Exercise, obesity and type 2 diabetes are associated with elevated plasma concentrations of interleukin-6 (IL-6). Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin secretion. Here we show that administration of IL-6 or elevated IL-6 concentrations in response to exercise stimulate GLP-1 secretion from intestinal L cells and pancreatic alpha cells, improving insulin secretion and glycemia. IL-6 increased GLP-1 production from alpha cells through increased proglucagon (which is encoded by GCG) and prohormone convertase 1/3 expression. In models of Reprints and permissions information is available online at www.nature.com/reprints/index.html.

Activation of the innate immune system in obesity is a risk factor for the development of type 2 diabetes. The aim of the current study was to investigate the notion that increased numbers of macrophages exist in the islets of type 2 diabetes patients and that this may be explained by a dysregulation of islet-derived inflammatory factors. Increased islet-associated immune cells were observed in human type 2 diabetic patients, high-fat-fed C57BL/6J mice, the GK rat, and the db/db mouse. When cultured islets were exposed to a type 2 diabetic milieu or when islets were isolated from high-fat-fed mice, increased isletderived inflammatory factors were produced and released, including interleukin (IL)-6, IL-8, chemokine KC, granulocyte colony-stimulating factor, and macrophage inflammatory protein 1␣. The specificity of this response was investigated by direct comparison to nonislet pancreatic tissue and ␤-cell lines and was not mimicked by the induction of islet cell death. Further, this inflammatory response was found to be biologically functional, as conditioned medium from human islets exposed to a type 2 diabetic milieu could induce increased migration of monocytes and neutrophils. This migration was blocked by IL-8 neutralization, and IL-8 was localized to the human pancreatic ␣-cell. Therefore, islet-derived inflammatory factors are regulated by a type 2 diabetic milieu and may contribute to the macrophage infiltration of pancreatic islets that we observe in type 2 diabetes. Diabetes 56:2356-2370, 2007 A ctivation of the innate immune system has long been reported in obesity, insulin resistance, and type 2 diabetics and is characterized by increased circulating levels of acute-phase proteins and of cytokines and chemokines (1-5). However, the notion that excess circulating nutrients may stimulate the ␤-cell to produce chemokines remains unexplored, and immune cell infiltration has not been shown in islets of type 2 diabetic patients.One of the most classical chemotactic agents in immunology is the CXC family chemokine, interleukin (IL)-8 (CXCL8) (6). IL-8 is produced by leukocytes, fibroblasts, and endothelial and epithelial cells and is commonly associated with infections, graft rejection, allergy, asthma, cancer, and atherosclerosis. In addition to its effect on neutrophils, the chemotactic effect of IL-8 also is important in mediating monocyte migration (7-9). The rodent does not express IL-8. Instead, the rodent functional homolog of IL-8 is thought to be chemokine KC (CXCL1, or Gro-␣ in the rat), which also has been reported to induce granulocyte and monocyte migration (9). Chemokine KC is thought to be an ortholog of human CXCL1. Circulating levels of IL-8 are elevated in type 2 diabetic individuals (10,11), in whom IL-8 has been implicated in systemic insulin resistance and atherosclerosis (12,13).Thus, we hypothesized that pancreatic islets in type 2 diabetes are characterized by increased macrophage infiltration and that a type 2 diabetic milieu could promote chemokine production in pancreatic islets. ...

A decrease in the number of functional insulin-producing ␤-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in ␤-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of ␤-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K ؉ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-B, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of ␤-cell secretory function and cell turnover. Thus, the mechanisms regulating ␤-cell proliferation, apoptosis, and function are inseparable processes. Diabetes 54 (Suppl. 2):S108 -S113, 2005 F or many years, the contribution of a reduction in ␤-cell mass to the development of type 2 diabetes was heavily debated. Recently, several publications have convincingly confirmed this hypothesis (1-3), leading to a rapid overemphasis of this etiological factor. Indeed, other mechanisms contributing to the failure of the ␤-cell to produce enough insulin appear more and more neglected. While we strongly believe that ␤-cell destruction is an important etiological factor in the development and progression of type 2 diabetes, in this review, we will highlight evidence that this is not dissociable from an intrinsic secretory defect. We will show that pathways regulating ␤-cell turnover are also implicated in ␤-cell insulin secretory function. It follows that adaptive mechanisms of function and mass share common regulatory pathways and will therefore act in concert. Depending on the prevailing concentration and the intracellular pathways activated, some factors may be deleterious to ␤-cell mass while enhancing insulin secretion, protective to the ␤-cell while inhibiting function, or even protective to the ␤-cell while enhancing function. It will become apparent that the failure of the ␤-cell in type 2 diabetes is akin to a multifactorial equation, with an overall negative result.Thus, although we will review the factors and mechanisms regulating ␤-cell mass individually, only in a minority of diabetic patients does one single etiological factor underlie the failure of the ␤-cell. In addition to maturityonset diabetes of the young, another example of this is autoimmune-mediated destruction of ␤-cells in young lean individuals. However, given that the incidence of type 1 diabetes increases with obesity (4), that insulin resistance is a risk factor for the progression of this condition (5), and that ϳ50% of the general population carry the same genetic predisposition (6), this example already implicates multiple etiological factors. Recognition of ␤-cell destruction not only in type 1 but also in type 2 diabetes led us to recently propose a unif...

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Proteinase inhibitors are important negative regulators of proteinase action in vivo. We have succeeded in isolating two previously unknown polypeptides (HF6478 and HF7665) from human blood filtrate that are parts of a larger precursor protein containing two typical Kazaltype serine proteinase inhibitor motifs. The entire precursor protein, as deduced from the nucleotide sequence of the cloned cDNA, exhibits 15 potential inhibitory domains, including the Kazal-type domains, HF6478, HF7665, and 11 additional similar domains. An inhibitory effect of HF7665 on trypsin activity is demonstrated. Because all of the 13 HF6478-and HF7665-related domains share partial homology to the typical Kazal-type domain but lack one of the three conserved disulfide bonds, they may represent a novel type of serine proteinase inhibitor. The gene encoding the multidomain proteinase inhibitor, which we have termed LEKTI, was localized on human chromosome 5q31-32. As shown by reverse transcriptase-polymerase chain reaction and Northern blot analysis, it is expressed in the thymus, vaginal epithelium, Bartholin's glands, oral mucosa, tonsils, and the parathyroid glands. From these results, we assume that LEKTI may play a role in antiinflammatory and/or antimicrobial protection of mucous epithelia.Proteinases are enzymes required for nonspecific processes of digestion and intracellular protein turnover as well as specific proteolytic activation of inactive precursors of many regulatory proteins, such as enzymes and peptide hormones. In addition, they are involved in several processes of extracellular matrix remodeling. Depending on the nature of their reactive center, they are subdivided into the classes of serine, cysteine, aspartate, and metalloproteinases (for review see Ref. 1). To control the action of proteinases in vivo, organisms produce another group of proteins, namely the proteinase inhibitors (for review see Refs. 2-4). Indeed, many pathological effects are due to the non-regulated action of endogenously produced proteinases or such proteinases encoded or synthesized by viruses, bacteria, and parasites (for review see Ref. 5). For instance, a genetically determined fault of the ␣ 1 -proteinase inhibitor may lead to an enhanced proneness to lung emphysema caused by uncontrolled action of leukocyte elastase (6 -8). Thus, proteinase inhibitors represent an important therapeutic tool for a large number of different disorders.Here we report the isolation of two peptides (HF6478 and HF7665) from human blood filtrate (hemofiltrate), which may represent a novel class of proteinase inhibitor. Blood filtrate, a by-product of ultrafiltration of the blood from patients with acute renal failure, is routinely used by us as a source for the systematic as well as random isolation of novel human peptides (9). Due to the cut-off limit of the hemofilters (approximately 20,000 Da), it mainly contains peptides exhibiting a molecular mass below 20,000 Da. Nevertheless, we succeeded in isolating members of many different peptide/protein families suc...