Insulin promotes adipogenesis and weight gain through effects mediated directly at the adipocyte. Specifically, insulin up-regulates Glut4, acetyl-CoA carboxylase, fatty acid synthase, and lipoprotein lipase.30
Insulin resistance caused by hepatic/muscle dysfunction promotes reflex hyperinsulinemia and can promote the metabolic syndrome in children.31,32
Insulin hypersecretion caused by CNS/pancreatic dysfunction is less common and usually exists as an effector of “hypothalamic obesity” because of brain tumor or cranial radiation.33
We have previously shown that these two insulin disorders can be dissociated from each other by assessing the insulin response to OGTT and measuring insulin secretion with the CIRgp and insulin sensitivity with the CISI.15
We have also shown that insulin hypersecretion is the predominant insulin abnormality both in obese black children, and in children with hypothalamic obesity.15
Previous studies of pharmacotherapy in obese children have yielded considerable variability in efficacy. We postulated that insulin dynamics might offer a method for “triaging” patients to therapy on the basis of the cause of their obesity. Therefore we evaluated patients within clinical observational protocols who had received metformin for insulin resistance and octreotide for insulin hypersecretion. Although these studies are suboptimal because of their open-label nature, possible placebo effects, and inconsistent compliance, the ability of an a priori pretreatment metabolic parameter variable to distinguish the clinical response validates this approach. By using multiple linear regression analysis, we were able to determine which of the different predictor variables modified the efficacy of each medication. In addition to insulin dynamics, demographic variables such as age, sex, pubertal status, and initial BMI and z-score were also evaluated but were not as predictive.
Metformin improves insulin sensitivity, predictably decreases fasting hyperinsulinemia, and prevents the onset of type 2 diabetes mellitus34
but demonstrates variable efficacy in promoting weight loss in adults.17,35
The mechanism of action of metformin on body weight remains unclear. Although some postulate that metformin promotes weight loss though a primary anorectic effect,36
it is more likely that the decline in caloric intake observed with metformin is related to its reduction in insulin resistance through its enhancement of hepatic glucose turnover, reduction of hepatic glucose output37,38
and through its actions on hepatic AMP kinase.39
Another possible mechanism of metformin action is through central effects on glucagon-like peptide-1 (GLP-1),40
which would reduce food intake.
In white children, metformin was effective in promoting loss of BMI and BMI z-score, provided that the patient was insulin resistant (ie, a low CISI) but not an insulin hypersecretor. As the CISI increased, the effect of metformin was mitigated. Most of the response was achieved in the first 4 months of therapy, but a beneficial effect was observed for the next year as well. Interestingly, metformin had greater effect in females than in males. Our results suggest efficacy of metformin in prepubertal children with severe obesity caused by insulin resistance. Most practitioners have reserved metformin for treatment of adolescents only, because its current Food and Drug Administration indication in pediatric type 2 diabetes mellitus extends down to 10 years of age.
Octreotide binds to a somatostatin receptor on the β-cell membrane,41
which is coupled to a voltage-gated calcium channel, which limits its opening, thus attenuating insulin release.42–44
Insulin suppression using octreotide has been shown to be effective in reducing BMI in children with hypothalamic obesity caused by CNS insult20,21
; however, patients have demonstrated variable responsiveness. The results of this study demonstrate that both insulin hypersecretion and insulin sensitivity (as measured by CIRgp and CISI) are necessary to predict a beneficial BMI response to octreotide.
Studies by Bergman et al45
using intravenous glucose tolerance testing have suggested that insulin secretion is merely an epiphenomenon of insulin resistance, obeying a hyperbolic relationship known as the “disposition index.” However, the intravenous glucose tolerance testing does not take into account other stimuli to β-cell insulin release, such as vagal innervation46
and intestinal incretins such as GLP-1,47
which would only activate with an oral challenge. By performing OGTT, we have shown that insulin hypersecretion is a phenomenon that is separate and distinct from insulin resistance.15
This study also supports this contention, in that metformin’s efficacy on BMI reduction is predicted by insulin resistance, whereas octreotide’s efficacy is predicted by both insulin hypersecretion and insulin sensitivity.
With our data, an adjusted disposition index can be defined such that when logarithmically transformed, it would equal the sum of log(CIRgp) and log(CISI). This implies that it would work well in the models of and when the coefficients shown for CIRgp and CISI are approximately equal and there is no interaction between the 2. This appears to be the case in and but is suspect for II, C, and clearly violated for II, A (because the coefficients differ) and III, A and B (because of the interaction between CIRgp and CISI).
One conundrum posed by these results is that despite marked insulin resistance (mean CISI of 1.6), black children did not respond to metformin with BMI or BMI z-score reduction.48
Other investigators have documented excessive insulin secretion49,50
and defective insulin clearance51
in black children, which is not explained by either the degree of insulin sensitivity or adiposity. Although the reasons for this are still not completely clear, our previous study demonstrated that when controlled for the degree of insulin secretion, the difference in insulin resistance between black and white children is obviated, but when controlled for the degree of insulin resistance, the difference in insulin secretion between the 2 races remains dichotomous.15
This suggests that the primary defect in black children is actually insulin hypersecretion, and that insulin resistance may be an epiphenomenon. We have previously shown that obese black adults have an accentuated GLP-1 response to OGTT,52,53
which may account for the insulin hypersecretion directly at the β-cell, and would not be amenable to metformin therapy, whose primary effects are on the liver. Other possible reasons for this racial dichotomy in efficacy include differences in dietary choices or compliance with medication.
Lifestyle intervention continues to be the standard of care for pediatric obesity and should remain the initial option for therapy. However, the results of most studies suggest that efficacies of lifestyle approaches are quite variable. We have noted that individual differences in insulin dynamics may also contribute to this variability.54
Our results support the concept of using the OGTT with insulin dynamics to discern both insulin hypersecretion and resistance and as a method for directing adjunct pharmacotherapeutic decisions in obese children who have not responded to lifestyle intervention alone. However, before OGTT with insulin dynamics can be proposed as a clinical tool for general use, randomized controlled trials of pharmacotherapy in childhood obesity will be required. Neither metformin nor octreotide has been approved by the FDA for the treatment of pediatric obesity. However, a randomized controlled study of metformin efficacy with pre-hoc insulin dynamics is currently ongoing within the Glaser Pediatric Research Network, as is a study of efficacy of the long-acting octreotide-LAR in hypothalamic obesity conducted by its manufacturer.
Last, our results suggest a “decision-tree” evaluation point in the workup and treatment of obese children. It is clear that “one size does not fit all” when it comes to obesity therapy. There is clearly a role for pharmacotherapy in select patients, and it appears that assessing the biologic mechanism of the weight gain is an important consideration in terms of predicting response. Assessing insulin dynamics by OGTT is simple, relatively inexpensive, and prescient in terms of understanding the causes of obesity and targeting of patients with available medical therapies.