Sympathetic Mechanisms of Hypoglycemic Counterregulation

Abstract

In normal individuals hypoglycemic counterregulation is a multifactorial, redundant process that involves reduction of insulin secretion, increasing glucagon secretion, adrenergic activation, and increased growth hormone and cortisol secretion. Metabolically, these lead to increased glucose production, initially through glycogenolysis and later through gluconeogenesis, decreased muscle glucose oxidation and storage and increased release and use of alternative fuels, primarily free fatty acids. They also lead to hypoglycemic symptoms and hunger which increase food intake. These systems are designed to provide as much glucose as possible for brain glucose use. In patients with type 1 diabetes there are multiple impairments of these responses. Insulin does not decrease. Glucagon secretion is decreased or absent. Recovery from hypoglycemia is therefore dependent on the adrenergic response. Hypoglycemia increases plasma levels of both epinephrine and norepinephrine. These catechols are released primarily from the adrenal medulla. However, it is well documented that hypoglycemic increases muscle sympathetic nerve activity, and that both alpha and beta adrenergic activity increase. Increased beta-activity increases free fatty acid release which increase glucose production and decrease glucose utilization. The increased alpha-adrenergic activity's primary role is to counteract beta-adrenergic vasodilation. It may also reduce neurogenic and neuroglycopenic symptoms. Lastly, there is evidence that both cardiac and adrenergic sensitivity are altered in type 1 diabetes. It is hoped that this information can be used in the future to help develop ways to protect patients with type 1 diabetes from hypoglycemia and its adverse effects.

Involvement of α₂-Adrenoceptor Subtypes A and C in Glucose Homeostasis and Adrenaline-Induced Hyperglycaemia

“…The hyperglycaemic effect of adrenaline mediated by hepatic gluconeogenesis and glycogenolysis has been demonstrated in clinical studies employing the euinsulinaemic-hyperadrenergic clamp approach, in which plasma insulin concentrations are kept constant by infusing somatostatin and replacing basal insulin while infusing adrenaline continuously. In the presence of basal plasma insulin and glucagon concentrations, a physiological increase in plasma adrenaline concentrations stimulates glucose production via α 1 - and β-adrenoceptors with an initial phase caused by stimulation of hepatic glycogen breakdown and a second phase attributed to an increased rate of gluconeogenesis [18,19]. Mice with altered α 2C -adrenoceptor expression do not markedly differ from their WT controls in their aggressiveness when normally housed in groups.…”

Regulation of Peripheral Metabolism by Substrate Partitioning in the Brain

“…A key signal mediating these neuroendocrine responses to nutritional deprivation is the adipose-derived hormone leptin, reflecting adipose stores, acting on hypothalamic neurons expressing the leptin receptor [30]. However, it should be noted that these same neuroendocrine responses are produced when blood glucose levels fall below about 2.5 mM glucose (normal blood glucose levels is about 4-5 mM) even when plasma leptin and insulin are normal or even elevated [31]. Similarly, although insulin serves as a key signal to stimulate peripheral glucose disposal, insulin-induced hypoglycemia reduces peripheral glucose disposal even though insulin (and leptin) are elevated [32].…”

“…As suggested above, hypoglycemia produces similar metabolic [31] and molecular [95] effects as produced by fasting [34, 100]. In turn, metabolic responses to fasting require Ppar-alpha [100-103].…”

Heart failure in diabetes: effects of anti-hyperglycemic drug therapy

“…Последствия гипогли-кемии, как известно, могут влиять на течение СН, появ-ление симптомов СН и, следовательно, необходимость госпитализации. В частности, это может быть связано с активацией симпатической и ангиотензин-альдостеро-новой системы, особенно в тех случаях, когда речь идет о повторяющихся эпизодах у пациентов группы высокого риска [38]. Следует, однако, отметить, что повышение частоты гипогликемий было отмечено только в группе комбинированного приема саксаглиптина и ПСМ, при этом субанализ именно этой подгруппы пациентов не показал различий по частоте госпитализаций по по-воду СН [31].…”