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Endocrinology Vol. 145, No. 5 2115-2117
Copyright © 2004 by The Endocrine Society

Enough Is Enough: Nutrient Sensors and Insulin Resistance

Bentley Cheatham, Director

Biology Ribonomics, Durham, North Carolina 27703

Address all correspondence and requests for reprints to: Bentley Cheatham, Ph.D., Director, Biology, Ribonomics, 3908 Patriot Drive, Durham, North Carolina 27703. E-mail: bentley.cheatham{at}ribonomics.com.


   Introduction
Top
 Introduction
Intracellular Nutrient Sensing...
 Molecular Mechanisms of...
 References
 
When filling our automobiles with gasoline, we simply place the hose into the tank, set the flow rate on high, and then rely on a feedback sensor to shut off the flow of fuel before it winds up on our clothes. The human body’s feedback sensors for our fuel intake seem to work in a much less abrupt and much more complex manner. Although this analogy is overly simplistic, our society is plagued with the symptoms of overnutrition (overfilling the tank), and in combination with a sedentary lifestyle (not running the engine); this has led to epidemic levels of obesity. Chronic exposure to elevated nutrients such as glucose and lipids is a predisposing factor in the development of obesity and insulin resistance, and lack of intervening therapies can result in ß-cell failure and overt type 2 diabetes.

With obesity being a primary factor in type 2 diabetes, studies to uncover the system-wide and the intracellular pathways governing food intake and energy expenditure are intense areas of investigation. Communication of nutrient satiety from energy storage tissues, such as adipose, to the areas of the central nervous system that control eating behavior is, in part, mediated by circulating proteins such as leptin. Studies on the regulation of plasma leptin levels and leptin signaling have provided insight into the mechanisms of action of a system-wide satiety factor (1). Much less is known regarding the pathways mediating intracellular satiety. However, numerous in vitro and in vivo studies have strongly suggested a role for the hexosamine biosynthetic pathway (HBP) as a nutrient sensor that modulates insulin sensitivity (2, 3, 4, 5, 6, 7). In support of this hypothesis, recent in vivo studies using transgenic mice show that overexpression of the rate-limiting enzyme for hexosamine biosynthesis, glutamine:fructose-6-phosphate amidotransferase (GFAT), in insulin-sensitive tissues (skeletal muscle and adipose tissue) can lead to insulin resistance (3, 8, 9).

In this issue of Endocrinology, Hazel et al. (10) have further examined the contribution of the HBP specifically in adipose tissue using a transgenic mouse model. Their findings suggest that elevated production of hexosamines in adipose alone is sufficient to promote peripheral insulin resistance. Previous studies have suggested hexosamine-induced posttranslational modification on specific transcription factors and cytosolic proteins (see below) as a partial molecular mechanism for nutrient-induced insulin resistance (11, 12, 13, 14). Interestingly, Hazel et al. (10) provide new evidence that the observed insulin resistance in these animals may also be due, in part, to fluctuations in the circulating levels of the insulin-sensitizing protein adiponectin.


   Intracellular Nutrient Sensing by the Hexosamine Biosynthetic Pathway
Top
 Introduction
 Intracellular Nutrient Sensing...
Molecular Mechanisms of...
 References
 
Insulin resistance as a result of chronic nutrient excess may be an adaptive response employed to limit oxidation of the excessive available energy and increase weight gain. Initiation of insulin resistance as a response to excessive nutrients would require a nutrient sensor that, once activated, would initiate a mechanism leading to a decline in insulin’s ability to mediate nutrient uptake and use. The flux of nutrients through the HBP appears to provide such a mechanism (2, 3, 15, 16).

Upon entry into the cell, glucose is converted to glucose-6-phosphate for glycogen synthesis or converted to fructose-6-phosphate. The majority of the fructose-6-phosphate pool enters glycolysis; however, a small percentage is converted to glucosamine-6-phosphate by GFAT, the first and rate-limiting step in hexosamine biosynthesis (Fig. 1Go). Glucosamine-6-phosphate is then converted to uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc). GlcNAc serves as a donor substrate for synthesis of nucleotides, glycosyl phosphatidylinositol anchors, complex protein glycosylation, and O-linked-ß-N-acetylglucosamine (O-GlcNAc) protein modification. The intracellular levels of GlcNAc are not only sensitive to glucose, but also amino acids, fatty acids, and nucleotide availability. This characteristic makes GlcNAc a likely candidate for a nutrient sensor (2, 3, 15, 16).



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  		FIG. 1. The ability of the HBP to act as a nutrient sensor centers on the availability of UDP-GlcNAc. Glucose enters the cell and is converted to glucose-6-phosphate (G-6-P), which proceeds to glycogen synthesis or is converted to fructose-6-phosphate (F-6-P), the majority of which enters glycolysis. A small percentage of F-6-P is converted to glucosamine-6-phosphate GlcNAc-6-P by the rate-limiting enzyme in HBP, GFAT. This is rapidly converted to UDP-GlcNAc that acts as a substrate for complex protein and lipid glycosylation and nucleotide biosynthesis. O-linked GlcNAc (O-GlcNAc) modification of nuclear and cytosolic proteins occurs through the action of O-GlcNAc transferase (OGT). This unique posttranslational modification is thought to play a crucial role in mediating inhibition of glucose uptake and glycogen synthesis as well as alteration in transcription factor activity, modulation of the expression of genes involved in glucose metabolism and energy production, and changes in the circulating levels of leptin and adiponectin.

 

   Molecular Mechanisms of Hexosamine-Induced Insulin Resistance
Top
 Introduction
 Intracellular Nutrient Sensing...
 Molecular Mechanisms of...
References
 
Elevated levels of GlcNAc inhibit insulin-stimulated glucose uptake (via Glut4 glucose transporter translocation) and glycogen synthesis (2, 6, 17, 18, 19). Cell culture-based models, as well as in vivo models, of GlcNAc infusion have shown that increased flux through the HBP can have effects on various points in the insulin signaling cascade, including insulin receptor substrate phosphorylation and activation of glycogen synthase (5, 6, 11, 20). O-GlcNAc modification of nuclear and cytosolic proteins on serine and threonine residues increases concomitant with elevated nutrient flux through the HBP. The effect of this unique posttranslational modification on substrate protein activity is in many ways similar to phosphorylation and has been implicated as a potential molecular mechanism mediating hexosamine-induced insulin resistance (Fig. 1Go). A growing list of O-GlcNAc-modified proteins includes glycogen synthase, glycogen synthase kinase-3, several RNA binding proteins, and several transcription factors (11, 12, 13, 14, 20). The transcription factor Sp1 is modified by O-GlcNAc and has been implicated in mediating the observed hexosamine-induced decrease in a number of key genes involved in skeletal muscle oxidative phosphorylation (7, 14). Identification of other O-GlcNAc-modified proteins that regulate protein expression and/or have a function specific to glucose and lipid metabolism will no doubt shed more light on this unique mechanism.

In this issue of Endocrinology, Hazel et al. (10) provide new insight into an additional pathohysiological component of HBP-induced insulin resistance. Their data suggest the involvement of a circulating factor(s) that modulates insulin sensitivity via nutrient sensing of the HBP. Adipocytes secrete several proteins such as leptin, resistin, and adiponectin that act as endocrine messengers to affect energy balance and insulin sensitivity. Indeed, elevated GlcNAc induces leptin protein and gene expression (9). However, this would not explain the insulin resistance observed because leptin acts to increase insulin sensitivity. Most likely the elevated levels of leptin are an attempt to notify the hypothalamus of the abundant nutrient availability and shift toward decreased food intake and increased energy expenditure. In light of emerging evidence for the insulin-sensitizing activity of adiponectin (21, 22), Hazel et al. (10) find decreased circulating levels of adiponectin in GFAT-transgenic mice that parallel the observed insulin resistance. This is even more interesting in lieu of the recent cloning of the adiponectin receptors (AdipoR1 and R2) that are abundantly expressed in skeletal muscle and liver (23).

In summary, as discussed above, insulin resistance may be an adaptive response to abundant nutrient availability. Although much is still unclear, the nutrient sensing capability of the HBP orchestrates a diverse range of complex signals that seem to occur early in the development of insulin resistance. These signals appear to culminate in a strong message: enough is enough.


   Footnotes
 
Abbreviations: GFAT, Glutamine:fructose-6-phosphate amidotransferase; GlcNAc, N-acetylglucosamine; HBP, hexosamine biosynthetic pathway; UDP, uridine diphosphate.

Received February 5, 2004.

Accepted for publication February 9, 2004.


   References
Top
 Introduction
 Intracellular Nutrient Sensing...
 Molecular Mechanisms of...
 References
 

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