Insulin resistance is a risk factor for various age-related diseases. In the Leiden Longevity study, we recruited long-lived siblings and their offspring. Previously, we showed that, compared to... Show moreInsulin resistance is a risk factor for various age-related diseases. In the Leiden Longevity study, we recruited long-lived siblings and their offspring. Previously, we showed that, compared to controls, the offspring of long-lived siblings had a better glucose tolerance. Here, we compared groups of offspring from long-lived siblings and controls for the relation between insulin and glucose in nonfasted serum (n = 1848 subjects) and for quantitation of insulin action using a two-step hyperinsulinemic-euglycemic clamp (n = 24 subjects). Groups of offspring and controls were similar with regard to sex distribution, age, and body mass index. We observed a positive bi-phasic linear relationship between ln (insulin) levels and nonfasted glucose with a steeper slope from 10.7mU L(-1) insulin onwards in controls compared to offspring (P = 0.02). During the clamp study, higher glucose infusion rate was required to maintain euglycemia during high-dose insulin infusion (P = 0.036) in offspring, reflecting higher whole-body insulin sensitivity. After adjustment for sex, age, and fat mass, the insulin-mediated glucose disposal rate (GDR) was higher in offspring than controls (42.5 ± 2.7 vs. 33.2 ± 2.7 micromol kg(-1) min(-1) , mean ± SE, P = 0.025). The insulin-mediated suppression of endogenous glucose production and lipolysis did not differ between groups (all P > 0.05). Furthermore, GDR was significantly correlated with the mean age of death of the parents. In conclusion, offspring from long-lived siblings are marked by enhanced peripheral glucose disposal. Future research will focus on identifying the underlying biomolecular mechanisms, with the aim to promote health in old age. Show less
Aziz, N.A.; Pijl, H.; Frolich, M.; Snel, M.; Streefland, T.C.M.; Roelfsema, F.; Roos, R.A.C. 2010
Background Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an increased number of CAG repeats in the HTT gene. Apart from neurological impairment, the disease is also... Show moreBackground Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an increased number of CAG repeats in the HTT gene. Apart from neurological impairment, the disease is also accompanied by progressive weight loss, abnormalities in fat and glucose homeostasis and a higher prevalence of diabetes mellitus, the causes of which are unknown. Therefore, a detailed analysis of systemic energy homeostasis in HD patients in relation to disease characteristics was performed. Methods Indirect calorimetry combined with a hyperinsulinaemic-euglycaemic clamp with stable isotopes ([6,6-2H2]-glucose and [2H5]- glycerol) was performed to assess energy expenditure and glucose and fat metabolism in nine early stage, medication free HD patients and nine age, sex and body mass index matched controls. Results Compared with controls, fasting energy expenditure was higher in HD patients (1616 +/- 72 vs 1883 +/- 93 kcal/24 h, p=0.037) and increased even further after insulin stimulation (1667 +/- 87 vs 2068 +/- 122 kcal/24 h, p=0.016). During both basal and hyperinsulinaemic conditions, glucose and glycerol disposal rates, endogenous glucose production and hepatic insulin sensitivity were similar between HD patients and controls. In HD patients, energy expenditure increased with disease duration but not with a greater degree of motor or functional impairment. Moreover, a higher mutant CAG repeat size was associated with lower insulin sensitivity (r=-0.84, p=0.018). Conclusion These findings suggest sympathetic hyperactivity as an underlying mechanism of increased energy expenditure in HD, as well as peripheral polyglutamine length dependent interference of mutant huntingtin with insulin signalling that may become clinically relevant in carriers of mutations with large CAG repeat sizes. Show less
