Brain Insulin Action Regulates Hypothalamic Glucose Sensing and the Counterregulatory Response to Hypoglycemia

Abstract

OBJECTIVEAn impaired ability to sense and appropriately respond to insulin-induced hypoglycemia is a common and serious complication faced by insulin-treated diabetic patients. This study tests the hypothesis that insulin acts directly in the brain to regulate critical glucose-sensing neurons in the hypothalamus to mediate the counterregulatory response to hypoglycemia.RESEARCH DESIGN AND METHODSTo delineate insulin actions in the brain, neuron-specific insulin receptor knockout (NIRKO) mice and littermate controls were subjected to graded hypoglycemic (100, 70, 50, and 30 mg/dl) hyperinsulinemic (20 mU/kg/min) clamps and nonhypoglycemic stressors (e.g., restraint, heat). Subsequently, counterregulatory responses, hypothalamic neuronal activation (with transcriptional marker c-fos), and regional brain glucose uptake (via 14C-2deoxyglucose autoradiography) were measured. Additionally, electrophysiological activity of individual glucose-inhibited neurons and hypothalamic glucose sensing protein expression (GLUTs, glucokinase) were measured.RESULTSNIRKO mice revealed a glycemia-dependent impairment in the sympathoadrenal response to hypoglycemia and demonstrated markedly reduced (3-fold) hypothalamic c-fos activation in response to hypoglycemia but not other stressors. Glucose-inhibited neurons in the ventromedial hypothalamus of NIRKO mice displayed significantly blunted glucose responsiveness (membrane potential and input resistance responses were blunted 66 and 80%, respectively). Further, hypothalamic expression of the insulin-responsive GLUT 4, but not glucokinase, was reduced by 30% in NIRKO mice while regional brain glucose uptake remained unaltered.CONCLUSIONSChronically, insulin acts in the brain to regulate the counterregulatory response to hypoglycemia by directly altering glucose sensing in hypothalamic neurons and shifting the glycemic levels necessary to elicit a normal sympathoadrenal response.

Mechanisms of Hypoglycemia-Associated Autonomic Failure in Diabetes

“…Studies of the cellular and molecular biology and pathophysiology of CNS control of glucose counterregulation in rodent models have focused largely, but not exclusively, on the ventromedial hypothalamus. Potential mechanisms 32,33,[63][64][65] include decreased glucose sensing by glucose-excited or glucose-inhibited neurons in the hypothalamus, elsewhere in the brain, and in the periphery; decreased activation of AMP kinase; increased glucokinase activity; loss of a decrease in the counterregulatory inhibitor γ-aminobutyric acid; loss of an increase in the counterregulatory stimulator glutamine; increased urocortin release; and reduced actions of insulin on the brain.…”

Inhibitory effect of somatostatin on insulin secretion is not mediated via the CNS

“…For example, insulin acts indirectly via insulin receptors expressed on the ventromedial hypothalamus to modulate peripheral glucose homoeostasis in addition to its direct action on target tissues (Diggs-Andrews et al 2010, Paranjape et al 2010. We therefore proposed the hypothesis that the inhibitory effect of SST on insulin release may similarly be at least partly dependent on central activation of SSTRs by SST.…”

Role of nesfatin-1 in the metabolism of skeletal tissues

“…Intravenous nesfatin-1 injections lower plasma glucose in obese mice with phenotype db/db as well as in non-diabetic and non-obese mice (51). Moreover, elevated glucose in blood increases the release of nesfatin-1 from endocrine cells of the pancreas (11), suggesting that nesfatin-1 may affect the control of blood glucose by insulin. However, as shown by some researchers, nesfatin-1 serves only a local function in the pancreas (7).…”