Glucagon, the counter-regulatory hormone to insulin, is secreted from pancreatic ␣ cells in response to low blood glucose. To examine the role of glucagon in glucose homeostasis, mice were generated with a null mutation of the glucagon receptor (Gcgr ؊/؊ ). These mice display lower blood glucose levels throughout the day and improved glucose tolerance but similar insulin levels compared with control animals. Gcgr ؊/؊ mice displayed supraphysiological glucagon levels associated with postnatal enlargement of the pancreas and hyperplasia of islets due predominantly to ␣ cell, and to a lesser extent, ␦ cell proliferation. In addition, increased proglucagon expression and processing resulted in increased pancreatic glucogen-like peptide 1 (GLP-1) (1-37) and GLP-1 amide (1-36 amide) content and a 3-to 10-fold increase in circulating GLP-1 amide. Gcgr ؊/؊ mice also displayed reduced adiposity and leptin levels but normal body weight, food intake, and energy expenditure. These data indicate that glucagon is essential for maintenance of normal glycemia and postnatal regulation of islet and ␣ and ␦ cell numbers. Furthermore, the lean phenotype of Gcgr ؊/؊ mice suggests glucagon action may be involved in the regulation of whole body composition.

OBJECTIVETo determine the role of glucagon action in the metabolic phenotype of untreated insulin deficiency.RESEARCH DESIGN AND METHODSWe compared pertinent clinical and metabolic parameters in glucagon receptor-null (Gcgr−/−) mice and wild-type (Gcgr+/+) controls after equivalent destruction of β-cells. We used a double dose of streptozotocin to maximize β-cell destruction.RESULTSGcgr+/+ mice became hyperglycemic (>500 mg/dL), hyperketonemic, polyuric, and cachectic and had to be killed after 6 weeks. Despite comparable β-cell destruction in Gcgr−/− mice, none of the foregoing clinical or laboratory manifestations of diabetes appeared. There was marked α-cell hyperplasia and hyperglucagonemia (∼1,200 pg/mL), but hepatic phosphorylated cAMP response element binding protein and phosphoenolpyruvate carboxykinase mRNA were profoundly reduced compared with Gcgr+/+ mice with diabetes—evidence that glucagon action had been effectively blocked. Fasting glucose levels and oral and intraperitoneal glucose tolerance tests were normal. Both fasting and nonfasting free fatty acid levels and nonfasting β-hydroxy butyrate levels were lower.CONCLUSIONSWe conclude that blocking glucagon action prevents the deadly metabolic and clinical derangements of type 1 diabetic mice.

Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes1, 2, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene3, 4, the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide−/− mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction5, 6. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE’s physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.

Hafnium carbide (HfC) phase, with a high melting point, excellent strength, and high electrical conductivity, could be a suitable addition to enhance the microwave absorption properties of one-dimensional silicon carbide (SiC) nanomaterials without sacrificing its high-temperature thermal stability. In the present work, HfC/SiC hybrid nanofiber mats with different HfC loading contents are fabricated by electrospinning and high-temperature pyrolysis. HfC hybrids with sizes of 5-10 nm are embedded in the SiC nanofibers. As the HfC content increases from 0 to 6.3 wt %, the average diameter of the fibers drops from 2.62 μm to 260 nm. Meanwhile, the electrical conductivity rises from 7.9 × 10 to 4.2 × 10 S/cm. Moreover, the flexibility of the nanofiber mats is also greatly improved, according to a 200-times 180° bending test. Furthermore, compared with pure SiC fiber mats, the HfC/SiC nanofiber mats possess much larger dielectric loss because of higher electrical conductivity. At the optimal HfC content of 2.5 wt %, the HfC/SiC nanofibers/silicon resin composite (10 wt %) exhibits a minimal reflection loss (RL) of -33.9 dB at 12.8 GHz and a 3 mm thickness with a broad effective absorption bandwidth (RL < -10 dB) of 7.4 GHz. The above results prove that introducing HfC into SiC nanofiber mats is an effective way to enhance their flexibility, dielectric properties, and microwave absorption performance.