A novel simple disposition index (SPINA-DI) from fasting insulin and glucose concentration as a robust measure of carbohydrate homeostasis.

AIMS: The widely used dynamic disposition index, derived from oral glucose tolerance testing, is an integrative measure of the homeostatic performance of the insulin-glucose feedback control. Its collection is, however, time consuming and expensive. We, therefore, pursued the question if such a measure can be calculated at baseline/fasting conditions using plasma concentrations of insulin and glucose. METHODS: A new fasting-based disposition index (structure parameter inference approach-disposition index [SPINA-DI]) was calculated as the product of the reconstructed insulin receptor gain (SPINA-GR) times the secretory capacity of pancreatic beta cells (SPINA-GBeta). The novel index was evaluated in computer simulations and in three independent, multiethnic cohorts. The objectives were distribution in various populations, diagnostic performance, reliability and correlation to established physiological biomarkers of carbohydrate metabolism. RESULTS: Mathematical and in-silico analysis demonstrated SPINA-DI to mirror the hyperbolic relationship between insulin sensitivity and beta-cell function and to represent an optimum of the homeostatic control. It significantly correlates to the oral glucose tolerance test based disposition index and other important physiological parameters. Furthermore, it revealed higher discriminatory power for the diagnosis of (pre)diabetes and superior retest reliability than other static and dynamic function tests of glucose homeostasis. CONCLUSIONS: SPINA-DI is a novel simple reliable and inexpensive marker of insulin-glucose homeostasis suitable for screening purposes and a wider clinical application.

Thyroid Allostasis-Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming.

The hypothalamus-pituitary-thyroid feedback control is a dynamic, adaptive system. In situations of illness and deprivation of energy representing type 1 allostasis, the stress response operates to alter both its set point and peripheral transfer parameters. In contrast, type 2 allostatic load, typically effective in psychosocial stress, pregnancy, metabolic syndrome, and adaptation to cold, produces a nearly opposite phenotype of predictive plasticity. The non-thyroidal illness syndrome (NTIS) or thyroid allostasis in critical illness, tumors, uremia, and starvation (TACITUS), commonly observed in hospitalized patients, displays a historically well-studied pattern of allostatic thyroid response. This is characterized by decreased total and free thyroid hormone concentrations and varying levels of thyroid-stimulating hormone (TSH) ranging from decreased (in severe cases) to normal or even elevated (mainly in the recovery phase) TSH concentrations. An acute versus chronic stage (wasting syndrome) of TACITUS can be discerned. The two types differ in molecular mechanisms and prognosis. The acute adaptation of thyroid hormone metabolism to critical illness may prove beneficial to the organism, whereas the far more complex molecular alterations associated with chronic illness frequently lead to allostatic overload. The latter is associated with poor outcome, independently of the underlying disease. Adaptive responses of thyroid homeostasis extend to alterations in thyroid hormone concentrations during fetal life, periods of weight gain or loss, thermoregulation, physical exercise, and psychiatric diseases. The various forms of thyroid allostasis pose serious problems in differential diagnosis of thyroid disease. This review article provides an overview of physiological mechanisms as well as major diagnostic and therapeutic implications of thyroid allostasis under a variety of developmental and straining conditions.