Islet amyloid is a characteristic feature of type 2 diabetes. Its major component is the normal beta-cell secretory product amylin, or islet amyloid polypeptide (IAPP). To determine whether increased or disproportionate release of amylin may explain the propensity for amyloid deposition in type 2 diabetes, we measured plasma amylin-like immunoreactivity (ALI) and immunoreactive insulin (IRI) release in response to an oral glucose load in 94 Japanese-American subjects with normal glucose tolerance (NGT; n = 56), impaired glucose tolerance (IGT; n = 10), and type 2 diabetes (n = 28) as defined by World Health Organization criteria. The incremental increase In AI,I, IRI, and glucose (G) at 30 min after oral glucose ingestion was used to calculate Delta ALI/Delta G and Delta IRI/Delta G as measures of beta-cell function. Overall glucose metabolism was assessed as the incremental glucose area (glucose AUG) during the 2 h of the oral glucose tolerance test. As expected, plasma glucose concentrations at both fasting (NGT, 5.0 +/- 0.4; IGT, 5.5 +/- 0.1; type 2 diabetes, 6.2 +/- 0.3 mmol/l; P < 0.0001) and 2 h (NGT, 6.7 +/- 0.1; IGT, 9.4 +/- 0.3; type 2 diabetes, 13.2 +/- 0.5 mmol/l; P < 0.0001) were elevated in individuals with IGT and type 2 diabetes. In response to glucose ingestion, plasma IRI and ALI increased in all subjects, but these increments were lower in individuals with reduced glucose tolerance, as reflected in the Delta IRI/Delta G (NGT, 119 +/- 10.3; IGT, 60.7 +/- 7.1; type 2 diabetes, 49.7 +/- 5.4 pmol/l; P < 0.0001) and Delta ALI/Delta G (NGT, 2.6 +/- 0.2; IGT, 1.8 +/- 0.3; type 2 diabetes, 1.2 +/- 0.1 pmol/l; P < 0.0001). Moreover, these reductions in the 30-min incremental ALI and IRI responses were proportionate such that the molar ratio of ALI to IRI was not different among the three groups (NGT, 2.6 +/- 0.2; IGT, 2.9 +/- 0.3; type 2 diabetes, 2.9 +/- 0.3%; NS). Further, the relationship between beta-cell function, measured as either Delta IRI/Delta G or Delta ALI/Delta G, and glucose metabolism, assessed as glucose AUG, was nonlinear and inverse in nature, with r(2) values of 0.38 (P < 0.0001) and 0.33 (P < 0.0001), respectively. We conclude that the reduced beta-cell function of IGT and type 2 diabetes includes proportionate reductions in both IRI and ALI release. Thus, it is unlikely that the development of islet amyloid in type 2 diabetes is the result of increased release of ALI.
