A B S T R A C T Endogeniouis release of epiinephlrine alter stress as well as exogenouis epinephrine infusion are known to resuilt in imiipaired glucose tolerance. Previouis stuidies of man and animals have demonoestrated that this effect of epinephrine results fromn inhibitioni of insulin secretion and aiugiimentation of hepatic glucose production. However, the effect of epiniephrine oii tissue sensitivity to insulin, and the relative contribuitions of peripheral vs. hepatic resistanice to imnpairedl insulin action, have not l)een defined. Nine young normal-weight stubjects were sttuldied with the insuilin clamp technique. Plasma insuilin was raised by -100 gU/nil wilie plasiiia glticose conicentrationi Wcas Imlainitaine(d at basal levels by a variable glucose infuision. Under these conditions of euglycemiiia, the amnouniit of glucose metabolized e(quals the glucose inftusion rate ancd is a measure of tissue sensitivity to insulin. Sulbjects receive(l four studies: (a) insulini (42.6 mlU/in2 -min), (b) insulini plus epiniephrine (0.05 ,ug/kgmniin), (c) insulimi pltus epinephrine plus propranolol (1.43 ,ug/kg mmii), and ((d) insulin pltus propra100 ,TU/mI,1. Wlheni propranolol svis admlliinistered witlh epiniephrine, total glucose mnetabolism wvas restored to cotntrol values and hepatic glucose production suippressed normally. Propranolol alone had no effect on1 iusulin-mediated gltucose metabolism. Thlese results indicate that epinephrine, acting primarilx througl a fl-adrenergic receptor, mlarkedly imnpairs tisstie sensitivity to ani inecrease in plasmiia instulini levels, and( that this effect results fromn both peripheral and hepatic resistance to the actiomi of insulin.Received for publication 21 Attemi-pts to categorize the metalbolic effects of epinephrine as either alpla (a) or-beta (,f) receptorme(liate(l have yielded contradlictorv results. It hslS been reported that neither a-nor 8-blockade alone is sufficienit to prevent the hyperglycem-lic effect of epinephiine inifusion in normiiial mnan, buIt that coml)inedl p)ropranolol and phentolamine pretreatmiient alolishes the hy'perglycemnic effect of epinephrinie infuLisioni (15). In dialbetic suibjects (16) propranolol 1)retreatmment alone p)artially Iprevented eL)inephrine-induced hyperglyceinia, but phentol](anine hladl nio effect oni the rise in plasma g4lucose conicentratiomi. In vitro studlies have shown-that propranolol is capable of preventinig the epinlephrine-induced inhibition of in sul imi-m ne(liate(d gluccose uiptake by riat diaphragmn (12,14).In the present stmm(ly we halve employed the e...

A B S T R A C T Tissue sensitive to insulin and insulin binding to monocytes were evaluated in 15 nonobese maturity-onset diabetics and in 16 healthy controls. Insulin sensitivity was determined by the insulin clamp technique in which the plasma insulin is acutely raised and maintained 100 .U/ml above the fasting level and plasma glucose is held constant at fasting levels by a variable glucose infusion. The amount of glucose infused is a measure of overall tissue sensitivity to insulin.In the diabetic group, the fasting plasma glucose concentration (168±4 mg/dl) was 85% greater than controls (P < 0.01) whereas the plasma insulin level (15±1 ,U/ml) was similar to controls. During the insulin clamp study, comparable plasma insulin levels were achieved in the diabetics (118±5) and the controls (114±5 ,uU/ml). However, the glucose infusion rate in the diabetics (4.7±0.4 mg/kg min) was 30% below controls (P < 0.01). Among the diabetics, the glucose infusion rate correlated directly with the fasting plasma glucose level (r = 0.57, P < 0.05). In five diabetic subjects, glucose metabolism was similar to controls, and these diabetics had the highest fasting glucose levels. When they were restudied after prior normalization (with insulin) of the fasting plasma glucose (100±1 mgldl), the glucose infusion rate during the insulin clamp was 30% lower than observed in association with hyperglycemia (P < 0.01). Studies that employed tritiated glucose to measure endogenous glucose production indicated comparable 90-95% inhibition of hepatic glucose production during hyperinsulinemia in the diabetic and control subjects.1251-insulin binding to monocytes in the diabetics (5.5±0.6%) was 30% below that in controls (P < 0.01).

We studied the effect of physical training on in vivo tissue sensitivity to insulin and insulin binding to monocytes in six previously untrained healthy adults. Physical training (one hour of cycle-ergometer exercise four times per week for six weeks) failed to alter body weight but resulted in a 20 per cent increase (P less than 0.02) in maximal aerobic power (VO2 max) and a 30 per cent increase (P less than 0.01) in insulin-mediated glucose uptake (determined by the insulin clamp technique). The increase in insulin sensitivity correlated directly with the rise in VO2 max (P less than 0.05). Binding of [125I]insulin to monocytes also rose by 35 per cent after physical training (P less than 0.02), primarily because of an increase in the concentration of insulin receptors. Our data indicate that physical training increases tissue sensitivity to insulin in proportion to the improvement in physical fitness. Physical training may have a role in the management of insulin-resistant states, such as obesity and maturity-onset diabetes, that is independent of its effects on body weight.

With the recently approved IEC 61511 and ANSI/ISA-84.00.01 standards, process industry companies are being challenged to determine the level of performance required from their safety instrumented functions (SIF) and to verify that the design, installation, operation, and maintenance employed is sufficient to ensure that the required performance is sustained until the SIF is decommissioned. As a practical matter, user companies must self-certify or user approve their SIF equipment, since they are responsible for the correct operation of the SIF in the operating environment, not just individual components as manufactured. To accomplish this, user companies need lifecycle assistance from equipment manufacturers, irrespective of hardware or software certification status related to IEC 61508. One of the best means to communicate the necessary information is via a safety manual for those involved in instrument system design installation and operation. IEC 61508 requires that equipment manufacturers provide a safety manual with any product claimed to comply with IEC 61508. Although required for product certification, it is the authors' current experience that quality and consistency in safety manuals is lacking. Part of this is due to IEC 61508 not providing a clear concise template with minimum requirements. The safety manual requirements are scattered throughout the rather complex standard. This article seeks to provide a user's perspective of what essential information is needed from equipment manufacturers to not only comply with IEC 61508, but also to provide enough information to the user of the product to allow the essential balance of reliability and safety in both SIF and instrumented protective function applications.