The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test Heralds Biomarkers of Type 2 Diabetes Risk in Obese Youth

Abstract

Objective: The shape of the glucose response curve during an oral glucose tolerance test (OGTT), monophasic versus biphasic, identifies physiologically distinct groups of individuals with differences in insulin secretion and sensitivity. We aimed to verify the value of the OGTT-glucose response curve against more sensitive clamp-measured biomarkers of type 2 diabetes risk, and to examine incretin/pancreatic hormones and free fatty acid associations in these curve phenotypes in obese adolescents without diabetes.

Research design and methods: A total of 277 obese adolescents without diabetes completed a 2-h OGTT and were categorized to either a monophasic or a biphasic group. Body composition, abdominal adipose tissue, OGTT-based metabolic parameters, and incretin/pancreatic hormone levels were examined. A subset of 106 participants had both hyperinsulinemic-euglycemic and hyperglycemic clamps to measure in vivo insulin sensitivity, insulin secretion, and β-cell function relative to insulin sensitivity.

Results: Despite similar fasting and 2-h glucose and insulin concentrations, the monophasic group had significantly higher glucose, insulin, C-peptide, and free fatty acid OGTT areas under the curve compared with the biphasic group, with no differences in levels of glucagon, total glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and pancreatic polypeptide. Furthermore, the monophasic group had significantly lower in vivo hepatic and peripheral insulin sensitivity, lack of compensatory first and second phase insulin secretion, and impaired β-cell function relative to insulin sensitivity.

Conclusions: In obese youth without diabetes, the risk imparted by the monophasic glucose curve compared with biphasic glucose curve, independent of fasting and 2-h glucose and insulin concentrations, is reflected in lower insulin sensitivity and poorer β-cell function, which are two major pathophysiological biomarkers of type 2 diabetes in youth.

Figure 1

Glucose (A), insulin (B), C-peptide (C), FFA (D), and glucagon (E) response curves during a 2-h OGTT in monophasic (filled circles and solid lines) and biphasic (open triangles and dashed lines) groups. *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 2

In vivo hepatic IS (A), peripheral IS (B), β-cell function relative to IS (DI) (C), and the hyperbolic relationship between IS and first-phase insulin secretion (D) in the monophasic group (filled circles and solid line) vs. the biphasic group (open triangles and dashed line). Hyperbolic curve is the nonlinear fitted regression line derived from the individual data points of the monophasic (R² = 0.314, P < 0.001) vs. the biphasic (R² = 0.199, P = 0.004) groups. Adjusted P value is for the difference after adjusting for age, Tanner stage, race, sex, and glycemic status.