Mechanisms of Insulin Resistance in Aging

Fink, Raymond; Kolterman, Orville G.; Griffin, Justin W.; Olefsky, Jerrold M.

doi:10.1172/jci110908

Cited by 534 publications

(338 citation statements)

References 40 publications

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“…During the CPS phase, subordinate mice developed hyperglycemia when fed both a STD or a HFD (Figure 3a), a finding which is consistent with our previous work (Sanghez et al., 2013) and that could have set the stage for a later metabolic dysregulation and impact later survival outcomes (Fink, Kolterman, Griffin & Olefsky, 1983; Houtkooper et al., 2011). Subordinate mice were also characterized by increased body weight when fed a STD (Figure 3b–d) despite eating comparably to dominant mice (Figure 3e) that resulted in a greater food efficiency (Figure 3f).…”

Section: Resultsmentioning

confidence: 99%

Social stress shortens lifespan in mice

et al. 2018

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SummaryStress and low socioeconomic status in humans confer increased vulnerability to morbidity and mortality. However, this association is not mechanistically understood nor has its causation been explored in animal models thus far. Recently, cellular senescence has been suggested as a potential mechanism linking lifelong stress to age‐related diseases and shorter life expectancy in humans. Here, we established a causal role for lifelong social stress on shortening lifespan and increasing the risk of cardiovascular disease in mice. Specifically, we developed a lifelong chronic psychosocial stress model in which male mouse aggressive behavior is used to study the impact of negative social confrontations on healthspan and lifespan. C57BL/6J mice identified through unbiased cluster analysis for receiving high while exhibiting low aggression, or identified as subordinate based on an ethologic criterion, had lower median and maximal lifespan, and developed earlier onset of several organ pathologies in the presence of a cellular senescence signature. Critically, subordinate mice developed spontaneous early‐stage atherosclerotic lesions of the aortic sinuses characterized by significant immune cells infiltration and sporadic rupture and calcification, none of which was found in dominant subjects. In conclusion, we present here the first rodent model to study and mechanistically dissect the impact of chronic stress on lifespan and disease of aging. These data highlight a conserved role for social stress and low social status on shortening lifespan and increasing the risk of cardiovascular disease in mammals and identify a potential mechanistic link for this complex phenomenon.

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Section: Resultsmentioning

confidence: 99%

Social stress shortens lifespan in mice

et al. 2018

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“…Group 1 comprised control rats, receiving daily subcutaneous injections of saline for 13 days, group 2 were Dex-treated rats subjected to a daily subcutaneous injection of Dex phosphate (0.125 mg/kg in saline) for 13 days, group 3 Dex -VOSO 4 -treated rats also received vanadyl sulphate (0.5 mg/ml in the drinking water) starting after 4 days of Dex treatment, when the effects of Dex were clearly apparent (7), and group 4 were rats treated with VOSO 4 for 9 days with oral VOSO 4 only. Daily VOSO 4 intake, calculated on the basis of water consumption, averaged 16.0^0.20 and 22.5^0.60 mg in 3-and 18-month-old animals respectively.…”

Section: Dexamethasone and Voso 4 Treatmentmentioning

confidence: 99%

Dexamethasone-induced insulin resistance and pancreatic adaptive response in aging rats are not modified by oral vanadyl sulfate treatment

Fierabracci

Novelli

Bombara

et al. 2001

European Journal of Endocrinology

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Objective: To explore the adaptive response of the endocrine pancreas in vivo and in vitro and the possible beneficial effect of the insulino-mimetic agent vanadyl sulfate (VOSO 4 ), using glucocorticoid treatment to increase insulin resistance, in aging rats. Design and Methods: Dexamethasone (Dex) (0.13 mg/kg b.w.) was administered daily for 13 days to 3-and 18-month old Sprague-Dawley rats and oral VOSO 4 was given from the 5th day. Plasma glucose, insulin and free fatty acids (FFA) concentrations were measured during these treatments and the insulin secretory response of the isolated perfused pancreas was assessed at the end of the experiment. Results and Conclusions: In both young and aging rats, particularly in the latter, hyperinsulinemia and increased in vitro insulin responsiveness to glucose were observed in response to Dex treatment, concomitant with an increase in plasma FFA concentrations. Thus, in glucocorticoid-treated animals, the b-cell adaptive response occurred in both age groups and could possibly be mediated by increased circulating FFA; however, it was insufficient to prevent hyperglycemia in 60% of aging animals. Oral VOSO 4 administration failed to correct Dex-induced alterations in glucose and lipid metabolism, although it influenced in vitro b-cell responsiveness to stimuli in aging rats.

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“…Blood glucose was measured every 5 -10 min by the glucose oxidase method at the patient's bedside (YSI 2300 stat plus glucose analyser, YSI Incorporated, Yellow Springs, OH, USA). Fifty units recombinant human insulin (Actrapid; Novo Nordisk, North Rocks, Australia) were added to 500 ml of 4% succinylated gelatin solution (Gelofusine; B Braun, Castle Hill, Australia) and then a primed infusion of 50 mU/m 2 /min, which is in excess of that required to completely suppress hepatic gluconeogenesis in older men (13,56), was commenced. A variable rate of infusion of 20% glucose (Baxter Healthcare, Toongabbie, Australia) was titrated (57) to maintain a blood glucose of 4.5 mmol/l.…”

Section: Insulin Sensitivitymentioning

confidence: 99%

“…In older men, low serum testosterone can predict future development of NIDDM (8 -10) and central obesity (11). Since normal ageing is associated with progressive impairment of carbohydrate tolerance (12) which is partly due to increasing insulin resistance (13), older individuals are an appropriate target group in whom timely intervention (perhaps with androgen supplementation) may delay progression to NIDDM and associated morbidity. Conversely, interventions that worsen insulin resistance may be particularly harmful due to increased background risk and reduced compensatory reserve.…”

Section: Introductionmentioning

confidence: 99%

Do reproductive hormones modify insulin sensitivity and metabolism in older men? A randomized, placebo-controlled clinical trial of recombinant human chorionic gonadotropin

Liu

Wishart

Celermajer

et al. 2003

European Journal of Endocrinology

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Objective: In order to assess the hormonal determinants of insulin sensitivity and related components of the metabolic syndrome, we evaluated the effect of subcutaneous recombinant human chorionic gonadotropin (r-hCG; Ovidrel) on insulin sensitivity, vascular reactivity, leptin, insulin-like growth factor-I (IGF-I) and lipids in ambulant, community dwelling men .60 years of age with serum testosterone # 15 nmol/l on two occasions. Design: Forty eligible men were randomized to receive 250 mg (5000 IU) r-hCG subcutaneously twice each week ðn ¼ 20Þ or placebo ðn ¼ 20Þ injections for 3 months, and all subjects (mean age 67 (range 60 -85) years) completed the study. Methods and results: Groups were well matched for height, weight, anthropometry and insulin sensitivity. Insulin sensitivity was assessed by homeostasis model (HOMA) and euglycemic hyperinsulinemic clamp at baseline and at the end of the treatment period in the first 30 men who did not have diabetes mellitus. Insulin sensitivity (HOMA and euglycemic clamp) or b cell function (HOMA) were not significantly changed by r-hCG despite a significant increase in lean body mass (,2 kg, P , 0:001) and reduced fat mass (, 1 kg, P , 0:05). Subcutaneous fat (skinfold measurements), abdominal girth and serum leptin all decreased and IGF-I tended to increase, but these changes were not significant. Recombinant hCG significantly reduced total and low density lipoprotein cholesterol, and triglycerides, but did not significantly alter high density lipoprotein cholesterol. Endothelial function (vascular reactivity) was not significantly worsened. We conclude that three-months of treatment with r-hCG demonstrates expected hormonal effects, improved lipids and did not worsen vascular endothelial function. Insulin sensitivity was not altered despite suggestive changes in body composition. Conclusions: These findings suggest short-term metabolic and cardiovascular safety and argue against an important role for androgens in the hormonal control of insulin sensitivity in older men.

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Mechanisms of Insulin Resistance in Aging

Cited by 534 publications

References 40 publications

Social stress shortens lifespan in mice

Social stress shortens lifespan in mice

Dexamethasone-induced insulin resistance and pancreatic adaptive response in aging rats are not modified by oral vanadyl sulfate treatment

Do reproductive hormones modify insulin sensitivity and metabolism in older men? A randomized, placebo-controlled clinical trial of recombinant human chorionic gonadotropin

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