Diabetes. 2013 Feb;62(2):392-400.
Portal vein glucose entry triggers a coordinated cellular response that potentiates hepatic glucose uptake and storage in normal but not high-fat/high-fructose-fed dogs.
Coate KC, Kraft G, Irimia JM, Smith MS, Farmer B, Neal DW, Roach PJ, Shiota M, Cherrington AD.
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
The cellular events mediating the pleiotropic actions of portal vein glucose (PoG) delivery on hepatic glucose disposition have not been clearly defined. Likewise, the molecular defects associated with postprandial hyperglycemia and impaired hepatic glucose uptake (HGU) following consumption of a high-fat, high-fructose diet (HFFD) are unknown. Our goal was to identify hepatocellular changes elicited by hyperinsulinemia, hyperglycemia, and PoG signaling in normal chow-fed (CTR) and HFFD-fed dogs. In CTR dogs, we demonstrated that PoG infusion in the presence of hyperinsulinemia and hyperglycemia triggered an increase in the activity of hepatic glucokinase (GK) and glycogen synthase (GS), which occurred in association with further augmentation in HGU and glycogen synthesis (GSYN) in vivo. In contrast, 4 weeks of HFFD feeding markedly reduced GK protein content and impaired the activation of GS in association with diminished HGU and GSYN in vivo. Furthermore, the enzymatic changes associated with PoG sensing in chow-fed animals were abolished in HFFD-fed animals, consistent with loss of the stimulatory effects of PoG delivery. These data reveal new insight into the molecular physiology of the portal glucose signaling mechanism under normal conditions and to the pathophysiology of aberrant postprandial hepatic glucose disposition evident under a diet-induced glucose-intolerant condition.
The role of the liver as a source of glucose has been extensively defined, but its contribution to glucose disposal has been less well examined. The regulation of hepatic glucose uptake and glycogen deposition takes on particular importance in view of the fact that the human liver is in a glycogen storage mode for ~16h each day and that hepatic glycogen repletion is abnormal in individuals with type 1 or type 2 diabetes. Further, abnormal post-prandial glycemia is an important determinant of the HbA1c level, and it contributes to the development of cardiovascular disease and other diabetic complications. For these reasons, studies relating to the control of hepatic glucose uptake (HGU) and its role in post-prandial glycemia are highly significant.
Examining the regulation of HGU in the human has been difficult because of inability to catheterize the hepatic portal vein, difficulty in catheterizing the hepatic vein and difficulty in controlling the insulin and glucagon levels reaching the liver (i.e. delivering hormones into the portal vein). Likewise, such studies have been hard to carry out in the rodent because the hepatic vein cannot be catheterized. The dog therefore represents a unique model with which to study HGU in vivo. Both the hepatic and portal veins can be catheterized, allowing hormones and substrates to be infused directly into the portal vein. Furthermore, the metabolic phenotype can be correlated with changes at the cellular level since hepatic tissue can be easily obtained.
It is clear, based on the measurement of net splanchnic glucose balance in man and net hepatic glucose balance in the dog, that neither hyperinsulinemia nor hyperglycemia within the physiologic range can independently cause much net hepatic glucose uptake (NHGU). NHGU remains modest (0.5 to 2.0 mg/kg/min) even when hyperinsulinemia and hyperglycemia (resulting from glucose infusion into a peripheral vein) are combined. On the other hand, 25 to 40% of a moderately sized oral glucose load is taken up by the splanchnic bed or liver, with peak uptake rates of 5-6 mg/kg/min. Thus glucose uptake by the liver is 2 to 3 fold greater when glucose enters the body via the gut, rather than a peripheral vein, even when the glucose and insulin levels at the liver are made equivalent. DeFronzo et al. (3) initially proposed the existence of a gut factor that augments HGU following administration of an oral glucose load to the human. However, using the dog, several groups bypassed the gut and produced hyperglycemia by infusing glucose intraportally at a rate that mimicked the absorption profile of an oral glucose load. They found that NHGU was the same after intraportal and oral glucose entry and that both were greater than the rate resulting from peripheral vein glucose infusion. This led us to hypothesize that the liver responds differently to glucose delivered into the hepatic portal vein than it does to glucose delivered into a peripheral vein. Our laboratory made the first direct demonstration of a portal glucose effect using the conscious dog. In the presence of somatostatin, insulin and glucagon were fixed at basal values and hyperglycemia (220 mg/dl) was brought about by peripheral glucose infusion. Net hepatic glucose output fell to near zero, but there was no NHGU. With the same hormonal conditions and the same glucose load to the liver, but in the presence of portal glucose delivery, the liver took up 32% of the delivered glucose. We also showed, using the hindlimb balance technique, that a reciprocal decrease in muscle glucose uptake occurred in response to portal glucose delivery. Thus the signal generated by portal vein glucose entry ensures the appropriate distribution of an oral glucose load between skeletal muscle (35-45%), liver (25-35%) and the rest of the body (30%). It should not be forgotten that to some extent non-insulin sensitive tissues take up some of the ingested glucose as a result of the cessation of hepatic glucose production. This means that modification of liver function is actually responsible for the disposal of ~60-65% of an oral glucose load. Any impairment in liver function, therefore, will lead to excessive post-prandial glycemia, making understanding the regulation of hepatic glucose uptake highly significant.
Our previous work established that the arterial-portal vein glucose gradient triggers the response to portal vein glucose delivery and that the comparison of the arterial and portal vein glucose levels occurs within the liver. Coordination of the hepatic and muscle responses to portal glucose delivery appears to involve the nervous system, but the means by which information perceived within the liver and the way in which it triggers the efferent response is unknown, as is the molecular explanation for the hepatic response.
Increased dietary fat and fructose have both been linked to glucose intolerance, obesity and type 2 diabetes. We demonstrated that a diet high in fat and fructose markedly impairs the ability of the liver to take up and store glucose (2). Interestingly this occurs even though hepatic lipid levels are not abnormal. In our recently published study (1) the abstract of which is reproduced here, we explored both the cellular mechanism by which portal glucose delivery enhances HGU and the cellular mechanism by which a diet rich in fat and fructose impairs the liver’s ability to take up glucose and store it as glycogen.
1. Coate KC, Kraft G, Irimia JM, Smith MS, Farmer B, Neal DW, Roach PJ, Shiota M, and Cherrington AD. Portal vein glucose entry triggers a coordinated cellular response that potentiates hepatic glucose uptake and storage in normal but not high-fat/high-fructose-fed dogs. Diabetes 62: 392-400, 2013.
2. Coate KC, Scott M, Farmer B, Moore MC, Smith MS, Roop J, Neal DW, Williams PE, and Cherrington AD. Chronic consumption of a high fat/high fructose diet renders the liver incapable of net hepatic glucose uptake. Am J Physiol Endocrinol Metab 299: E887-898, 2010.
3. DeFronzo RA, Ferrannini E, Hendler R, Wahren J, and Felig P. Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc Natl Acad Sci U S A 75: 5173-5177, 1978.