For this review, I want to summarize the findings on the dietary carbohydrate to protein ratio and how it may influence body composition and blood lipid profiles in adult women.
There is evidence that older adults experience age-related changes in body composition, such as increase in body fat and decrease in lean body mass (Kim, O’Connor, Sands, Slebodnik, & Campbell, 2016). A moderate energy restricted diet is often an effective way for overweight adults to reduce bodyfat mass, and improve their health profile, but it often comes with the price of a loss of 25% of body mass being lost as lean body mass (Kim et al., 2016). Accumulating data suggests that increased protein content of the diet, in combination with exercise training, can reduce the loss of lean body mass in overweight and obese subjects following a weight loss diet. This preservation of lean body mass has been attributed to the increased level of essential amino acids, especially leucine, provided by the protein (Mettler, Mitchell, & Tipton, 2010).
Current dietary guidelines recommend a daily macro-nutrient intake of 55% carbohydrate, 30% protein and 15% fat (Layman et al., 2003). However, this balance has been challenged by evidence from epidemiological, clinical and experimental studies, reporting that a higher carbohydrate intake can reduce oxidation of body fat and increase blood triglycerides (Layman et al., 2003). In particular, the optimal ratio of carbohydrate to protein has been challenged on the basis of glucose homeostasis in the context of body mass reduction. Under a higher carbohydrate intake, the body has to rely on insulin to metabolize and dispose large quantities of dietary glucose, whereas under lower carbohydrate intakes (<200g per day), the body would rely more on hepatic production to maintain blood glucose via gluconeogenesis or glycogenolysis (Layman et al., 2003).
A study conducted in 2003 by Layman et al (2003), compared the results of a moderate protein and lower carbohydrate intake to a higher carbohydrate with lower protein intake, and the influence on body mass and blood lipids. In this study, the total energy intake, fat and fiber were consistent among the two groups: 1700 kcal/day, total fat intake was 50g/day and total fiber at 20g per day. In the higher protein group (Protein Group) protein intake averaged 125g/day with a carbohydrate intake of 171g/day. The higher carbohydrate group (CHO) consisted of 68g pf protein per day and 239g of carbohydrates. The relative proportions of energy in the Protein Group were 30% protein, 41% carbohydrate and 29% fat with a ratio of carbohydrate to protein (CHO/protein) of 1.4. The proportion in the CHO Group was 16% protein, 58% carbohydrate and 26% fat with a ratio of 3.5 (Layman et al., 2003). Obviously, the cholesterol and saturated fatty acid intake was higher in the Protein group than the CHO group.
The study duration was 10 weeks. The results of the study indicated the following:
- There was not a big change in body weight between the two groups. The Protein Group lost a total weight of 7.53kg and the CHO group lost 6.96kg.
- Changes in body composition indicate the weight loss was mostly bodyfat. The Protein group lost 14.4% of initial body fat, the CHO group lost 12.2% of initial bodyfat. Loss of lean body mass tended to be greater in the CHO Group compared to the Protein Group. When changes in body composition were expressed as a ratio of fat/lean loss, the Protein group achieved a fat/lean loss of 6.36 vs. 3.92 in the CHO group. The higher protein group clearly had a stronger improvement in body composition.
- There were some differences seen in thyroid hormones, blood lipids and fasting and postprandial glucose and insulin levels, but it was not explained in detail as it was not the main objective of this study.
In summary, the results of this study indicate that the positive changes in body composition associated with the higher protein diet may be associated with either targeting of body fat or sparing of muscle protein, or both. For the purposes of improving body composition, a higher protein diet may be effective for adults.
Before I end this summary, I do want to mention I did stumble upon an interesting study in 2016 that indicates that a high protein intake eliminates the weight loss induced improvement of insulin action on postmenopausal women (Smith et al., 2016). This study indicates that a high protein diet can have adverse effects on postprandial insulin sensitivity. According to the authors, “the beneficial effect of 10% weight loss on muscle insulin action (assessed as glucose disposal rate and phosphorylation of AKT in muscle during a HECP) was eliminated by high protein (HP) intake” (Smith et al., 2016). The failure to improve muscle insulin sensitivity in the higher protein group is clinically important, because it reflects a failure to improve a major mechanism involved in the development of T2D. It also indicates more insulin is required in the higher protein group to dispose of a given amount of glucose. This can be due to:
- BCAA’s, particularly leucine, that can impair insulin mediated uptake of glucose through a negative feedback inhibition
- There may be an association of glycine and tryptophan and metabolites of acylcarnitine in the development of insulin resistance, regardless of the amount of circulating amino acid metabolites measured in the serum.
- There may be a metabolic process related to oxidative stress that is expressed in the higher protein group, as evidenced by gene expression of GSTA4 and PRDX3 that are both associated with oxidative stress. These results suggest that the adverse effect of high protein intake on insulin action during weight loss therapy may have been mediated through its effects on oxidative stress because it prevented the WL-induced decrease, and even increased, metabolic pathways involved in oxidative stress response in muscle.
- Both groups had improved liver insulin sensitivity, but the higher protein group experienced a reduction in muscle insulin sensitivity. This is attributed to the fact that protein is a potent insulin secretagogue, which may overcome the adverse effect of protein on insulin sensitivity by increasing the secretion of insulin (Smith et al., 2016).
I must mention however, protein causes greater satiation and has a greater thermogenic effect of feeding than carbohydrate and fat. This alone can lead to greater weight loss with a higher protein than a standard protein diet. “Therefore, the adverse effect of dietary protein on muscle insulin action could be offset by its effect on hepatic insulin sensitivity, insulin secretion and energy balance” (Smith et al., 2016).
In summary, this review demonstrates that the protein content of a weight loss diet can have significant effects on metabolic function and weight loss outcome. I personally believe that diets should be personalized for the individual. A high protein diet is not suitable for everyone. Neither is a high carbohydrate diet. The individual’s needs should be taken into consideration, along with various markers of health that can be measured in a blood chemistry panel, their nutritional needs (such as macronutrient deficiencies) and even nutrigenomics, health predispositions and family history. The one size fits all approach is not appropriate when prescribing nutrition therapy, as the results of these studies also demonstrate.
What do I think? The evidence is good for a higher protein diet, but I wonder if they looked into the glucogenic amino acids and their effect on insulin sensitivity. In my review, I found another journal that indeed indicated that various amino acids can actually decrease insulin sensitivity. Interestingly, it was leucine that was contributing to this change in muscle insulin sensitivity, and that is actually a ketogenic amino acid! If I find the free time at some point, I would love to research the effects of glucogenic and ketogenic amino acids and how they affect insulin sensitivity and type 2 diabetes. I personally have not been a fan of high protein diets. I feel it is too hard on the kidneys, and considering glycine is often a problem with oxalate metabolism, especially in the context B1 deficiency, I feel the risk of kidney stones is too great to recommend high protein across the board (See image). I prefer a more balance approach, with a balance of macronutrients and incorporating intermittent fasting as a way to improve blood lipids and insulin sensitivity.
Kim, J. E., O’Connor, L. E., Sands, L. P., Slebodnik, M. B., & Campbell, W. W. (2016). Effects of dietary protein intake on body composition changes after weight loss in older adults: a systematic review and meta-analysis. Nutr Rev, 74(3), 210-224. doi:10.1093/nutrit/nuv065
Layman, D. K., Boileau, R. A., Erickson, D. J., Painter, J. E., Shiue, H., Sather, C., & Christou, D. D. (2003). A Reduced Ratio of Dietary Carbohydrate to Protein Improves Body Composition and Blood Lipid Profiles during Weight Loss in Adult Women. J Nutr, 133(2), 411-417. doi:10.1093/jn/133.2.411
Mettler, S., Mitchell, N., & Tipton, K. D. (2010). Increased protein intake reduces lean body mass loss during weight loss in athletes. Med Sci Sports Exerc, 42(2), 326-337. doi:10.1249/MSS.0b013e3181b2ef8e
Smith, G. I., Yoshino, J., Kelly, S. C., Reeds, D. N., Okunade, A., Patterson, B. W., . . . Mittendorfer, B. (2016). High-Protein Intake during Weight Loss Therapy Eliminates the Weight-Loss-Induced Improvement in Insulin Action in Obese Postmenopausal Women. Cell Rep, 17(3), 849-861. doi:10.1016/j.celrep.2016.09.047
Zinc is a very interesting mineral. It is also one I commonly see low in hair tissue mineral analysis (HTMA).
It plays an important role in facilitating hundreds of biochemical reactions. Due to its role in enzymatic function, it can impact metabolic pathways such as carbohydrate, protein, nucleic acid, and lipid metabolism. It is also a structural component in thousands of transcription factors and can affect gene expression that impacts many physiological processes in the body. “Zinc appears to be part of more enzyme systems than all the rest of the trace minerals combined; over 300 enzymes from every enzyme class (oxidoreductases, hydrolases, lyases, isomerases, transferases, and ligases) require zinc” (Gropper, n.d.). Some of these zinc dependent enzymes include:
- Carbonic anhydrase: acid base balance- found in erythrocytes and renal tubule cells, essential for maintaining acid-base balance/buffering and respiration. The enzyme catalyzes the reaction that allows rapid disposal of carbon dioxide. Activity of this enzyme in red blood cells diminishes with chronic low zinc status in the diet.
- Alkaline phosphatase: Contains four zinc atoms per enzyme molecule, in which two are required for enzyme activity. This enzyme is found in bones and the liver.
- Alcohol dehydrogenase: contains 4 zinc molecules per enzyme molecule, two are required for catalytic activity. This enzyme is important in the NADH-dependent conversion of alcohols to aldehydes. For example, this enzyme converts retinol (form of Vitamin A) to retinal, which is needed for night vision. It also is required for acetyl aldehyde for alcohol metabolism
- Carboxypeptidases A and B and Aminopeptidases- which is involved in protein digestion. These enzymes are secreted by the pancreas into the duodenum. Zinc is bound tightly to carboxypeptidases and is essential for enzymatic activity; in fact, enzyme activity decreases with zinc deficiency (Gropper, n.d.). Aminopeptidases consist of a group of enzymes also involved in protein digestion which contains 1-2 zinc atoms for catalytic activity.
- Delta (Δ)-Aminolevulinic Acid Dehydratase: Heme Synthesis- needed for heme synthesis is zinc dependent. Interestingly, lead when present in the body in high concentrations can replace zinc in the dehydratase and diminishes heme synthesis.
- Superoxide dismutase (SOD1)- an antioxidant found in the cell cytosol requires two atoms of zinc (and two copper) to function. An extracellular form of the enzyme (SOD3) that is also zinc and copper dependent has been characterized and appears to be more sensitive to zinc than is the cytosolic form of the enzyme. Both the cytosolic and extracellular forms of superoxide dismutase serve important antioxidant defense roles in the body by catalyzing the removal of superoxide radicals, O2
- Phospholipase C-this enzyme hydrolyzes the glycerophosphate bond in phospholipids (a structural component of cell membranes!). It requires 3 zinc atoms for catalytic activity.
- Matrix Metalloproteinases-The matrix metalloproteinases are zinc containing endopeptidases (zinc is located in the catalytic site where substrate binds). They generally function in wound healing, degrading components of the extracellular matrix (among other roles) to allow for remodeling of extracellular matrix proteins and tissue repair
- Polymerases, Kinases, Nucleases, Transferases, Phosphorylases, and Transcriptases- Nucleic Acid Synthesis and Cell Replication and Growth Polymerases, kinases, nucleases, transferases, phosphorylases, and transcriptases all require zinc.
- Gene expression- Zinc plays a major structural role in regulating gene transcription by promoting a confirmation change in the shape of the transcription factor protein. You may have heard the term zinc fingers which is often used to indicate the secondary shape (configuration) of the transcription factor proteins when bound to zinc.
In addition to the above roles, zinc helps maintain cell membranes through multiple actions on membrane proteins including direct effects on membrane proteins’ conformation, on protein-to-protein interactions, and on other membrane components
Zinc itself also is believed to stabilize membrane structure by stabilizing phospholipids and thiol (SH) groups in enzymes and membrane proteins that need to be maintained in a reduced state.
Zinc may also stabilize membranes by quenching free radicals as part of metallothionein and by promoting associations between membrane skeletal and cytoskeletal proteins
Additionally, zinc in cells is found bound to tubulin, a protein that makes up the microtubules. Microtubules are thought to act as a framework for structural support of the cell as well as enable movement.
Zinc is also involved with insulin and thus influences carbohydrate metabolism. Zinc is transported into pancreatic b-cells by zinc transporter ZnT8, which also enables uptake into secretory vesicles. Pancreatic b-cells are responsible for insulin production and secretion (Gropper, n.d.).
Zinc can also influence the basal metabolic rate (BMR). A decrease in thyroid hormones and basal metabolic rate has been observed with consumption of a zinc-restricted diet (Gropper, n.d.).
Zinc is also important for taste; it is a component of gustin, a protein involved in taste acuity (Gropper, n.d.).
Cell mediated and humoral immunity are also influenced by zinc. T-cells are critical to immune system function and with zinc deficiency, thymulin activity diminishes and profoundly affects T-cell numbers and functions, and pre-T-cell apoptosis (programmed cell death) (Gropper, n.d.).
Some signs and symptoms of deficiency in adults include anorexia, diarrhea, lethargy, depression, skin rash/ lesions/dermatitis, hypogeusia (blunting of sense of taste), alopecia (some hair loss; remaining hair make take on a reddish hue), vision problems, and impaired immune function, protein synthesis, and wound healing (Gropper, n.d.).
Zinc deficiency can be associated with decreased mobilization of retinol from the liver (even with adequate liver vitamin A stores) as well as decreased plasma retinol-binding protein concentrations (Gropper, n.d.).
An overall deficiency of zinc stores within the body has been implicated in the systemic susceptibility of infection and in the pathogenesis of some cancers (Liu et al., 2011)
Zinc also demonstrates an important role within the lumen of the alimentary canal, as evidenced on the observations that supplementation of oral diets with Zn2+ has beneficial effects on diarrhea and inflammatory conditions of the gastrointestinal tract (Liu et al., 2011). “In gastric mucosa, adequate intracellular stores and luminal content of Zn2+ may regulate integrity of and acid secretion by the gastric glands and enhance protection of the mucosa as a whole against acid-peptic injury (Liu et al., 2011).
Evaluating zinc nutriture is difficult, owing to homeostatic control of body zinc. A variety of indices have been used to assess zinc status, including measurements of zinc in red blood cells, leukocytes, neutrophils, and plasma or serum.
The most common basis for assessment is serum or plasma zinc, with fasting concentrations less than about 70 µg/dL (10 µmol/L) suggesting deficiency. A cutoff of 50 µg/dL, however, may better predict clinical signs of zinc deficiency (Gropper, n.d.). Plasma zinc concentrations range from about 70 to 120 μg/dL (10–18 µmol/L), with plasma containing about 3 mg of zinc. Plasma zinc concentrations decrease after eating, as well as under conditions of infection and trauma
Low fasting plasma zinc concentrations indicate that little zinc is present in the exchangeable zinc pool and may reflect a loss of tissue zinc (especially from the liver). Plasma zinc concentrations, however, must be interpreted with caution because concentrations are influenced by many factors unrelated to zinc depletion, including meals, time of day (diurnal variation), stress, infection, and medications such as steroid therapy. In fact, postprandial (after eating) plasma zinc concentrations have been found to be more sensitive to low dietary zinc intake than fasting plasma zinc concentrations (Gropper, n.d.)..
Metallothionein has also been used to assess zinc status. Concentrations of metallothionein respond to changes in dietary zinc. For example, liver and red blood cell metallothionein concentrations diminish as dietary zinc intake decreases and are thought to reflect zinc status or stores (Gropper, n.d.).
Serum zinc and serum metallothionein concentrations can be used to indicate poor zinc status if both are low. Elevations in serum metallothionein coupled with low serum zinc, however, usually suggest an acute-phase response, and in such conditions these indices are not reliable. Urinary zinc excretion remains fairly constant over a range of intakes and is thought to be a useful marker of status in those with moderate to severe zinc deficiency (Gropper, n.d.)..
Low hair zinc may be associated with chronic intake of dietary zinc in suboptimal amounts; however, the concentration of zinc in hair depends not only on delivery of zinc to the root but also on the rate of hair growth, which is affected by other conditions (including protein status)(Gropper, n.d.).
.Measurement of the activity of zinc-dependent enzymes has also been employed as an index of zinc status. Studies using enzymes as indicators typically have measured carbonic anhydrase or alkaline phosphatase, which “hold” zinc less securely than other zinc metalloenzymes.
Ideally, measurements of activity should be taken before and after zinc supplementation (Gropper, n.d.)..
Supporting deficiency in adults typically requires oral zinc supplementation; doses of 10–20 mg/day are recommended. Although higher doses (often up to 50 mg given two to three times per day) may be prescribed, use of such doses is more likely to impair copper status.
Some population groups—especially older adults, vegetarians, and those with alcoholism and with limited income—have been found to consume less than adequate amounts of zinc.
Alcohol ingestion additionally reduces intestinal zinc absorption and increases urinary zinc excretion.
Additional conditions associated with an increased need for intake include trauma, sickle-cell anemia, and disorders causing malabsorption such as Crohn’s disease, short bowel syndrome, celiac disease, and liver failure, as well as surgical bariatric procedures, especially Roux-en-Y gastric bypass and duodenal switch, used to treat obesity. Diarrhea and intestinal fistulas also substantially increase fecal zinc losses; supplementation with up to 20 mg of zinc/day may be needed under such conditions.
ZINC and COPPER
The detrimental effect of excessive zinc intake on copper absorption is thought to be attributable to zinc’s stimulation of the synthesis of metallothionein, which has a higher affinity for copper than for zinc. With increased intestinal concentrations of metallothionein induced by high zinc levels, ingested copper readily binds to the metallothionein within the enterocyte and becomes “trapped,” preventing its passage into the plasma. The increased risk of copper deficiency precipitated by zinc supplementation led to the Tolerable Upper Intake Level for elemental zinc of 40 mg daily.
Recent reports have begun to explore the mechanisms that regulate cellular homeostasis of Zn2+ in mucosal cells of the gastrointestinal tract (Liu et al., 2011)
There is a relationship to zinc uptake is dependent on intracellular Ca2+ stores.According to Liu et al (2011), baseline conditions, uptake of Zn2+ across the basolateral membrane depends on adequate stores of intracellular calcium ion (Ca2+) . With stimulation by powerful agonists such as forskolin and carbachol, demand for extracellular Zn2+ increases and depends on influx of extracellular Ca2+ .
“In the current set of studies, we find that Ca2+ facilitates optimal uptake of Zn2+ across the cell membrane, implying that it is either a counter-ion in exchange or it is acting as a regulatory second messenger. Membrane proteins that facilitate Zn2+ transport constitute the SLC30A (ZnT) and SLC39A (Zip) gene families” (Liu et al., 2011).
Diminished calcium absorption has been observed with the ingestion of zinc supplements when calcium intake is low (<300 mg/day of calcium). However, calcium absorption appears to be unaffected by zinc when calcium intake is at adequate (recommended) levels.
Cadmium, if present in high concentrations in the body, appears to bind to sites to which zinc would normally bind and thus disrupts normal zinc functions. For example, cadmium can replace zinc in zinc fingers, preventing the fingers from functioning as they would with zinc present.
Zinc is found in foods complexed with nucleic acids and with amino acids that are part of peptides and proteins. The zinc content of foods varies widely.
Very good sources of zinc are red meats (especially organ meats) and seafood (especially oysters and mollusks). Other relatively good animal sources of zinc include poultry, pork, and dairy products. Animal products are thought to provide 40–70% of zinc consumed by most people in the United States.
Whole grains and legumes also provide moderate amounts of zinc.
Cereals, some of which may be fortified, are thought to provide about 30% of the zinc in the U.S. diet. Fruits contain little zinc.
Plant sources, however, not only have lower zinc contents, but zinc from plants is also absorbed to a lesser extent than zinc from animal sources (e.g., meat).
Zinc absorption is enhanced with:
Ligands or chelators including organic acids (like citric acid and picolinic acid) and prostaglandins may bind and promote zinc absorption
Glutathione and products of protein digestion, such as amino acids, serve as ligands (such as sulfur, cysteine, or nitrogen). Interestingly, amino acids serving as ligands help maintain zinc’s solubility in the gastrointestinal tract
Absorption of zinc is also enhanced by an acidic environment. Thus, the use of medication such as antacids, H2 receptor blockers (such as Zantac [ranitidine], Tagamet [cimetidine], or Pepcid [famotidine]), and proton pump blockers (such as Prevacid [lansoprazole] or Prilosec [omeprazole]), which are commonly taken to treat heartburn, gastroesophageal reflux disease, and ulcers, increases gastric and proximal intestinal pH and decreases zinc absorption
Phytic acid found in plant foods, particularly legumes, lentils, nuts, seeds, and whole-grain cereals decrease absorption
Other minerals such as iron and calcium negatively impact absorption
Gropper, Sareen S.; Smith, Jack L.; Carr, Timothy P.. Advanced Nutrition and Human Metabolism (Page 509). Wadsworth Publishing. Kindle Edition.
Liu, J., Kohler, J. E., Blass, A. L., Moncaster, J. A., Mocofanescu, A., Marcus, M. A., . . . Soybel, D. I. (2011). Demand for Zn2+ in acid-secreting gastric mucosa and its requirement for intracellular Ca2+. PLoS ONE, 6(6), e19638. doi:10.1371/journal.pone.0019638
The relationship between thiamine and diabetes mellitus (DM) has been reported in the literature (Luong & Nguyen, 2012). Thiamine acts as a coenzyme for transketolase (Tk) and for the pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes. These enzymes play a fundamental role for intracellular glucose metabolism by increasing Krebs cycle activity (Luong & Nguyen, 2012). Low thiamine has been reported to be decreased by 76% in T1D and 75% in T2D patients, as evidenced by low blood thiamine levels, erythrocyte transketolase activity and high erythrocyte thiamine pyrophosphate (TPP).
Additionally, thiamine transporter protein concentration has been shown to be increased in erythrocyte membranes of T1D and T2D patients. “Therefore, changes in thiamine levels may be masked by an increase in thiamine transporter expression” (Luong & Nguyen, 2012). The low thiamine values in diabetic patients might also be a reduced apo-enzyme level from the disease itself rather than thiamine deficiency (Luong & Nguyen, 2012)
I think it is important to mention, there are four distinct biochemical pathways that have been identified as mechanisms in which intracellular hyperglycemia can promote some of the complications of diabetes (such as vascular damage, renal impairment, neurological damage and endothelial damage in the retina) (Brownlee, 2005). These include: increased flux through the polyol pathway, formation of AGE’s, activation of protein C kinase pathway and increase flux through hexosamine biosynthetic pathway. I will briefly discuss each below (Luong & Nguyen, 2012).
- Polyol pathway- This pathway focuses on the enzyme aldose reductase, which is responsible for reducing toxic aldehydes in the cell to inactive alcohols. But when the glucose concentration is too high in the cell, aldose reductase reduces the glucose to sorbitol. NADPH is used to drive this reaction forward, but it runs the risk of being overconsumed in this process. When there is elevated blood glucose and energy overload in the cell, we start to waste NADPH which is essential for regeneration of GSH. When we are running through this pathway, it can cause a glutathione deficit in the cell, which is why sometimes diabetes is associated with GSH deficiency. By reducing the amount of reduced glutathione, the polyol pathway can increase susceptibility to intracellular oxidative stress (Luong & Nguyen, 2012).
- Intracellular production of AGE precursors. AGE’s are toxic compounds deriving from non-enzymatic glycoxidation reactions of reducing sugars with proteins, which then result as being structurally and functionally compromised. Protein glycation occurs in vivo in physiological conditions as a post-translational modification that takes place slowly and continuously during the life span, driving AGE accumulation in tissues during aging. AGE’s have been associated with age related conditions such as diabetes and insulin resistance. In addition, accumulation of AGE’s is accelerated leading to other conditions (Aragno & Mastrocola, 2017).
- Activation of the protein Kinase C pathway- High levels of fatty acids and hyperglycemia activate DAG, which turns on PKC. This promotes various processes that results in decreased nitric oxide (NO) bioavailability. Reducing NO availability and produces oxidative stress in the nervous and vascular system, and reduce ability to synthesize NO which can increase oxidative stress(neuro and vascular) and reduce the ability to synthesize NO which can increase vasoconstriction, poor blood flow and oxygenation of tissue (Roberts & Porter, 2013).
- Hexosamine pathway– Chronic high blood pressure can upregulate this pathway. Fructose 6-P is transformed to glucosamine 6-P by the enzyme glutamine fructose 6-P amidotransferase (GFAT). Glucosamine then promotes the synthesis of uridine diphosphate-N-acetylhexosamine (UDP-GlcNAc) that then serves as a substrate for N- or O-glycation of numerous proteins (Luo, Wu, Jing, & Yan, 2016). “This posttranslational modification can enhance glucotoxicity by impairing protein function and has been demonstrated to be involved in insulin resistance and pathogenesis of diabetes” (Luo et al., 2016). If transketolase activity is low, it is likely that fructose 6 pathway will go through hexosamine pathway, instead of the pentose phosphate pathway which thiamine is a cofactor.
Diabetics are associated with tissue specific thiamine deficiency. This is often demonstrated by: a marked decrease of plasma thiamine concentration; decreased activity of the thiamine-dependent enzyme of transketolase (TK); decreased levels of TK protein in renal glomeruli linked to a profound increase in renal clearance of thiamine (Thornalley et al., 2007). According to Thornalley et al (2007), diabetics are statically more likely to be more thiamine deficient since they waste it through kidneys making their requirement higher.
Insulin deficiency is also associated with reduced rate of thiamine transport across the intestine. High prevalence of low plasma concentrations is prevalent in patients with T1 and T2 diabetes, associated with thiamine clearance
What all this means?
Transketolase acts as a bridge between PPP and glycolytic pathway requiring B1 as a cofactor. Thiamine deficiency slows down transketolase. With thiamine, the pentose phosphate pathway can take the extra intermediates of the glycolytic pathway until we need to make more energy. When there is thiamine deficiency, we are unable to effectively shunt these intermediates down the pentose phosphate pathway( PPP), we end up with build up of intermediates. When this energetic block occurs, such as in mitochondrial dysfunction, the intermediates are shunted into alternative pathways. These yield inflammatory products, and it is the products of these pathways that are central in the damage caused by diabetes or involved in diabetic complications.
In diabetes, there is an overload of energy, which causes reverse the electron flow which can then increase reactive oxygen species. Decreased availability of thiamine in vascular cells in diabetes exacerbates metabolic dysfunction in hyperglycemia (Thornalley et al., 2007). These yield inflammatory products as indicate above, and it is the products of these pathways that are central in the damage caused by diabetes or involved in diabetic complications.
It is thought that thiamine supplementation is helpful in diabetes. Thiamine supplementation can reduce AGE formation, reduce flow through hexosamine and polyol pathway, reduce protein kinase C activity, inhibits NF-KB activation and normalize markers associated with methylglyoxal and glycation.
High dose supplementation as befothiamine and thiamine hydrochloride possess antioxidant properties, reduces lipid peroxidation, reduces oxidative stress associated with diabetes and activates eNOS (EONutrition, 2019). It may also improve endothelial dysfunction in a hyperglycemic state. In addition, it may improve pain associated with diabetic polyneuropathy and reduce urinary albumin excretion, reducing renal AGE’s and oxidative damage (EONutrition, 2019).
Aragno, M., & Mastrocola, R. (2017). Dietary Sugars and Endogenous Formation of Advanced Glycation Endproducts: Emerging Mechanisms of Disease. Nutrients, 9(4). doi:10.3390/nu9040385
Brownlee, M. (2005). The pathobiology of diabetic complications: a unifying mechanism. Diabetes, 54(6), 1615-1625. doi:10.2337/diabetes.54.6.1615
EONutrition (2019). Retrieved (2020, June 22) from https://www.youtube.com/watch?v=m3DopqTz1Q4&t=801s
Luo, X., Wu, J., Jing, S., & Yan, L. J. (2016). Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity. Aging Dis, 7(1), 90-110. doi:10.14336/ad.2015.0702
Luong, K. V., & Nguyen, L. T. (2012). The impact of thiamine treatment in the diabetes mellitus. J Clin Med Res, 4(3), 153-160. doi:10.4021/jocmr890w
Roberts, A. C., & Porter, K. E. (2013). Cellular and molecular mechanisms of endothelial dysfunction in diabetes. Diab Vasc Dis Res, 10(6), 472-482. doi:10.1177/1479164113500680
Thornalley, P. J., Babaei-Jadidi, R., Al Ali, H., Rabbani, N., Antonysunil, A., Larkin, J., . . . Bodmer, C. W. (2007). High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia, 50(10), 2164-2170. doi:10.1007/s00125-007-0771-4
It is no secret that exercise is very important for optimal health. But many people still do not see the connection and it seems to be a low priority for them when it comes to managing their health. However, I realize that many people truly do not understand how important it really is, even from the perspective of glycolytic pathway, so I want to take the time to summarize it here. Exercise is known to stimulate glycogenolysis, especially when it is conducted first thing in the morning after an overnight fast. In fact, I often tell my clients to do their exercise fasted when they want to optimize weight loss. But how does it work?
Before I review that, I want to do a quick summary of biochemistry.
In our muscles, glycogen supplies glucose-6-phosphate for ATP synthesis in the glycolytic pathway. Any enzyme known as glycogen phosphorylase in the muscle is stimulated during exercise by the increase of AMP and by phosphorylation. The phosphorylation is stimulated by calcium released during contraction and by epinephrine, the fight or flight hormone, as well as hypoglycemia during stressful situations or exercise where there is an immediate need for glucose. It is important to understand that liver glycogen stores are principally for the support of blood glucose during fasting or extreme need such as exercise, and the degradative and biosynthetic pathways are regulated principally by changes in the insulin/glucagon ratio and by blood glucose levels. The key point to remember is that muscle glycogenolysis is regulated principally by AMP, which signals a lack of ATP, and by Ca2+ released during contraction. Epinephrine, which is released in response to exercise and other stress situations, also activates skeletal muscle glycogenolysis.
Let’s take a practical look at what happens when someone begins to contract their muscles during exercise. If someone were to immediately begin running as fast as possible, the following cascade would take place.
- Within 3 seconds, muscle cells exhaust stored ATP.
- As exercise continues, this ATP must be regenerated, so the ATP–PCr system kicks in to shoulder most of the load. This lasts for about 10 seconds. And because time is required for ATP to be regenerated, you start to slow down a bit.
- As exercise continues and the ATP–PCr stores are depleted, the glycolytic system will begin to provide most of the energy transfer for ATP regeneration. This lasts for about 90 to 120 seconds or so, depending on the intensity of the exercise. Since the glycolytic system generates ATP more slowly than the ATP–PCr system, again, you have to slow down a bit more.
- If exercise continues beyond this time frame, the oxidative system will start to provide most of the energy transfer for ATP regeneration. And again, because the oxidative systems are slower than the anaerobic systems, the pace must slow again. In fact, if the pace is slow enough, the exercise can last for quite a long time.
There are two main types of exercise: anaerobic exercise and aerobic exercise. Anaerobic exercise is defined as higher-intensity, shorter-duration (less than 2 minutes) activity, whereas aerobic exercise occurs when the exercise is longer than 2 minutes in which the oxidative system must kick in to provide the remaining energy for ATP regeneration. As our initial energy stores can only supply energy for about three seconds, our ATP must be regenerated in large amounts, and quickly, to support this type of exercise.
Short-burst activities such as the following:
- The golf swing
- Field events (shot put, discuss)
- The tennis swing
- The 100-meter sprint
- The baseball swing
Oxidative energy transfer takes place in the mitochondria of our cells and utilizes a combination of muscle glycogen, intramuscular fatty acids, free fatty acids, and amino acids. As the oxidative processes utilize breakdown products from both glycolysis (glucose through to pyruvate) and beta oxidation (fatty acids through to acetyl-coA), energy transfer occurs at a slower rate. However, what this system lacks in speed, it makes up for in ATP regeneration. As a result, oxidative metabolism can support activities including the following:
- 800-meter run
- 2000-meter rowing
- 1500-meter skating
- Cross-country skiing
- Long-distance swimming
Indeed, any activity done at a high intensity for longer than two minutes derives a large percentage of its energy transfer from the oxidative system. There is a “switchover point” at which an activity moves from anaerobic to aerobic, as seen in this interesting comparison.
- 200-meter run: 29% aerobic; 71% anaerobic
- 400-meter run: 43% aerobic; 57% anaerobic
- 800-meter run: 66% aerobic: 34% anaerobic
- 1500-meter run: 84% aerobic; 16% anaerobic
The primary muscle fiber types that contribute to aerobic exercise are the oxidative type I and type IIA fibers. As aerobic exercise is heavily oxygen dependent, training adaptations occur in order to support oxygen transport and delivery in these fibers. Specifically, aerobic exercise can increase the number and size of the blood vessels. This occurs through increased capillarization. Specifically, with aerobic training, there is a greater number of capillaries per unit of muscle. This allows for enhanced delivery of oxygen (fuel) to muscle cells, enhanced removal of CO2 and waste products, and the transfer of heat away from the muscle. In addition to enhanced oxygen delivery, there is an increase in the size and number of mitochondria along with greater myoglobin content within cells. While the greater capillarization leads to more oxygen transport, the greater myoglobin leads to increased muscle oxygen uptake, and the larger and more numerous mitochondria allow for greater oxygen use. Of course, in addition to these adaptations, the enzymes involved with aerobic energy transfer will adapt as well.
Let’s talk a bit about oxygen and the adaptations that occur with regular exercise.
After a full exercise session, or even after a single interval within an entire exercise session, the oxygen deficit that’s accumulated must be paid back. This means that after you’ve stopped exercising and the amount of mechanical work you’re doing is no different than you’d be doing at rest, you still continue to consume more oxygen. This period of increased oxygen consumption and energy demand has been called the period of oxygen debt or EPOC (excess post-exercise oxygen consumption). In essence, after exercise, the amount of oxygen consumed can be elevated for minutes to hours. This is due to the fact that the body must:
- a) metabolize additional nutrients,
- b) replenish the energy stores that have been used up, and
- c) reload the depleted oxygen stores in the muscle and blood.
In addition to these recovery-type activities, the following also contribute to the EPOC:
- Elevated post-exercise body temperature
- Increased activity of the heart and respiratory muscles
- Elevated levels of metabolism-boosting hormones
- Increased conversion of energy transfer products such as lactate into other substrates
- Increased protein synthesis
- Recovery of muscles stressed and damaged with the activity
It is important to note, however, that the energy systems do not work independently from one another. During various types of exercise, from aerobic to anaerobic, all three energy systems are activated. However, the extent to which they are activated, and the amount of ATP they regenerate relative to the total ATP regeneration required, determines the description of the activity. For example, during short-burst activity, the ATP–PCr system is most important. When immediate and explosive movement is desired, the brain initiates the contraction with a signal that’s passed along the nerves to the muscles. The muscles then contract, using ATP and depleting these immediate energy stores within a second or two. In order for the muscles to continue to contract, the resulting ADP and P must be regenerated to ATP.
Adaptations to Exercise.
In response to regular exercise training, whether anaerobic or aerobic, certain changes occur in the muscle. These changes improve the body’s ability to respond to similar exercise challenges in the future. Each of these processes is regulated by protein synthetic mechanisms initiated within our genetic material (our DNA). Cellular communication through hormones is intimately involved in this process. The hormone insulin, in the presence of adequate nutrient availability, encourages the stimulation of protein synthesis and a positive nitrogen balance. Insulin availability is greatest during well-fed conditions and during periods of energy surplus. Protein and amino acid intake is key here as protein-containing meals stimulate a positive protein status. In addition, hormones like testosterone and growth hormone have a stimulatory effect on muscle adaptation.
On the other hand, the counter-regulatory hormones such as glucagon, catecholamines, and glucocorticoids have a contradictory effect, promoting protein breakdown and a negative nitrogen balance. These hormones are released in large numbers during periods of fasting or energy deficit
Protein synthesis and exercise adaptation are also affected by:
- The amount of mRNA in our cells
- Ribosomal number
- Ribosomal activity
- Amino acid availability
- The hormonal environment
- Our native genetic code
Interestingly, even the process of recovering and adapting to our exercise training demands is metabolically costly. As proteins are degraded and amino acids re-synthesized into proteins, this process of protein turnover builds more functionally adapted enzymes, contractile units, etc. And this process accounts for between 10% and 25% of resting energy expenditure. Therefore, as you can see, not only does exercise increase total daily energy expenditure during the activity, it also increases post-exercise expenditure through two mechanisms. Energy expenditure is increased due to both the oxygen debt being paid back and to the increased protein turnover and synthesis just described.
Adaptations of anerobic exercise such as weight training and sprint training:
- muscle fibers both increase in size and in myofibrillar number
- mitochondrial size and number
- increases in myoglobin number
- increases in intracellular storage capacity and availability (such as stored glycogen)
- increases in intracellular glycogen storage can also contribute to muscle hypertrophy
- In addition to changes in muscle cross-sectional area, anaerobic exercise can enhance the activity of ATP–PCr system enzymes (creatine kinase, myokinase) and the glycolytic system enzymes (glycogen phosphorylase, phosphofructokinase).
These changes help to increase the rate of energy transfer within the muscle, allowing for more rapid responses to energy demands in the future.
Adaptations to aerobic exercise such as jogging, steady state cardio or swimming:
Please note, this type of lower-intensity, longer-duration activity primarily influences muscle quality (as opposed to muscle size).
- Enhancement of oxidative or mitochondrial enzyme activity
- Increase in intramuscular glycogen and triglyceride content
- Increase in blood volume due to increase uptake and delivery of aerobic activity- due to increase in red blood cell content and the oxygen-carry capacity of the body.
- Capillary density of trained muscles increases- meaning there will be a great number of capillaries per muscle fiber
- With this lengthened border between blood vessels and muscle fibers, oxygen delivery, carbon dioxide removal, waste removal, fuel delivery to muscle, and the transfer of heat are all amplified.
- Beyond this, the myoglobin content of skeletal muscles will increase, improving oxygen delivery across muscle cells
- Finally, the number and size of mitochondria are increased with aerobic activity of high enough intensity. This promotes greater oxygen utilization through the process of pyruvate, fatty acid, and ketone utilization through the Krebs cycle and electron transport chain
Additional benefits of both aerobic and anaerobic exercise training include:
- The attenuation of sympathetic nervous system activity.In essence, “stress” to the body with exercise is minimized over time, and therefore greater workloads are required to promote the same amount of adaptation.
- Greater insulin sensitivity.With exercise training, the body responds to carbohydrate intake with less insulin release, allowing insulin to act in carbohydrate update and protein synthesis without preventing fat loss/stimulating fat gain.
- Improved fatty acid uptake and transport.Another positive response to exercise training is that fats can be more easily mobilized from adipose tissue, transported, taken up, and broken down.
- Less lactate produced per intensity.At every intensity, less lactate will be produced. This is due to greater aerobic production of ATP at every intensity, lower catecholamine response, reduced carbohydrate metabolism, and changes in the isoenzymes of lactate dehydrogenase to forms that favor the conversion of lactate to pyruvate.
- More lactate removed per unit of intensity.At every intensity, more lactate will be removed. Increased rates of lactate removal are due to increased blood flow to the liver and enhanced uptake of lactate by cardiac and skeletal muscles.
- Better lactate tolerance.With training at the highest intensities, the body can better deal with high acid conditions and high levels of lactate. This means higher intensities can be achieved and sustained for short periods of time.
sympathetic nervous system: One division of the autonomic nervous system that is always active and provides sympathetic tone. Its activity increases during times of bodily stress.
So, what qualifies as “intense exercise”? Resistance training (strength training), interval training(through activities such as running, climbing, cycling, and rowing), circuit training, rope jumping, running hills, squat thrusts, plyometrics, explosive medicine ball work, explosive kettlebell exercises, and strongman activities are all high-intensity activities.
Basically, high-intensity activity includes any physically demanding task that:
- a) incorporates many muscle groups, and
- b) is done near your maximum heart rate.
The high-intensity activities listed above require a maximum of muscle activity, which leads to high amounts of cellular stress and the need for muscle adaptation. It’s this muscle stress and adaptation that brings about the maximum number of benefits, including increased protein turnover, muscle preservation and building, a high energy cost, and even cardiovascular benefits.
However, as important as exercise is to this process, nutrition is equally critical.
Firstly, nutritional status can impact energy transfer. Therefore, a good nutrition program will help facilitate top performance of each of the energy systems: ATP–PCr, glycolysis, and oxidative phosphorylation. Both macronutrients and micronutrients are important here.
A sub-optimal nutritional intake can reduce enzyme efficiency (due to deficiencies of co-enzymes and co-factors) and lead to substrate deficiencies. And this means poor exercise performance and fewer calories burned both at rest and during exercise. So much for the metabolic and muscle preserving and building benefits of exercise. In addition, with an inadequate intake of dietary protein and fat, amino acid availability and the ratio of anabolic to catabolic hormones can be compromised. This can lead to an inability to build and preserve muscle mass, even in the face of a solid exercise program.
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