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Disorders of Carbohydrate Metabolism – Pediatrics - LecturioCarbohydrate metabolism and metabolic syndrome -
These plaques can narrow and harden your arteries, which can lead to a heart attack or stroke. A healthy lifestyle includes: Getting at least 30 minutes of physical activity most days Eating plenty of vegetables, fruits, lean protein and whole grains Limiting saturated fat and salt in your diet Maintaining a healthy weight Not smoking.
By Mayo Clinic Staff. May 06, Show References. Ferri FF. Metabolic syndrome. In: Ferri's Clinical Advisor Elsevier; Accessed March 1, National Heart, Lung, and Blood Institute. Metabolic syndrome syndrome X; insulin resistance syndrome.
Merck Manual Professional Version. March 2, About metabolic syndrome. American Heart Association. Meigs JB. Metabolic syndrome insulin resistance syndrome or syndrome X. Prevention and treatment of metabolic syndrome.
Lear SA, et al. Ethnicity and metabolic syndrome: Implications for assessment, management and prevention. News from Mayo Clinic. Mayo Clinic Q and A: Metabolic syndrome and lifestyle changes. More Information. Show the heart some love!
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Financial Assistance Documents — Arizona. Financial Assistance Documents — Florida. A causal association is supported by evidence that intake of 1 liter of SSB daily for 6 months increased visceral and liver fat, but increases were not observed in those consuming isocaloric semiskim milk, noncaloric diet soda, or water While increased visceral adiposity is a major cardiometabolic risk factor, SSBs may increase risk independently of adiposity.
For instance, daily SSB consumption is associated with an unhealthy metabolic profile across BMI strata and with increased risk for type 2 diabetes independently of obesity 11 , Hypertriglyceridemia is a major cardiovascular risk factor and is another mechanism by which SSBs might increase cardiovascular risk.
Few large cross-sectional studies have examined the risk of dyslipidemia with SSB intake, and these studies show that dyslipidemia prevalence increases with higher SSB intake 13 , SSB consumption also associates with hypertension, another major cardiovascular risk factor.
Thus, SSB intake may contribute to hypertension, but it may play a lesser role in this risk factor compared with other cardiometabolic risk factors. On the basis of short-term overfeeding studies conducted predominantly in animals, the fructose component of SSBs and added sugar appears to be particularly harmful.
Feeding animals large amounts of fructose can rapidly produce multiple features of the metabolic syndrome, including obesity, dyslipidemia, fatty liver, hypertension, insulin resistance, and diabetes 18 , Some, but not all, short-term dietary intervention studies in humans also demonstrate that overfeeding fructose, but not glucose, can increase visceral adiposity, postprandial hypertriglyceridemia, and insulin resistance, and effects on specific traits may be impacted by gender 20 , One concern with such studies is that the amount of fructose consumed often exceeds that commonly found in ad libitum diets.
Large randomized controlled dietary intervention studies assessing the effects of added sugars on cardiometabolic risk factors over long periods of time are lacking.
Complexity, cost, compliance, and potential ethical issues likely prohibit the conducting of such studies. Several recent reviews comprehensively discuss the physiological effects of added fructose or sugar on pathophysiological endpoints in human subjects 26 , Understanding the mechanisms by which the isolated monosaccharide fructose might contribute to the development of metabolic disease may provide fundamental insights into pathogenic mechanisms that can be used to develop new diagnostic, preventative, and therapeutic strategies.
Here we will review the biochemistry and molecular genetics of fructose metabolism as well as potential mechanisms by which excessive fructose consumption contributes to cardiometabolic disease.
We hope that lessons learned from improved understanding of fructose metabolism and fructose-induced cardiometabolic risk may also apply to other forms of diet-induced and genetically induced metabolic disease. These features are suggestive of fructose malabsorption, frequently cited as a cause of gastrointestinal symptoms in humans 30 , Unabsorbed fructose can impose an osmotic load on the distal small intestine and the colon, which may contribute to gastrointestinal symptoms Moreover, fructose can serve as a substrate for bacterial fermentation, leading to formation of gas and other bacterial metabolites, which can affect intestinal motility and cause various symptoms such as abdominal pain and bloating Intestinal GLUT5 mRNA levels and fructose transport rates are very low prenatally and rapidly increase with weaning independently of diet, but they can be further induced following weaning to diets containing fructose Recent data showed that high-fructose feeding induces intestinal thioredoxin-interacting protein TXNIP , which binds and regulates GLUT5-mediated intestinal fructose transport Consistent with this, we recently showed that carbohydrate-responsive element—binding protein ChREBP , a transcription factor that responds to intracellular carbohydrate nutrients and a known transcriptional regulator of TXNIP 37 , also regulates intestinal GLUT5 expression and is required for systemic fructose tolerance In the future, it will be interesting to determine whether variability in the expression or function of GLUT5 or its regulatory factors contributes to the variability in fructose absorption in humans.
Fructose concentrations in peripheral plasma are typically about 0. This rapid clearance is mediated in large part by efficient extraction by the liver. Following fructose ingestion, plasma fructose can achieve low millimolar concentrations in the portal vein accompanied by peripheral circulation levels of approximately 0.
GLUT2 is a minor contributor to intestinal fructose transport 45 , whereas it is likely a major contributor to hepatic fructose uptake, since GLUT5 is not robustly expressed in the liver 46 , SLC2A8, also known as GLUT8, may also contribute to hepatocellular fructose transport Fructose is a poor substrate for the hepatic hexokinase glucokinase GCK.
Instead, ketohexokinase KHK, also known as fructokinase rapidly phosphorylates fructose to generate fructosephosphate F1P. Fructose biochemistry. Upon entering hepatocytes, fructose is phosphorylated by KHK to F1P. F1P is cleaved to DHAP and glyceraldehyde by ALDOB.
Glyceraldehyde is phosphorylated by triose-kinase TKFC, also known as dihydroxyacetone kinase 2 or DAK to form the glycolytic intermediate glyceraldehyde 3-phosphate GA3P. F1P also allosterically regulates metabolic enzymes red and green lines to regulate the disposition of fructose-derived substrate and other metabolic products like uric acid.
AMPD3, adenosine deaminase; GA, glyceraldehyde; IMP, inosine monophosphate; MTTP, microsomal triglyceride transfer protein; PYGL, glycogen phosphorylase L; GYS2, glycogen synthase 2; PKLR, pyruvate kinase, liver and red blood cell; PEP, phosphoenolpyruvate; TAG, triacylglycerol.
Cellular metabolic status and energy status tightly regulate the phosphofructokinase PFK step in glycolysis, which limits hepatic glycolytic flux In contrast, fructose-derived metabolites enter the triose-phosphate pool distal to PFK and therefore bypass this restriction.
As hepatic fructolysis is unrestricted, fructose loads can lead to large, rapid expansions in the hexose- and triose-phosphate pools, potentially providing increased substrate for all central carbon metabolic pathways, including glycolysis, glycogenesis, gluconeogenesis, lipogenesis, and oxidative phosphorylation.
The disposition of fructose-derived carbon among the major metabolic pathways depends on the overall nutritional and endocrine status of the animal as well as the status of key regulatory checkpoints in intermediary metabolism.
For instance, in starved animals, low levels of fructose-2,6-biphosphate inhibit PFK activity and glycolysis and activate fructose-1,6-biphosphatase and glucose production Thus, in a starved animal, fructose-derived triose-phosphates are preferentially routed through the gluconeogenic path 51 , The fate of ingested fructose may also depend on coingested nutrients.
For instance, infusing physiological concentrations of fructose to fed rats and humans increases serum glucose and lactate levels without affecting hepatic glycogen accumulation 53 , However, when fructose is infused with glucose, which stimulates insulin secretion, marked glycogen accumulation occurs Chronic fructose consumption can affect metabolic gene expression programs that further affect fructose disposition.
These mechanisms will be described in greater detail below. All of the fructolytic enzymes are highly expressed in the small intestine and notably in the jejunum, where the highest levels of GLUT5 are observed Similarly to GLUT5, intestinal expression of fructolytic and gluconeogenic enzymes including glucosephosphatase G6PC increases upon fructose feeding 59 and depends on GLUT5 and KHK activity However, most prandial fructose is not metabolized in the intestine but rather passes via the portal vein to the liver 61 , In addition to providing substrate for metabolic processes, hepatic fructose metabolism generates specific metabolites that also perform signaling functions Figure 2.
Importantly, F1P, the fructose-specific metabolite produced by KHK, exerts strong positive regulatory control on GCK by promoting its release from the inhibitory GCK regulatory protein GCKR.
GCKR sequesters GCK in an inactive state in the nucleus 63 — F1P may also enhance glycogen synthesis by allosterically inhibiting glycogen phosphorylase 67 , Lastly, F1P also allosterically activates pyruvate kinase, the terminal step in glycolysis, contributing to increased circulating lactate levels following fructose ingestion In rodent liver, hepatic F1P levels increase fold to approximately 1 mM within 10 minutes after fructose ingestion and remain elevated for several hours F1P concentrations of only approximately μM are sufficient to alleviate the inhibitory effect of GCKR on GCK Thus, fructose ingestion is likely to have rapid, robust, and sustained effects on hepatic glucose uptake and intermediary metabolism.
Fructose-induced gene expression programs. Fructose metabolism activates transcription factors including ChREBP and SREBP1c and their coactivator PGC1β to coordinately regulate gene expression of metabolic enzymes that contribute to fructolysis, glycolysis, lipogenesis, and glucose production.
These metabolic pathways contribute to steatosis, VLDL packaging and secretion, as well as glucose production and the generation of lipid intermediates that may affect hepatic insulin sensitivity and other biological processes.
ACACA, acetyl-CoA carboxylase α; FASN, fatty acid synthase; GPAT, glycerolphosphate acyltransferases; AGPAT, acylglycerolphosphate acyltransferase; DGAT, diacylglycerol acyltransferase; DAG, diacylglycerol.
While the efficiency and rapidity with which the liver can extract and phosphorylate ingested fructose are likely important for its role in integrating nutritional and systemic fuel metabolism, this robust metabolism may also have deleterious consequences.
For instance, decreases in intracellular free phosphate due to rapid hepatic fructose phosphorylation can increase uric acid production through activation of AMP deaminase, which leads to catabolism of AMP to uric acid 72 , Fructose feeding may also stimulate purine synthesis, contributing to uric acid production Increased circulating uric acid levels increase the risk of gout, a condition characterized by painful inflammation due to deposition of uric acid crystals in joints.
Indeed, a growing body of evidence implicates sugar intake as a risk factor for gout Moreover, elevated serum uric acid levels and gout are associated with other cardiometabolic risk factors in diverse populations 76 — A substantial body of work suggests that increased uric acid levels may independently regulate important aspects of metabolism and contribute to cardiometabolic risk 79 — However, Mendelian randomization studies do not strongly support a causal role for circulating uric acid in mediating cardiometabolic disease The association between uric acid levels and cardiometabolic risk may be indirect and may reflect activation of distinct fructose-regulated processes that contribute both to uric acid production and cardiometabolic risk.
The liver is at a metabolic crossroads and is crucial for gauging nutrient consumption and integrating peripheral nutrient status to regulate systemic fuel storage versus provisioning.
While hormones like insulin and glucagon help inform the liver of systemic fuel status, the liver is also well configured to integrate signals derived directly from fuel substrates.
Robust physiological activation of hepatic GCK occurs only when fructose-containing sugars are consumed. This activation enhances net hepatic glucose uptake and storage as glycogen and lipid. Thus, in the setting of uncontrolled diabetes, the liver may aberrantly sense hyperglycemia as a state of increased sugar consumption.
KHK exists as two alternatively spliced isoforms produced by mutual exclusion of the adjacent exons 3C and 3A within the KHK gene 87 , Mice deficient in both isoforms were fully protected from fructose-induced metabolic disease even though blood and urinary fructose levels were markedly increased Thus, elevated blood fructose itself is not deleterious; rather, fructose metabolism is essential for fructose-induced metabolic disease.
Loss-of-function mutations in KHK cause the benign human disorder essential fructosuria, characterized by impaired hepatic fructose metabolism leading to high blood and urine fructose levels after sucrose or fructose consumption Consistent with observations in mice, there are no documented adverse health effects observed in people with this condition.
Altogether, these results suggest that inhibiting KHK may be a safe therapeutic strategy to prevent fructose-induced metabolic disease. In contrast with global KHK deletion, selective deletion of the A isoform exacerbates the adverse metabolic effects of fructose feeding These results suggest two important hypotheses: a fructose metabolism outside of tissues that express the C isoform is non-negligible and contributes to whole-body fructose clearance, and b fructose metabolism within the tissues expressing KHK-C is critical for fructose-induced metabolic disease.
This is supported by recent data showing that selective knockdown of KHK in mouse liver protects against fructose-induced steatosis Recent data also indicate that altered splicing between KHK-A and KHK-C isoforms may contribute to the development of distinct diseases like hepatocellular carcinoma and heart failure 94 , Hereditary fructose intolerance HFI is a rare autosomal recessive disease caused by a deficiency of aldolase B ALDOB , which is highly expressed in the liver, kidney, and small intestine People with HFI develop abdominal pain, vomiting, diarrhea, symptomatic hypoglycemia, hyperuricemia, and potentially liver failure and death following ingestion of foods containing fructose, sucrose, or sorbitol The precise mechanisms by which ALDOB deficiency causes symptoms are not entirely clear.
An Aldob- deficient mouse model mimics the human HFI condition These mice fail to thrive and die when exposed to high-fructose diets. Interestingly, even on a fructose-free diet, Aldob- deficient mice develop steatosis 98 , possibly due to impaired metabolism of endogenously synthesized fructose While the vast majority of metabolized fructose is derived from dietary sources of sugar, animals including humans are capable of synthesizing fructose endogenously.
The sorbitol polyol pathway, which is active in a wide range of tissues, is responsible for endogenous fructose formation from glucose , In this pathway, glucose is first reduced to sorbitol by aldose reductase Sorbitol is then oxidized to fructose by sorbitol dehydrogenase Physiologically, endogenously synthesized fructose is the primary energy source for sperm and may be important for fertility — The placenta may also synthesize sorbitol that the developing fetus may use to synthesize fructose, suggesting a broader role for endogenous fructose in reproductive and developmental biology Sorbitol pathway activity increases during diabetic hyperglycemia Endogenous fructose synthesis and polyol metabolites are considered key players in the development of diabetic microvascular complications Interestingly, semen fructose concentrations are increased in type 1 diabetes and in obesity, in which it is associated with impaired sperm parameters , Whether endogenous fructose synthesis might occur at sufficient rates to contribute to other aspects of fructose-induced cardiometabolic risk has only recently been addressed.
Glucose dose-dependently induces aldolase reductase in human tissues, and chronic exposure to a high-glucose diet induces polyol pathway activation in mice 99 , This may be a mechanism by which severe hyperglycemia may exacerbate cardiometabolic risks.
Additionally, Lanaspa et al. report that endogenous fructose production and KHK activation within the kidney contribute to the development of diabetic nephropathy Although sorbitol dehydrogenase is expressed at high levels in human liver , whether this pathway is sufficiently active in humans to play an adverse metabolic role will require further investigation.
As noted above, excessive fructose consumption may have significant effects on lipid metabolism, contributing both to steatosis and to increased circulating triglyceride levels in the form of very low-density lipoprotein VLDL.
Hepatic lipid accumulation results from a combination of increased hepatic de novo lipogenesis DNL , esterification of preformed fatty acids derived from the diet or adipose stores, decreased VLDL secretion, and decreased hepatic fatty acid oxidation. Activation of the lipogenic program is observed immediately after a single load of fructose and contributes to increased VLDL triglyceride secretion , Fructose also acutely suppresses hepatic fatty acid oxidation Thus, fructose contributes to hepatic triglyceride production both by providing substrate for fatty acid and triglyceride synthesis and by activating signaling systems to enhance lipid production Figure 2.
The liver is the primary site of DNL, the process by which fatty acids are synthesized from dietary precursors, predominantly carbohydrates Due to the differences in hepatic glucose and fructose metabolism, a larger fraction of diet-derived fructose than glucose metabolites are available for conversion to fat in the liver via DNL in animals and humans 20 , — Additionally, fructose metabolites entering the triose-phosphate pool are in equilibrium with glycerol 3-phosphate, which is used to synthesize the glycerol backbone in triglyceride.
Moreover, the metabolite malonyl-CoA generated via DNL limits fatty acid oxidation by inhibiting carnitine palmitoyltransferase 1A CPT1A , the enzyme required for translocation of fatty acids into the mitochondria CPT1A inhibition further increases the availability of fatty acids for triglyceride production.
Triglyceride can be incorporated into lipid droplets, leading to steatosis, or can be incorporated into VLDL and secreted from the liver. In addition to providing substrate for lipogenesis, chronic fructose consumption increases transcriptional regulation of DNL by activating key transcription factors, including sterol regulatory element—binding protein 1c SREBP1c and carbohydrate-responsive element—binding protein ChREBP SREBP1c promotes lipid synthesis and is regulated at the transcriptional and posttranslational levels by nutrients and hormones.
Insulin is a major hormonal activator of hepatic SREBP1c , Although acute fructose feeding does not directly stimulate insulin secretion, chronic fructose ingestion can lead to hyperinsulinemia, which may increase hepatic SREBP1c expression and activation , Fructose may also activate SREBP1c independently of insulin, since SREBP1c responds to high-fructose feeding in liver-specific insulin receptor—knockout LIRKO mice Fructose consumption may also promote ER stress, which may induce proteolytic cleavage of SREBP1c and the lipogenic program , Fructose-induced ER stress may also enhance lipogenesis via activation of the transcription factor x box-binding protein 1 independently of other lipogenic transcription factors ChREBP couples carbohydrate metabolites to lipid synthesis by inducing enzymes required for DNL ChREBP may also suppress fatty acid oxidation by downregulating enzymes like CPT1A, in part by antagonizing peroxisome proliferator—activated receptor α PPARα , a key transcriptional regulator of the fatty acid oxidation gene program , ChREBP is highly expressed in key metabolic tissues, including liver, adipose tissue, small intestine, pancreatic islets, and kidney, where it regulates carbohydrate metabolism in an insulin-independent manner 37 , , The observation that ChREBP-deficient mice are intolerant to diets containing fructose but not to diets containing dextrose suggests a specific role for ChREBP in regulating fructose metabolism 37 ,
Despite Senior nutrition tips fact that the prevalence Carbohydratee obesity in early childhood has been stable and is no longer increasing in many developed and industrialized countries, Carbohydrate metabolism and metabolic syndrome incidence of both metbaolism and full-blown metabolic Carbohydrate metabolism and metabolic syndrome in metabloic and adolescents is still very high. Obesity is a major disease burden in all societies and needs to be prevented early in life. New approaches are eagerly sought and absolutely necessary. This book presents a comprehensive and state-of-the-art summary of current and new knowledge in this critical field. Crucial issues such as nutrition and genetics are described in detail. In addition, new ideas such as e-health and the consequences of urban living conditions are explored.
Metabolic disorders, also known as African Mango Pure errors of metabolism, are a group of inherited genetic abd due Carbohydrate metabolism and metabolic syndrome metabooism deficiency caused by some defective metagolic. There are anx genetic metabolic disorders discovered so far, many Carbohydrate metabolism and metabolic syndrome them are present in newborns or after a short time thereafter. People affected with these disorders often remain asymptomatic and healthy for even years. The symptoms usually start appearing when the metabolism undergoes some stress conditions as in prolonged fasting or in febrile illness. Metabolic disorders due to impaired carbohydrate metabolism are usually a result of deficiency of some enzymes which are involved in the normal metabolic pathways of carbohydrates. They are mostly autosomal recessive disorders.
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