Insulin first becomes attached to muscle or adipose tissue. At the sur face of the muscle fiber it may initiate a series of molecular rearrangements with these consequences:
•R E S E A R C H ι·
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i>iew însunn Mnîagt>nï5ï Abnormal profein found in plasma may be responsible for insulin resistance in diabetics in ketosis
• Access of glucose to th Intracellu lar phase is facilitated. The channels so provided must be selective in admit ting sugars of certain configurations but not others. • T h e molecular rearrangements are propagated from the cell boundary in such a manner as to remove intracellu lar barriers between hexokinase and its substrates, thus increasing activity of the hexokinase system. • Following the changes in intra cellular environment induced by* the first two actions, the structure of mito chondria (particles within the cell rich in certain enzymes) may be sufficiently altered to change the efficiency of en ergy transport which occurs in these particles.
Diabetics some- creases glucose uptake is a highly con times get in the troversial, even polemical, subject, says situation where a M. E. Krahl, University of Chicago. given quantity of There are a number of explanations insulin no longer sufficient to account for the action of ^'•Misît^-^Cl' reduces the con- insulin, but none which is well enough centration of established to exclude the others, Krahl blood sugar a s it should. This is believes. Part of the difficulty arises frequently seen in ketosis-acidosis, a po- because reproducible effects of insulin tentially fatal situation; fatty acid are obtainable only with intact cells, metabolism is upset, and ketones and where individual molecular events can related acids accumulate in the blood. not b e identified. Krahl lists these Treatment with much larger doses of possibilities: Reserpine's "Hot" . . . insulin generally brings the patient • Insulin may increase efficiency of around, but clinicians have long ponNot only in sales, but also dered this apparent insulin resistance energy transport in living systems. • Insulin may release hexokinase, the of the diabetic patient i n ketosis. in radioactivity, as C14 DeWitt Stetten, Jr., of the National enzyme which initiates utilization of l a b e l e d drug offers tool for Institute of Arthritis and Metabolic glucose, from some inliibitor. metabolism studies Diseases, studying the chemical basis • Insulin may increase the effective of this resistance, believes it is attrib- concentration of glucose available to Spiraling sales utable to an abnormal protein found hexokinase. A related proposal is that of tranquilizing in the alpha-globulin fraction of blood it may increase the intracellular concen drugs, which may plasma proteins. It appears to re- tration of some active form of glucose hit the $135 mil semble none of the previously de- needed by this enzyme. lion mark this scribed antagonists of insulin (antiyear, have em Krahl has come up with a speculative bodies to insulins from other animals, phasized the lack enzymes such as insulinase, hormones scheme illustrating insulin action on of pituitary and possibly of adrenocor- muscle which includes all these hypo of concrete data en the biological role of these agents. However, a step in theses (see diagram). tical origin). The material is of high molecular weight, not of adrenocortical origin, not a lipoprotein, is destroyed by heat Speculative Scheme of Insulin Action (as are most proteins), and is relatively resistant to degradation by trypsin. Nothing else is known of origin, mechanism of action, or composition of the antagonist since so little has been available for study. Characteristically ' ·· · it vanishes from the blood stream ;o\. o. within a few hours after institution of therapy against ketosis. Stetten has INSULIN d oobtained the material for study from . */o. the blood serum of diabetics in ketosis. Ό V The problems of diabetes today revolve largely about the complications |o ·;. of the disease rather than the disease itself, Stetten says. Ketosis is one such ι ο Όcomplication, and a serious one; his new findings will help increase the unEXTRACELL Ι INTRACELL. derstanding of the origin and mechaPHASE PHASE nism of this complication, Stetten told the symposium on carbohydrate metabolism and disease, sponsored by the G = GLUCOSE MOLECULES H = HEXOKINASE , ETC. Division of Biological Chemistry and Β * CELL BOUNDARY F = CONTRACTILE FIBER the Division of Medicinal Chemistry. R * RETICULUM M s MITOCHONDRION ρ StiSi in Doubt. H o w insulin in
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C & E N SEPT. 24,
1956
