A family history of type 2 diabetes increases risk factors associated with overfeeding

Abstract

Springer's Self-Archiving Policy Springer is a green publisher, as we allow self-archiving, but most importantly we are fully transparent about your rights. Publishing in a subscription-based journal If you publish an article in the traditional way, without open access our Copyright Transfer Statements reads "An author may self-archive an author-created version of his/her article on his/her own website and or in his/her institutional repository. He/she may also deposit this version on his/her funder's or funder's designated repository at the funder's request or as a result of a legal obligation, provided it is not made publicly available until 12 months after official publication. He/ she may not use the publisher's PDF version, which is posted on www.springerlink.com, for the purpose of self-archiving or deposit. Furthermore, the author may only post his/her version provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at www.springerlink.com". Aims: To test prospectively whether healthy individuals with a family history of type 2 4 diabetes are more susceptible to adverse metabolic effects during experimental overfeeding. 5Methods: We studied the effects of 3-and 28-days of overfeeding by 1250 kcal/day in 41 6 sedentary individuals with and without a family history of type 2 diabetes (FH+ and FH-). 7Measures included weight, fat distribution (CT) and insulin sensitivity (hyperinsulinemic-8 euglycemic clamp). 9Results: Body weight was increased at +3 and +28-days in both groups (p<0.001), with FH+ 10 gaining significantly more weight at +28-days (3.4 ± 1.6 vs. 2.2 ± 1.4 kg, p=0.02). Fasting 11 serum insulin and C-peptide were increased at +3 and +28-days in both groups, with greater 12 increases in FH+ for insulin at +3 and +28-days (p<0.01) and C-peptide at +28-days 13 (p<0.05). Fasting glucose also increased at both time points, but without significant group 14 effect (p=0.1). Peripheral insulin sensitivity decreased in the whole cohort at +28-days 15 (54.8±17.7 to 50.3±15.6 µmol min -1 kgFFM -1 , p=0.03), and insulin sensitivity by HOMA-IR 16 decreased at both time points (p<0.001) and to a greater extent in FH+ (p=0.008). Liver fat, 17 subcutaneous and visceral fat increased similarly in both groups (p<0.001).

Diabetes Risk Among Overweight and Obese Metabolically Healthy Young Adults

“…While obesity seems to mediate the incidence of diabetes, independent of the above-mentioned classic risk factors, it may still be mediated by significant insulin resistance and/or b-cell dysfunction that have not yet resulted in dysglycemia or dyslipidemia. In addition, it has also been demonstrated that diabetes risk associated with a positive family history of the disease may be mediated, at least in part, by obesity (21,22). Given the relatively young age of our cohort, it is likely that first degree relatives of participants reporting a negative family history for diabetes might still develop diabetes in the future.…”

Future management of human obesity: understanding the meaning of genetic susceptibility

“…The physiological mechanism(s) responsible has/have not been established, but the genetic and physiological information currently available remain consistent with the neurobehavioral hypothesis (NBH) proposed by O'Rahilly and Farooqi. 23 In NBH, common obesity is the result of widespread genetic susceptibility to environmental cues related to food intake, 18,24 mediated by appetite-regulating pathways within the hypothalamus. The mechanisms linking OE to the expression of obesogenic gene variant effects are not yet clear.…”

“…The physiological evidence implicates hypothalamic appetite-regulating pathways with their various sensor and effector systems, 23,24 and the genomic evidence (see "Obesogenic genetic variants") still supports the basic structure of the NBH. In this scheme, reduced (or increased) function in various components leads to either an increased drive to eat in the presence of OE and/or, equivalently, a decreased restraint of an appropriate drive in response to feedback signals.…”

“…21 Other causes of severe (syndromic) obesity associated with generalized developmental CNS disturbances are also linked to disruption of appetite regulation (Bardet-Biedl syndrome, Prader-Willi syndrome, pseudohypoparathyroidism, WAGR syndrome). 21 When taken together with our evidence of increased sensitivity to food-related cues in healthy family-history-positive individuals, 24 the genomic evidence continues to point to hypothalamic appetite regulation pathways as the most likely location of rare variants driving the susceptibility to obesity in response to increased OE as proposed in the NBH. The effects of common variants in FTO illustrate how such mechanisms can operate, and have increased interest in the potential roles of noncoding RNAs.…”

“…A family history of T2DM may be a particularly powerful discriminator as it identifies a group with history of obesity with pathogenic consequences. 18,24 There is strong desire in many quarters to intervene early, in children or in utero, in part because childhood obesity is a strong predictor of adult obesity and its consequences. As we now understand, this relationship reflects the shared genetic makeup of child and adult and is unlikely to be causative.…”