mg) or placebo. Double-tracer technique was used to quantify EGP. Antagonist selectivity towards related incretin receptors was determined in vitro. Results: Compared to placebo, LY2409021 lowered fasting plasma glucose from 9.1 to 7.1 mmol/L in patients and from 5.6 to 5.0 mmol/L in controls (both P<0.001) by mechanisms involving reduction of EGP. Postprandial plasma glucose excursions (baseline-subtracted area under the curve) were unaffected by LY2409021 in patients and increased in controls compared to placebo. Glucagon concentrations more than doubled during glucagon receptor antagonism. The antagonist interfered with both glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptors, complicating the interpretation of the postprandial data. Conclusions: LY2409021 lowered fasting plasma glucose concentrations but did not improve postprandial glucose tolerance after a meal in patients with T2D and controls. The metabolic consequences of postprandial hyperglucagonemia are difficult to evaluate using LY2409021 because of its antagonizing effects on the incretin receptors.

Alanine, arginine, cysteine, and proline, but not glutamine, are substrates for, and acute mediators of, the liver-α-cell axis in female mice

The aim of this study was to identify the amino acids that stimulate glucagon secretion in mice and whose metabolism depends on glucagon receptor signaling. Pancreata of female C57BL/6JRj mice were perfused with 19 individual amino acids and pyruvate (at 10 mM), and secretion of glucagon was assessed using a specific glucagon radioimmunoassay. Separately, a glucagon receptor antagonist (GRA; 25–2648, 100 mg/kg) or vehicle was administered to female C57BL/6JRj mice 3 h before an intraperitoneal injection of four different isomolar amino acid mixtures (in total 7 µmol/g body wt) as follows: mixture 1 contained alanine, arginine, cysteine, and proline; mixture 2 contained aspartate, glutamate, histidine, and lysine; mixture 3 contained citrulline, methionine, serine, and threonine; and mixture 4 contained glutamine, leucine, isoleucine, and valine. Blood glucose, plasma glucagon, amino acid, and insulin concentrations were measured using well-characterized methodologies. Alanine ( P = 0.03), arginine ( P < 0.0001), cysteine ( P = 0.01), glycine ( P = 0.02), lysine ( P = 0.02), and proline ( P = 0.03), but not glutamine ( P = 0.9), stimulated glucagon secretion from the perfused mouse pancreas. However, when the four isomolar amino acid mixtures were administered in vivo, the four mixtures elicited similar glucagon responses ( P > 0.5). Plasma concentrations of total amino acids in vivo were higher after administration of GRA when mixture 1 ( P = 0.004) or mixture 3 ( P = 0.04) were injected. Our data suggest that alanine, arginine, cysteine, and proline, but not glutamine, are involved in the acute regulation of the liver-α-cell axis in female mice, as they all increased glucagon secretion and their disappearance rate was altered by GRA.

Z-Selective Hydrofunctionalization of Dienes

Olefins play a fundamental role in synthetic organic chemistry because they are useful building blocks that create molecules. However, geometry control (E- vs Z-) in olefin synthesis is of utmost importance because the olefin geometry has a tremendous impact on its physical, chemical and biological properties. Additionally, Z-olefins are less stable compared to their E-olefin counterparts; due to this difference, general methods to make olefins results in more cases of E-olefins production with relatively fewer Z-olefins caused by its instability. It has been reported that Z-olefins can be synthesized from dienes through a rhodium-catalyzed formate mediated transformation, with tolerance to several reducible functional groups. With this successful method in hand, the focus is to make functionalized Z-alkenes while still maintaining tolerance to reducible functional groups under mild reaction conditions. Thus, this project presents the production of Z-olefins through rhodium-catalyzed hydrofunctionalization using the starting materials, dienes and aldehydes. This method requires an inert atmosphere and the reaction progress can be monitored by Nuclear Magnetic Resonance (NMR) using an internal standard to quantify the amount of product formed. In this process, it was observed that the starting material was consumed until more than 95% conversion. In addition, the possibility of using different dienes, such as diene esters and phenyl dienes, as well as different aldehydes could further broaden the scope of this method. The usefulness of this process can be applied to the production of complex molecules. For example, in the synthesis of a glucagon receptor antagonist, which is a drug that is used in the treatment of diabetes. Currently, there is a limited number of methods used to create Z-olefins; however, this proven procedure can be further applied in other hydrofunctionalization