β-Cell Function, Incretin Effect, and Incretin Hormones in Obese Youth Along the Span of Glucose Tolerance From Normal to Prediabetes to Type 2 Diabetes

Abstract

Using the hyperglycemic and euglycemic clamp, we demonstrated impaired β-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled β-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. β-Cell function parameters were derived from established mathematical models yielding β-cell glucose sensitivity (βCGS), rate sensitivity, and insulin sensitivity in 255 obese adolescents (173 with normal glucose tolerance [NGT], 48 with impaired glucose tolerance [IGT], and 34 with type 2 diabetes [T2D]). The incretin effect was calculated as the ratio of the OGTT-βCGS to the 2-h hyperglycemic clamp-βCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, βCGS was 30 and 65% lower in youth with IGT and T2D, respectively; rate sensitivity was 40% lower in T2D. Youth with IGT or T2D had 32 and 38% reduced incretin effect compared with NGT in the face of similar changes in GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in response to oral glucose. We conclude that glucose sensitivity deteriorates progressively in obese youth across the spectrum of glucose tolerance in association with impairment in incretin effect without reduction in GLP-1 or GIP, similar to that seen in adult dysglycemia.

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

“…Body composition was evaluated with DEXA by the measurement of total body fat mass, fat-free mass, and percentage of body fat. Abdominal total adipose tissue (TAT), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were assessed by either computed tomography (CT) or MRI at the L 4–5 intervertebral space (10,22). The switch from CT to MRI was imposed by the study section during the competitive grant renewal process.…”

“…Total GLP-1 was measured on a microplate reader (BioTek, Winooski, VT) using a multispecies total GLP-1 ELISA kit (catalog #EZGLP1T-36 K; Millipore). GIP and PP were measured on the 200 IS System (Luminex, Austin, TX) using a two-plex human gut hormone MILLIPLEX Kit (catalog #HGT-68K-02; Millipore), as described before (10). FFA was determined using enzymatic colorimetric methods with a (nonesterified fatty acids) NEFA-HR Test Kit (Wako, Osaka, Japan).…”

“…Considering that insulin resistance, impaired β-cell function, and impaired incretin effect constitute the pathophysiological mechanisms of youth prediabetes and type 2 diabetes (8–10), there is increasing interest in identifying simple biomarkers that can detect impairment in β-cell function heralding type 2 diabetes. Among these are the fasting (11), 1-h (12), and 2-h glucose concentrations during an OGTT, which signal β-cell failure, measured by the clamp-derived disposition index (DI), and presage progression to type 2 diabetes (8,13).…”

Inside out the Ragbag of Glucose Intolerance in Obese Adolescents

“…A very recent study [28] investigating β-cell performance using the Mari model [14] found that youth with IGT or T2D have a reduced incretin effect compared with their NGT peers without any reduction in GLP-1 and GIP concentrations. Interestingly, the authors speculated that the diminished incretin effect is due to the defective βCGS [28]. …”

The importance of prediabetes and therapeutic approach

“…Obez disglisemik gençlerde yapılan çalışmada glukoz duyarlılığı azaldıkça, glukagon-benzeri peptid-1 (GLP-1) veya glukoz bağımlı insülinotropik polipeptit (GIP) düzeylerinde herhangi bir azalma olmaksızın inkretin etkide bozulma gösterilmiştir (23).…”