Hypothermia Is Critical for Survival During Prolonged Insulin-Induced Hypoglycemia in Rats Thomas A. Buchanan, Patricia Cane, Calvin C. Eng, George F. Sipos, and Charles Lee zyxwvutsrqponmlkjihgfedcb Hypothermia is a well-known concomitant of hypoglycemia in mammals. We tested the hypothesis that this hypothermia is an important adaptive response to hypoglycemia in 11 normal Sprague-Dawley rats. Twelve-hour fasted, conscious animals received primed, continuous insulin infusions for up to 8 hours. Plasma glucose was clamped between 30 and 40 mg/dL and core body temperature was monitored continuously during the insulin infusions. Five of the animals were maintained in a room temperature environment (22 to 24°C) during the hypoglycemia; all became hypothermic (mean rf: SE nadir core temperature, 31 2 0.5%). Spontaneous activity was reduced in these animals, but they remained conscious and responsive to external stimuli. All five returned to normal behavior after euglycemia was restored at the end of the insulin infusions. In the remaining six animals, hypothermia was prevented during hypoglycemia by warming of the air in their cages (mean of hourly core temperatures, 37 * O.l”C). None of these animals survived more than 7 hours. The severity of the hypoglycemia was no greater in the euthermic than in the hypothermic group, as judged by the mean of individual nadir plasma glucose levels (25 f 1 v 24 ? 1 mg/dl, respectively) and by the mean number of glucose values per animal that were less than 30 mg/dL (2 + 1 Y 7 f 1). Plasma osmolality did not change significantly in either group during the period of hypoglycemia, suggesting that dehydration was not the cause of death in the euthermic animals. Our findings indicate that hypothermia is an important adaptive response that allows survival durina orolonaed oeriods of insulin-induced hypoglycemia. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLK Copyright 0 1991 by WA-iaund& C~mpeny zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA G LUCOSE is the predominant metabolic fuel of the central nervous system (CNS). Accordingly, an acute reduction in circulating glucose normally triggers a complex physiological response that includes the release of several counterregulatory hormones,“’ as well as a decline in core body temperature.4-b The hormonal components of this response, in particular the increased levels of glucagon and epinephrine, act primarily to increase the glucose supply by increasing hepatic glucose production.‘~” Epinephrine also reduces pancreatic B-cell sensitivity to glucose’3.‘4 and, in concert with growth hormone,15 may reduce glucose utiliza- tion by peripheral tissues.“‘.” Together, these hormones tend to limit the duration of hypoglycemia and thus protect the organism from the deleterious effects of prolonged glucose deprivation. Failure of the normal hormonal responses to insulin- induced hypoglycemia, as occurs in some patients with long-standing type I diabetes,‘.16.‘” can lead to prolonged and severe glucopenia.‘” In this situation, any mechanism that reduces the metabolic requirements of the organism could prolong survival by reducing tissue glucose demands to better match the limited glucose supply. Several observa- tions suggest that systemic hypothermia may be one such mechanism. A decrease in body temperature has been noted in association with hypoglycemia in man6 and other mammals.6~20 This response usually follows the onset of hypoglycemia by 40 to 60 minutes and may persist for several hours after normal glucose levels are restored. The hypothermia appears to be mediated at least in part by CNS zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA From the Section zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA of Diabetes and Metabolism, Depamnent of Medicine, University of Southern California School of Medicine, Los Angeles, CA. Suppotied by zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA grants zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA from the Juvenile Diabetes Foundation and the California AfJiliate of the American Diabetes Association. Address reprint requests to Thomas A. Buchanan, MD, Diabetes Section, OCD-252, 2025 Zonal Ave, Los Angeles, CA 90033. Copyright 0 I991 by W.B. Saunders Company 0026-0495/91/4003-0019$03.00l0 330 glucopenia, since instillation of 2-deoxy-D-glucose into the lateral ventricles or brains of mice causes a decrease in body temperature despite normal or elevated circulating glucose levels. 6.20-23 Since the hypothermic response to CNS glucope- nia has been associated with a decrease in the metabolic rate,Zo~2’ we postulated that hypothermia may become impor- tant for survival when hormonal counterregulatory mecha- nisms fail and hypoglycemia is prolonged. In the present report, we have tested that hypothesis by preventing the hypothermic response during prolonged insulin-induced hypoglycemia in rats. METHODS Animals Male and female Sprague-Dawley rats weighing 250 to 300 g were obtained from Charles River Breeding Laboratories, Wilming- ton, MA. Animals were maintained in a controlled light (dark cycle, 6:00 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJI PM to 6:00 AM) and temperature (22 * 2C) environ- ment with free access to food and water, except during insulin infusions (below). All procedures and experimental end points were approved by the University of Southern California Animal Research Committee. Preparation for Infusion At least 4 hours before insulin infusions, each animal was briefly restrained to allow the percutaneous placement of three polyethyl- ene catheters into tail blood vessels during local anesthesia with lidocaine: an infusion catheter was placed in each of the lateral tail veins and a blood sampling catheter was placed in the ventral tail artery. The latter catheter was kept patent with a slow infusion of heparin-saline (50 U pork heparin per mL of 0.9% saline). An indwelling rectal thermistor probe was also inserted at this time. The distal third of the tail, the thermistor wire, and the exposed portions of the catheters were drawn through a hole in the cage bottom and secured there with a rubber stopper. This arrangement allowed the infusion of insulin and glucose into and the sampling of arterial blood from conscious, mobile animals during continuous monitoring of their core temperatures. Metabolism, Vol 40, No 3 (March), 1991: pp 330-334