Fatal opioid overdose typically occurs due to bradypnea , hypoxemia , and decreased cardiac output ( hypotension occurs due to vasodilation , & bradycardia further contributes to decreased cardiac output).    A potentiation effect occurs when opioids are combined with ethanol , benzodiazepines , or barbiturates , which results in an increased risk for overdose to occur.   Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses.  However, tolerance to respiratory depression is lost just as quickly during withdrawal.  Many overdoses occur in people who misuse their medication after being in withdrawal long enough to lose the tolerance to respiratory depression. Less commonly, massive overdoses have been known to cause circulatory collapse .
PTPase (Protein Tyrosine Phosphatases) catalyze the dephosphorylation of insulin receptor and its substrates, leading to attenuation of insulin action. A number of PTPases have been implicated as the negative regulator of insulin signaling. Among them, the intracellular PTPase, PTP1B, has been shown to function as the insulin receptor phosphatase. PTEN (Phosphatase and Tensin Homolog Deleted On Chromosome-10) negatively regulates insulin signaling. SHIP2 (SH2-containing Inositol Phosphatase-2) is another negative regulator of insulin signaling and such negative regulation depends on its 5'-phopshatase activity. Overexpression of SHIP2 protein decreases Insulin-dependent PIP3 production as well as insulin-stimulated Akt activation, GSK3 inactivation, and glycogen synthetase activation. Insulin increases glucose uptake in muscle and fat, and inhibits hepatic glucose production, thus serving as the primary regulator of blood glucose concentration. Insulin also stimulates cell growth and differentiation, and promotes the storage of substrates in fat, liver and muscle by stimulating lipogenesis, glycogen and protein synthesis, and inhibiting lipolysis, glycogenolysis and protein breakdown. Insulin resistance or deficiency results in profound dysregulation of these processes, and produces elevations in fasting and postprandial glucose and lipid levels.
Design and uptake mechanism of the BBB shuttle. (A). Transferrin is transported across the BBB by binding to iron and the TfR. The complex is endocytosed and with an altered pH in the endosomes the affinity changes so that transferrin and iron are released in the endosomes and will eventually reach the brain parenchyma. An antibody that binds monovalently to the TfR, will according to the same mechanism also be released in the endosomes. Bivalent TfR binders have higher affinity to the TfR and hence less antibody will be released, and as a consequence, more antibody will instead be degraded. When the antibody is released in the brain parenchyma it can find and bind to its intra-brain target. (B). Schematic picture of the RmAb158-scFv8D3 fusion protein design. RmAb158 binds to Aβ protofibrils, involved in AD pathogenesis. The scFv of 8D3, which binds to TfR, is attached to the C-terminus of the RmAb158 light chain with short linkers. (C). The short linker length between RmAb158 and scFv8D3 combined with the placement of scFv8D3 on the C-terminus of the light chains ensures that there cannot be bivalent binding to the TfR dimer (left). The presence of two rather than one scFv8D3 will increase the concentration of TfR binders and hence increase the likelihood of uptake. In contrast, 8D3 can bind bivalently to the TfR dimer (right).