Effects of recurrent hypoglycemia on brainstem function in diabetic BB rats: protective adaptation during acute hypoglycemia.

To determine whether antecedent recurrent hypoglycemia protects the brain from the adverse effects of a standardized hypoglycemic stimulus, we implanted electrodes in the inferior colliculi of diabetic rats to directly record inferior colliculi auditory-evoked potentials (ICEPs). Awake, chronically catheterized BB rats were studied after 2 weeks of insulin therapy designed to produce either chronic hyperglycemia (hyper-DM, glycated hemoglobin 7.6 +/- 0.4%) or recurrent hypoglycemia (hypo-DM, glycated hemoglobin 6.2 +/- 0.7%), and the results were compared with those observed in nondiabetic rats. When plasma glucose was lowered to and clamped at 2.8 mmol/l, the release of catecholamines was suppressed in the hypo-DM rats (epinephrine: 2.5 +/- 0.4 nmol/l) as compared with hyper-DM and the nondiabetic rats (9.3 +/- 2.3 and 32.7 +/- 6.1 nmol/l, respectively). ICEP latency was significantly delayed in hyper-DM and nondiabetic rats (P < 0.001), but it was unchanged in hypo-DM rats. A more pronounced reduction in plasma glucose (2.0 mmol/l), however, provoked a greater adrenergic response than that seen at 2.8 mmol/l and delayed ICEP latency by 23% in a separate group of hypo-DM animals. These data demonstrate that antecedent recurrent hypoglycemia attenuates the brainstem dysfunction associated with mild to moderate, but not severe, hypoglycemia in diabetic rats. This phenomenon may contribute to the alterations in hypoglycemia counterregulation seen in diabetic patients during intensive insulin therapy.

Time course of the defective alpha-cell response to hypoglycemia in diabetic BB rats.

Although it is understood that patients with insulin-dependent diabetes mellitus (IDDM) lose the ability to release glucagon during a hypoglycemic challenge, the relationship of this defect to the disease onset and loss of beta-cell function is not well defined. To address this issue, we measured the counterregulatory response in three groups of BB/wor rats during sequential 90-minute euglycemic (7 mmol/L) and hypoglycemic (3 mmol/L) insulin clamps (180 pmol/kg.min). Group 1 (n = 8) consisted of nondiabetic BB rats (aged 84 +/- 3 days), and groups 2 and 3 were rats studied 1 day (n = 7) or 7 days (n = 6) after diabetes onset. Plasma glucagon concentrations were similar in all groups during euglycemia (244 +/- 47 ng/L for nondiabetic, 308 +/- 38 for 1 day of diabetes, and 277 +/- 30 for 7 days of diabetes). Moreover, after 1 day of diabetes, the increase in plasma glucagon during hypoglycemia was similar to that seen in controls (to 581 +/- 94 and 650 +/- 118 ng/L, respectively) even though insulin production by the pancreas was virtually absent. However, after 7 days of diabetes, plasma glucagon only increased to 339 +/- 59 ng/L during hypoglycemia (P = nonsignificant v basal), despite normal pancreatic glucagon content (11.5 +/- 1.2 v 10.8 +/- 0.6 micrograms/g in nondiabetic controls). In conclusion, the hypoglycemia-associated defect in glucagon release occurs early in the course of diabetes in BB rats and is not associated with decreased baseline plasma or pancreatic glucagon levels. This impairment, although not immediately linked to the decrease in pancreatic insulin content, occurs soon afterward, implying that the two events are related.

Brainstem dysfunction is provoked by a less pronounced hypoglycemic stimulus in diabetic BB rats.

Recent studies suggest that moderate hypoglycemia impairs brainstem function in normal humans and rats. To examine whether diabetes alters this response, simultaneous auditory-evoked potentials were recorded directly from the inferior colliculus (IC) and from the brainstem before and after controlled hypoglycemia (clamp) in awake insulin-dependent diabetic BB/Wor rats. Hyperglycemic diabetic animals were studied either during hyperinsulinemic euglycemia (5.6 mmol/l, n = 4) or mild hypoglycemia (3.5 mmol/l, n = 9). Nondiabetic controls were also studied at 3.5 mmol/l (n = 7) and at 2.8 mmol/l (n = 6). Brainstem function was not affected during euglycemia in diabetic rats. However, when plasma glucose was lowered to 3.5 mmol/l, the diabetic rats showed a 10% delay in IC evoked potential (ICEP) latency, whereas nondiabetic animals did not. This occurred despite similar counterregulatory hormones in both groups. The brainstem auditory-evoked potential (BAEP) localized the defect in the diabetic group to an area in or near the IC. When glucose levels were lowered to 2.8 mmol/l, however, brain function was impaired in nondiabetic rats as well. Again the defect was restricted to an area in or near the IC. We conclude that mild hypoglycemia causes a functional impairment in the IC region of the brainstem in both nondiabetic and diabetic rats. However, in the diabetic rats, this alteration occurs after a less pronounced hypoglycemic stimulus. Our findings suggest that chronic hyperglycemia leads to metabolic adaptions that render the diabetic brain more susceptible to mild hypoglycemia.