Lack of Wdr13 Gene in Mice Leads to Enhanced Pancreatic Beta Cell Proliferation, Hyperinsulinemia and Mild Obesity

WD-repeat proteins are very diverse, yet these are structurally related proteins that participate in a wide range of cellular functions. WDR13, a member of this family, is conserved from fishes to humans and localizes into the nucleus. To understand the in vivo function(s) of Wdr13 gene, we have created and characterized a mutant mouse strain lacking this gene. The mutant mice had higher serum insulin levels and increased pancreatic islet mass as a result of enhanced beta cell proliferation. While a known cell cycle inhibitor, p21, was downregulated in the mutant islets, over expression of WDR13 in the pancreatic beta cell line (MIN6) resulted in upregulation of p21, accompanied by retardation of cell proliferation. We suggest that WDR13 is a novel negative regulator of the pancreatic beta cell proliferation. Given the higher insulin levels and better glucose clearance in Wdr13 gene deficient mice, we propose that this protein may be a potential candidate drug target for ameliorating impaired glucose metabolism in diabetes

Protektivnyy effekt T-aktivina pri eksperimental'nom sakharnom diabete

Актуальность. В инициации и прогрессирующей гибели (бета-клеток существенную роль отводят активации процессов свободнорадикального окисления, возникающего в результате действия факторов окружающей среды с последующим появлением "новых" модифицированных антигенов и иммунной атакой против инсулинпродуцирующих клеток. Актуальным является поиск методов и средств патогенетической терапии, направленных на блокаду иммунометаболической агрессии бета-клеток на ранних стадиях развития ИЗСД. Перспективным направлением профилактики ИЗСД является антиоксидантная и иммунотерапия, включающая в себя иммуносупрессию и иммуномодуляцию. Цель. Изучение влияния Т-активина на развитие стрептозотоцининдуцированного диабета. Материалы и методы Работа выполнены на 53 белых крысах-самцах линии WISTAR массой тела 130?11 г. Диабет вызывали 3-кратным внутрибрюшинным введением стрептозотоцина. 1-я группа (n=19) получала подкожно 0.1 мл физиологического раствора в течение 10 дней; 2-я группа (n=22) получала Т-активин в дозе 2 мкг/кг массы тела 1 раз в сутки подкожно в течение 10 дней; 3-я группа (n=12) ? интактные животные. Проводилось определение концентрации глюкозы крови, концентрация инсулина в плазме крови, оценка состояния суммарной активности процессов перекисного окисления липидов (ПОЛ), гистологическое исследование поджелудочной железы. Результаты. Защитный эффект Т-активина в развитии диабета был статистически значимым. Таким образом, имеет место выраженное протективное влияние полипептидов тимуса, входящих в состав Т-активина, на индукцию ИЗСД. Выводы. Можно полагать, что метаболические и иммунологические эффекты пептидов тимуса, в частности, Т-активина, и объясняют их протективное действие в развитии экспериментального диабета

The effect of separate and combined use of t-activin and a-tocopherol on the course of experimental diabetes mellitus

Effects of T-activin and a-tocopherol alone and together on lipid peroxidation (LPO) and carbohydrate metabolism are studied in rats with streptosotocin diabetes (male rats, n=102). Antioxidative activity of T-activin is compatible to that of a.-tocopherol. The antioxidative effect of combined therapy with both agents is more expressed than of monotherapy. T-activin normalized LPO and glycaemic values and increased blood plasma insulin level, which can be regarded as the onset of reparative regeneration of insulin-producing cells; v.-tocopherol did not notably increase the level of insulin or normalize blood glucose level. Thus, T-activin is characterized by a wider spectrum of therapeutic effects in experimental diabetes than a tocopherol.</jats:p

Identification of a WD40 Repeat-Containing Isoform of PHIP as a Novel Regulator of β-Cell Growth and Survival▿

The pleckstrin homology domain-interacting protein (PHIP) was originally identified as a 902-amino-acid (aa) protein that regulates insulin receptor-stimulated GLUT4 translocation in skeletal-muscle cells. Immunoblotting and immunohistological analyses of pancreatic β-cells reveal prominent expression of a 206-kDa PHIP isoform restricted to the nucleus. Herein, we report the cloning of this larger, 1,821-aa isoform of PHIP (PHIP1), which represents a novel WD40 repeat-containing protein. We demonstrate that PHIP1 overexpression stimulates insulin-like growth factor 1-dependent and -independent proliferation of β-cells, an event which correlates with transcriptional upregulation of the cyclin D2 promoter and the accumulation of cyclin D2 protein. RNA interference knockdown of PHIP1 in INS-1 cells abrogates insulin receptor substrate 2 (IRS2)-mediated DNA synthesis, providing for a specific role for PHIP1 in the enhancement of IRS2-dependent signaling responses leading to β-cell growth. Finally, we provide evidence that PHIP1 overexpression blocks free fatty acid-induced apoptosis in INS-1 cells, which is accompanied by marked activation of phosphoprotein kinase B (PKB)/AKT and the concomitant inhibition of caspase-9 and caspase-3 cleavage. Our finding that the restorative effect of PHIP1 on β-cell lipotoxicity can be attenuated by the overexpression of dominant-negative PKB suggests a key role for PKB in PHIP1-mediated cytoprotection. Taken together, these findings provide strong support for PHIP1 as a novel positive regulator of β-cell function. We suggest that PHIP1 may be involved in the induction of long-term gene expression programs to promote β-cell mitogenesis and survival

Developmental biology of gut-probiotic interaction

While our current knowledge of probiotic interaction in the developing gut remains poorly understood, emerging science is providing greater biological insight into their mechanism of action and therapeutic potential for human disease. Given their beneficial effects, probiotics remain promising agents in neonatal gastrointestinal disorders. Probiotics may restore or supply essential bacterial strains needed for gut maturation and homeostasis, particularly in hosts where this process has been disrupted. Here we highlight the unique characteristics of developing intestinal epithelia with a focus on gut development and colonization as well as the inflammatory propensity of immature epithelia. Additionally, we review potential mechanisms of beneficial probiotic interaction with immature intestinal epithelia including immunomodulation, upregulation of cytoprotective genes, prevention and regulation of apoptosis and maintenance of barrier function. Improved knowledge of gut-probiotic interaction in developing epithelia will allow for a better understanding of how probiotics exert their beneficial effects and help guide their therapeutic use

A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency

Genotype-first combined with reverse phenotyping has shown to be a powerful tool in human genetics, especially in the era of next generation sequencing. This combines the identification of individuals with mutations in the same gene and linking these to consistent (endo) phenotypes to establish disease causality. We have performed a MIP (molecular inversion probe)based targeted re-sequencing study in 3,275 individuals with intellectual disability (ID) to facilitate a genotype-first approach for 24 genes previously implicated in ID. Combining our data with data from a publicly available database, we confirmed 11 of these 24 genes to be relevant for ID. Amongst these, PHIP was shown to have an enrichment of disruptive mutations in the individuals with ID (5 out of 3,275). Through international collaboration, we identified a total of 23 individuals with PHIP mutations and elucidated the associated phenotype. Remarkably, all 23 individuals had developmental delay/ID and the majority were overweight or obese. Other features comprised behavioral problems (hyperactivity, aggression, features of autism and/or mood disorder) and dysmorphisms (full eyebrows and/or synophrys, upturned nose, large ears and tapering fingers). Interestingly, PHIP encodes two protein-isoforms, PHIP/DCAF14 and NDRP, each involved in neurodevelopmental processes, including E3 ubiquitination and neuronal differentiation. Detailed genotype-phenotype analysis points towards haploinsufficiency of PHIP/DCAF14, and not NDRP, as the underlying cause of the phenotype. Thus, we demonstrated the use of large scale re-sequencing by MIPs, followed by reverse phenotyping, as a constructive approach to verify candidate disease genes and identify novel syndromes, highlighted by PHIP haploinsufficiency causing an ID-overweight syndrome