Hypovitaminosis D is common in general medical inpatients, including those with vitamin D intakes exceeding the recommended daily allowance and those without apparent risk factors for vitamin D deficiency.

The endocrine cells of the rat pancreatic islets of Langerhans, including insulin-producing ␤-cells, turn over every 40 -50 days by processes of apoptosis and the proliferation and differentiation of new islet cells (neogenesis) from progenitor epithelial cells located in the pancreatic ducts. However, the administration to rats of islet trophic factors such as glucose or glucagon-like peptide 1 for 48 h results in a doubling of islet cell mass, suggesting that islet progenitor cells may reside within the islets themselves. Here we show that rat and human pancreatic islets contain a heretofore unrecognized distinct population of cells that express the neural stem cell-specific marker nestin. Nestin-positive cells within pancreatic islets express neither the hormones insulin, glucagon, somatostatin, or pancreatic polypeptide nor the markers of vascular endothelium or neurons, such as collagen IV and galanin. Focal regions of nestinpositive cells are also identified in large, small, and centrolobular ducts of the rat pancreas. Nestin-positive cells in the islets and in pancreatic ducts are distinct from ductal epithelium because they do not express the ductal marker cytokeratin 19 (CK19). After their isolation, these nestin-positive cells have an unusually extended proliferative capacity when cultured in vitro (ϳ8 months), can be cloned repeatedly, and appear to be multipotential. Upon confluence, they are able to differentiate into cells that express liver and exocrine pancreas markers, such as ␣-fetoprotein and pancreatic amylase, and display a ductal/endocrine phenotype with expression of CK19, neural-specific cell adhesion molecule, insulin, glucagon, and the pancreas/duodenum specific homeodomain transcription factor, IDX-1. We propose that these nestin-positive islet-derived progenitor ( T he mammalian pancreas consists of three distinct tissue types: the ductal tree, the exocrine acini that produce digestive enzymes, and the endocrine islets of Langerhans. Embedded in the exocrine tissue are the islets (which contain ␣-, ␤-, ␦-, and PP-cells that produce the hormones glucagon, insulin, somatostatin, and pancreatic polypeptide, respectively) involved in the regulation of physiological nutrient homeostasis (1). Ductal cells of the adult pancreas include latent progenitor cells of the islet endocrine cells that can be induced to differentiate into islet endocrine cells given the appropriate morphogen stimuli-a process referred to as neogenesis (2-6). The differentiation of duct cells of the pancreas into endocrine hormone-producing cells is believed to recapitulate the embryonic development (ontogeny) of the pancreas, whereby the exocrine and endocrine pancreases arise from the differentiation and proliferation of patterned endodermal cells in the early embryonic foregut that first form a ductal tree by branching morphogenesis (1). During early embryonic development, neural and islet cells share many phenotypic properties. Developing islet cells express several neuronal-specific markers such as synaptophysins,...

Considerable progress has been made in the understanding of the sequential activation of signal transduction pathways and the expression of transcription factors during pancreas development. Much of this understanding has been obtained by analyses of the phenotypes of mice in which the expression of key genes has been disrupted (knockout mice). Knockout of the genes for Pdx1, Hlxb9, Isl1, or Hex results in an arrest of pancreas development at a very early stage (embryonic d 8-9). Disruption of genes encoding components of the Notch signaling pathway, e.g. Hes1 or neurogenin-3, abrogates development of the endocrine pancreas (islets of Langerhans). Disruption of transcription factor genes expressed more downstream in the developmental cascade (Beta2/NeuroD, Pax4, NKx2.2, and Nkx6.1) curtails the formation of insulin-producing beta-cells. An understanding of the importance of transcription factor genes during pancreas development has provided insights into the pathogenesis of diabetes, in which the mass of insulin-producing beta-cells is reduced.

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Activin and myostatin are related members of the TGF-␤ growth factor superfamily. FSTL3 (Follistatin-like 3) is an activin and myostatin antagonist whose physiological role in adults remains to be determined. We found that homozygous FSTL3 knockout adults developed a distinct group of metabolic phenotypes, including increased pancreatic islet number and size, ␤ cell hyperplasia, decreased visceral fat mass, improved glucose tolerance, and enhanced insulin sensitivity, changes that might benefit obese, insulin-resistant patients. The mice also developed hepatic steatosis and mild hypertension but exhibited no alteration of muscle or body weight. This combination of phenotypes appears to arise from increased activin and myostatin bioactivity in specific tissues resulting from the absence of the FSTL3 antagonist. Thus, the enlarged islets and ␤ cell number likely result from increased activin action. Reduced visceral fat is consistent with a role for increased myostatin action in regulating fat deposition, which, in turn, may be partly responsible for the enhanced glucose tolerance and insulin sensitivity. Our results demonstrate that FSTL3 regulation of activin and myostatin is critical for normal adult metabolic homeostasis, suggesting that pharmacological manipulation of FSTL3 activity might simultaneously reduce visceral adiposity, increase ␤ cell mass, and improve insulin sensitivity.embers of the TGF-␤ superfamily of growth factors play diverse roles in embryonic development as well as in organ homeostasis and injury/pathogen response in adults (1). Activin and myostatin form one structurally related branch of the TGF-␤ family that utilizes common cell-surface receptors and Smad second messengers (2-4). Activin is a critical regulator of embryonic cell fate determination and organ development as well as adult organ homeostasis (5). Activin deletion in mice results in developmental defects and early neonatal death (6), whereas activin overexpression results in cancer, cachexia, and liver necrosis (3,7,8). Loss of myostatin expression results in increased muscle mass and reduced adiposity (9-11), whereas overexpression of myostatin leads to a severe reduction of both muscle and adipose tissue mass, along with cachexia (12, 13). These findings demonstrate the requirement for tight regulation of activin and myostatin activity to maintain normal adult physiology.Regulation of activin and myostatin activity occurs at multiple levels. Among the extracellular regulators, FSTL3 (follistatin like-3) and FST (follistatin) are structurally and functionally related glycoproteins that bind and antagonize actions of both activin and myostatin (14, 15). FSTL3 expression is highest in placenta, followed by testis, pancreas, and heart, whereas FST expression is high in ovary, testis, and kidney, suggesting that they may have nonoverlapping actions in different organs (16). Circulating FST was largely bound to activin (17), whereas FSTL3 was isolated from human and mouse serum as a complex with myostatin (18), indicating that F...

OBJECTIVE-Diabetes is caused by a deficiency of pancreatic ␤-cells that produce insulin. Approaches to enhance ␤-cell mass by increasing proliferation and survival are desirable. We determined whether stromal cell-derived factor (SDF)-1/CXCL12 and its receptor, CX chemokine receptor (CXCR)4, are important for the survival of ␤-cells. RESEARCH DESIGN AND METHODS-Mouse pancreata andclonal ␤-cells were examined for expression of SDF-1 and CXCR4, activation of AKT and downstream signaling pathways by SDF-1, and protection against apoptosis and diabetes induced by streptozotocin (STZ). RESULTS-CXCR4is expressed in ␤-cells, and SDF-1 is expressed in microvascular endothelial cells within the islets and in surrounding interstitial stromal tissue. Transgenic mice overexpressing SDF-1 within their ␤-cells (RIP-SDF-1 mice) are resistant to STZ-induced ␤-cell apoptosis and diabetes. In MIN6 ␤-cells, a CXCR4 antagonist (AMD3100) induces apoptosis, increases reactive oxygen species, decreases expression levels of the anti-apoptotic protein Bcl-2, and reduces phosphorylation of the proapoptotic protein Bad. Active phosphorylated prosurvival kinase Akt is increased both in the ␤-cells of RIP-SDF-1 mice and in INS-1 cells treated with SDF-1 and sensitive to AMD3100. Inhibition of AKT expression by small interfering RNA attenuates the ameliorative effects of SDF-1 on caspase-dependent apoptosis induced by thapsigargin or glucose deprivation in INS-1 ␤-cells. Specific inhibition of Akt activation by a soluble inhibitor (SH-5) reverses the anti-apoptotic effects of SDF-1 in INS-1 cells and mouse islets.CONCLUSIONS-SDF-1 promotes pancreatic ␤-cell survival via activation of Akt, suggesting that SDF-1 agonists may prove beneficial for treatment of diabetes.

Aims/hypotheses Ceramides and other sphingolipids comprise a family of lipid molecules that accumulate in skeletal muscle and promote insulin resistance. Chronic endurance exercise training decreases muscle ceramides and other sphingolipids, but less is known about the effects of a single bout of exercise. Methods We measured basal relationships and the effect of acute exercise (1.5 h at 50% V ⋅ O 2max ) and recovery on muscle sphingolipid content in obese volunteers, endurance trained athletes and individuals with type 2 diabetes. Results Muscle C18:0 ceramide (p = 0.029), dihydroceramide (p = 0.06) and glucosylceramide (p = 0.03) species were inversely related to insulin sensitivity without differences in total ceramide, dihydroceramide, and glucosylceramide concentration. Muscle C18:0 dihydroceramide correlated with markers of muscle inflammation (p = 0.04). Transcription of genes encoding sphingolipid synthesis enzymes was higher in athletes, suggesting an increased capacity for sphingolipid synthesis. The total concentration of muscle ceramides and sphingolipids increased during exercise and then decreased after recovery, during which time ceramide levels reduced to significantly below basal levels.Conclusions/interpretation These data suggest ceramide and other sphingolipids containing stearate (18:0) are uniquely related to insulin resistance in skeletal muscle. Recovery from an exercise bout decreased muscle ceramide concentration; this may represent a mechanism promoting the insulinsensitising effects of acute exercise.