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Objective: Beta-cell regeneration is a fundamental but elusive goal for type 1 diabetes research. Our objective is to review newer human and animal studies of beta-cell destruction and regeneration and consider the implications for treatment of type 1 diabetes.Research Design and Methods: Recent human and animal studies of beta-cell destruction and regeneration in type 1 diabetes are reviewed.Results: The loss of beta-cells that characterizes type 1 diabetes reflects the net effects of destruction and regeneration. These processes have been examined in the nonobese diabetic (NOD) mouse; uncertainty remains about beta-cell dynamics in humans. Islet inflammation stimulates beta-cell replication that produces new insulin-positive cells. The regenerative process may tide the loss of overall beta-cell function, but it also may enhance the autoimmune attack on beta-cells by providing new epitopes. The highest rates of beta-cell replication are at the time of diagnosis of diabetes in NOD mice, and if autoimmunity and islet inflammation are arrested, new beta-cells are formed. However, the majority of beta-cells after treatment with immune modulators such as anti-CD3 monoclonal antibody, and most likely during the "honeymoon" in human disease, are recovered beta-cells that had been degranulated but present at the time of diagnosis of diabetes.Conclusions: Residual beta-cells play a significant role for the design of therapeutic trials: they not only may respond to combination therapies that include stimulants of metabolic function but are also the potential source of new beta-cells. [ABSTRACT FROM AUTHOR]

Diabetes is associated with increased basal hypothalamo-pituitary-adrenal (HPA) activity and impaired stress responsiveness. Previously, we demonstrated that the HPA response to hypoglycemia is significantly impaired in diabetic rats. In this study our goals were to 1) differentiate between the effects of hyperinsulinemia and those of hypoglycemia per se, and 2) establish whether diabetes lowers peak stress responses. Normal and streptozotocin-diabetic rats were subjected to hyperinsulinemic-euglycemic glucose clamps to evaluate central and peripheral responses. These were compared with peak ACTH and corticosterone responses to restraint and hypoglycemia. Hyperinsulinemia increased CRH and vasopressin mRNA, and plasma ACTH and corticosterone in normal and diabetic rats. In normal animals, insulin-induced activation of ACTH and corticosterone was lower than the responses during either restraint or hypoglycemia. In contrast, ACTH and corticosterone activation in diabetic rats was similar with all three stressors. Pituitary-adrenal axis activation in diabetic animals was also much lower compared with that in normal controls. The response to hyperinsulinemia (euglycemia) was associated with increases in glucocorticoid receptor mRNA in the anterior pituitary and paraventricular nucleus. Hippocampal mineralocorticoid receptor mRNA expression was increased in normal, but not in diabetic, animals. We speculate that the ability to appropriately match the HPA response to the potency of a stressor is related to the ability to alter hippocampal mineralocorticoid receptor expression. In diabetes, this ability is impaired; hence, maximal HPA activation is greatly diminished. This is a novel observation that may have important implications in the treatment of impaired counterregulatory mechanisms in human diabetes.

In summary, our data suggest that in uncontrolled diabetes, increased HPA activity is caused by increased central drive at or above the level of the PVN. Insulin treatment only restores HPA activity at and below the pituitary level, presumably by GC-mediated suppression of ACTH secretion. We hypothesize that the defective HPA response to hypoglycaemia is at least in part due to a lack of a decrease in MR mRNA in response to hypoglycaemia, and diminished sensitivity of the pituitary and adrenal gland to stimulation. Interestingly, insulin treatment restores the HPA response, but not the defective epinephrine response. Therefore, defective epinephrine responses are not linked to defective HPA responses. Similarly, antecedent hypoglycaemia specifically impairs epinephrine responses, but not HPA responses to hypoglycaemia. These studies have revealed some of the mechanisms of impaired HPA function in diabetes and its impaired responsiveness to hypoglycaemia. Further investigations are essential for understanding poor counterregulation in insulin-treated diabetes and may lead to new strategies for preventing hypoglycaemia.