Edited by Helaine E. Resnick, PhD, MPH

Data in this issue of Diabetes (p. 1453) show that fibroblast growth factor 21 (FGF21), a fasting-induced hormone secreted by the liver, is an important mediator of glucagon’s long-term metabolic actions. Glucagon is a counter-regulatory hormone to insulin and is released during periods of hypoglycemia to regulate glucose homeostasis. Glucagon agonism is considered to be a potentially promising avenue for the treatment of obesity and diabetes. Because native glucagon has molecular properties that make the hormone difficult to study, Habegger et al. developed a soluble, long-acting, selective glucagon receptor (GcgR) agonist (IUB288). When treated with IUB288, both chow-fed and DIO mice showed increased blood glucose. Chronic GcgR agonism resulted in lower levels of circulating cholesterol. In DIO mice, chronic GcgR activation also decreased body and fat mass while increasing both hepatic FGF21 expression and plasma FGF21. In isolated primary hepatocytes from wild-type (WT) mice, glucagon increased FGF21 expression in a dose-dependent manner. This effect was not seen in GcgR knockout hepatocytes. Chronic GcgR activation lowered circulating cholesterol and prevented fat mass accumulation in WT but not in FGF21–/– mice. To evaluate clinical relevance, investigators gave obese healthy subjects a 1 mg intramuscular injection of glucagon or placebo. Plasma FGF21 concentrations increased significantly in the human volunteers who received glucagon. Regarded as a whole, these results indicate that glucagon’s long-term metabolic effects on glucose and lipid metabolism are mediated in part by FGF21. — Laura Gehl, PhD

Habegger et al. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 2013;62:1453–1463

Work by Leboucher et al. in this issue of Diabetes (p. 1681) shows that diet-induced obesity (DIO) worsens τ phosphorylation and learning abilities in the THY-Tau22 transgenic mouse model of progressive Alzheimer disease (AD)-like τ pathology. In the new report, investigators studied the effects of early high-fat diet (HFD) feeding on later development of τ transgenic mice. The τ pathology encountered in AD, specifically the aggregation of hyperphosphorylated τ proteins into neurofibrillary tangles, is known to contribute to cognitive decline. Development of obesity in midlife is also a known risk factor for insulin resistance and type 2 diabetes. Further, development of obesity in midlife has been shown to increase the risk of dementia and AD, a relationship that is thought to be related to central insulin resistance, secondary to peripheral insulin resistance. However, the effects of DIO on τ pathology and cognitive decline have not been previously investigated. Work presented in this issue shows that τ transgenic mice demonstrated increased escape latency and path length as compared with wild-type (WT) mice; HFD-fed τ transgenic mice showed greater cognitive decline compared with chow-fed τ transgenic mice. While HFD did not induce a global increase in τ phosphorylation in τ transgenic mice, phosphorylation was significantly increased on specific τ phosphoepitopes. Peripheral insulin resistance is thought to promote central insulin resistance, contributing to τ phosphorylation and other AD pathophysiology. However, the data indicate that, unlike WT mice, HFD-fed τ transgenic mice do not develop peripheral insulin resistance. These results show that early-life DIO worsens τ phosphorylation and spatial memory in later life and that these changes are independent of peripheral/central insulin resistance. — Laura Gehl, PhD

Leboucher et al. Detrimental effects of diet-induced obesity on τ pathology are independent of insulin resistance in τ transgenic mice. Diabetes 2013;62:1681–1688

Immunohistochemical analyses of hippocampal τ phosphorylation

Immunohistochemical analyses of hippocampal τ phosphorylation

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In this issue of Diabetes (p. 1730), Ferrannini et al. examine data from two large prospective studies to evaluate new predictive biomarkers for dysglycemia. These candidates, α-hydroxybutyrate (α-HB) and linoleoyl-glycerophosphocholine (L-GPC), emerged from previous screening of numerous metabolites, with α-HB concentration being positively and L-GPC negatively associated with glycemia. The current report explored the ability of these two markers to predict dysglycemia and also examined the underlying physiology using in vitro and in vivo methods. Data from the two studies were strikingly similar with regard to the distributions of α-HB and L-GPC in relation to insulin sensitivity and diabetes. Clear increases in α-HB were observed as baseline glycemia categories worsened. Importantly, differences were observed even across quartiles of insulin sensitivity among normoglycemic individuals. The converse was true for L-GPC: this marker decreased as baseline glucose category worsened, a trend that could be observed across quartiles of normal glucose tolerance (NGT). At the conclusion of follow-up of NGT participants, individuals with glycemic progression showed increases in α-HB and decreases in L-GPC. Further, individuals who remained stable had decreased α-HB and increased L-GPC. Overall, the predictive value for dysglycemia was positive for α-HB and negative for L-GPC, of equal strength and statistically significant for each marker. In vitro experiments indicated dose-dependent increases in insulin secretion for L-GPC and dose-dependent suppression of secretion for α-HB. These results suggest that these novel biomarkers may be helpful in efforts to more accurately identify individuals at risk of developing diabetes. — Brendan Horton

Ferrannini et al. Early metabolic markers of the development of dysglycemia and type 2 diabetes and their physiological significance. Diabetes 2013;62:1730–1737

Despite the introduction of the Edmonton protocol in 2000, there has been limited progress toward insulin independence through islet cell transplantation. Although advances continue to be made, the limitations of existing graft sites in humans prevent this approach from being a viable treatment for type 1 diabetes. Islet cell transplants must meet a number of requirements to be a realistic therapeutic option. They must produce faster vascularization around allografts to avoid β-cell loss to ischemia and its subsequent immune recruitment, overcome limitations due to adverse auto- and alloimmune responses, allow islet cells better access to blood glucose, provide an outlet for secreted insulin that more closely matches that of a healthy pancreas, and be accessible through minimally invasive surgical procedures. In this issue of Diabetes (p. 1357), Smink et al. review current limitations associated with islet grafting and explore the engineering of new ectopic transplant sites with biopolymer scaffolds that resemble the pancreatic environment. The three-dimensional scaffolds would integrate extracellular components, such as collagen IV, fibronectin, or laminin, and would also localize selective immunosuppression, angiogenic signaling, and growth factors. The authors point out that a number of biopolymers already have FDA approval for other uses and could be targets for efficient exploration for islet cell grafting. Further, the new scaffolding could facilitate investigation of multiple sites that are surgically accessible, such as the gastric submucosa or peritoneum/omentum, thereby moving away from invasive transplantation in the spleen or pancreas. The authors emphasize that this approach may reduce the requisite number of cells for transplant, thus mitigating the impact of tissue shortages and related logistical hurtles that currently inhibit successful treatment of type 1 diabetes. — Brendan Horton

Smink et al. Toward engineering a novel transplantation site for human pancreatic islets. Diabetes 2013;62:1357–1364

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