1. NTR 644- Advanced Metabolism:
Carbohydrates and Lipids -
Metabolic Syndrome Case Study
Presented By: Emily Apitz, Erin Burke, Therese Hrncirik, Nicole Rieman
2. Outline
• Introduction of metabolic syndrome
• Case presentation of Bill
• Literature review and metabolic concerns
• Disease pathophysiology and biochemistry
• Carbohydrate metabolism
• Lipid metabolism
• Nutrition recommendations
3. Introduction: MetS
• Metabolic Syndrome (MetS) is a cluster of
conditions that occur together increasing
the risk of heart disease, stroke, and
diabetes
– Hypertension
– Hyperglycemia
– Visceral adiposity
– Dyslipidemia
Bello-Rodrieguez BM, 2013; Ross AC, 2014 ; Lakka H, 2002.
4. Underlying Risk Factors of MetS
• Causes
o Obesity and physical inactivity
o Insulin resistance
o Age
o Race
o Gender
o Gestational Diabetes
Kaur J, 2014; Bello-Rodrieguez BM, 2013; Valizadeh M, 2015;
Nsiah K, 2015; Regitz-Zagrosek V, 2006, Deboer M, 2011) Medscape.org/viewarticle/558472
5. Symptoms
• Similar to Diabetes
– Increased thirst
– Increased urination
– Fatigue
– Blurred vision
Clark N, 2007
6. Case Study: Bill S.
Image retrieved from http://www.dynamicchiropractic.com/content/images/metabolic_syndrome__1_1_2019.jpg.
Accessed July 7, 2015.
7.
8. Bill S: Diagnostic Laboratory and
Anthropometric Presentation
1. Jialal I. ACJP, 2009
2. Rosendorff et al. Journal of the American Society of Hypertension, 2015.
3. Ross AC, Modern Nutrition in Health and Disease, 2014.
9. Image available at http://www.nhlbi.nih.gov/health-pro/guidelines/current/obesity-guidelines/e_textbook/txgd/4142.htm. Accessed August 4, 2015
10. Bill’s Metabolic Concerns
Image retrieved from
http://atvb.ahajournals.org/content/32/9/2052/F1.l
arge.jpg. Accessed July 6, 2015.
11. Bill’s Main Metabolic and
Nutritional Issues
Image retrieved from http://www.microbiota-
therapeutics.umn.edu/assets/img/metabolic-syndrome.png. Accessed July 6,
2015.
12. Literature Review to Support Metabolic
Syndrome Case Recommendations
Article Subjects Study Design Results Conclusion
Suliga E, Koziel D, Ciesla
E, Gluszek S.1
2,479 men and women
ages 37-66 with a normal
BMI (18.5-25 kg/m2)
Cross-Sectional Study Those who ate the
healthiest diet had the
lowest odds ratio for
metabolic obesity and
HDL levels
A diet that consists of fish
and whole grains in
addition to a low intake of
refined grains, sugar,
sweets, and cold meat is
connected to lower levels
of metabolic syndrome.
Von Bibra H, Wulf G, St
John Sutton M,Pfutzner,
Schuster T, Heilmeyer P.2
32 overweight men and
women between the ages
of 30-70 with type 2
diabetes
Prospective, controlled,
matched pair parallel arm
with a cross-over study for
comparison of 2 diets
Both those who followed
the LC and the LF diets
experienced significant
reductions in weight,
HgA1C and cholesterol.
The LC diet resulted in
improved insulin
resistance, fasting and
postmeal triglycerides,
blood pressure, and
cardiac function.
Proinsulin remained intact
with the LF diet.
LC but not LF diets can
improve cardiac function
in overweight type 2
diabetic patients and
improve insulin
resistance. This may
prevent or delay a future
diagnosis of metabolic
syndrome and the onset
of diabetic
cardiomyopathy.
Ionela & Georgescu3
12 Men and 18 women
ages 30-60
Retrospective 10 month
Correlation Study
Reverse correlation
between healthy lifestyle
and MetS
Most valuable treatment
for MetS focuses on
sustained behavior
change and increased
physical activity
13. Literature Review:
Metabolic Needs to Manage Case
• General Dietary Recommendations
– 1600-1800 kcal intake per day
– 55% carbohydrates of mixed glycemic index
– 20% low-fat protein
– 25% fat
• 10-15% of which is mono-unsaturated fat
Von Bibra, IJC Metabolic & Endocrine, 2014
14. Literature Review:
Exercise Needs to Manage Case
• Exercise at a low to moderate intensity
daily in order to burn at least 200-400 kcal
per day
Dragusha, Bosn J Basic Med Sci, 2010.
Image retrieved from https://cdn.psychologytoday.com/sites/default/files/styles/article-inline-
half/public/blogs/102616/2014/08/157864-161988.jpg?itok=3xnP0lj0. Accessed July 6,
2015.
15. Working Diagnosis: Metabolic Syndrome
Management of the Case
• Low-carbohydrate/high protein diet
• Increased exercise
• Medication management if needed
Von Bibra et al. IJC Met & End. 2014; Iolena et al. Procedia Soc & Bev Sci. 2013; Dragusha et al. J Basic Med Sci. 2010
16. Biochemical Pathophysiology:
Insulin Resistance
• Decreased GLUT4 activity in muscles
• Causes excess secretion of insulin from
pancreatic beta cells
• Can lead to many metabolic dysregulations.
– Inhibits lipolysis in adipose
– Prevents glucose production in liver
– Stimulates glucose disposal in muscle
• IR leads to increased
risk of developing DM
Petersen KF, Am J Med, 2006; Ross AC, 2014.
19. Biochemical Pathophysiology: Obesity
• Results from increased energy
consumption, lack of exercise, and
neurohormonal dysfunction
• Increased energy consumption alters
function of adipocytes
• Fatty acid oxidation begins to decline
• Releases large amounts of fatty acids
• Decrease in perilipin synthesis
• Increase in lipolysis
Lieberman et al. 2009.
20. http://scientopia.org/
Biochemical Physiology: Obesity - Gut-brain signaling
Neural and endocrine signals from and to the brain and gut affect energy expenditure via the autonomic nervous system and the
vagus nerve.
Beezhold B. Benedictine University.
23. Biochemical Pathophysiology:
Hypertension
• Non-insulin resistant setting
– Insulin is a vasodilator
– Secondary effects on sodium reabsorption in
the kidney
• Insulin resistant setting
– Vasodilatory effect of insulin can be lost
– Secondary renal effect preserved
– Fatty acids can cause vasoconstriction
Eckels RH, Lancet. 2010
29. Carbohydrate Metabolism in the Fed State
GLYCOLYSIS
•Upregulated when ATP
is low and cells need
energy
GLYCOGEN SYNTHESIS
•Muscle and liver will
store glucose when ATP
is high
Both happen in the
cytosol and upregulated
by insulin
Image-TutorVista, 2015
38. Medical Nutrition Therapy for Bill
• Because Bill says that “diets don’t work and are hard to
control,” the RD needs to emphasize that he is not going
on a “diet”
• Rather, changing eating habits and making overall
lifestyle changes will need to be maintained long term.
• There isn’t a quick fix to resolve/control metabolic
syndrome.
39. Medical Nutrition Therapy for MetS
• The following slides contain information
regarding other diet plans that have been
studied to help with MetS and/or certain
components of the disorder
– DASH
– Mediterranean
– Low Carb
• Physical activity is also mentioned
as a lifestyle/behavior change to
aid in weight loss
40. DASH Diet
• DASH diet has been shown to
reduce blood pressure2
• Because hypertension is one
component of MetS, Hikmat et
al studied the DASH diet in
subjects with MetS (n=99)3
– Results: the DASH diet lowered BP
(-4.9/-1.9) in patients with MetS3
• DASH diet has also been shown
to prevent osteoporosis, cancer,
heart disease, stroke, and
diabetes as well as reducing
cardiometabolic risks in DM24
1. Image-Sabitoni, AE, 2014.
2. Chobanian AV, Hypertension, 2003.
3. Hikmat F, J Human Hypertension, 2014.
4. Azadbakht L, Diabetes Care, 2011.
41. Mediterranean Diet
• Mediterranean diet can “reverse” MetS1
– Of the 3392 participants with MetS at
baseline, 958 reversed the condition (28.2%)
after 4.8 years
– Participants were able to reduce obesity and
lower fasting blood glucose
• Following the Mediterranean diet can also
lessen risk of CVD, heart attack, stroke,
and pulmonary embolism2
1. Babio N, CMAJ, 2014.
2. Hoevenaar-Blom MP, PLoS ONE, 2012.
42. Low Carbohydrate Diet
• Newer research is showing that low carb diets
can prevent CVD (n=148)1
• Comparing a low fat diet (<30% total calories) to
a low carb diet (~30% total calories), Bazzano et
al found that the low carb diet had greater mean
difference in change of the measured variables:
– Weight loss (-3.5 kg, p=0.002)
– Fat mass (-1.5%, p=0.011)
– Ratio of total:HDL (-.44, p=0.002)
– Triglycerides (-14.1 mg/dL, p=0.038)
– HDL (+7 mg/dL, p<0.001)
– CRP (-15.2 nmol/L, p=0.024)
1. Bazzano LA, Ann Intern Med, 2014.
43. Physical Activity
• Research review of 13 investigations and 2 review
articles for consensus of physical activity guidelines1
• Any exercise is better than no exercise but these are
the recommendations:
– 30 mins/day 5 days/week (helps to increase HDL)
– At least moderate intensity aerobic exercise (high intensity is
needed to reduce LDL and TG)
– Increased calorie expenditure positively influences LPL
enzyme activity
– High weight/low reps weight lifting can
be more impactful compared to low
weight/high reps
1. Mann S, Sports Medicine, 2013.
44. Recommendations for Bill
• Based on the research on the previous
slides, overall recommendations for Bill:
– Choose healthy fats (MUFAs), not low fat1
– Fruits, vegetables, whole grains, legumes, nuts1,2
– Lower sodium content in food choices1,2
– Reduce overall CHO intake3
– Alcohol consumption in moderation1
– Exercise 30 mins/day, at least 5 days/week
and incorporate cardio and weight lifting4
1. Hoevenaar-Blom MP, PLoS ONE, 2012.
2. Chobanian AV, Hypertension, 2003.
3. Bazzano LA, Ann Intern Med, 2014
4. Mann S, Sports Medicine, 2013.
45. Summary
• MetS is a cluster of conditions that when
presented together increase the risk of
heart disease, stroke, and diabetes
• Bill presents with risk factors for MetS
• MNT for Bill includes recommendations for
a low-carbohydrate/high protein diet, low
salt intake, and increased exercise.
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Editor's Notes
In a study of Finnish men it was found that the highest risk associated with MetS was for cardiovascular disease and all cause mortality (Lakka et al, 2002).
Characteristics include (need 3 of the 5):
High blood pressure: Systolic Blood Pressure (BP) of &gt; 130 mmHg or diastolic BP of &gt; 85 mmHg
High blood glucose: Fasting blood glucose of &gt; 100 mg/dL
Abdominal obesity: Waist Circumferance (WC) &gt; 40” in men WC &gt; 35” in women
Abnormal lipid levels: Triglyceride (TG) level of &gt; 150 mg/dL
Low High density lipid (HDL): &lt; 40 mg/dL in men
&lt; 50 mg/dL in women
MetS is mostly caused by obesity and physical inactivity. Obesity has been shown to increase the risk of MetS almost 6 times, as was seen in one study by Nsiah K, et al. (2015). Physical inactivity leads to an imbalance in kcalories in (dietary consumption) vs. kcalories out (physical exercise). When the calories consumed is higher than the calories burned through physical exercise the body will have excess lipid levels and accumulate fat which can lead to obesity, among other health risks.
Apple shape and Pear shape in abdominal obesity have higher risk because of the visceral adiposity associated with these shapes.
Insulin resistance (IR) has been associated with the primary underlying cause of MetS, characterized by large amounts of adipokines (involved in the regulation of inflammatory responses) and the production of abnormal adipocytokines such as interleukin-1 (IL-1), IL-6, leptin (an adipokine) , and adiponectin (Kaur J, 2014; Bello-Rodrieguez BM, 2013 ). IL-1 and IL-6 are both macrophage-derived cytokines associated with inflammation (Ross AC, 2014). Adiponectin plays a role in the modulation of glucose and lipid metabolism.
There are two things influencing the development of T2D; genetic predisposition and lifestyle. IR causes increased insulin secretion and reduced hepatic insulin clearance. This results in hyperinsulinemia. Insulin plays an important role in the regulation of lipid metabolism and studies have shown that IR subjects had greater VLDL and plasma insulin concentrations, which could result in dyslipidemia and hypertension (HTN) (Ross AC , 2013).
Age has been associated with MetS because of the lack of physical activity and proper nutrition: 40% of people over the age of 60 have MetS.
Race has been associated with Mets; Hispanics and non-Hispanic white populations show a greater prevalence of Mets in one study that used a pediatric adaptation of the Adult Treatment Panel III definition of MetS. Hispanics were at 12.9% of the male population and 9.4 in the female population; Non-Hispanic White were at 11.8% in the male population and 5.8% in the female population. These were relative to Non-Hispanic Black at 3.9% and 4.2% in males and females, respectively (Deboer M, 2011).
Gender can be a cause as men have a greater risk than women. This was shown in a 2006 study on the gender differences in MetS. There was a higher prevalence of MetS reported in men than in women in Europe with a very consistent finding worldwide (Regitz-Zagrosek V et al, 2006).
Gestational diabetes in pregnant women increases the risk of MetS. Gestational diabetes is an impaired glucose tolerance that women experience during pregnancy and is a risk factor for Type 2 Diabetes (T2D). Women with a history of Gestational Diabetes have a seven-fold higher risk for T2D (Valizadeh M, et al. 2015).
Most do not have symptoms, except for possible signs and symptoms of diabetes such as increased thirst and urination, fatigue, and blurred vision. These symptoms are highly associated with the diagnosis of Type 2 Diabetes. Slow healing wounds and reoccurring infections may also be seen as warning signs for T2D. The onset of these symptoms may be more gradual and less noticeable for T2D, so many times is it not caught early on.
Bill S. presents to his clinician as a reported “type A” personality who believes that diets don’t work. He reports he struggles to control his diet, and currently weighs 285 pounds and is of 70 inches tall.
The diagnosis of metabolic syndrome requires 3 of 5 clinical findings: abdominal obesity, elevated triglycerides (TG), low levels of high-density lipoprotein (HDL-C), elevated blood pressure, and impaired glucose metabolism/insulin resistance. (JIALAL)
Bill S. presents with abnormal laboratory and clinical data in 5 out of the 5 metabolic diagnostic categories. Usually, men should have a waist measurement less than 40 inches. However, Bill’s waist circumference measures at 42 inches, and in conjunction with his BMI of 40.9 kg/m2, his elevated waist circumference put him at a heightened risk for type 2 diabetes, dyslipidemia, hypertension, and CVD. Typically, as waist measurements decrease patient’s risk for further complications decline as well. JIALAL
Those patients who have elevated blood pressure levels, the American Society of Hypertension recommends blood pressure targets &lt;130/80. Bill’s blood pressure of 178/90 puts him at an elevated risk for a heart attack, stroke, or other coronary morbidities. His high blood pressure could result from his high stress levels, obesity, or hypercholesterolemia. (ROSENDORFF)
Typically, fasting blood glucose levels should be less than 100 mg/dL. (JIALAL) Over time, elevated blood glucose levels can impact glucose tolerance and indicate lead to insulin resistance if damage to the beta cells in the pancreas occurs. If not controlled, continuous blood glucose levels over 125 can lead to diabetes (JIALAL; ROSS)
Triglyceride levels of 150 mg/dL result from increased production, reduced clearance, or a combination of both factors. Often, insulin resistance can elevates the release of free fatty acids, and in response, apolipoprotein-B-100 increases as well. VLDL-TG will subsequently rise, and in turn, transport both HDL-C and VLDL molecules from the body. This leads to a decrease in HDL-C as well as an increase in the remaining TG left in the blood. (ROSS)
References:
Jialal I. The role of the laboratory in the diagnosis of the metabolic syndrome. ACJP. 2009;132:161-162.
Rosendorff C, Lackland D, Allison M, Aronow WS, Black H, Blumenthal RS, Cannon CP, de Lemos JA, Elliott WJ, Findeiss L, Gersh BJ, Gore JM, Levy D, Long JB, O’Connor CM, O’Gara PT, Ogedegbe O, Oparil S, White WB. Treatment of hypertension in patients with coronary artery disease. Journal of the American Society of Hypertension. 2015; 9(6): 453-498. Available at : http://ajcp.ascpjournals.org/content/132/2/161.full. Accessed July 19, 2015.
Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR. Modern Nutrition in Health and Disease, (11th ed). Baltimore, MD: Lippincott Williams & Wilkins; 2014.
Bill’s BMI of 40.9 kg/m2 categorizes him as obesity class III. This in combination with his waist measurement of 40 inches places him at an extremely high risk of adverse health outcomes, including type 2 diabetes, hypertension, and CVD. Even though Bill currently has a BMI of 40.9 kg/m2, regardless of BMI value, men with a waist circumference greater than 40 inches are placed at higher risk of disease. (NIH)
National Heart, Lung, and Blood Institute, Guidelines on Overweight and Obesity: Electronic Textbook. Available at http://www.nhlbi.nih.gov/health-pro/guidelines/current/obesity-guidelines/e_textbook/txgd/4142.htm. Accessed August 4, 2015.
Bill’s family history of diabetes, cardiovascular disease, and hypertension put him at an increased risk for health issues later in life. His current hyperglycemia indicates that his body does not metabolize all of the sugar that he ingests, and indicates that he may suffer from impaired glucose metabolism. In addition, his hypertriglyceridemia and hypercholesterolemia may show a decline in his ability to metabolize the amount of fat that is in his food properly.
Reference:
Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR. Modern Nutrition in Health and Disease, (11th ed). Baltimore, MD: Lippincott Williams & Wilkins; 2014.
Bill’s diet directly impairs his insulin sensitivity and puts him at risk for obesity, diabetes, and high cholesterolemia. His obese stature, evidenced by his increased waist circumference and high BMI could be a result of hyper-caloric diet and/or impaired energy expenditure. His obesity, as evidenced by his increased waist circumference and high BMI, may be a result of an altered nutrition status. Typically, hypercaloric diets in addition to reduced energy expenditure can lead to altered metabolic processes that result in decreased insulin sensitivity.
Over time, increased blood sugar can lead to insulin resistance, and the body cannot effectively transport glucose into the cell during the fed state. Without insulin to trigger GLUT-4 to bring glucose into the muscle, blood sugar levels rise, but the body cannot effectively utilize or store it for energy via glycolysis or glycogen synthesis.(ROSS)
However, during the fasting state, glycogenolysis and gluconeogenesis remain unaltered. If the body does not receive ingested sugars, and also has a delayed insulin response, glucagon levels will rise and trigger gluconeogenesis and glycogenolysis. Glycogen stores begin to break down and the body now has extra circulating glucose that cannot be transferred into the cells. (ROSS)
Reference:
Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR. Modern Nutrition in Health and Disease, (11th ed). Baltimore, MD: Lippincott Williams & Wilkins; 2014.
Association between dietary patterns and metabolic syndrome in individuals with normal weight: A cross-sectional study1
A study by Suglia et al. determined that a diet similar to the DASH diet, or one high in fish and whole grains and lower in refined sugars, sweets, and cold meats, lowered the risk of metabolic syndrome and low HDL values, and also improved glucose control. The cross-sectional study evaluate the eating habits, anthropometric measurements, blood pressure, total cholesterol, triglycerides, and glucose levels of 2,479 men and women between the ages of 37-66. During the intervention, participants completed an historical questionnaire which ascertained how often on average they consumed certain food groups over the past year. Out of the responses, men and women fell into one of four categories: “Healthy diet”, “fat meat and alcohol diet,” “prudent diet”, and the “Coca-Cola, hard cheese and french fries” diet. A “healthy diet” consisted of fruits and vegetables, low fat milk, and whole grain foods, whereas the “fat, meat and alcohol” diet correlated with consumption of lard, red meat, cured cold meats, eggs, fried dishes, vegetable oils, mayonnaise, and alcoholic drinks. The prudent diet contained contained fish and whole grains, but also consisted of intake of sweets, cold cured meats, refined grains, and boiled potatoes. Finally, the “Coca-Cola” dieters tended to eat hard cheese and french fries.
Those who fell in the “healthy” category were primarily older women, non-smokers, held a university education, lived in cities, and tended to be physically active. The “red meat and alcohol” women had the lowest levels of education, and men had the youngest groups of representatives. Women tended to follow the “prudent diet” more often than men, and had higher levels of SES, and education. Those of the lowest SES tended to follow the “Coca-Cola” diet due to the higher cost of healthy food and/or poor access to health food. Those who also had diets high in fat, meat, alcohol, Coca-Cola, hard cheese and french fries also had lower HDL levels, higher fasting glucose and triglyceride values, and higher blood pressure than their prudent or healthy counterparts.
Low carbohydrate/high protein diet improves diastolic cardiac function and the metabolic syndrome in overweight-obese patients with type 2 diabetes2
A 2014 study by von Bibra et al. indicates that a low carbohydrate diet with high amounts of protein improves insulin resistance and may prevent or delay cardiomyopathy in patients with metabolic syndrome. Researchers studied 2 matched groups of men and women who had type 2 diabetes between the ages of 45-60 years of age. In a partial cross-over design, participants followed either a low-carbohydrate or low-fat diet for two weeks followed by the other diet (either low-carbohydrate or low-fat) for 2 weeks. Heart function was assessed before and after a standardized breakfast. Researchers found that both diets produced similar changes to HgA1C levels and cholesterol values. However, the low-carbohydrate diet resulted in greater changes in insulin resistance, post-meal triglyceride values, blood pressure, and diastolic cardiac function. Post-meal insulin levels remained unchanged for the low-fat group.
A correlational study of the relationship between lifestyle knowledge and metabolic disorders3
Ionela and Georgescu studied 30 adults (18 women and 12 men) with an average age of 56.4 years who had a history of or were susceptible to metabolic syndrome. During a series of structured interviews, participants discussed their participation within 5 domains associated with metabolic syndrome. The lifestyle factors addressed included healthy behavior, free time physical activity, vigorous physical activity, health and wellbeing, and nutrition. They also tested the participant’s weight, height, BMI, abdominal circumference, gluteus circumference, basal glucose readings, cholesterol, and blood pressure. Results showed that lifestyle factors can influence behavior interventions, and interventions are most successful when determined by the individual affected. They also concluded that lifestyle changes in the presence of 2 or more risk factors can result in reverse unhealthy lifestyle habits and decrease the presence of metabolic syndrome. In the end, both men and women who were more active had lower metabolic syndrome scores.
References:
1. Suliga E, Koziel D, Ciesla E, Stanislaw G. Association between dietary patterns and metabolic syndrome in individuals with normal weight: a cross-sectional study. Nutrition Journal, 2015;14(55). Doi 10.1186/s12937-015-0045-9.
2. Von Bibra H, Wulf G, St John M Sutton M, Pfutzner A, Schuster T, Heilmeyer P. Low-carbohydrate/high protein diet improves diastolic cardiac function and the metabolic syndrome in overweight-obese patients with type 2 diabetes. IJC Metabolic & Endocrine. 2014;11-18.
3. Iolena M, Tudor, Luminita, Georgescu. A correlational study of the relationship between lifestyle knowledge and metabolic disorders. Procedia Social and Behavioral Sciences. 2013; 76:842-847.
The low-fat diet consisted of a caloric intake of 1600-1800 kcal/day, 55% of which came from carbohydrates of mixed glycemic index foods, 20% from low-fat protein, and 25% from fat, 10-15% of which was mono-unsaturated fat. Participants were encouraged to eat fruits, vegetables, and whole grains. This diet improvements in weight management, glucose and cholesterol control for obese men and women at risk for metabolic syndrome.
The non-ketogenic, low-carbohydrate diet with free access to vegetables, salads, fruits, protein, and plant sources of fat and participants averaged an intake of 1600-1800 kcal/day. The carbohydrates available had low-glycemic index scores, and the diet resulted in an average intake of 25% carbohydrates, 30% protein, 45% fat, which included 25% of the mono-unsaturated and 10% of the polysaturated fats. This diet not only improved weight management, glucose and cholesterol control for men and women at risk for metabolic syndrome, but also showed significant improvements in insulin resistance, fasting and post meal triglycerides, blood pressure, and diastolic heart function.
Reference:
Von Bibra H, Wulf G, St John M Sutton M, Pfutzner A, Schuster T, Heilmeyer P. Low-carbohydrate/high protein diet improves diastolic cardiac function and the metabolic syndrome in overweight-obese patients with type 2 diabetes. IJC Metabolic & Endocrine. 2014;11-18.
Two hours of a daily low-intensity exercise training program remained the same for all patients, 2 hours daily can burn an average of 200-400 kcal per day from exercise . (VON BIBA) This level of exercise can decrease waist circumference, reduce BMI, triglycerides, blood pressure, and blood glucose levels, and improve HDL-C values. (DRAGUSHA) This metabolic change can improve symptoms associated with metabolic syndrome and implies that physical activity a necessary component of metabolic syndrome treatment.
Dragusha G, Elezi A, Dragusha S, Gorgani D, Begolli L. Treatment benefits on metabolic syndrome with diet and physical activity. Bosn J Basic Med Sci. 2010;10(2):169-76.
As obesity remains a a significant risk factor for metabolic syndrome, weight loss via a hypocaloric diet, increased exercise, and medication if lifestyle changes are not successful are warranted. A diet high in fish, whole grains, and low in refined grains, sugar, sweets, and cold cured meat can lower the risk for metabolic syndrome, low HDL levels, and increased glucose concentration. (SULIGA) Specifically, a diet low in carbohydrates, but high in protein can not only aid in weight loss efforts, but impact insulin sensitivity. This type of diet also has the potential to improve heart function, and reduce the risk of heart failure, in those with metabolic syndrome and diabetes. (BIBRA)
In addition, exercise remains a fundamental therapy necessary to control metabolic syndrome. (DRAGUSHA) Those who were physically active tend to have lower metabolic risk scores. Knowledge about the benefits of physical activity and nutrition as strategies to treat metabolic syndrome often have an inverse relationship with adverse metabolic outcomes. (Iolena). Finally, if lifestyle changes are not effective, medication management to aid in weight loss efforts, blood pressure, and/or cholesterol control may be the only option. (Ross)
References:
Suliga E, Koziel D, Ciesla E, Stanislaw G. Association between dietary patterns and metabolic syndrome in individuals with normal weight: a cross-sectional study. Nutrition Journal, 2015;14(55). Doi 10.1186/s12937-015-0045-9.
Von Bibra H, Wulf G, St John M Sutton M, Pfutzner A, Schuster T, Heilmeyer P. Low-carbohydrate/high protein diet improves diastolic cardiac function and the metabolic syndrome in overweight-obese patients with type 2 diabetes. IJC Metabolic & Endocrine. 2014;11-18.
Iolena M, Tudor, Luminita, Georgescu. A correlational study of the relationship between lifestyle knowledge and metabolic disorders. Procedia Social and Behavioral Sciences. 2013; 76:842-847.
Dragusha G, Elezi A, Dragusha S, Gorgani D, Begolli L. Treatment benefits on metabolic syndrome with diet and physical activity. Bosn J Basic Med Sci. 2010;10(2):169-76.
“Novel investigational techniques based on magnetic resonance spectroscopy (MRS) have allowed real-time insight into the molecular defects in patients with type 2 diabetes, revealing that insulin resistance is a product of decreased insulin-stimulated skeletal muscle glycogen synthesis, which can mostly be attributed to decreased insulin-stimulated glucose transport (Glut 4) activity.” Petersen, Am J Med, 2006
Free fatty acids (FFA) are released from adipose tissue mass (HSL) into circulation. In the liver, the FFAs, increase the production of glucose, triglycerides and very low-density lipoprotein (VLDL). In the muscle, FFA inhibit insulin-mediated glucose uptake. Increases in circulating glucose and FFA in the bloodstream increase beta cell production/workload and leads to hyperinsulinemia. Hyperinsulinemia increases sodium reabsorption and sympathetic nervous system leading to hypertension. (ECKELS)
Reference
Eckels RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005; 365: 1415-1428.
Insulin resistance is associated with increased circulating free fatty acid, and can lead to disorders in intracellular pathways after insulin binding to receptors, hormones secreted from adipose tissues, hypothalamus-hypophysis-adrenal axis, excessive accumulation of fat, and environmental/genetic factors.1
Intracellular pathways: Insulin activates tyrosine kinase at the cell’s surface, which phosphorylates insulin receptor substrate-1 (IRS-1) at tyrosine residue-896 (Tyr896) and is a necessary step in insulin stimulation of translocation of GLUT4 to the cell surface.2 Muscle IRS-1 can also be phosphorylated at six other sites; however, hyperphosphorylation of Ser636 reduces the insulin signal and decreases the translocation of GLUT4.2 Therefore glucose builds up in the blood stream as evidenced by the biomarker elevated fasting blood glucose.
Molecular mechanisms of insulin signalling. Important insulin signalling pathways in various cell types. IR indicates insulin receptor; LDLR, low–density receptor; MHC, myosin heavy chain; mTORC1, mammalian target of rapamycin complex 1; PCSK9, proprotein convertase subtilisin/kexin type 9; PKA, protein kinase A; TNF, tumor necrosis factor-α; IRS-1, insulin receptor substrate-1; SREBP-1c, sterol regulatory element binding protein-1c; eNOS, endothelial nitric oxide synthase; VCAM-1, vascular cell adhesion molecule-1; FoxO, Forkhead box, class O; IL, interleukin-6; P13K, phosphatidylinositol 3-kinases; ER, endoplasmic reticulum.
References:
Aydin S, Aksoy A, Aydin S, Kalayci M, et al. Today’s and yesterday’s of pathophysiology: Biochemistry of metabolic syndrome and animal models. Nutrition. 2014; (30) 1-9.
Stuart CA, Howell MEA, Cartwright BM, McCurry M, et al. Insulin resistance and muscle insulin receptor substrate-1 serine hyperphosphorylation. Physiological Reports. 2014; 2(12): 1-7. doi: 10.14814/phys2.12236
Original artwork by Leah A. Klein.
Weight reduction leads to a decline of the size of the adipose cells, not the number. Changes in diet can alter growth factors if the fat cells increase into early adulthood. After weight loss, the amount of lipoprotein lipase increases, which makes it difficult for obese people to lose weight. (MARKS)
Factors that affect energy homeostasis include: neural signals resulting from mechanical gut distention and chemical stimulation after consumption of nutrients orally, blood signals related to body energy stores, hormones and neurotranmitters ciculating in the blood. (BEEZHOLZ)
An overabundance of circulating fatty acids derived from adipose tissue triglyceride (TAG) stores released through the action of the cyclic AMP-dependent enzyme hormone sensitive lipase (HSL) contribute to insulin resistance by inhibiting insulin receptors and downstream signaling in insulin sensitive cells and tissues. (ECKELS)
Perilipins are adipocyte phosphoproteins that bind to triacylglycerol droplets. They regulate the accessibility of triglycerides to the lipases, and help to control the amount of fat stored in the body.
Fatty acid oxidation declines secondary to high circulating levels of insulin and low levels of glucagon. Glucagon stimulates hormone sensitive lipase (HSL) which release fatty acids for mitcohondrial beta oxidation.
Fatty acids are also derived through the lipolysis of triglyceride-rich lipoproteins in adipose tissues by the action of lipoprotein lipase. (ECKELS)
Alteration of hunger and satiety signals may cause and/or result from obesity. Damage to the psychologic and hormonal factors can lead to overeating obesity if the ventromedial center occurred, and anorexia and weight loss may happen if the destruction occurred in the lateral hypothalmic region, and results in impaired secretion of leptin and glucagon-like peptide-1 (GLP-1).
Obesity is a causative factor of Metabolic Syndrome; however those of normal weight may still experience insulin resistance. (AGANOVIK) Those who carry their weight in the visceral regions tend to have more trouble due to the influx of adipose-tissue derived fatty acids and increased lipogenesis.
Reference:
Lieberman M, Marks AD. Basic medical biochemistry: A clinical approach (3rd ed). Philadelphia, PA: Lippincott Williams & Wilkins; 2009.
Aganovic I, Dusek T. Pathogenesis of metabolic syndrome. International Federation of Clinical Chemistry and Laboratory Medicine. Available at Obesity is a causative factor of Metabolic Syndrome. (AGANOVIK)
Eckels RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005; 365: 1415-1428.
The autonomic nervous system transmits signals from peripheral organs to the CNS, and after integrating these signals, the brain can alter sympathetic and parasympathetic tone to regulate peripheral metabolism via autonomic neuronal pathways and directly alter target organ function. The autonomic nervous system’s parasympathetic nerves are mediators of digestion and absorption. The sympathetic nerves are stimulated with stress and activity and can inhibit digestion and absorption. The vagus nerve mediates gut peptide signaling which stimulates feeding or inhibits feeding for individual meals or over a longer time period. The Tehrani article describes gut-brain communication and the role of microbiota in energy balance.
Factors that affect energy homeostasis include: neural signals resulting from mechanical gut distention and chemical stimulation after consumption of nutrients orally, blood signals related to body energy stores, hormones and neurotranmitters ciculating in the blood. (BEEZHOLZ)
Alteration of hunger and satiety signals may cause and/or result from obesity. Damage to the psychologic and hormonal factors can lead to overeating obesity if the ventromedial center occurred, and anorexia and weight loss may happen if the destruction occurred in the lateral hypothalmic region, and results in impaired secretion of leptin and glucagon-like peptide-1 (GLP-1).
Reference:
Beezhold B. Homeostatic regulation [Power Point Lecture]. Benedictine University. Accessed August 5, 2015.
When the rate of fatty acid release from the triacylglycerol pool exceeds the rate of fatty acid removal, high cytosolic concentrations of unbound fatty acids develop, which induce mitochondrial damage. This results in a decline in the capacity to remove fatty acids and the release of large amounts of fatty acids into the circulation. Unless these are removed by muscle activity they form ectopic triacylglycerol deposits and induce whole-body insulin resistance and beta cell damage.
Reference
Maassen JA, Romijn JA, Heine RJ. Fatty acid-induced mitochondrial uncoupling in adipocytes as a key protective factor against insulin resistance and beta cell dysfunction: a new concept in the pathogenesis of obesity-associated type 2 diabetes mellitus. Diabetologia. 2005; 50(10): 2036-2041.
Insulin also works as a vasodilator in people of normal weight, and also acts to increase sodium re-absorption in the kidney. Insulin resistance impairs this function and leads to impairment of vasodialation; however, sodium reabsorption remains unchanged. This influx of sodium in addition to vasoconstriction mediated by serum flatty acid contributes to the development of hypertension.
Reference:
Eckels RH, Alberti KGMM, Grundy SM, Zimmett PZ. The metabolic syndrome. Lancet. 2010; 375(9710): 181-183. doi:10.1016/S0140-6736(09)61794-3.
Steps in β-oxidation: oxidation, hydration, oxidation, cleavage.
Oxidation: A fatty acyl-CoA is oxidized by Acyl-CoA dehydrogenase to yield a trans alkene. This is done with the aid of an [FAD] prosthetic group.
Hydration: The trans alkene is then hydrated with the help of Enoyl-CoA hydratase.
Oxidation: The alcohol of the hydroxyacly-CoA is then oxidized by NAD+ to a carbonyl with the help of Hydroxyacyl-CoA dehydrogenase.
Cleavage: Acetyl-CoA is cleaved off with the help of Thiolase to yield an Acyl-CoA that is two carbons shorter than before. The cleaved acetyl-CoA can then enter into the TCA and ETC because it is already within the mitochondria.
Reference
Benson D. Beta-Oxidation. US Davis website. http://chemwiki.ucdavis.edu/Biological_Chemistry/Metabolism/Beta-Oxidation. n.d. Accessed August 6, 2015.
Two molecules of acetyl CoA combine to form acetoacetyl CoA
Acetoacetyl CoA condenses with a third acetyl CoA to form hydroxymethylglutaryl CoA (HMG CoA)
HMG CoA reductase reduces HGM CoA to form mevalonate
Mevalonate produces isoprene units that condense to form squalene
Squalene forms a cyclical shape and through a number of reactions becomes cholesterol
Increase in acetyl CoA leads to increased triglycerides. Inactivity leads to low HDL levels.
Reference:
Lieberman M, Marks AD. Basic medical biochemistry: A clinical approach (3rd ed). Philadelphia, PA: Lippincott Williams & Wilkins; 2009.
Free fatty acids continues process of insulin resistance
β-cell begins to oxidize fatty acids
Raises levels of acetyl CoA in mitochondria
Significantly increases resting NADPH levels
β-Cell releases less insulin in response to high blood glucose levels
Results to hyperglycemia in tissues
Free fatty acids continues process of insulin resistance. Here, β-cells chronically exposed to high levels of free fatty acids in circulation begin to oxidize fatty acids. This ultimately raises levels of acetyl CoA in mitochondria, which activates pyruvate carboxylase, and enhances pyruvate cycling. This process significantly increases resting NADPH levels, which leads to blunted increases in NADPH levels when glucose levels increase, and since pyruvate cycling already at maximum activation, β-Cell releases less insulin in response to high blood glucose levels. In the end, the patient experiences hyperglycemia in tissues. (MARKS, 2009)
Salivary and brush border enzymes catalyze reactions that break CHO into monosaccharides
Amylase (starch -&gt; smaller CHO molecules)
Maltase (maltose -&gt; glucose + glucose)
Sucrase-isomaltase (sucrose -&gt; fructose + glucose)
Lactase (lactose -&gt; galactose + glucose)
Fructose, as well as minimal galactose/glucose, can enter the enterocyte via facilitated diffusion using the GLUT5 transporter protein. GLUT5 is not expressed in pancreatic β-cells and thus does not stimulate insulin secretion.
Most glucose/galactose utilizes active transport with sodium via the SGLT1 cotransporter protein. The electrical gradient inside the cell is stabilized also by the Na+/K+-ATPase pump found on the basolateral membrane of the cells. This shift of cations helps to move the glucose up the concentration gradient.
Once inside of the cell, the GLUT2 transporter brings the monosaccharides into the blood; does not need insulin for transport.
Glucose will primarily travel to the liver or muscle where it will participate in glycolysis or glycogen synthesis (more on this next slide)
Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR. Modern Nutrition in Health and Disease, (11th ed). Baltimore, MD: Lippincott Williams & Wilkins; 2014.
Study Blue. [image]. Available at: https://www.studyblue.com/notes/note/n/11-carbohydrate-protein-lipid--nucleic-acid-digestion--absorption-/deck/10229632. Accessed August 6, 2015.
Once the glucose is in circulation, it needs to be taken up by cells
The liver has GLUT2 transporter (doesn’t need insulin) in order to get into the liver cells. Glucokinase phosphorylates the glucose into G6P where it will undergo glycolysis in the cytosol, enter the Krebs cycle and produce ATP for cellular energy. Produces a net of 2 ATP and 2 NADH for each glucose molecule.
If the cells do not need ATP, the liver will store the excess glucose as glycogen in order to have it for energy during times of fasting.
Glucose utilization in the muscle is similar to the liver except a few key items. Muscle cells have GLUT4 transporters which need insulin in order to get the glucose into the cells. Also, hexokinase is the enzyme that phosphorylates the glucose. Again, the G6P will either be used for glycolysis (energy for the muscles to function) or stored as glycogen for a later use.
With insulin resistance, GLUT4 activity is decreased and pancreatic β-cells secrete excess insulin (as previously discussed earlier in presentation)
Tutor Vista. 2015. Glycogen. [image]. Available at: http://chemistry.tutorvista.com/organic-chemistry/glycogen.html. Accessed July 30, 2015.
Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR. Modern Nutrition in Health and Disease, (11th ed). Baltimore, MD: Lippincott Williams & Wilkins; 2014.
On the flip side, this diagram also shows fasted state pathways
Gluconeogenesis is upregulated during periods of fasting. When blood glucose levels are low, glucagon is secreted from α-cells in the pancreas to stimulate this pathway.
Lactate, amino acids, and glycerol can be converted back to glucose in the liver.
When glucagon and epinephrine levels are high (such as in exercise or when BG is decreasing), the glycogen is able to be broken apart and converted back to glucose-6-P. While the liver can convert G6P to glucose in order to raise the BG levels, the muscle does not have the G6Pase enzyme.
Hence, the muscle cells undergo glycolysis to form pyruvate, acetyl CoA, and ATP for muscle cellular energy, such as during exercise.
Without daily exercise, these muscle glycogen stores are never used up.
Instead of CHO being turned into glycogen after eating, they are stored as excess fat in adipose cells.
Pyruvate -&gt; acetyl CoA -&gt; citrate -&gt; acetyl CoA -&gt; malonyl CoA -&gt; fatty acid synthesis (discussed in detail in later slides)
Tutor Vista. 2015. Glycogen. [image]. Available at: http://chemistry.tutorvista.com/organic-chemistry/glycogen.html. Accessed July 30, 2015.
Biology Stack Exchange. 2015. [image]. Available at: http://biology.stackexchange.com/questions/29979/what-is-the-role-pyruvate-carboxylase-in-lipogenesis. Accessed August 6, 2015.
Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR. Modern Nutrition in Health and Disease, (11th ed). Baltimore, MD: Lippincott Williams & Wilkins; 2014.
There are two ways for FA synthesis to occur. The first is from the diet:
When we eat we ingest fat as triglycerides (TG). TG is broken down by bile salts and pancreatic lipase into glycerol and fatty acids. Fatty acids are absorbed by the small intestine and resynthesized into TG. TG is then packaged into chylomicrons and absorbed into the lacteals to enter the lymphatic system. The chylomicrons are then distributed throughout the body for either storage in the adipose tissue, or for energy use. Excess FA from the adipose tissue is released and VLDL is utilized.
The second way is from the adipose tissue:
Glucagon and epinephrine signal the G Protein Couple Receptor cascade which yields active PKA. PKA phosphorylates HSL for breakdown of the stored TG into glycerol and FA. Glycerol phosphorylates into glycerol-3-phosphate by glycerol kinase, which uses ATP, and is oxidized into dihydroxy acetone phosphate through glycolysis to yield pyruvate.
Glucagon activates hormone sensitive lipase (HSL), hydrolyzing fat in adipose tissue to FFA
Tissues with mitochondria can use these for energy, except brain.
HSL frees fat from storage in adipose tissue; activated by catecholamines and glucagon. Non-esteried fatty acids (NEFAs) are bound to serum albumin and transported to other tissues to be metabolized.
Ketogenesis (prolonged starvation) is the formation of ketone bodies in the liver mitochondria. In fasting, the carbohydrate stores become depleted and the oxidation of fats becomes the largest source of energy to the body.
Ketone bodies are oxidized to allow the brain to use as energy and reduces the need for glucose.
When tissues become insulin resistant, as seen in MetS, VLDL levels are higher than normal and HDL levels are lower than normal; dyslipidema.
Tissues are insulin resistant; insulin over produced
Causing HSL, releasing high levels of FFA by adipose cells
Β-oxidation occurs in the liver=accumulation of acetyl CoA
Insulin resistance causes inhibition of lipoprotein lipase
End product is an accumulation of TG-rich VLDL
Nutritional recommendations/concerns based on case and metabolic principles
Azadbakht et al studied 31 subjects with type 2 diabetes in a randomized, crossover trial.4
Reduction in body weight and waist circumference
Decrease in fasting BG (-29.4±6.3 mg/dL) and HgbA1c (-1.7±0.1%)
Increase HDL cholesterol (4.3±0.9 mg/dL) and lower LDL cholesterol (-17.2±3.5 mg/dL)
Reduction in blood pressure (-13.6±3.5 / -9.5±2.6)
The DASH diet is:
Low in sodium (1500-2300 mg/day)2
Low saturated and total fat, low dietary cholesterol2
High potassium, calcium, magnesium2
High in fruits, vegetables, and low-fat dairy2
Based on Bill’s REE=2184 kcal/day, he would fall between the first two calorie levels on the chart.
6-10 servings of grains (mostly whole grains)
4-6 servings vegetables
4-6 servings of fruit
2-3 servings of fat free or low fat milk/milk products
3-6 ounces of meat/poultry
3-7 servings nuts/seeds/legumes per week
2-3 servings of fat/oil
0-2 servings sweets
The PREDIMED trial was a multicenter RCT that studied the effects of an “energy-unrestricted healthy diet” on metabolic syndrome1
7447 subjects were randomized to one of three intervention diets: 1) Med diet supplemented with olive oil 2) Med diet supplemented with nuts 3) control diet was a low fat diet
Babio et al found that both Med diets did not cause MetS but actually caused reversion of the condition
Compared with the control diet, both Mediterranean diets were significantly more likely to revert metabolic syndrome (p &lt; 0.001)
Subjects following the Med diets were more likely to reduce central obesity (p &lt; 0.001) and fasting glucose (p = 0.02) compared to control
A cohort study by Hoevenaar-Blom followed 34,708 participants free of CVD at baseline for 10-15 years2
compared Mediterranean Diet Score (MDS) to incidence of CVD later in life
MDS was based on validated food frequency questionnaires and intake of veg, fruit, legumes, nuts, grains, fish, types of fatty acids, meat, dairy, and alcohol
Each two unit increment in MDS (range 0–9) was inversely associated with fatal CVD, total CVD, MI, stroke, and pulmonary embolism
The Mediterranean diet emphasizes plant based foods2
Fruits, vegetables, whole grains, legumes, nuts
Not a low fat diet but rather increases healthy unsaturated fats (i.e. nuts, olive oil)2
Lower in salt, higher in herbs and spices2
Limited red meat, fish, and poultry 2x/week2
Red wine in moderation2
Bill could switch from beer/liquor to wine (&lt;10 oz/day)
Bazzano et al – 148 men and women without CVD or DM, followed for 1 year, randomized to either low fat or low carb diet.
Based on Mifflin St. Jeor equation, Bill’s REE is 2184 calories per day. (Mifflin MD, Am J Clin Nutr, 1990)
For weight loss, an energy deficit of at least 200-400 calories per day (exercise and/or diet)
Metabolic Syndrome is a cluster of conditions that when presented together increase the risk of heart disease, stroke, and diabetes. These include Hypertension, Visceral adiposity, dyslipidemia, and hyperglycemia. Many things can effect a persons outcome of MetS including obesity, lack of physical exercise, insulin resistance, gender, age, and race. Symptoms of MetS usually present as symptoms of diabetes such as increased thirst and urination, blurred vision, and fatigue.
Bill is over the age of 40, is obese, has dyslipidemia, and has a family history of diabetes, hypertension, and cardiovascular disease. These are all risk factors for MetS.
We recommend for Bill that he change his eating habits by trying diets that are low in carbohydrate and includes lean meats. He could try the DASH diet or the Mediterranean diet. Also, physical exercise is recommended for him at 30 minutes a day for 5 days a week.
