This study was undertaken to explore whether increased GLP-1 levels could explain the increased β-cell activity, insulin level or lower insulin sensitivity reported in obese AA subjects. Higher fasting and stimulated insulin concentrations 6,28,29
in AAs have been explained by a diversity of mechanisms.6,7
Haffner et al6
reported both increased first-phase insulin secretion and reduced insulin sensitivity as the two major determinants of the higher insulin concentrations in AAs. Conversely, Jiang et al
in a biracial sample of 1157 adolescents from the Bogalusa Heart Study, reported that the higher insulin concentration in AAs was mainly explained by reduced hepatic insulin clearance as determined by a lower C-peptide/insulin ratio. Arslanian et al
suggested that the higher insulin secretion in AAs (50% first-phase and 38% second phase) represented a compensatory mechanism to overcome the 35% decrease in insulin sensitivity. In agreement with these reports, our study indicates that at comparable levels of insulin sensitivity, obese AAs have higher β-cell activity and impaired insulin clearance compared to obese C.
A novel finding in this study is that at similar levels of glucose, BMI, fat mass (DEXA, WHR, leptin), dietary intake, and insulin sensitivity, obese AAs have significantly higher fasting and stimulated GLP-1 concentrations than obese C. Changes in GLP-1 levels paralleled changes in β-cell activity (CIR30) and preceded the peak insulin response during the OGTT. Our results do not explain if higher concentrations of GLP-1 are the result of increased secretion, differences in metabolic clearance, or a combination of both.
Elimination of bioactive GLP-1 from the circulation may occur via at least three different mechanisms: renal clearance, 30–32
and degradation in the circulation by mainly dipeptidyl peptidase IV (DPP IV; EC 22.214.171.124).33,34
The differences in GLP-1 and insulin concentrations and dynamics between AAs and C, warrants further exploration.
Our study indicates that racial differences in the insulin concentrations could be explained by an increased enteroinsular axis (EIA) activity. Hyperfunction of the EIA, and increased GLP-1 levels, may account for the observed enhanced first- and second-phase of insulin secretion in AAs. GLP-1’s action is mediated by binding to cell surface receptors that are highly expressed on the cell membranes of pancreatic β-cells.10,11
GLP-1 stimulates the formation of the second messenger, cAMP, which activates a cAMP-dependent protein kinase and phosphorylation of key proteins in the control of insulin secretion.12,35
The binding of GLP-1 to its receptor also depolarizes the cellular membrane and induces a rise in free intracellular calcium concentration, followed by a potentiation of the glucose-induced insulin secretion dependent upon extracellular sodium.16
In addition to the insulin stimulatory effect, GLP-1 may affect the hepatic insulin extraction. Brandt et al
although not finding a direct effect of GLP-1 on the hepatic insulin clearance, suggested that the increased insulin secretion in response to GLP-1 itself may drive the reduction of hepatic insulin extraction.11
The reduced insulin clearance is presumably due to alterations in insulin receptor number and/or affinity, in view of the importance of the insulin receptor in mediating insulin clearance.36
The effect of higher GLP-1 concentration may also be a potential factor to explain the higher prevalence of obesity and type 2 diabetes in AAs by fostering a hyperinsulinemic state.1
Insulin is the primary hormonal mediator of energy storage in humans.37
Within the adipocyte, insulin regulates: (a) GLUT4 expression; (b) acetyl-CoA carboxylase; (c) fatty acid synthase; and (d) lipoprotein lipase.37
Hyperinsulinemia has also been associated with an enhanced craving for carbohydrates, hyperphagia, and decreased fat oxidation and physical activity. Furthermore, increased levels of GLP-1 induce homologous desensitization and internalization of the β-cell GLP-1R setting up a sequence of events that are thought to result from ligand-induced changes in receptor conformation. The desensitization of the β-cell GLP-1R occurs by homologous desensitization, which is caused by repeated stimulation of the same receptor, and by heterologous desensitization, which decreases the response of the receptor as a result of activation of other membrane receptors, as has been shown with the activation of the protein kinase C by phorbol esters.38
Receptor desensitization participates in the mechanisms to control insulin secretion, perhaps to reduce the risks of hypoglycemia, but it also could possibly play a role in type 2 diabetes by decreasing the sensitivity of the GLP-1R and consequently the secretory activity of the β-cells. Accumulation of GLP-1 after dipeptidyl peptidase IV (DPP IV) degradation in the circulation may also promote type 2 diabetes. Recently, it has been shown that GLP-1 (9–36) amide could antagonize the effects of GLP-1 (7–36).39
However, whether sufficient quantities of this metabolite GLP-1 (9–36) amide exist in vivo
to act as an antagonist of GLP-1, or possibly to mediate other biological activities, remains to be determined.
In summary, we have demonstrated that at comparable levels of insulin resistance, glucose tolerance, BMI, WHR, waist circumference, leptin, and fat mass, obese AAs have significantly higher fasting and stimulated GLP-1 concentrations. Changes in GLP-1 levels paralleled changes in β-cell activity and preceded the peak insulin response during the OGTT. Increased GLP-1 concentration might account for the greater insulin concentrations and the increased prevalence of hyperinsulinemia-associated disorders in AAs.