Commentary on the Impact of Obesity and Puberty on Insulin Sensitivity

Commentary

The hormonal changes of puberty are well recognized to affect insulin resistance although the physiology is not fully delineated even now. With puberty, increased growth hormone and insulin-like growth factor 1 secretion are accompanied by dramatic changes in plasma sex hormone concentrations resulting in increased caloric intake and body mass. Increased insulin requirements during puberty have been long observed in adolescent youth with type 1 diabetes mellitus, even when accommodating for increased carbohydrate intake. With the development of the insulin radioimmunoassay by Berson and Yalow (1) and subsequent generations of improvements in analytical techniques to measure plasma insulin using a variety of protocols, we can quantify the severity of insulin resistance occurring during puberty (2). However, insulin resistance is most commonly observed in individuals with obesity (3), regardless of age (4), as a result of defective postreceptor signaling (5). And yet, a number of questions remain, including the exact role of pubertal increases in insulin resistance in youth with and without obesity.

The true changes over the course of puberty in the presence and absence of obesity have never been so clearly demonstrated until the studies reported by Kelsey and coworkers (6). This report concludes a long, meticulous, and beautifully conducted prospective analysis of the metabolic changes during puberty in children of normal weight compared with those with obesity but without diabetes. This study characterized demographic, clinical, and metabolic characteristics using sophisticated measures to assess insulin secretion (acute insulin response to glucose, AIRg) and sensitivity (Si) in youth from Tanner stages 2 to 3 through stages 4 and 5. With advancing puberty, independent of body mass index, Si and AIRg increased in both groups. The fundamental difference was the lower Si and higher AIRg in youth with obesity compared with normal-weight peers, at every pubertal stage. The authors concluded that youth with obesity had sufficient β-cell secretory capacity to overcome their lower Si in the face of puberty. What remains to be determined is how we can use this information to stem the growing problem of prediabetes and type 2 diabetes in youth. Additional studies will be necessary to elucidate the factor(s) and the role of other modulators, such as leptin and insulin-like growth factor 1, to target prospectively adolescents with obesity who are at increased risk for type 2 diabetes.

To date, the clinical world continues to pursue mechanisms and drugs to manipulate plasma glucose concentrations to achieve better diabetes control. In fact, the problem is far broader than our usual glucocentric perspective. A paradigm shift toward a lipocentric approach is necessary and not new but was elegantly described by Denis McGarry, PhD, in his Banting lecture of 2002. Dr McGarry’s work supports the hypothesis that type 2 diabetes and its constellation of complications are the result of lipotoxicity at the cellular level in the pancreas, muscle, fat, liver, and other tissues (7). In his closing remarks, Dr McGarry stated, “….It is evident that if people would eat fewer calories and increase their activity level, then this would reverse ectopic fat accumulation and lessen insulin resistance. However, compliance with such a strategy is clearly difficult. If society is not willing to make major lifestyle changes, are other interventions available?”

Weight loss by diet effectively decreases insulin resistance and increases insulin secretion (8), but such improvements are generally not sustained because of the resumption of previous habitual diets and physical activities. For pubertal adolescents who are obese, adherence to intensive diet and physical activities is even more difficult; they must overcome the dual effects that increase insulin resistance: puberty and obesity. At present, there are no easy, long-term solutions in our clinical toolbox to promote sustained weight loss, especially in youth. Instead, we focus on behavior modification techniques that promote positive practices that are devoid of blame and failure. Yet we truly do not know the full spectrum of emotional, psychological, and social factors that contribute to disordered eating and decreased physical activity.

Dr McGarry’s supposition has now been most dramatically proven in the clinical arena. The loss of fat tissue as a result of bariatric surgery alone reverses many of the comorbidities of obesity, including diabetes, hypertension, hyperlipidemia, sleep apnea, hepatosteotosis, renal disease, and one might speculate on coronary artery disease as well as stroke (9). Additionally, these effects seemed to be sustained in the majority of individuals, including adolescents with obesity with or without diabetes (10). The American Academy of Pediatrics and the American Diabetes Association now endorse bariatric surgery as an important management tool in youth with severe obesity.

As more improvements are made in surgical techniques, we might anticipate fewer acute and chronic complications of bariatric surgery. Although bariatric surgery in adolescents (or adults) has risks, we must ask ourselves whether these risks are greater than effectively doing nothing to accomplish sustained weight loss despite our best efforts as physicians? Until we, as a society, can learn to alter our own behaviors to prevent or minimize the effects of social and environmental factors that decrease physical activity and increase caloric intake, the future is bleak in terms of stemming the tide of population adiposity and increasing numbers of individuals with type 2 diabetes, regardless of age. Our colleagues in the pharmaceutical industry have been unable to help us safely address this problem to date, and a weight-loss pill, lorcaserin, was recently recalled by the US Food and Drug Administration because it may increase cancer risk, further limiting our clinical armamentarium. As Dr McGarry suggested some 20 years ago, we have few alternatives as physicians to make a significant impact into this progressively more costly problem both in terms of health care expenditure but also in terms of human suffering on a world-wide basis.

Glossary

Abbreviations

AIRg

acute insulin response to glucose

Si

sensitivity

Additional Information

Disclosure Summary: The authors have no conflicts of interest to disclose. Dr Chung is an employee of the NIH and Co-Director of the Metabolic Research Unit.