The impact of insulin-dependent diabetes on ventilatory control in the mouse

Insulin-dependent diabetes mellitus (IDDM) can lead to ventilatory depressi on and decreased sensitivity to hypercapnia. We examined relationships betw een ventilation, plasma insulin, leptin, ketones, and blood glucose levels in two mouse models of IDDM: (1) streptozotocin-induced diabetes in C57BL/6 J mice on a regular diet or with induced obesity from a high fat diet; and (2) spontaneous diabetes mellitus in NOD-Ltj mice. In both mouse models, ID DM resulted in depression of the hypercapnic ventilatory response (HCVR). T his ventilatory depression was not associated with decreases in plasma insu lin or leptin levels. There was, however, a strong association between the duration of hyperglycemia, the decline in HCVR, and increased glycosylation of the diaphragm. Hyperventilation was observed in only six of 14 C57BL/6J obese wild-type mice, despite a significant degree of diabetic ketoacidosi s (DKA) in all 14 animals. In mice with DKA, there was a significant correl ation between the increase in baseline minute ventilation ((V) over dot(E)) and hyperleptinemia (r = 0.77, p < 0.01). In leptin-deficient C57BL/6J-Lep (ob) mice, low levels of both (V) over dot(E) and ketones were observed. Th ese results suggest that: (7) depression of the HCVR In IDDM is associated with hyperglycemia and glycosylation of the diaphragm; and (2) the hyperven tilation of PKA is leptin dependent.