Humanin: a novel central regulator of peripheral insulin action.

BACKGROUND: Decline in insulin action is a metabolic feature of aging and is involved in the development of age-related diseases including Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD). A novel mitochondria-associated peptide, Humanin (HN), has a neuroprotective role against AD-related neurotoxicity. Considering the association between insulin resistance and AD, we investigated if HN influences insulin sensitivity. METHODS AND FINDINGS: Using state of the art clamp technology, we examined the role of central and peripheral HN on insulin action. Continuous infusion of HN intra-cerebro-ventricularly significantly improved overall insulin sensitivity. The central effects of HN on insulin action were associated with activation of hypothalamic STAT-3 signaling; effects that were negated by co-inhibition of hypothalamic STAT-3. Peripheral intravenous infusions of novel and potent HN derivatives reproduced the insulin-sensitizing effects of central HN. Inhibition of hypothalamic STAT-3 completely negated the effects of IV HN analog on liver, suggesting that the hepatic actions of HN are centrally mediated. This is consistent with the lack of a direct effect of HN on primary hepatocytes. Furthermore, single treatment with a highly-potent HN analog significantly lowered blood glucose in Zucker diabetic fatty rats. Based upon the link of HN with two age-related diseases, we examined if there were age associated changes in HN levels. Indeed, the amount of detectable HN in hypothalamus, skeletal muscle, and cortex was decreased with age in rodents, and circulating levels of HN were decreased with age in humans and mice. CONCLUSIONS: We conclude that the decline in HN with age could play a role in the pathogenesis of age-related diseases including AD and T2DM. HN represents a novel link between T2DM and neurodegeneration and along with its analogues offers a potential therapeutic tool to improve insulin action and treat T2DM.

Safety and efficacy of growth hormone treatment in small for gestational age children.

PURPOSE OF REVIEW: Approximately 100,000 infants are born small for gestational age (birth weight <2 standard deviation) annually in the US alone. Because of catch-up growth, 10-20% of all children born small for gestational age will be eligible for growth hormone therapy. Growth hormone has been approved by the Food and Drug Administration in 2003 and by the European Agency for the Evaluation of Medical Products though at different enrollment and treatment criteria. Benefits and risks of growth hormone therapy for small for gestational age children are the purpose of the present review. RECENT FINDINGS: Mean height increased by as much as two standard deviation over 3 years of treatment in infants born small for gestational age. Rapid catch-up growth is desirable and will only be achieved with higher growth hormone doses (0.48 mg/kg/week) Treatment should be continuous and not interrupted. The safety profile of growth hormone treatment is excellent. Transient elevation of insulin levels returned to near normal after growth hormone treatment was discontinued. SUMMARY: Growth hormone treatment in small for gestational age children has been found to be well tolerated and is an important advance in the treatment of short stature in pediatrics. Treatment of short prematurely born infants with growth hormone may offer similar efficacy and safety as growth hormone treatment in small for gestational age infants.

Visceral adipose tissue modulates mammalian longevity.

Caloric restriction (CR) can delay many age-related diseases and extend lifespan, while an increase in adiposity is associated with enhanced disease risk and accelerated aging. Among the various fat depots, the accrual of visceral fat (VF) is a common feature of aging, and has been shown to be the most detrimental on metabolic syndrome of aging in humans. We have previously demonstrated that surgical removal of VF in rats improves insulin action; thus, we set out to determine if VF removal affects longevity. We prospectively studied lifespan in three groups of rats: ad libitum-fed (AL-fed), CR (Fed 60% of AL) and a group of AL-fed rats with selective removal of VF at 5 months of age (VF-removed rats). We demonstrate that compared to AL-fed rats, VF-removed rats had a significant increase in mean (p < 0.001) and maximum lifespan (p < 0.04) and significant reduction in the incidence of severe renal disease (p < 0.01). CR rats demonstrated the greatest mean and maximum lifespan (p < 0.001) and the lowest rate of death as compared to AL-fed rats (0.13). Taken together, these observations provide the most direct evidence to date that a reduction in fat mass, specifically VF, may be one of the possible underlying mechanisms of the anti-aging effect of CR.