Pyruvate Dehydrogenase Activation in Adipocyte Mitochondria by an Insulin-Generated Mediator from Muscle

Jarett, Leonard; Seals, Jonathan R.

doi:10.1126/science.505013

Cited by 220 publications

(46 citation statements)

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“…The actual changes in activity observed were small compared with those found in vivo, and also varied greatly between studies (compare [195,196] and [199]). Moreover the changes in activity may not necessarily reflect alterations in phosphorylation since estimates of the proportion of the total complex in its active form were not routinely made in these studies.…”

Section: Role Of a Peptide Mediatormentioning

confidence: 99%

“…Seals, Jarett and colleagues have reported that they are able to demonstrate an effect of insulin on fat cell pyruvate dehydrogenase in a cell free system comprising of fat cell plasma membranes and mitochondria [193][194][195][196][197][198][199][200]. They have concluded that insulin causes the release of a factor from the plasma membranes, similar if not identical to that described by Larner's group, which is then capable of activating pyruvate dehydrogenase phosphate phosphatase and thus increasing the activity of pyruvate dehydrogenase in the mitochondria.…”

Section: Role Of a Peptide Mediatormentioning

confidence: 99%

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A partial view of the mechanism of insulin action

1981

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Insulin was discovered 60 years ago [1]; since then its structure has been determined by the pioneer work of Sanger [2] and by Hodgkin, Blundell and colleagues [3]. Moreover the principle effects of insulin on carbohydrate, fat and protein metabolism have been well recognised, at least ingeneral terms, for some 20 years [4][5][6][7], yet, we do not have a satisfactory description at the molecular level of how this hormone brings about its wide range of effects on target cells. This is certainly not due to any lack of attention to the problem by research workers. The literature on this subject is vast and, in the absence of any generally acceptable hypothesis, it also tends to be rather confused and certainly conflicting. Since it is quite unrealistic to survey the whole field, we make no apology for concentrating on certain aspects in this article.Insulin has both long and short term effects on the metabolism of its target cells. The long term effects involve changes in both general and specific protein synthesis and breakdown, while short term effects are those brought about solely through changes in the activity of pre-existing enzymes and membrane transporters. To a large extent, we will neglect all aspects of long term regulation including protein synthesis and amino acid metabolism. In fact, advances in these areas have been delayed by the lack of satisfactory preparations suitable for probing the mechanisms involved in the specific induction and repression of enzymes by insulin in vitro. This situation will probably change rapidly as a number of such preparations have been reported recently. Particularly promising are the 3T3-L1 preadipocyte cell line [8,9] and also the maintenance liver cell cultures from young rats in which glucokinase activity has been shown to be rapidly induced on exposure to insulin in the presence of glucose [10].In the rest of this review we will concentrate on those studies concerned with short term effects of insulin on carbohydrate and fat metabolism in the cells of liver, muscle and, particularly, adipose tissue. All these cells have specific insulin receptors on the outward face of the plasma membrane but we will not be considering the nature of these receptors nor their interaction with insulin nor the mechanisms which may govern the number of insulin receptors. These aspects have all been well covered in other recent reviews [11][12][13]. We shall address ourselves to the problem of the process or processes whereby alterations in the level of occupancy of the plasma membrane insulinreceptors lead to a wide range of intracellular changes. The assumption will be made that neither the whole insulin molecule nor part of it needsto enter the cells of its target tissue to bring about the effects of insulin. There seems little doubt that insulin bound to its receptor can be "internalized" into liver and probably other cells [14, 15], however, the process appears to be too slow to represent the means whereby insulin could bring about its short term effects. On the other hand, antibo...

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Section: Role Of a Peptide Mediatormentioning

confidence: 99%

Section: Role Of a Peptide Mediatormentioning

confidence: 99%

A partial view of the mechanism of insulin action

1981

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confidence: 99%

Insulin mediators in man: effects of glucose ingestion and insulin resistance

et al. 1997

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Insulin generates/releases chemical substances that alter the activities of purified enzymes [1,2] and the metabolism of intact cells [3,4] in an insulin mimetic fashion. These substances have therefore been termed mediators or second messengers of insulin [5]. Two different insulin mediators have been separated from rat liver [6]. These mediators have been identified as inositol phosphoglycans (IPGs), containing inositol, non-acetylated amino sugars, neutral sugars, ethanolamine, phosphate and, possibly, amino acids [5]. One contains d -chiro-inositol and activates pyruvate dehydrogenase (PDH) phosphatase, whereas another contains myo-inositol and inhibits cyclic AMP-dependent protein kinase (PKA). Injection of each of these IPGs into low-dose streptozotocin-diabetic rats lowers blood glucose [7].Body fluids of patients with non-insulin-dependent diabetes mellitus (NIDDM) have abnormally low levels of Summary Insulin mediators (inositol phosphoglycans) have been shown to mimic insulin action in vitro and in intact mammals, but it is not known which mediator is involved in insulin action under physiological conditions, nor is it known whether insulin resistance alters the mediator profile under such conditions. We therefore investigated the effects of glucose ingestion on changes in the bioactivity of serum inositol phosphoglycan-like substances (IPG) in healthy men and insulin resistant (obese, non-insulin-dependent diabetic) men. Two classes of mediators were partially purified from serum before and after glucose ingestion. The first was eluted from an anion exchange resin with HCl pH 2.0, and bioactivity was determined by activation of pyruvate dehydrogenase in vitro. The second was eluted with HCl pH 1.3, and bioactivity was determined by inhibition of cyclic AMP-dependent protein kinase. In healthy men, the bioactivity of the pH 1.3 IPG was not altered by glucose ingestion, whereas bioactivity of the pH 2.0 IPG increased to approximately 120 % of the pre-glucose ingestion value at 60-240 min post-glucose ingestion (p < 0.05 vs pre-glucose). There was no change in either IPG after glucose ingestion in the insulin-resistant group. These data suggest that the pH 2.0 IPG plays an important role in mediating insulin's effect on peripheral glucose utilization in man under physiological conditions. The data further show, for the first time, a defective change in the bioactivity of an insulin mediator isolated from insulin-resistant humans after hyperinsulinaemia, suggesting that inadequate generation/release of IPGs is associated with insulin resistance. [Diabetologia (1997) 40: 557-563] Keywords Inositol phosphoglycans, non-insulin dependent diabetes mellitus, pyruvate dehydrogenase, cyclic AMP dependent protein kinase.

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“…At this time, Len Jarett at Washington University in St. Louis was searching for an insulin second messenger released from adipocyte cell membranes, which, when added to mitochondria, activated mitochondrial PDH. We sent him blind column fractions of our cAMP kinase inhibitor, and we published two adjoining papers in Science demonstrating the presence of the two bioactivities in the same column fractions (34,35). Our lab then set up both bioassays and started to purify both bioactivities.…”

Section: Minnesota Years: a Bookmentioning

confidence: 99%

Inositol, Glycogen, Insulin, and Six Nobelists

Larner

2013

Journal of Biological Chemistry

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Pyruvate Dehydrogenase Activation in Adipocyte Mitochondria by an Insulin-Generated Mediator from Muscle

Cited by 220 publications

References 10 publications

A partial view of the mechanism of insulin action

A partial view of the mechanism of insulin action

Insulin mediators in man: effects of glucose ingestion and insulin resistance

Inositol, Glycogen, Insulin, and Six Nobelists

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