Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production

Glucagon is secreted from pancreatic a cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in b cells demonstrated that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in vivo. We conclude that glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion

The free moment in walking and its change with foot rotation angle

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Systems signatures reveal unique remission-path of Type 2 diabetes following Roux-en-Y gastric bypass surgery

Roux-en-Y Gastric bypass surgery (RYGB) is emerging as a powerful tool for treatment of obesity and may also cause remission of type 2 diabetes. However, the molecular mechanism of RYGB leading to diabetes remission independent of weight loss remains elusive. In this study, we profiled plasma metabolites and proteins of 10 normal glucose-tolerant obese (NO) and 9 diabetic obese (DO) patients before and 1-week, 3-months, 1-year after RYGB. 146 proteins and 128 metabolites from both NO and DO groups at all four stages were selected for further analysis. By analyzing a set of bi-molecular associations among the corresponding network of the subjects with our newly developed computational method, we defined the represented physiological states (called the edge-states that reflect the interactions among the bio-molecules), and the related molecular networks of NO and DO patients, respectively. The principal component analyses (PCA) revealed that the edge states of the post-RYGB NO subjects were significantly different from those of the post-RYGB DO patients. Particularly, the time-dependent changes of the molecular hub-networks differed between DO and NO groups after RYGB. In conclusion, by developing molecular network-based systems signatures, we for the first time reveal that RYGB generates a unique path for diabetes remission independent of weight loss

Effects of knee joint angle on global and local strains within human triceps surae muscle: MRI analysis indicating in vivo myofascial force transmission between synergistic muscles

Purpose Mechanical interactions between muscles have been shown for in situ conditions. In vivo data for humans is unavailable. Global and local length changes of calf muscles were studied to test the hypothesis that local strains may occur also within muscle for which global strain equals zero. Methods For determination of globally induced strain in m. gastrocnemius in dissected human cadavers several knee joint angles were imposed, while keeping ankle joint angle constant and measuring its muscle-tendon complex length changes. In vivo local strains in both gastrocnemius and soleus muscles were calculated using MRI techniques in healthy human volunteers comparing images taken at static knee angles of 173° and 150°. Results Imposed global strains on gastrocnemius were much smaller than local strains. High distributions of strains were encountered, e.g. overall lengthened muscle contains locally lengthened, as well as shortened areas within it. Substantial strains were not limited to gastrocnemius, but were found also in synergistic soleus muscle, despite the latter muscle-tendon complex length remaining isometric (constant ankle angle: i.e. global strain = 0), as it does not cross the knee. Based on results of animal experiments this effect is ascribed to myofascial connections between these synergistic muscles. The most likely pathway is the neurovascular tract within the anterior crural compartment (i.e. the collagen reinforcements of blood vessels, lymphatics and nerves). However, direct intermuscular transmission of force may also occur via the perimysium shared between the two muscles. Conclusions Global strains imposed on muscle (joint movement) are not good estimators of in vivo local strains within it: differing in magnitude, as well as direction of length change. Substantial mechanical interaction occurs between calf muscles, which is mediated by myofascial force transmission between these synergistic muscles. This confirms conclusions of previous in situ studies in experimental animals and human patients, for in vivo conditions in healthy human subjects. © 2011 Springer-Verlag

Secretin release after Roux-en-Y gastric bypass reveals a population of glucose-sensitive S cells in distal small intestine

Abstract: Objectives: Gastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB) on glycemic control. Secretin is secreted from duodenal S cells in response to low luminal pH, but it is unknown whether its secretion is altered after RYGB and if secretin contributes to the postoperative improvement in glycemic control. We hypothesized that secretin secretion increases after RYGB as a result of the diversion of nutrients to more distal parts of the small intestine, and thereby affects islet hormone release. Methods: A specific secretin radioimmunoassay was developed, evaluated biochemically, and used to quantify plasma concentrations of secretin in 13 obese individuals before, 1 week after, and 3 months after RYGB. Distribution of secretin and its receptor was assessed by RNA sequencing, mass-spectrometry and in situ hybridization in human and rat tissues. Isolated, perfused rat intestine and pancreas were used to explore the molecular mechanism underlying glucose-induced secretin secretion and to study direct effects of secretin on glucagon, insulin, and somatostatin secretion. Secretin was administered alone or in combination with GLP-1 to non-sedated rats to evaluate effects on glucose regulation. Results: Plasma postprandial secretin was more than doubled in humans after RYGB (P < 0.001). The distal small intestine harbored secretin expressing cells in both rats and humans. Glucose increased the secretion of secretin in a sodium-glucose cotransporter dependent manner when administered to the distal part but not into the proximal part of the rat small intestine. Secretin stimulated somatostatin secretion (fold change: 1.59, P < 0.05) from the perfused rat pancreas but affected neither insulin (P = 0.2) nor glucagon (P = 0.97) secretion. When administered to rats in vivo, insulin secretion was attenuated and glucagon secretion increased (P = 0.04), while blood glucose peak time was delayed (from 15 to 45 min) and gastric emptying time prolonged (P = 0.004). Conclusions: Glucose-sensing secretin cells located in the distal part of the small intestine may contribute to increased plasma concentrations observed after RYGB. The metabolic role of the distal S cells warrants further studies