Periodic food shortages are a major challenge faced by organisms in natural habitats. Cave-dwelling animals must withstand long periods of nutrient deprivation, as—in the absence of photosynthesis—caves depend on external energy sources such as seasonal floods1. Here we show that cave-adapted populations of the Mexican tetra, Astyanax mexicanus, have dysregulated blood glucose homeostasis and are insulin-resistant compared to river-adapted populations. We found that multiple cave populations carry a mutation in the insulin receptor that leads to decreased insulin binding in vitro and contributes to hyperglycaemia. Hybrid fish from surface–cave crosses carrying this mutation weigh more than non-carriers, and zebrafish genetically engineered to carry the mutation have increased body weight and insulin resistance. Higher body weight may be advantageous in caves as a strategy to cope with an infrequent food supply. In humans, the identical mutation in the insulin receptor leads to a severe form of insulin resistance and reduced lifespan. However, cavefish have a similar lifespan to surface fish and do not accumulate the advanced glycation end-products in the blood that are typically associated with the progression of diabetes-associated pathologies. Our findings suggest that diminished insulin signalling is beneficial in a nutrient-limited environment and that cavefish may have acquired compensatory mechanisms that enable them to circumvent the typical negative effects associated with failure to regulate blood glucose levels.

BACKGROUND: Atopic dermatitis (AD) has been associated with atopic manifestations (AMs), such as food allergies, asthma, allergic rhinitis, and allergic conjunctivitis.OBJECTIVES: To (1) compare the risk of developing AMs in patients with AD versus those without AD, (2) estimate the incremental costs attributable to AMs in patients with AD, and (3) examine the factors associated with incremental costs.METHODS: In this retrospective cohort study, the authors used MarketScan research databases containing medical and pharmacy claims with dates of service from January 1, 1999, to December 31, 2004. Patients were considered to have AD if they had at least 1 medical claim with a primary or secondary diagnosis of AD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 691.8x) or contact dermatitis or other eczema of unspecified cause (ICD-9-CM codes 692.9x). To create comparable study cohorts, patients with AD were matched with non-AD patients using propensity scores that represented the likelihood of developing AD as predicted by logistic regression. After propensity score matching, the AD and non-AD cohorts did not statistically differ with respect to age, gender, geographic region, type of health insurance, Charlson Comorbidity Index, or baseline measures of medical and prescription drug utilization. The relative risks of developing AMs in the AD and non-AD cohorts were estimated using competing risk-survival analysis. AM was defined by ICD-9-CM codes for asthma (493.xx), allergic rhinitis (477.xx), allergic conjunctivitis (372.05 or 372.14), and food allergy (693.1x, 692.5x, 995.60). The annual incremental cost attributable to AMs in these AD patients was calculated from medical claims with AM and AD diagnosis codes and from pharmacy claims for prescription drugs used to treat asthma, allergic rhinitis, allergic conjunctivitis, or food allergy, and 95% confidence intervals (CIs) were calculated using the bootstrap method.RESULTS: Patients with AD were significantly more likely to develop AMs than patients without AD (21.8% versus 16.9%, adjusted relative risk [RR] = 1.33, 95% CI, 1.28-1.38). Among AD patients who developed AMs, allergic rhinitis was the most frequent manifestation (66.3%), followed by asthma (24.8%), allergic conjunctivitis (7.6%), and food allergy (1.8%). The incidence and adjusted RRs of developing AM for AD patients versus comparison patients were 5.3% versus 4.5% for asthma (RR = 1.20, 95% CI, 1.12-1.29), 14.6% versus 11.2% for allergic rhinitis (RR = 1.35, 95% CI, 1.29-1.41), 1.6% versus 1.1% for allergic conjunctivitis (RR = 1.50, 95% CI, 1.31-1.72), and 0.3% versus 0.1% for food allergy (RR = 2.35, 95% CI, 1.66-3.32). The annual AD + AM treatment costs for patients with AD increased substantially after they developed AMs. The additional financial burden attributable to AMs was estimated to be $482 per year, an almost 1.5-fold increase compared with AD cost alone (from $338 before AM development to $820 afterward, P < 0.001), with approxima...

Periodic food shortage is one of the biggest challenges organisms face in natural habitats. How animals cope with nutrient limited conditions is an active area of study, of particular relevance in the context of the current increasing destabilization of global climate. Caves represent an extreme setting where animals have adapted to nutrient-limited conditions, as most cave environments lack a primary energy source. Here we show that cave-adapted populations of the Mexican Tetra, Astyanax mexicanus, have dysregulated blood glucose homeostasis and are insulin resistant compared to the river-adapted population. We found that multiple cave populations carry a mutation in the insulin receptor that leads to decreased insulin binding in vitro. Surface/cave hybrid fish carrying the allele weigh more than non-carriers, and zebrafish genetically engineered to carry the mutation similarly have increased body weight and insulin resistance. Higher bodyweight may be advantageous in the cave as a strategy to cope with infrequent food. In humans, the identical mutation in the insulin receptor leads to a severe form of insulin resistance and dramatically reduced life-span. However, cavefish have a similar lifespan to surface fish (of greater than fourteen years) and do not accumulate advanced glycated end products (AGEs) in the blood that are typically associated with progression of diabetes-associated pathologies. Our findings raise the intriguing hypothesis that cavefish have acquired compensatory mechanisms that allow them to circumvent the typical negative effects associated with failure to regulate blood glucose.

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