No abstract

Although glucagon (GLU) plays a pivotal role in glucose homeostasis, its role in the regulation of fetal growth and maturation is poorly understood. These issues were examined in a line of mice with a global deletion of the GLU receptor (Gcgr-/-), which are characterized by lower blood glucose levels and by alpha- and delta-cell hyperplasia in adults. Ablation of Gcgr was deleterious to fetal survival; it delayed beta-cell differentiation and perturbed the proportion of beta- to alpha-cells in embryonic islets. In adults, the mutation inhibited the progression of alpha-cells to maturity, affected the expression of several beta-cell-specific genes, and resulted in an augmentation of the alpha-, beta-, and delta-cell mass. This increase was due to an augmentation in both islet number and in the rate of proliferation of cells expressing GLU or insulin. These findings suggest that GLU participates in a feedback loop that regulates the proportion of the different endocrine cell types in islets, the number of islets per pancreas, and development of the mature alpha-cell phenotype.

It has been shown that inhibition of de novo sphingolipid synthesis increases insulin sensitivity. For further exploration of the mechanism involved, we utilized two models: heterozygous serine palmitoyltransferase (SPT) subunit 2 (Sptlc2) gene knockout mice and sphingomyelin synthase 2 (Sms2) gene knockout mice. SPT is the key enzyme in sphingolipid biosynthesis, and Sptlc2 is one of its subunits. Homozygous Sptlc2-deficient mice are embryonic lethal. However, heterozygous Sptlc2-deficient mice that were viable and without major developmental defects demonstrated decreased ceramide and sphingomyelin levels in the cell plasma membranes, as well as heightened sensitivity to insulin. Moreover, these mutant mice were protected from high-fat diet-induced obesity and insulin resistance. SMS is the last enzyme for sphingomyelin biosynthesis, and SMS2 is one of its isoforms. Sms2 deficiency increased cell membrane ceramide but decreased SM levels. Sms2 deficiency also increased insulin sensitivity and ameliorated high-fat diet-induced obesity. We have concluded that Sptlc2 heterozygous deficiency-or Sms2 deficiency-mediated reduction of SM in the plasma membranes leads to an improvement in tissue and whole-body insulin sensitivity.Metabolic syndrome is a collection of abnormalities in metabolism, including obesity, nonalcoholic fatty liver disease, macrophage inflammation, impaired fasting glucose clearance, dyslipidemia, and hypertension. Insulin resistance appears to be a key feature in metabolic syndrome (47). The de novo sphingolipid synthesis pathway is considered a promising target for pharmacological intervention in insulin resistance. It has been shown that inhibition of serine palmitoyltransferase (SPT; the first enzyme for sphingolipid biosynthesis) increases insulin sensitivity (17). However, the mechanism is incompletely understood, since such an inhibition decreases many bioactive sphingolipids, including sphingomyelin (44), ceramide, and glycosphingolipids. Ceramide levels appear to be important in mediating inflammation, obesity, and insulin sensitivity (4, 17, 18). Sphingomyelin (SM) levels also appear to be important in mediating inflammation and atherosclerosis (11,27,34). However, few in vivo studies have been conducted to investigate the functions of these two metabolism-related sphingolipids separately, since animal models are lacking.The biochemical synthesis of SM occurs through the actions of SPT, 3-ketosphinganine reductase, ceramide synthase, dihydroceramide desaturase, and sphingomyelin synthase (SMS) (36). Mammalian SPT contains two subunits, Sptlc1 and Sptlc2, encoding 53-and 63-kDa proteins, respectively (13, 64). These subunits are homologous, sharing roughly 20% sequence identity (13, 64), and form a heterodimer. A third subunit, Sptlc3, has also been reported (19), but its function remains to be elucidated. Recently, the discovery of two proteins, ssSPTa and ssSPTb, was reported. Each substantially enhances the activity of mammalian SPT, expressed in either yeast or mammalian cells, and...