Glucose Allostasis

Abstract

In many organisms, normoglycemia is achieved by a tight coupling of nutrient-stimulated insulin secretion in the pancreatic ␤-cell (acute insulin response [AIR]) and the metabolic action of insulin to stimulate glucose disposal (insulin action [M]). It is widely accepted that in healthy individuals with normal glucose tolerance, normoglycemia can always be maintained by compensatorily increasing AIR in response to decreasing M (and vice versa). This has been mathematically described by the hyperbolic relationship between AIR and M and referred to as glucose homeostasis, with glucose concentration assumed to remain constant along the hyperbola. Conceivably, glucose is one of the signals stimulating AIR in response to decreasing M. Hypothetically, as with any normally functioning feed-forward system, AIR should not fully compensate for worsening M, since this would remove the stimulus for the compensation. We provide evidence from cross-sectional, longitudinal, and prospective data from Pima Indians (n ‫؍‬ 413) and Caucasians (n ‫؍‬ 60) that fasting and postprandial glucose concentrations increase with decreasing M despite normal compensation of AIR. For this physiologic adaptation to chronic stress (insulin resistance), we propose to use the term "glucose allostasis." Allostasis (stability through change) ensures the continued homeostatic response (stability through staying the same) to acute stress at some cumulative costs to the system. With increasing severity and over time, the allostatic load (increase in glycemia) may have pathological consequences, such as the development of type 2 diabetes. Diabetes 52:903-909, 2003 I nsulin action and secretion are the principal determinants of glycemia. In people with normal glucose tolerance (NGT), a decrease in insulin action (M) is accompanied by upregulation of insulin secretion (and vice versa). This is interpreted as compensation of insulin secretion for insulin resistance to maintain normoglycemia (1,2). Insulin resistance is a common consequence of obesity, for example, and represents a key factor in the pathogenesis of type 2 diabetes (3). Mathematically, the relationship between insulin secretion and insulin sensitivity is thought to be best expressed twodimensionally by a hyperbola with the product of the two variables equalling a constant (4), named the "disposition index" (DI). The DI is considered to measure the ability of the ␤-cells to compensate for insulin resistance. It decreases when glucose tolerance becomes impaired (5).While the insulin secretion/M hyperbola elegantly conceptualizes many cross-sectional and longitudinal observations (reviewed in 5), the physiologic signal that stimulates the compensatory increase in ␤-cell function in response to decreasing M remains unexplained. Insulin secretion is primarily substrate controlled, and glucose, the preeminent secretagogue among nutrient molecules, would be a good candidate for such a signal. Glucosestimulated insulin secretion is primarily controlled by the enzyme glucokinase, which governs the ge...

Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance

“…It is also well established that beta cell function is, at least in some respect, inversely related to insulin sensitivity (IS) [3][4][5][6]. Thus, insulin-resistant states are not necessarily associated with glucose intolerance because insulin secretion can be upregulated to cope with the increased demand.…”

Reactive oxygen species, reactive nitrogen species and antioxidants in etiopathogenesis of diabetes mellitus type-2

“…Diabetes mellitus with an alarmingly rising incidence (1) is a cluster of abnormal metabolic paradigm having a common of environmental factors which may act independently or in concert with genetic disposition, fifth, in due course of time a large number of DMT-2 patients develop multiple macro-or micro-vascular complications or both, sixth, the new molecular mechanisms involved in pathogenesis of the disease are now emerging, are more vigorously investigated and their interaction among themselves and their superimposition or intertwining with genetic factors are being critically evaluated, yet the etiopathogenesis of the disease is not fully understood (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Obviously, clinicians have limited armamentarium for the treatment of the disease, and so far no drug is known to cure it permanently.…”

“…Insulin secreted by beta-cells of Langerhans in pancreas, is the key hormone in the regulation of blood and tissue glucose homeostasis. Among the cluster of risk cascade in diabetes are obesity (20)(21)(22), insulin resistance (23)(24)(25)(26)(27), beta-cell dysfunction (28)(29), formation of AGEs and RAGEs, autooxidation of glucose, activation of protein kinase C, polyol pathway, hexosamine pathway, numerous intracellular metabolic disturbances (30)(31)(32) smoking (33)(34)(35)(36)(37) and genetic disposition (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Many of these abnormalities are intricately interconnected.…”

Effects of brief perturbations in energy balance on indices of glucose homeostasis in healthy lean men

“…1,19 --21 Diet-induced changes in both these measures were found to vary substantially among healthy subjects to maintain normal glucose tolerance. 1,21 Previous research has tended to focus on either OF or CR, rather than on consecutive periods of OF and CR. However, brief periods of excess or reduced energy intake often succeed one another.…”