In experimental physiology, a number of signals have been demonstrated that affect insulin sensitivity independent of obesity. A number of pathways linking behaviour to insulin signalling are reviewed by Watve.

They include fertility selection hypothesis of Corbett et al. They include the fast life-cycle hypothesis 44 or mechanistic target of rapamycin mTOR over-activation hypothesis. James Neel, the father of thrifty gene hypothesis, did not consider obesity as a cause of type 2 diabetes. Thus, a number of alternative possibilities exist, but currently, we know little about them because they have not been sufficiently explored. Our analysis reveals the limited role of obesity and thereby highlights the importance of investigating alternative possibilities.

A possible clinical implication of our finding is that obesity control will have only a limited success in preventing type 2 diabetes. More research needs to be focused on the other possible causes of insulin resistance and their importance at the clinical level.

Any effort in this direction can be extremely enlightening and useful for the prevention, control and treatment of type 2 diabetes. Acknowledgements The authors would like to thank Manawa Diwekar, Shubhankar Kulkarni and Pramod Patil for useful comments on an earlier draft of the manuscript.

They would also like to thank Raj Bhopal and others of the Newcastle Heart project, England, and Chittaranjan Yajnik and others of the Pune Maternal Nutrition study and Coronary Risk of Insulin Sensitivity in Indian Subjects, Pune, study for giving them access to their raw data and also for their useful comments on the manuscript. Competing interests The authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article.

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Myokines in insulin resistance and type 2 diabetes. Exercise-induced myokines in health and metabolic diseases. Int Med Res. J Diab Res. Am J Physiol Endocrinol Metab. Costill D. Impaired muscle glycogen resynthesis after eccentric exercise. J Appl Physiol. Asp S, Richter E.

Decreased insulin action on muscle glucose transport after eccentric contractions in rats. Mechanisms of insulin resistance following injury. Ann Surg. Severity, duration, and mechanisms of insulin resistance during acute infections. Lang C. Sepsis-induced insulin resistance in rats is mediated by a b-adrenergic mechanism.

Acute pain induces insulin resistance in humans. Diabet Med. Perceived psychological stress and serum leptin concentrations in Japanese men. Transient increase in obese gene expression after food intake or insulin administration. Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro. Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects.

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Doves, diplomats and diabetes: A Darwinian interpretation of type 2 diabetes and related disorders. New York: Springer; Watve M, Diwekar-Joshi M, What to expect from an evolutionary hypothesis for a human disease: The case of type 2 diabetes. Homo — J Comp Hum Biol.

Type 2 diabetes, cardiovascular disease, and the evolutionary paradox of the polycystic ovary syndrome: A fertility first hypothesis. Am J Hum Biol. Evolutionary origins of insulin resistance: A behavioral switch hypothesis. BMC Evol Biol. Linking nutrition, maturation and aging: From thrifty genes to the spendthrift phenotype.

Aging Milano. TOR-centric view on insulin resistance and diabetic complications: Perspective for endocrinologists and gerontologists. Cell Death Dis. Am J Hum Genet. Decreased fetal size is associated with beta-cell hyperfunction in early life and failure with age. The influence of obesity and consequent insulin resistance on coronary risk factors in medically treated patients with coronary disease.

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Papers ; 1 — Waist circumference as a predictor of cardiovascular and metabolic risk factors in obese girls European Journal of Clinical Nutrition. In a joint international effort, we here retrospectively report long-term up to 6 years real-life follow-up data on children and adults with MCT8 deficiency treated with Triac.

Methods Study Design and Participants In this international pragmatic real-life cohort, data were collected retrospectively in patients with MCT8 deficiency, within our consortium of 33 hospitals in 18 countries, who have been treated with the T3 analogue Triac on an off-label use basis.

Eligible subjects were those with MCT8 deficiency confirmed by the presence of a pathogenic mutation in the SLC16A2 gene , irrespective of age or comorbidities, who were treated with Triac on an off-label use basis following our previously established dose escalation protocol 11 , and had their biochemical parameters measured in the central laboratory of the Erasmus MC, The Netherlands.

This approach allowed for a uniform strategy of Triac dosing and monitoring of effects. The cohort consisted of 1 patients who finished the Triac Trial I protocol and continued on Triac treatment on an off-label use basis; and 2 additional patients who were identified after the recruitment phase of Triac Trial I or could not be enrolled in the Triac Trial I due to the absence of study sites in their country. For patients who had been enrolled in the Triac Trial I, data from the assessments at baseline and after 1 year of Triac treatment have been re-utilized and extended by novel long-term follow-up data.

The parents or guardians of all patients provided consent for off-label use of Triac to their caregiving physician. Under off-label use and with retrospective collection of data that are part of routine clinical care from medical files, no institutional board approval was needed in the majority 30 of hub centers.

Data were collected prospectively during Triac Trial I, for which institutional board approval was granted at all study sites Procedures All patients discontinued antithyroid drugs, levothyroxine, or other thyroid hormone analogs if applicable, eg, diiodothyropropionic acid [DITPA] before treatment with Triac was initiated. After a washout period of 2 weeks, baseline measurements were recorded.

Patients were assessed for study outcomes and drug-related adverse events at baseline and during follow-up visits. Guidance on Triac dosing was provided by Erasmus MC based on thyroid function tests see Supplementary Methods 12 , which together with other blood components were measured in a central laboratory Erasmus MC, Rotterdam, The Netherlands according to routine procedures. Outcomes The primary prespecified endpoint of this study was the change in serum T3 concentrations between baseline and last available measurement.

The prespecified secondary endpoints were the change between baseline and last available body weight and body height expressed as kg and cm, or weight-for-age and weight-for-height and height-for-age Z-scores, respectively, or as relative differences to the natural history reference; see Supplementary Methods 12 ; heart rate expressed as beats per minute, or heart-rate-for-age Z-score ; serum thyroid-stimulating hormone TSH; thyrotropin , free and total T4 concentrations; established biochemical markers that reflect thyroid hormone action in the liver sex hormone-binding globulin [SHBG] , in the kidney creatinine and in muscle creatine kinase [CK] ; and Tanner stage of sexual maturation in patients who were aged between 8 and 18 years during treatment.

Safety The occurrence of severe adverse events related to Triac was actively monitored during treatment see Supplementary Methods Statistical Analyses Analysis on the primary outcome was based on the full analysis dataset, which included all patients who received at least 1 dose of Triac and who had at least 1 follow-up visit after the baseline assessment. Analyses on all prespecified secondary outcomes were done in all subjects who had a treatment duration that exceeded the mean time of dose escalation defined as time from baseline measurement to the first follow-up visit on optimal dose , to ensure that treatment effects on secondary outcomes could be reliably assessed.

Complementary analyses of secondary outcomes were performed on the full analysis dataset. Missing data can mainly be attributed to the poor clinical condition of patients including restricted availability of serum ; common manifestations of MCT8 deficiency, such as scoliosis and dystonic posturing that hamper investigations for which patients needed proper positioning; and patients receiving clinical care outside the designated hub centers.

With the assumption that omission of data occurred randomly, and given the broad age range of the participants and small group size, pairwise deletion was used to adjust when the baseline data point was missing; for missing data that were captured throughout the treatment period, the last available measurement was used if available. Two-sided P values of less than 0. Role of the Funding Source The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Results Between October 15, , and January 1, , 67 patients from 62 different families with 46 different MCT8 mutations had received Triac and were eligible for inclusion in this study.

Among them, 27 patients had been enrolled in Triac Trial I and continued Triac treatment on an off-label use basis after completion of the trial protocol. Patients were treated in 33 different sites in 18 countries: 19 sites were located in Europe, 4 in the Americas, 5 in Asia, 4 in Oceania and 1 in Africa Supplementary Figure 2

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