The islet-infiltrating and disease-causing leukocytes that are a hallmark of insulin-dependent diabetes mellitus produce and respond to a set of cytokine molecules. Of these, interleukin 1β, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ are perhaps the most important. However, as pleiotropic molecules, they can impact the path leading to β cell apoptosis and diabetes at multiple points. To understand how these cytokines influence both the formative and effector phases of insulitis, it is critical to determine their effects on the assorted cell types comprising the lesion: the effector T cells, antigen-presenting cells, vascular endothelium, and target islet tissue. Here, we report using nonobese diabetic chimeric mice harboring islets deficient in specific cytokine receptors or cytokine-induced effector molecules to assess how these compartmentalized loss-of-function mutations alter the events leading to diabetes. We found that islets deficient in Fas, IFN-γ receptor, or inducible nitric oxide synthase had normal diabetes development; however, the specific lack of TNF- α receptor 1 (p55) afforded islets a profound protection from disease by altering the ability of islet-reactive, CD4+ T cells to establish insulitis and subsequently destroy islet β cells. These results argue that islet cells play a TNF-α–dependent role in their own demise.

Type I diabetes mellitus is an autoimmune disease characterized by the selective destruction of the insulinsecreting ␤-cell found in pancreatic islets of Langerhans. Cytokines such as interleukin-1 (IL-1), interferon-␥ (IFN-␥), and tumor necrosis factor-␣ (TNF-␣) mediate ␤-cell dysfunction and islet degeneration, in part, through the induction of the inducible isoform of nitric-oxide synthase and the production of nitric oxide by ␤-cells. Cytokines also stimulate the expression of the inducible isoform of cyclooxygenase, COX-2, and the production of prostaglandin E 2 (PGE 2 ) by rat and human islets; however, the role of increased COX-2 expression and PGE 2 production in mediating cytokine-induced inhibition of islet metabolic function and viability has been incompletely characterized. In this study, we have shown that treatment of rat islets with IL-1␤ or human islets with a cytokine mixture containing IL-1␤ ؉ IFN-␥ ؎ TNF-␣ stimulates COX-2 expression and PGE 2 formation in a time-dependent manner. Coincubation of rat and human islets with selective COX-2 inhibitors SC-58236 and Celecoxib, respectively, attenuated cytokine-induced PGE 2 formation. However, these inhibitors failed to prevent cytokine-mediated inhibition of insulin secretion or islet degeneration. These findings indicate that selective inhibition of COX-2 activity does not protect rat and human islets from cytokine-induced ␤-cell dysfunction and islet degeneration and, furthermore, that islet production of PGE 2 does not mediate these inhibitory and destructive effects.Type I diabetes mellitus is an autoimmune disease characterized by the selective destruction of insulin-secreting ␤-cells found in pancreatic islets of Langerhans. Although the initiation events leading to the development of disease are not well characterized, inflammatory cytokines and the free radical nitric oxide (NO) 1 appear to play an important role. We and others have shown that treatment of isolated rat and human islets with cytokines such as IL-1, IFN-␥, and TNF-␣ results in the inhibition of glucose-stimulated insulin secretion and islet degeneration. The inhibitory and destructive effects of cytokines on ␤-cell function and islet viability are mediated, in part, through the expression of the inducible form of nitric-oxide synthase (iNOS) and increased production of NO by ␤-cells (1-5). NO inhibits insulin secretion by targeting iron-sulfurcontaining enzymes such as aconitase and electron-transporting chain complexes I and II, resulting in decreased oxidative phosphorylation and ATP production (6 -9). Evidence in support of a role for NO in mediating cytokine-induced islet damage includes the protective actions of iNOS inhibitors aminoguanidine (AG) or N G -monomethyl L-arginine (L-NMMA) on cytokine-induced inhibition of insulin secretion and islet degeneration (2, 4, 10, 11), as well as the lack of an inhibitory action of cytokines on glucose-stimulated insulin secretion in islets isolated from iNOS-deficient mice (12). These results suggest that inflammatory cytokines m...

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IntroductionAn orally administered amino acid-based test supplement was recently shown to increase human growth hormone (hGH) in healthy adults. This prospective, observational, single-center, single-arm cohort study investigated the effects of 24 weeks of daily oral administration of the test supplement in individuals with stress-related weight gain, fibromyalgia (FM) and stress-related low-normal hGH production (15-30th percentile for age-appropriate levels) on insulin-like growth factor 1 (IGF-1), an indicator of hGH levels caused by stress related stimulation of somatostatin.MethodsParticipants continued to receive standard care. The primary endpoint was the change from baseline to endpoint (Week 24) in serum IGF-1. Additional endpoints included the change in body weight, clinical symptoms (assessed with the Revised Fibromyalgia Impact Questionnaire [FIQR], range 0-100, and Perceived Stress Scale [PSS], range 0-40), fasting cardiometabolic markers, tolerability, and safety. The study enrolled 84 fibromyalgia patients with low-normal age-adjusted IGF-1 serum levels. High mean ± Standard Deviation (SD) baseline FIQR and PSS scores of 76 ± 16 and 32 ± 5, respectively, indicated poor to moderate symptom management with standard care. All individuals completed 24 weeks.ResultsSerum IGF-1 levels increased with a Week 24 mean± Standard Error (SE) change of 28.4 ± 3.0 ng/mL (p<0.001). Body weight was reduced with a Week 24 mean ± SE change of -5.5 ± 0.3 kg (p<0.001) (a 6.5% weight loss from baseline). The change from baseline in FIQR and PSS scores were -29.1 ± 1.1 and -20.0 ± 0.8, respectively (both p<0.001), indicating a substantial improvement. Statistically significant improvements from baseline to Week 24 were observed in systolic and diastolic blood pressure, HbA1c, LDL and HDL cholesterol, and triglycerides (all p<0.001). The supplement was well tolerated; no adverse events were reported.DiscussionSustained augmentation of IGF-1 with the test supplement may represent a novel method of improving clinical symptoms, including stress-related weight gain, in individuals with fibromyalgia and stress-associated low-normal hGH.

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