This is the first study in youth demonstrating that both insulin sensitivity and insulin secretion are impaired in adolescents with type 2 diabetes compared with matched obese control subjects. Even though our findings are in agreement with the literature on adults with type 2 diabetes (2
), the disconcerting observation is the severe impairment in insulin secretion (FPIS ~75% lower; SPIS ~50% lower) at a very young age with a relatively short duration of diabetes. The implication of such findings could potentially be the early need for insulin replacement therapy to maintain glycemic control. Moreover, the present investigation shows an inverse relationship between HbA1c
and FPIS. This relationship may either reflect the impact of deficient insulin secretion on the outcome of glycemic control or may be viewed as a glucotoxic phenomenon of poor glycemic control on insulin secretion.
Metabolic studies in type 2 diabetes of youth are scarce in the literature. A Japanese study (14
) using the frequently sampled intravenous glucose tolerance test revealed that obese nondiabetic adolescents and obese adolescents with type 2 diabetes were equally insulin resistant. This is in contrast to our findings of ~50% lower insulin sensitivity in the type 2 diabetic group compared with obese control subjects. The former study, however, did not match the groups with respect to body composition and body fat distribution. Our finding of increased insulin resistance in youth with type 2 diabetes is in agreement with various cross-sectional and longitudinal studies in adult populations with (or at risk for developing) type 2 diabetes that identified insulin resistance as a key component of type 2 diabetes pathophysiology (3
). In further support of the lower insulin sensitivity in type 2 diabetes is our finding of significantly lower adiponectin levels in type 2 diabetic patients, despite similar body composition and visceral adiposity to obese control subjects. Hotta et al. (18
) demonstrated decreased plasma adiponectin levels in adults with type 2 diabetes compared with obese control subjects. Weyer et al. (19
) reported lower plasma adiponectin levels in Pima Indians with IGT and type 2 diabetes than in those with normal glucose tolerance (NGT). In a recent investigation of nondiabetic youth, we demonstrated that hypoadiponectinemia is a strong and independent correlate of insulin resistance (7
). Our findings with respect to lower FPIS and GDI in adolescents with type 2 diabetes are in agreement with the Japanese study in adolescents (14
Another study in 9- to 20-year-old type 2 diabetic patients revealed relative hypoinsulinemia and hyperglucagonemia in response to a mixed liquid meal tolerance test (20
). However, the insulin deficiency was not expressed relative to the degree of insulin resistance (not measured).
The increased fasting hepatic glucose production in adolescents with type 2 diabetes in our study () is also in accordance with the longitudinal study by Weyer et al. (3
), who identified an increase in basal endogenous glucose output as a critical component of transition from IGT to type 2 diabetes in adult Pima Indians who already had impairment in insulin sensitivity and BCF.
Impairments in the insulin biosynthetic process have been described in adults with type 2 diabetes. Levels of circulating proinsulin and its cleavage intermediate des-31,32-proinsulin are disproportionately elevated (4
). The fasting proinsulin-to-insulin ratio was significantly higher in our youth with type 2 diabetes compared with obese control subjects, similar to the findings of Roder et al. (21
) in adults with type 2 diabetes and obese control subjects. This is another metabolic phenotype of impaired BCF in youth with type 2 diabetes.
There are no reported longitudinal studies in pediatric subjects with type 2 diabetes assessing the evolution of the disease. PCOS is a condition characterized by severe insulin resistance and is a major risk factor for type 2 diabetes (1
). Our previous cross-sectional studies in this high-risk group demonstrated that PCOS adolescents with NGT are insulin resistant and hyperinsulinemic compared with matched obese girls (13
). However, PCOS adolescents with IGT have impaired FPIS with no derangement in SPIS (11
). Our current study in type 2 diabetic adolescents shows severe impairments in both FPIS and SPIS. These studies, although cross-sectional, collectively suggest that the essential metabolic determinant of the progression from NGT to IGT to type 2 diabetes is BCF. Our cross-sectional observations are in agreement with longitudinal data in insulin-resistant Pima Indian adults demonstrating progressive loss of acute insulin response to intravenous glucose throughout transition from NGT to IGT to type 2 diabetes (3
). The Botnia study of type 2 diabetes pathogenesis in at-risk European populations depicted a lower insulin sensitivity when comparing NGT with IGT and IGT with type 2 diabetes, cross-sectionally with the homeostasis model assessment (HOMA) approach (17
). This study further demonstrated an inverted U-shaped insulin secretion pattern (determined with the oral glucose tolerance test) such that subjects with type 2 diabetes showed markedly impaired insulin secretion that could no longer compensate for insulin resistance and elevated glucose levels (17
The U.K. Prospective Diabetes Study found that BCF was 50% of normal at the time of clinical diagnosis of type 2 diabetes (22
). The clinically recognized progressive nature of adult type 2 diabetes as an ongoing decline in BCF without a change in insulin sensitivity has been reaffirmed by the U.K. Prospective Diabetes Study (22
) and the Belfast diet intervention study (24
) with the HOMA approach. As our study is a cross-sectional evaluation, we are unable to comment on the progressive nature of β-cell failure in type 2 diabetes of youth. However, in a recent case study we detected an ~15% decline in BCF per year over the 6-year duration of diabetes, with no substantial changes in insulin sensitivity (25
). Further studies are needed to explore whether this observation of an accelerated loss in BCF with increasing duration of diabetes can be generalized to all youth with type 2 diabetes. If the early and severe impairment in pancreatic BCF is indeed coupled with an accelerated pace of BCF deterioration in youth with type 2 diabetes, then early insulin therapy rather than “insulin as the last resort” should carefully be considered.
In conclusion, when type 2 diabetes is clinically present in the pediatric population, both insulin sensitivity and BCF are impaired and hepatic glucose output is increased. The impairment in BCF appears to be of greater magnitude relative to that of insulin sensitivity compared with a nondiabetic obese group. Further studies are needed to investigate not only the natural history of BCF in youth with type 2 diabetes, but also strategies to retard and/or prevent its progressive failure.