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2023 APR 29 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Researchers detail new data in Peptide Proteins - Proinsulin. According to news [...]

2023 APR 15 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- A new study on Nutritional and Metabolic Diseases and Conditions - Type [...]

2023 JAN 28 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Fresh data on Peptide Proteins - Proinsulin are presented in a new [...]

2022 DEC 10 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators discuss new findings in Nutritional and Metabolic Diseases and Conditions - [...]

2022 DEC 10 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators discuss new findings in Nutritional and Metabolic Diseases and Conditions - [...]

2022 NOV 5 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators publish new report on Nutritional and Metabolic Diseases and Conditions - [...]

2022 SEP 24 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Data detailed on type 2 diabetes have been presented. According to news [...]

2022 AUG 27 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Current study results on endocrinology have been published. According to news originating [...]

2022 JUL 30 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators publish new report on Nutritional and Metabolic Diseases and Conditions - [...]

2022 APR 9 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- New research on Nutritional and Metabolic Diseases and Conditions - Type 2 [...]

2022 MAR 19 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Current study results on Peptide Proteins - Pituitary Gonadotropins have been published. [...]

2022 MAR 5 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators publish new report on Drugs and Therapies - Antidiabetic Agents. According [...]

2022 FEB 26 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Current study results on Life Science Research - Molecular Metabolism have been [...]

The transcription factor neurogenin3 (Ngn3) triggers islet cell differentiation in the developing pancreas. However, little is known about the molecular mechanisms coupling cell cycle exit and differentiation in [Ngn3.sup.+] islet progenitors. We identified a novel effector of Ngn3 endocrinogenic function, the p21 protein-activated kinase Pak3, known to control neuronal differentiation and implicated in X-linked intellectual disability in humans. We show that Pak3 expression is initiated in [Ngn3.sup.+] endocrine progenitor cells and next maintained in maturing hormone-expressing cells during pancreas development as well as in adult islet cells. In Pak3-deficient embryos, the proliferation of [Ngn3.sup.+] progenitors and β-cells is transiently increased concomitantly with an upregulation of Ccnd1. β-Cell differentiation is impaired at E15.5 but resumes at later stages. Pak3-deficient mice do not develop overt diabetes but are glucose intolerant under high-fat diet (HFD). In the intestine, Pak3 is expressed in enteroendocrine cells but is not necessary for their differentiation. Our results indicate that Pak3 is a novel regulator of β-cell differentiation and function. Pak3 acts downstream of Ngn3 to promote cell cycle exit and differentiation in the embryo by a mechanism that might involve repression of Ccnd1. In the adult, Pak3 is required for the proper control of glucose homeostasis under challenging HFD. Diabetes 2014;63-203-215 | DOI:10.2337/db13-0384, Understanding the mechanisms controlling the differentiation of pancreatic progenitor cells into highly specialized insulin-secreting β-cells is a major issue for future cell-based therapies for type 1 diabetes. In the last [...]

In subjects with type 1 diabetes, autoimmune destruction of pancreatic β-cells leads eventually to an absolute requirement for insulin replacement therapy. Insulin delivered exogenously is not subject to normal physiological [...]

OBJECTIVE--Cellular stress and proinflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-1 signaling. Here, we examined the role of Set phosphorylation of IRS-2 in mediating the inhibitory effects of proinflammatory cytokines and cellular stress on β-cell function. RESEARCH DESIGN AND METHODS--Five potential inhibitory Ser sites located proximally to the P-Tyr binding domain of IRS-2 were mutated to Ala. These IRS-2 mutants, denoted [IRS-2.sup.5A], and their wild-type controls ([IRS-2.sup.WT]) were introduced into adenoviral constructs that were infected into Min6 cells or into cultured murine islets. RESULTS--When expressed in cultured mouse islets, [IRS-2.sup.5A] was better than [IRS-2.sup.WT] in protecting β-cells from apoptosis induced by a combination of IL-Iβ, IFN-γ TNF-α, and Fas ligand. Cytokine-treated islets expressing [IRS2.sup.5A] secreted significantly more insulin in response to glucose than did islets expressing [IRS-2.sup.WT]. This could be attributed to the higher transcription of Pdx1 in cytokine-treated islets that expressed [IRS-2.sup.5A]. Accordingly, transplantation of 200 islets expressing [IRS2.sup.5A] into STZ-induced diabetic mice restored their ability to respond to a glucose load similar to naive mice. In contrast, mice transplanted with islets expressing [IRS2.sup.WT] maintained sustained hyperglycemia 3 days after transplantation. CONCLUSIONS--Elimination of a physiological negative feedback control mechanism along the insulin-signaling pathway that involves Ser/Thr phosphorylation of IRS-2 affords protection against the adverse effects of proinflammatory cytokines and improves β-cell function under stress. Genetic approaches that promote [IRS2.sup.5A] expression in pancreatic β-cells, therefore, could be considered a rational treatment against β-cell failure after islet transplantation. Diabetes 59:2188-2197, 2010, Islet transplantation is the only treatment of type-1 diabetes that achieves insulin-independence (1). Still, islet allografts lose function over time with an increasing proportion of subjects returning to insulin dependence [...]

OBJECTIVE--C57B1/6 mice develop obesity and mild hyperglycemia when fed a high-fat diet (HFD). Although diet-induced obesity (DIO) is a widely studied model of type 2 diabetes, little is known about β-cell failure in these mice. RESEARCH DESIGN AND METHODS--DIO mice were separated in two groups according to body weight gain: low- and high-HFD responders (LDR and HDR). We examined whether mild hyperglycemia in HDR mice is due to reduced β-cell mass or function and studied islet metabolism and signaling. RESULTS--HDR mice were more obese, hyperinsulinemic, insulin resistant, and hyperglycemic and showed a more altered plasma lipid profile than LDR. LDR mice largely compensated insulin resistance, whereas HDR showed perturbed glucose homeostasis. Neither LDR nor HDR mice showed reduced β-cell mass, altered islet glucose metabolism, and triglyceride deposition. Insulin secretion in response to glucose, KCI, and arginine was impaired in LDR and almost abolished in HDR islets. Palmitate partially restored glucose- and KCl-stimulated secretion. The glucose-induced rise in ATP was reduced in both DIO groups, and the glucose-induced rise in [Ca.sup.2+] was reduced in HDR islets relatively to LDR. Glucose-stimulated lipolysis was decreased in LDR and HDR islets, whereas fat oxidation was increased in HDR islets only. Fatty acid esterification processes were markedly diminished, and free cholesterol accumulated in HDR islets. CONCLUSIONS--β-Cell failure in HDR mice is not due to reduced D-cell mass and glucose metabolism or steatosis but to a secretory dysfunction that is possibly due to altered ATP/[Ca.sup.2+] and lipid signaling, as well as free cholesterol deposition. Diabetes 59:2178-2187, 2010, While insulin resistance is a common feature in most obese subjects, insulin secretion is increased to compensate for its reduced action and normoglycemia is maintained (1,2). In obese type 2 [...]

OBJECTIVE--This study was designed to determine whether the transcription factor FoxM1 was required for regeneration of β-cell mass via proliferation and/or neogenesis in the adult after 60% partial pancreatectomy (PPx). RESEARCH DESIGN AND METHODS--Adult mice with a pancreas-wide deletion of Foxml ([Foxml.sup.flox/flox]; Pdxl-Cre [FoxM1.sup.Δpanc]) and their control littermates ([Foxm1.sup.flox/flox]) were subjected to PPx or a sham operation, after which islet expression of Foxm1 and several target genes, β-cell mass, proliferation, β-cell size, islet size, islet density, and neurogenin-3 expression were analyzed. RESULTS--In control mice, PPx stimulated β-cell proliferation and neogenesis and upregulated Foxml and several of its known targets (Plk1, Cenp-α, Birc5/Survivin, and Ccnb1) in islets. Within 1 week post-PPx, control mice underwent significant regeneration of β-cell mass, and average islet size within the regenerating lobe was similar to that after a sham operation. However, [FoxM1.sup.Δpanc] mice exhibited specific impairments in β-cell mass regeneration and islet growth after PPx, with reduced proliferation of α- and β-cells but no impairments in acinar or ductal cell proliferation. Interestingly, FoxM1 was not required for proliferation of β-cells within small endocrine cell clusters located in the regenerating portion of the pancreas but was specifically required for proliferation of β-cells within larger islets. Additionally, FoxM1 was not required for β-cell neogenesis following PPx. CONCLUSIONS--Our results indicate that FoxM1 is partially required for increased β-cell proliferation, but not β-cell neogenesis, stimulated by PPx. Furthermore, FoxM1 seems to be dispensable for proliferation of β-cells following neogenesis but is required for proliferation of preexisting β-cells. Diabetes 57: 3069-3077, 2008, As type 1 and type 2 diabetes result from absolute or relative deficiencies in β-cell number, respectively, understanding how β-cell number is determined and can be manipulated may lead to [...]

OBJECTIVE--In diabetes, glucose toxicity affects different organ systems, including pancreatic islets where it leads to β-cell apoptosis, but the mechanisms are not fully understood. Recently, we identified thioredoxindnteracting protein (TXNIP) as a proapoptotic β-cell factor that is induced by glucose, raising the possibility that TXNIP may play a role in β-cell glucose toxicity. RESEARCH DESIGN AND METHODS--To assess the effects of glucose on TXNIP expression and apoptosis and define the role of TXNIP, we used INS-1 β-cells; primary mouse islets; obese, diabetic BTBR.ob mice; and a unique mouse model of TXNIP deficiency (HcB-19) that harbors a natural nonsense mutation in the TXNIP gene. RESULTS--Incubation of INS-1 cells at 25 mmol/l glucose for 24 h led to an 18-fold increase in TXNIP protein, as assessed by immunoblotting. This was accompanied by increased apoptosis, as demonstrated by a 12-fold induction of cleaved caspase-3. Overexpression of TXNIP revealed that TXNIP induces the intrinsic mitochondrial pathway of apoptosis. Islets of diabetic BTBR.ob mice also demonstrated increased TXNIP and apoptosis as did isolated wild-type islets incubated at high glucose. In contrast, TXNIP-deficient HcB-19 islets were protected against glucose-induced apoptosis as measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and caspase-3, indicating that TXNIP is a required causal link between glucose toxicity and β-cell death. CONCLUSIONS--These findings shed new light onto the molecular mechanisms of β-cell glucose toxicity and apoptosis, demonstrate that TXNIP induction plays a critical role in this vicious cycle, and suggest that inhibition of TXNIP may represent a novel approach to reduce glucotoxic β-cell loss., Type 2 diabetes is a growing public health issue characterized by peripheral insulin resistance and decompensation of the pancreatic β-cells that can no longer keep up with the increased insulin [...]

OBJECTIVE--β-Cells are particularly susceptible to fatty acid-induced apoptosis associated with decreased insulin receptor/ phosphatidylinositol-3 kinase/Akt signaling and the activation of stress kinases. We examined the mechanism of fatty acid-induced apoptosis of mouse β-cells especially as related to the role played by endoplasmic reticulum (ER) stress-induced Foxo1 activation and whether decreasing Foxo1 activity could enhance cell survival. RESEARCH DESIGN AND METHODS--Mouse insulinoma (MIN6) cells were administered with fatty acids, and the role of Foxo1 in mediating effects on signaling pathways and apoptosis was examined by measuring Foxo1 activity and using dominant-negative Foxo1. RESULTS--Increasing fatty acid concentrations (100-400 µmol/1 palmitate or oleate) led to early Jun N[H.sub.2]-terminal kinase (JNK) activation that preceded induction of ER stress markers and apoptosis. Foxo1 activity was increased with fatty acid administration and by pharmacological inducers of ER stress, and this increase was prevented by JNK inhibition. Fatty acids induced nuclear localization of Foxo1 at 4 h when Akt activity was increased, indicating that FoxO1 activation was not mediated by JNK inhibition of Akt. In contrast, fatty acid administration for 24 h was associated with decreased insulin signaling. A dominant-negative Foxo1 adenovirus (Adv-DNFoxo) conferred cells with protection from ER stress and fatty acid-mediated apoptosis. Microarray analysis revealed that fatty acid induction of gene expression was in most cases reversed by Adv-DNFoxo, including the proapoptotic transcription factor CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein). CONCLUSIONS--Early induction of JNK and Foxo1 activation plays an important role in fatty acid-induced apoptosis. Expressing a dominant-negative allele of Foxo1 reduces expression of apoptotic and ER stress markers and promotes B-cell survival from fatty acid and ER stress, identifying a potential therapeutic target for preserving β-cells in type 2 diabetes., Insulin-resistant states are characterized by an initial adaptive expansion of β-cell mass to increase insulin production for maintaining euglycemia. However, a significant number of insulin-resistant individuals develop impaired insulin secretion [...]

Advanced glycation end products (AGEs) are implicated in β-cell oxidant stress. Diet-derived AGE (dAGE) are shown to contribute to end-organ toxicity attributed to diabetes. To assess the role of dAGE on type 1 diabetes, NOD mice were exposed to a high-AGE diet (H-AGE) and to a nutritionally similar diet with approximate fivefold-lower levels of [N.sup.ζ]-carboxymethyllysine (CML) and methylglyoxal-derivatives (MG) (L-AGE). Suppression of serum CML and MG in L-AGE-fed mice was marked by suppression of diabetes (H-AGE mice >94% vs. L-AGE mice 33% in founder [[F].sub.0], 14% in [F.sub.1], and 13% in [F.sub.2] offspring, P < 0.006) and by a delay in disease onset (4-month lag). Survival for L-AGE mice was 76 vs. 0% after 44 weeks of H-AGE mice. Reduced insulitis in L-AGE versus H-AGE mice (P < 0.01) was marked by GAD- and insulin-unresponsive pancreatic interleukin (IL)-4-positive CD4+ cells compared with the GAD and insulin-responsive interferon (IFN)-γ-positive T-cells from H-AGE mice (P < 0.005). Splenocytes from L-AGE mice consisted of GAD- and insulin-responsive IL-10-positive CD4+ cells compared with the IFN-γ-positive T-cells from H-AGE mice (P < 0.005). Therefore, high AGE intake may provide excess antigenic stimulus for T-cell-mediated diabetes or direct β-cell injury in NOD mice; both processes are ameliorated by maternal or neonatal exposure to L-AGE nutrition., Insulin-dependent diabetes (type 1 diabetes) is an autoimmune disease resulting from T-cell-mediated destruction of pancreatic islet β-cells (1). However, the initial events of this process are incompletely understood. While both [...]

Insulin-dependent type 1 diabetes (T1D) is attributable to the destruction of pancreatic β-cells by autoreactive T lymphocytes (T cells). Antibodies to various β-cell autoantigens also are detected in T1D that [...]

Type 1 diabetes is characterized by T-cell-mediated destruction of insulin-producing β-cells. Progression of β-cell autoimmunity is simplistically viewed as a functional imbalance favoring the development of β-cell-specific pathogenic type 1 [...]

A drug currently prescribed for people with type 2 diabetes might also prove useful for individuals who are newly diagnosed with the type 1 form of the disease. Whereas type […]