Mechanism of hyperinsulinemia in endotoxicosis

Abstract

Hyperinsulinemia subsequent to endotoxemia is a key factor leading to the disturbance of glucose homeostasis in endotoxin shock. This study investigated the mechanism(s) of hyperinsulinemia during endotoxicosis in the rat. Two primary mechanisms for the hyperinsulinemia were evaluted: 1) decreased removal of insulin by the endotoxic liver, and 2) increased secretion of insulin by the endotoxic pancreas. Endotoxin treatment of donor rats did not impair the removal of TCA-precipitable 125I-labeled insulin by the isolated perfused liver. Perfused pancreases from endotoxic donors secreted more insulin tha control pancreases in response to a provocative stimulus of glucose. In vivo measurements of plasma immunoreactive insulin and glucose indicated an elevated hepatic portal vein insulin:glucose ratio associated with endotoxicosis. Therefore, the hyperinsulinemia of endotoxicosis is due primarily to hypersecretion of insulin by the endotoxic pancreas.

GLP-1 Secretion Is Increased by Inflammatory Stimuli in an IL-6–Dependent Manner, Leading to Hyperinsulinemia and Blood Glucose Lowering

“…Any blood glucose lowering, also if done to the normal range, might however increase the vulnerability of the organism to other hypoglycemic stimuli. Endotoxin is thereby known to suppress hepatic gluconeogenesis via activation of TLR4, MyD88, and NF-kB, enhance systemic glucose consumption, and deplete glycogen stores, which in conjunction can lead to hypoglycemia (13)(14)(15). Indeed, blockade of the GLP-1 system by use of GLP-1 receptor antagonists or IL-6 knockouts markedly blunted endotoxin-dependent hyperinsulinemia in our experiments but only modestly and temporarily counteracted the glucose-lowering effects of LPS.…”

“…Whereas this secondary raise can be attributed to the occurrence of insulin resistance, a variety of mechanisms contribute to the early drop of blood glucose (11,12). These include hyperinsulinemia, enhanced systemic glucose consumption, depletion of glycogen stores, and suppression of gluconeogenesis (13)(14)(15). Relevance of inflammation-dependent hyperinsulinemia has consistently been found in mice, rats, dogs, cows, and men (15)(16)(17)(18)(19), with inhibition of insulin secretion being able to prevent hypoglycemia in the inflammatory setting (20).…”

“…These include hyperinsulinemia, enhanced systemic glucose consumption, depletion of glycogen stores, and suppression of gluconeogenesis (13)(14)(15). Relevance of inflammation-dependent hyperinsulinemia has consistently been found in mice, rats, dogs, cows, and men (15)(16)(17)(18)(19), with inhibition of insulin secretion being able to prevent hypoglycemia in the inflammatory setting (20). Interestingly, lipopolysaccharide (LPS)-dependent insulin secretion was found to occur in a glucose-dependent manner, with pronounced insulin secretion only occurring under hyperglycemic but not euglycemic conditions (21).…”

Hypoglycemia and Risk Factors for Death in 13 Years of Pediatric Admissions in Mozambique

“…*Number and proportion of children who died with hypoglycemia and severe malnutrition (i.e., WAZ < −3). factors have been previously described in the literature, three major groups of factors stand out as significantly associated in our series with the risk of having hypoglycemia: 1) not being able to feed 35 (as directly reported by the mother or as a consequence of an altered clinical condition decreasing the capacity to feed [altered consciousness or coma, 25,[36][37][38] prostration, a history of seizures]); 2) malnutrition (including edema as a common sign typically associated with this condition); and 3) concomitant infections such as invasive bacterial disease or P. falciparum malaria. In addition, jaundice was also identified as an important risk factor for hypoglycemia, a finding also previously reported in Tanzania.…”

“…In bacterial disease, hypoglycemia has been attributed to a series of factors, including high circulating levels of cytokines such as tumor necrosis factor and interleukin-6, both powerful stimulators of insulin secretion, which can then cause among other things inhibition of the gluconeogenic pathways. 36,42 Decreased levels of glycemia secondary to the consumption of glucose by the Plasmodium parasite, hyperinsulinism caused by quinine, impaired gluconeogenesis, and lack of adequate supplementation/oral intake are possible explanations in malaria. 37,38,40,43 Independent risk factors associated with hypoglycemia mortality are similar to those found associated with the risk of hypoglycemia.…”