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Fig. 2. (A) Insulin levels during the hyperglycemic clamp. (B) Insulin sensitivity during a 3-hour hyperinsulinemic (80 mu/m2/min)-euglycemic clamp in adolescents with T2DM versus obese controls. (C) Glucose disposition index in adolescents who have T2DM and obese controls. (Adapted from Gungor N, Bacha F, Saad R, et al. Youth type 2 diabetes: insulin resistance, beta-cell failure, or both? Diabetes Care 2005;28:641-2; with permission.)

P = 0.025). This relationship may either reflect the impact of deficient insulin secretion on the outcome of glycemic control or be viewed as a glucotoxic phenomenon of poor glycemic control on insulin secretion. Intensive glycemic control may be important to prevent further deterioration in beta-cell function. These findings of severe impairment in insulin secretion at such an early age could imply the potential need of starting insulin replacement therapy early in youth T2DM to maintain glycemic control and prevent hyperglycemia-driven complications.

Impairments in insulin biosynthetic process have been described in adults with T2DM. Levels of circulating proinsulin and its cleavage intermediate des-31, 32 proinsulin are disproportionately elevated [41]. In our study of youth who have T2DM, fasting proinsulin/insulin ratio was significantly higher compared with controls, similar to findings in adult T2DM [19,49]. This is another metabolic phenotype of impaired beta-cell function in youth who have T2DM.

In summary, when T2DM is clinically present, insulin action and insulin secretion are impaired. The proposed pathophysiology of T2DM in youth is outlined in Fig. 3 [50].

Genetics + Environment

Genetics + Environment

Fig. 3. Proposed pathophysiology of youth-onset T2DM. (Adapted from Arslanian SA. Type 2 diabetes mellitus in children: clinical aspects and risk factors. Horm Res 2002;57(Suppl 1):23; with permission.)

Natural history of youth type 2 diabetes mellitus

There are no longitudinal studies in children to follow the evolution of T2DM in high-risk individuals. Studies in adults suggest that the metabolic determinant of the progression from NGT to IGT to T2DM is pancreatic beta-cell function. Observations in insulin-resistant Pima Indian adults demonstrated progressive loss of acute insulin response to intravenous glucose throughout transition from NGT to IGT to T2DM [45]. The Botnia cross-sectional study of T2DM pathogenesis in at-risk European populations depicted a lower insulin sensitivity, using the homeostasis model assessment, when comparing IGT to NGT and T2DM to IGT [51]. This study further demonstrated a markedly impaired insulin secretion in T2DM subjects who no longer could compensate for insulin resistance and elevated glucose levels.

The United Kingdom Prospective Diabetes Study (UKPDS) found that beta-cell function was 50% of normal at the time of clinical diagnosis of T2DM [52]. The UKPDS and the Belfast diet intervention study reaffirmed the progressive nature of adult T2DM as an ongoing decline in beta-cell function without a change in insulin sensitivity [52-54]. In a recent case report of an adolescent with T2DM followed over 6 years, we demonstrated approximately 15% decline in beta-cell function with no substantial changes in insulin sensitivity [55]. This is almost a threefold faster decline in beta-cell function compared with adult UKPDS data. Because this is only a case report, additional studies are needed to explore whether this observation of an accelerated loss of beta-cell function is generalizable to all youth who have T2DM. If the early and severe impairment in insulin secretion in youth with T2DM is followed by an accelerated decline in beta-cell function, insulin therapy early in the course of the disease rather than "insulin as the last resort'' should be considered carefully. Further studies are needed to investigate not only the natural history of beta-cell function in youth with T2DM but also strategies to retard or prevent its progressive failure.

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