Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production

Calorie restriction (CR) slows aging and is thought to improve insulin sensitivity in laboratory animals. In contrast, decreased insulin signaling and/or mild insulin resistance paradoxically extends maximal lifespan in various genetic animal models of longevity. Nothing is known regarding the long-term effects of CR on glucose tolerance and insulin action in lean healthy humans. In this study we evaluated body composition, glucose, and insulin responses to an oral glucose tolerance test and serum adipokines levels in 28 volunteers, who had been eating a CR diet for an average of 6.9 ± 5.5 years, (mean age 53.0 ± 11 years), in 28 age-, sex-, and body fat-matched endurance runners (EX), and 28 age- and sex-matched sedentary controls eating Western diets (WD). We found that the CR and EX volunteers were significantly leaner than the WD volunteers. Insulin sensitivity, determined according to the HOMA-IR and the Matsuda and DeFronzo insulin sensitivity indexes, was significantly higher in the CR and EX groups than in the WD group (P = 0.001). Nonetheless, despite high serum adiponectin and low inflammation, ∼40% of CR individuals exhibited an exaggerated hyperglycemic response to a glucose load. This impaired glucose tolerance is associated with lower circulating levels of IGF-1, total testosterone, and triiodothyronine, which are typical adaptations to life-extending CR in rodents

Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents

Type 2 diabetes (T2D) is among the most common and costly disorders worldwide(1). The goal of current medical management of T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more anti-diabetic drugs. Hypoglycemia and weight are common side effects of therapy, and sustained disease remission is not obtainable with non-surgical approaches. Based on the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors(2–4), we explored the anti-diabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes(5). We report that a single intracerebroventricular (i.c.v.) injection of FGF1 at a dose one-tenth of that needed for systemic anti-diabetic efficacy induces sustained diabetes remission in both mouse and rat models of T2D. This anti-diabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has the inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal

Allele-specific recognition of the 3' splice site of INS intron 1

Genetic predisposition to type 1 diabetes (T1D) has been associated with a chromosome 11 locus centered on the proinsulin gene (INS) and with differential steady-state levels of INS RNA from T1D-predisposing and -protective haplotypes. Here, we show that the haplotype-specific expression is determined by INS variants that control the splicing efficiency of intron 1. The adenine allele at IVS1-6 (rs689), which rapidly expanded in modern humans, renders the 3?splice site of this intron more dependent on the auxiliary factor of U2 small nuclear ribonucleoprotein (U2AF). This interaction required both zinc fingers of the 35-kD U2AF subunit (U2AF35) and was associated with repression of a competing 3' splice site in INS exon 2. Systematic mutagenesis of reporter constructs showed that intron 1 removal was facilitated by conserved guanosine-rich enhancers and identified additional splicing regulatory motifs in exon 2. Sequencing of intron 1 in primates revealed that relaxation of its 3? splice site in Hominidae coevolved with the introduction of a short upstream open reading frame, providing a more efficient coupled splicing and translation control. Depletion of SR proteins 9G8 and transformer-2 by RNA interference was associated with exon 2 skipping whereas depletion of SRp20 with increased representation of transcripts containing a cryptic 3? splice site in the last exon. Together, these findings reveal critical interactions underlying the allele-dependent INS expression and INS-mediated risk of T1D and suggest that the increased requirement for U2AF35 in higher primates may hinder thymic presentation of autoantigens encoded by transcripts with weak 3? splice sites. <br/

Aging in male primates: reproductive decline, effects of calorie restriction and future research potential

Although less dramatic than in females, male mammals experience decreasing reproductive function during aging. In primates, multiple facets of the hypothalamic-pituitary-gonadal axis show evidence of gradual age-related decline, including behavioral, neuroendocrine and endocrine alterations such as decreased testosterone levels, reduced circulating dehydroepiandrosterone sulfate (DHEAS) levels, increased numbers of sperm abnormalities, and a general decline in physiological responses. In this review we consider a range of age-related changes in males. These measures, including more subtle aging characteristics, are interesting additional indices for detecting the timing of age-related changes in behavioral, neuroendocrine, and endocrine responses. Evidence of potential effects of calorie restriction as an intervention in reproductive aging is also discussed. A discernable decline occurs in both metabolic and reproductive endocrine processes during male aging. This cascade of events includes neuroendocrine and behavioral changes; biomarkers such as circulating DHEAS also show clear age-related decline. The varied changes that occur during male aging are considered in the context of primate aging in general

A pathophysiological framework of hippocampal dysfunction in ageing and disease

The hippocampal formation has been implicated in a growing number of disorders, from Alzheimer's disease and cognitive ageing to schizophrenia and depression. How can the hippocampal formation, a complex circuit that spans the temporal lobes, be involved in a range of such phenotypically diverse and mechanistically distinct disorders? Recent neuroimaging findings indicate that these disorders differentially target distinct subregions of the hippocampal circuit. In addition, some disorders are associated with hippocampal hypometabolism, whereas others show evidence of hypermetabolism. Interpreted in the context of the functional and molecular organization of the hippocampal circuit, these observations give rise to a unified pathophysiological framework of hippocampal dysfunction