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Throughout the year, the class worked on the case of a woman named Anna Garcia, who had many health issues leading to a mysterious death.
The following is a compilation of the suspects and evidence of Anna Garcia's mysterious death, organized into one concept map linking the information together. As we thoroughly studied diabetes, we were shown hypothetical patients and given their medical information, and we graphed their insulin and glucose levels to see if they were diabetic or borderline diabetic.
Anna Garcia was diabetic, and we took the food logs of her last two days alive and analyzed them online. My lab partner, Joseph, and I made a brochure that would be found at a doctor's office for someone who may have recently been diagnosed with diabetes. My lab team and I were assigned to create a new invention that would change the lives of diabetics. My class studied feedback loops in homeostasis, and used blood sugar regulation as an example.
As we studied the heart, my lab partner and I got to take electrocardiograms of our hearts, and this is a copy of mine. We made a chart of information about infectious agents, categorizing their type, how they are spread, what they affect, and how it can be prevented.
As our last project for the class, we were assigned to make a powerpoint about a specific body system. The first thing we focused on in Human Body Systems was forensic anthropology with bone identification by gender, race, height, and age. The General Biometrics Project was a project where we designed a security system for an amusement park.
This project was a case where we were given a patient's description of her symptoms and we had to diagnose her neurological disorder. Below is a picture of my Maniken that my partners and I made by modelling muscles, veins, arteries, bones, and organs out of clay. My partner and I studied height correlation with different bones in the body, and this is a graph of tibia length compared to height.
This is a feedback loop that I made while learning the role that the thyroid gland has on homeostasis.
This is a project where my team used a spirometer to measure our breathing rates and lung capacity, and then we did the calculations of one of our team member's graph. This is my report that calculates my client's TDEE, BMI, and BMR, and gives recommendations on nutrition balance. This is a worksheet that was done about Ankle-Brachial Index, calculating it, and answering questions on it. In the following two activities we had to discover where an outbreak began, and which disease it was based on symptoms. The following are audiograph worksheets that were done to help us learn to read hearing impairments on a graph. The following is a map that explains what cancer screenings a woman needs to go through throughout her lifetime (when and how often). This is a worksheet that answers questions and has my drawn diagrams of how DNA Microarray works.
Science, Technology and Medicine open access publisher.Publish, read and share novel research. Investigating the effects of juvenile diabetes on general craniofacial growth and skeletal maturation.Analyzing the pattern of association between craniofacial morphology and skeletal maturation.
Cephalometric measurements are still one of the most widely spread diagnostic aids crucial for the diagnosis of various abnormalities in the craniofacial complex [22]. The Diabetes Forum - find support, ask questions and share your experiences with 209,001 people. We can brand all posters for your organisation, surgery or business should you require it.
Find support, ask questions and share your experiences with 209,001 members of the diabetes community.
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Are there racial or ethnic differences in the percentage of total dietary kilocalories consumed from sugar drinks? Are there income differences in the percentage of total dietary kilocalories consumed from sugar drinks?
Non-Hispanic black children and adolescents consume more sugar drinks in relation to their overall diet than their Mexican-American counterparts. Low-income persons consume more sugar drinks in relation to their overall diet than those with higher income.
Most of the sugar drinks consumed away from home are obtained from stores and not restaurants or schools. Consumption of sugar drinks in the United States has increased over the last 30 years among both children and adults (1a€“3).
Overall, males consume an average of 178 kcal from sugar drinks on any given day, while females consume 103 kcal.
Approximately one-half of the population aged 2 and older consumes sugar drinks on any given day. Higher-income persons consume fewer kilocalories from sugar drinks as a percentage of total daily kilocalories than do lower-income individuals.
Sugar drinks: For these analyses, sugar drinks include fruit drinks, sodas, energy drinks, sports drinks, and sweetened bottled waters, consistent with definitions reported by the National Cancer Institute (8).
Location of sugar-drink consumption: Respondents to the 24-hour dietary recall interview were asked if each reported food was consumed at home or away from home. Source of sugar drinks: Respondents to the 24-hour dietary recall interview were asked where they obtained each food consumed. Poverty income ratio (PIR): A measure representing the ratio of household income to the poverty threshold after accounting for inflation and family size.
Data from the National Health and Nutrition Examination Survey (NHANES) were used for these analyses. The NHANES sample is selected through a complex, multistage design that includes selection of primary sampling units (counties), household segments within the counties, households within segments, and, finally, sample persons from selected households.
Sample weights, which account for the differential probabilities of selection, nonresponse, and noncoverage, were incorporated into the estimation process.
All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.
Note: Since your browser does not support Javascript, you must press the Continue button once to proceed. We made a nutrition report of the food she was eating to see if diabetic complications could have played a part in her death. We explained each organ in the system and how the diseases we have studied would affect that system. It is a map of all the lobes of the brain and areas, with little symbols that tell us what each lobe controls. A) The changes in mineral apposition rate (MAR) of the mandible between the control group and the DM group.
Osteoclast counts in a horizontal section of the mandibular second molar region stained with Tartarate-resistant acid phosphatase (TRAP). IntroductionDiabetes mellitus (DM) is one of the systemic diseases affecting a considerable number of patients worldwide [1]. Garcia-Roves2, 3[1] Diabetes and Obesity Laboratory, August Pi i Sunyer Biomedical Research Center (IDIBAPS),, Spain[2] Diabetes and Obesity Laboratory, August Pi i Sunyer Biomedical Research Center (IDIBAPS),, Spain[3] Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona,, Spain1. Non-Hispanic black and Mexican-American adults consume more than non-Hispanic white adults. Sugar drinks have been linked to poor diet quality, weight gain, obesity, and, in adults, type 2 diabetes (4,5).
Mean consumption of sugar drinks is higher in males than females at all ages except among 2- to 5-year-olds. Among adult women, the percentage is lower, with 40% consuming sugar drinks on any given day, while among boys aged 2a€“19, 70% consume sugar drinks on any given day (Figure 2).
Of these sugar-drink kilocalories, the vast majority is purchased in stores (92%), and just over 6% is purchased in restaurants or fast-food establishments. For example, males consume more than females, and teenagers and young adults consume more than other age groups. Most sugar drinks consumed away from home are obtained from stores, but more than one-third are obtained in restaurants or fast-food establishments. Sugar drinks do not include diet drinks, 100% fruit juice, sweetened teas, and flavored milks. To determine source of food, respondents were offered 26 options, categorized for this brief as store, restaurant (including fast-food), school or child care, and other.
In 2008, a PIR of 350% was equivalent to approximately $77,000 for a family of four; a PIR of 130% was equivalent to approximately $29,000 for a family of four. NHANES is a cross-sectional survey designed to monitor the health and nutritional status of the civilian, noninstitutionalized U.S. The sample design includes oversampling to obtain reliable estimates of health and nutritional measures for population subgroups.
The standard errors of the percentages were estimated using Taylor Series Linearization, a method that incorporates the sample weights and sample design. Trends in food and nutrient intakes by adults: NFCS 1977a€“78, CSFII 1989-91, and CSFII 1994-95.
Effects of soft drink consumption on nutrition and health: A systematic review and meta-analysis. Defining and setting national goals for cardiovascular health promotion and disease reduction: The American Heart Association's strategic impact goal through 2020 and beyond.
Dietary sources of energy, solid fats, and added sugars among children and adolescents in the United States.
The blood glucose level in DM group increased significantly 48h post-STZ injection and during the entire experimental period. Numerous experimental and clinical studies on the complications of DM have demonstrated extensive alterations in bone and mineral metabolism, linear growth, and body composition [2]. Animal and Experimental diabetic ModelThe animal studies using diabetic model presents various advantages when compared to studies carried out on human diabetic cases. Changes in the Transverse X-rayIn transverse X-ray only the maximum cranial width (C1-C2) and the bizygomatic width (Z1-Z2) were statistically decreased in DM group (Table 6, Fig. Introduction“Let food be your medicine and medicine be your food” stated Hippocrates, the father of Western medicine, in 400 B.C. Consumption of sugar drinks increases until ages 12a€“19 years and then decreases with age. Among adults, non-Hispanic black and Mexican-American persons consume more than non-Hispanic white persons, and low-income individuals consume more sugar drinks in relation to their total diet than higher-income individuals. Percentage of daily kilocalories from sugar drinks is the percentage of total daily energy obtained from sugar drinks. Population estimates of sugar-drink kilocalories are based on data from one in-person, 24-hour dietary recall interview. The black rectangle (540 X 120 ?m) indicates the area on the distal surface of the alveolar bone adjacent to the middle third of the mesio-buccal root of the second molar in which the osteoclast cells were counted. Depletion of insulin in Type 1 Diabetes Mellitus (T1DM) causes a reduction of bone mineral density and decreases skeletal mass, thus altering linear growth, body composition and delaying fracture healing. 3) to maintain standardized head posture and contact with the film (SGP-3, Mitsutoy, Tokyo, Japan) where the head of each rat is fixed firmly with a pair of ear rods oriented vertically to the sagittal plane and the incisors are fixed into a plastic ring. For the histomorphometric assessment of resorption, the number of tartrate-resistant acid phosphatase-positive multinucleated cells (osteoclasts) on the distal surface of the alveolar bone adjacent to the mesio-buccal root of the second molar were counted in each 540 ?m x 120 ?m area in five consecutive sections, at the middle third of the root selected at least 25?m apart from each specimen (n = 5) of each group [39, 40]. Controversy about the effects of high fat diet feeding in skeletal muscle oxidative capacity7.2. This statement was based on the belief that food was able to influence disease, a concept that was revived several times in later years by painters, writers, scientists, and philosophers.
Consumption of sugar drinks is lowest among the oldest females (42 kcal per day) and highest among males aged 12a€“19 (273 kcal per day) (Figure 1). Over 20% of sugar-drink kilocalories consumed away from home are obtained in other places such as vending machines, cafeterias, street vendors, and community food programs, among others (Figure 6).
Census Bureau data (9).The cut point for participation in the Supplemental Nutrition Assistance Program is 130% of the poverty level. The survey consists of interviews conducted in participants' homes, standardized physical examinations in mobile examination centers, and laboratory tests utilizing blood and urine specimens provided by participants during the physical examination. In 2007a€“2008, African-American and overall Latino subgroups were oversampled, with sufficient sample sizes for separate analysis of the Mexican-American subgroup. Carroll are with the Centers for Disease Control and Prevention's (CDC) National Center for Health Statistics, Division of Health and Nutrition Examination Surveys. Diabetic modelExperimental diabetic models include the streptozotocin-induced diabetic rat and the spontaneously diabetic BioBreeding [12] rat.
After STZ injection by 48 hours the urine test showed that the entire DM group had a high glucose level and this was confirmed by the high blood glucose measurements as shown in Fig. Changes in the MandibleIn the DM group, the posterior corpus length (Go-Mn), total mandibular length (Co-Il) and the ramus height (Co-Gn) were significantly shorter than in the control group (Table 5, Fig.
One such philosopher, Ludwig Feuerbach, famously wrote in his 1863-4 essay “man is what he eats” introducing the idea that if we want to improve the spiritual conditions of people we must first improve their material conditions (Feuerbach, 2003). Moreover, the American Heart Association has recommended a consumption goal of no more than 450 kilocalories (kcal) of sugar-sweetened beveragesa€”or fewer than three 12-oz cans of carbonated colaa€”per week (7).
The age patterns of percentage of total daily kilocalories from sugar drinks (not shown) are similar to those for kilocalories from sugar drinks.
Dietary information for this analysis was obtained via an in-person, 24-hour dietary recall interview in the mobile examination center. Sohyun Park is with CDC's National Center for Chronic Disease Prevention and Health Promotion, Division of Nutrition, Physical Activity, and Obesity. The occurrence of different abnormalities indicating altered bone formation after inducing DM with streptozotocin (STZ) is well documented [3, 13, 14].
Fluorescent dyes used for double labeling in histomorphometric analysis Fluorochromes are calcium binding substances that are preferentially taken up at the site of active mineralization of bone known as the calcification front, thus labeling sites of new bone formation. Histological analysisBone-resorption activity was assessed by counting the number of tartrate-resistant acid phosphatase-positive multinucleate cells (osteoclasts) on the distal surface of the alveolar bone adjacent to the mesio-buccal root of the second molar (Fig.
However, for years his warnings remained unheeded, at least in Western countries, in contrast to the teachings of Indian and Chinese medicine which for millennia have argued that a living organism has to assume a healthy diet.
This brief presents the most recent national data on sugar-drink consumption in the United States. Each year of data collection is based on a representative sample covering all ages of the civilian, noninstitutionalized population.
Streptozotocin-induced diabetes mellitus (STZ-DM), caused by the destruction of pancreatic ?-cells and is similar to T1DM in human, is characterized by mild to moderate hyperglycemia, glucosuria, polyphagia, hypoinsulinemia, hyperlipidemia, and weight loss. 4) were derived from previous studies on rodents.[11, 24-26] Selected linear measurements were then obtained (Table 2). Like diet, physical activity has been also considered an important starting point for people's health. To ensure reliability and replicability of each measurement, each distance was digitized twice and the two values were averaged. Labeling bones with fluorochrome markers provides a means to study the dynamics of bone formation. Hippocrates wrote in his book Regimen "if we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health" (Hippocrates, 1955). The rate and extent of bone deposition and resorption can be determined using double and triple fluorochrome labeling sequences. Our knowledge about the links between diet, exercise, and disease has vastly increased since Hippocrates time.


Type 1 diabetes mellitus (T1DM) is an endocrine–metabolic syndrome of childhood and adolescence, characterized by hyperglycemia as a cardinal biochemical feature, with important consequences for physical and emotional development.
Inducing diabetic conditionAll the experimental protocols followed had been approved by the Institutional Animal Care and Use Committee of Tokyo Medical and Dental University, and the experiments were carried out under the control of the University’s Guidelines for Animal Experimentation. All of the data in each experiment were confirmed the normal distribution, so a Student’s t-test was used to compare the mean of each data recorded in the control group and in the DM group. The sequential use of fluorochromes of clearly contrasting colors permits a more detailed record of events relating to calcification.
A healthy lifestyle based on diet and physical activity is now considered the keystone of disease prevention and the basis for a healthy aging. In our investigation we explored the various effects of DM using the streptozotocin DM model.
All statistical analyses were performed at a 5% significance level using statistic software (v. Flurochromes commonly used in mammals include tetracycline, calcein green, xylenol orange, alirazin red, and hematoporphyrin. However, modern society has created conditions with virtually unrestricted access to food resources and reduced physical activity, resulting in a positive overall energy balance.
This is far from the environment of our ”hunter-gathered ancestros” whose genes were modulated over thousands of years adapting our metabolism to survive when food was scarce and maximizing energy storage when food became available. They were randomly divided into two groups, the control group and the diabetes group (DM group), each group consists of 6 rats.
In terms of evolution, this radical and sudden lifestyle change in modern society has led to a dramatic increase in the incidence of metabolic diseases including obesity and type 2 diabetes mellitus (T2DM). Changes in the NeurocraniumCranial vault length (Po-E), total cranial base length (Ba-E), anterior cranial base length (So-E), Occipital bone length (Ba-CB1), and posterior cranial base length (Ba-So) showed statistically significant decrease in DM group (Table 3, Fig. It seems clear that the development of T2DM has a genetic component that becomes obvious when individuals are exposed to western lifestyle. It has been suggested that hyperglycemia is associated with decreased salivary secretion and high salivary glucose levels, particularly in cases of severe insulin deficiency. The time difference between the 2 injections is one week to be able to compare the amount of bone formed during this period (Fig. However, environment plays a critical role in the incidence of the disease being obesity the main etiological cause of T2DM.
Mitochondrial dysfunction as a potential mechanism underlying skeletal muscle insulin resistance6.1.
Thus, modest weight loss is enough for obese glucose intolerant subjects to prevent the development of T2DM (National Task Force on the Prevention and Treatment of Obesity, 2000).T2DM also known as “non-insulin-dependent diabetes mellitus” or “adult-onset diabetes”, is a metabolic disorder characterized by high blood glucose, insulin resistance, and relative insulin deficiency. However, no clear evidence has been found for an association between dental caries and diabetes mellitus [3].
Body weights, the presence of glucose in urine and blood glucose levels were recorded on day 0,2,7,14,21 and 28 after STZ injection.Diabetes condition was determined by the presence of glucose in urine and blood. The main aim of this chapter is to discuss the complexity of the dento-craniofacial system and how it is affected by T1DM condition. T2DM is now considered to be a global epidemic with significant social and economic consequences both at the individual and population level. The International Diabetes Federation estimates that 366 million people suffered from this disease in 2011 and predicts that these numbers will increase to 552 million people by 2030.
The pathophysiology of prediabetes is characterized by alterations in insulin sensitivity and pancreatic beta-cell function, usually associated with increased adiposity (Dagogo-Jack et al., 2009).
Method of analysisThe bone around the lower second molar is centrally located within the mandibular arch, and because of the parallel alignment of the buccal and lingual roots this made a precise reference when frontal sections are produced [29]. To conduct the histomorphometric analysis it is essential to use a digitizing morphometry system to measure bone formation indices. While these data are encouraging, these interventions are costly, require a very high degree of commitment of the subjects, and are not always successful. Although the progress in understanding the metabolic derangements of T2DM has led to significant advances in the treatment of this disease, it remains unclear whether current therapeutic approaches can really improve the underlying metabolic defects. Therefore, there is an urgent need to characterize the complex pathophysiology of the disease, to identify and target specific mechanisms in order to slow down the worldwide diabetes epidemic.2. Insulin action and insulin resistanceInsulin essentially provides an integrated set of signals that allow for the balancing of nutrient availability and caloric demands (Samuel et al., 2010). In collaboration with the opposing hormone glucagon, it is responsible for maintaining glucose homeostasis, which is necessary to ensure proper function and survival of all organs. Based on the reference line along the long axis of the buccal root, the area superior to the root apex was considered alveolar bone, while the area inferior to the root apex was considered the jaw bone. The regulation of plasma glucose concentrations is vital for the entire body and both hypoglycemia and hyperglycemia can impair whole-body physiology, ultimately leading to cellular death. The lingual side of the bone is excluded, because the existence of the incisor root may influence bone formation. This is why it is critical to regulate and maintain plasma glucose levels around 5mM, the physiological set point in mammals (Saltiel, 2001).The primary targets of insulin action to maintain glucose homeostasis are skeletal muscle, liver, and adipose tissue.
Under physiological conditions, carbohydrates provided by the diet increase plasma glucose levels and promote insulin secretion from pancreatic ? cells of the islets of Langerhans. The periosteal surfaces were delimited into 4 areas as alveolar crest (region 1), alveolar bone (region 2), buccal surface of the jaw bone (region 3), and inferior border of the jaw bone (region 4).The periosteal surfaces of the mandible are divided into four regions for analysis (Fig.
Once secreted, insulin binds to its receptor, triggering a cascade of downstream phosphorylation events that expand the initial signal (Figure 1). Insulin binds to its receptor and activates its intrinsic protein tyrosine kinase activity, resulting in the phosphorylation of tyrosine residues located in the cytoplasmic face. Histomorphometric indicesThe obtained results in our study showed that in the alveolar bone (region 2), there was a significant decrease in the MAR (Fig. The activated receptor, in turn, recruits and phosphorylates a group of substrate molecules.
They have the role of docking proteins and are known as “insulin receptor substrates” (IRS).
However, in the alveolar crest (region 1), the MAR and the BFR in the control and the DM groups were not significantly different.
Among these, IRS1 and IRS2 appear to be the major adapter molecules that play a role in insulin cascade. Most of the periosteal surfaces in the mandibular regions of the control group showed significantly higher values recorded for the mineral apposition rate and the bone formation rate when compared to the DM group. These results agree with previous studies that recorded diminished lamellar bone formation in DM rats’ femur and may suggest an association between the DM condition and the decreased number and function of osteoblasts [16, 19]. The alveolar crest region was the only region that did not show a significant difference in the mineral apposition rate and the bone formation rate parameters among the two groups; this may be attributed to the unique nature of this region exhibiting a highly intensive bone remodeling process especially during the teeth eruption that decreases toward the base of the socket [33], however further studies are needed to elaborate the detailed pattern of bone growth at the alveolar crest region. This event relieves the inhibitory phosphorylation of glycogen synthase (GS), which becomes activated and promotes glycogen synthesis;insulin-stimulated translocation of the glucose transporter GLUT4 at the plasma membrane, resulting in increased glucose uptake. Figure 15.A) The changes in mineral apposition rate (MAR) of the mandible between the control group and the DM group. AS160 normally inhibits translocation of GLUT4 through its interaction with RabGTPase protein. The inhibitory phosphorylation of AS160 favors the GTP-loaded state of Rab and relieves the inhibitory effect on GLUT4, stimulating its translocation to the plasma membrane. Pathogenesis of Type 2 Diabetes MellitusAn important early phenotype associated with increased T2DM risk is insulin resistance. Given these data, it is alarming that the high prevalence of insulin resistance in the population predicts further dramatic increases in the worldwide epidemic of T2DM.
Individuals with established T2DM show several physiological abnormalities, including elevation in fasting glucose levels, elevation in postprandial glucose levels, or both.
In adipose tissue, the major fat storage tissue in mammals, insulin resistance results in increased lipolysis and fatty acid release. Increased circulating fatty acids decrease the ability of insulin to suppress hepatic glucose production and allow a constant increase in fatty acid synthesis. This dysregulation of carbohydrate and lipid metabolism accelerates the progression of insulin resistance. During the first stages of the development of the disease, pancreatic beta-cells have the ability to compensate for insulin resistance by increasing basal and postprandial insulin secretion to correct hyperglycemia. When pancreatic beta-cells can no longer compensate they become unable to respond appropriately to glucose levels.
Microtomography of the mandible (Micro-CT) Micro-computed tomography (micro-CT) has rapidly become a standard technique for the visualization and quantification of the 3D structure of trabecular bone.
This pancreatic beta-cell failure leads to the deterioration of glucose homeostasis and the development of T2DM. Bone architecture and mineralization are generally considered to be important components of bone quality, and determine bone strength in conjunction with bone mineral density.
This pattern of physiological abnormalities in skeletal muscle, adipose tissue, liver, and pancreas presents itself in the late stages of the disease (Saltiel, 2001).
Additionally, abnormal secretion and regulation of incretins in the gastrointestinal tract, hyperglucagonemia due to alterations in pancreatic alpha-cells, increased glucose reabsorption in kidney, and altered balance of central nervous system pathways involved in food intake and energy expenditure play an important role in the development of T2DM (Defronzo, 2009). This complex pathophysiology makes difficult to identify the primary events responsible for the development of T2DM.4.
Skeletal muscle insulin resistance and T2DMAs mentioned above, insulin resistance is a key component for the development of T2DM.
Then, slice images are prepared using multi-tomographic image reconstruction software (MultiBP; Imagescript, Tokyo, Japan). The resulting gray-scale images are segmented using a low-pass filter to remove noise and a fixed threshold to extract the mineralized bone phase. Himsworth and Kerr, using a combined oral glucose and intravenous tolerance test, were the first to demonstrate that tissue-specific insulin sensitivity was lower in T2DM individuals (Himsworth, 1940). The volume of interest (VOI) is drawn on a slice-based method starting from the first slice containing the crown of the first molar and moving dorsally 100 slices [34, 35], in the area of the alveolar crest (Between the buccal and lingual roots of the second molar at the cervical region); and the buccal surface of the jaw bone [29]. Ginsberg and colleagues provided another important evidence related to the decreased ability of insulin to promote glucose uptake in subjects with T2DM (Ginsberg et al., 1975).
Trabecular bone was carefully contoured on the first and the last slice, while the intermediate slices were first interpolated by morphing. Later on, clear evidences about skeletal muscle insulin resistance in T2DM subjects were provided by DeFronzo and colleagues, who used the euglycemic-hyperinsulinemic clamp technique to quantify insulin-stimulated glucose uptake.
Reconstructed 3D images were prepared from slice images using the volume rendering method, to analyze the microstructure of the bone (Fig.
Skeletal muscle is the largest insulin-sensitive organ in humans accounting for more than 80% of insulin stimulated glucose disposal (DeFronzo et al., 1985).
Moreover, several evidences linked mitochondrial defects to insulin resistance and T2DM (Lowell and Shulman, 2005), suggesting that these organelles are key players in maintaining energy homeostasis.In this chapter we will discuss the potential role that mitochondrial dysfunction plays in T2DM etiology. Microtomography of the DM mandible The quantification of micro-CT trabecular bone changes (mean±SD) is shown for the DM and the control groups in (Table 4). All trabecular parameters in both alveolar bone and buccal surface of jaw bone showed significant changes. Skeletal muscle fiber types and metabolismSkeletal muscle is a complex tissue composed of different fiber types, which have distinct mechanical and metabolic properties. Each of these functional systems is composed of a motor neuron and a group of muscle fibers.
In adult human skeletal muscle type 2B fibers are not detectable and the oxidative capacity of type 2X fibers is lower than that observed in rats and mice (Schiaffino and Reggiani, 2011). For additional reading we recommend a review published in Physiological Reviews written by Stefano Schiaffino and Carlo Reggiani that provides an up to date and detailed understanding of this topic (Schiaffino and Reggiani, 2011).
These results agree with other research work suggesting that the glycaemic levels play an important role in modulating the trabecular architecture especially in mandibular bone [15].The DM condition resulted in alteration of the trabecular distance and thickness as compared to the control group indicating profound impact on the histological integrity of the bone. For the purposes of this discussion, it is important to keep in mind skeletal muscle diversity: distinct skeletal muscle fibers differ in their energy requirements for cellular function, including contractile activity. The reduction in trabecular bone volume accompanied by the expansion of the bone marrow space is in agreement with another investigation [37]. Energy is provided by adenosine triphosphate (ATP) hydrolysis to adenosine diphosphate (ADP) and inorganic phosphate (Pi). ATP can be generated by three main mechanisms that vary in their capacity and velocity to resynthesize ATP.
The Phosphocreatine (PCr)-creatine kinase (CK) system corresponds to a high-power and low-capacity ATP production reservoir. Specimens are then dehydrated in an ascending ethanol series and embedded in paraffin (Fig. Glycolysis is the metabolic process by which glycogen and glucose are metabolized to pyruvate and subsequently to lactate; this process has a lower power but a higher capacity for ATP generation than the PCr-CK system. The other energy production resource is the mitochondrial oxidative phosphorylation system, which can obtain ATP from different substrates: pyruvate, fatty acids, amino acids, and ketone bodies. The oxidative phosphorylation system has a very high capacity for ATP generation but a lower power when compared to the other two ATP production systems. It is also important to highlight that mitochondrial mediated ATP resynthesis is highly dependent on oxygen and substrate availability.Due to its intrinsic characteristics, slow and fast muscle fibers differ in their relative contribution to energy production from PCr-CK, glycolysis, and oxidative phosphorylation processes. The relative contribution of these metabolic pathways is mostly established during differentiation according to the specific function and energy demands of each fiber type.
Thus, skeletal muscle is able to predominantly utilize both glucose and free fatty acids as fuel sources for energy production. This event, together with the activation of key enzymes in glucose metabolism, leads to a marked increase in muscle glucose oxidation.
After glucose is transported into the myocytes trough the GLUT4 transporter, it is immediately phosphorylated by hexokinase II, and the phosphorylated glucose is stored as glycogen or enters the glycolytic pathway for energy production. Thus, during feeding conditions, the main source for energy production in skeletal muscle is glucose.Therefore, muscle energy metabolism has to be capable of switching from predominant oxidation of fatty acids during fasting state, to predominant oxidation of glucose during feeding state.
However, obese and type 2 diabetic subjects are unable to shift between substrates (fatty acids or glucose) demonstrating a high degree of metabolic inflexibility (Kelley et al., 1999). This inability to oxidize one substrate or another results in impaired glucose and fatty acid storage as glycogen and triglycerides, respectively. Pathogenesis of Insulin Resistance in Skeletal MuscleBoth obese subjects with or without T2DM have marked skeletal muscle insulin resistance compared to lean non-diabetic subjects.
The severity of the insulin resistance positively correlates with BMI (DeFronzo, 1982, Wedick et al., 2009).
The mechanism through which obesity causes insulin resistance in skeletal muscle seems to be associated with the accumulation of fatty acids in the myocytes. Among the various types of fatty acids, saturated long-chain ones, including palmitic and stearic acids, are strong inducers of insulin resistant state (Hirabara et al., 2009). Obese subjects with or without T2DM are characterized by an increase in plasma fatty acid concentration, which strongly correlates with reduced insulin-stimulated glucose disposal in skeletal muscle.In normal conditions, fatty acids are stored in the adipose tissue as triglycerides and released during fasting. During the postprandial state, blood glucose stimulates insulin secretion, which inhibits lipolysis in adipose tissue, therefore limiting the release of fatty acids. In insulin resistant individuals, the ability of insulin to inhibit lipolysis and reduce plasma fatty acid concentration is markedly impaired (Groop et al., 1991). They observed that incubation of rat heart with fatty acids was associated with an increase in intracellular concentrations of glucose-6-phosphate (G6P) and glucose. Moreover, incubation of diaphragm muscle with fatty acids led to an increase in glycogen accumulation. Accumulation of citrate inhibits phosphofructokinase and increases intracellular concentrations of G6P, leading to activation of glycogen synthesis, inhibition of hexokinase II, increase in intracellular glucose content and, consequently, reduction in glucose uptake. Thus, this model is based on the inverse relationship between fatty acid availability and glucose utilization.
If there was a block at the hexokinase step, as proposed by Randle, intra-myocellular glucose concentrations would be expected to increase. Instead, they noted that plasma fatty acid concentrations decreased the accumulation of intra-myocellular glucose, indicating that insulin-stimulated glucose transport activity was reduced. ER is an intracellular membranous network responsible for synthesis, folding, maturation, trafficking and targeting of secreted and transmembrane proteins. In some diseases, protein synthesis increases in ER-lumen and proteins cannot fold correctly, affecting ER homeostasis.


Impairment of ER homeostasis activates an elaborate adaptive stress response, known as “unfolded protein response” (UPR), and results in the phosphorylation and activation of JNK. The link between T2DM, insulin resistance and ER stress in skeletal muscle is still unclear. It has been demonstrated that ER stress occurs in vivo in skeletal muscle when mice are fed a high fat diet (Deldicque et al., 2010a).
Fatty acids activate inflammatory signals by promoting secretion of pro-inflammatory cytokines including TNFalpha, IL-1beta, and IL-6.
Furthermore, fatty acids can directly interact with members of the Toll-like receptor (TLR) family, promoting activation of JNK and IKKbeta.
This activation leads to degradation of the inhibitor of kappa beta (IKB) and Nuclear factor-kappa beta (NFKB) activation. Biology of the mitochondriaMitochondria are doubled-membrane organelles that constitute the major site for oxidative energy production in the cell.
Mitochondria are the only mammalian organelles that contain extra-nuclear DNA (mtDNA), which encodes for 37 genes including 13 subunits of the electron transport chain (Kelly and Scarpulla, 2004).
Besides generating the majority of cellular ATP via oxidative phosphorylation (OXPHOS), many other essential cellular functions take place in this organelle. Oxidative phosphorylation (OXPHOS)Mitochondria are able to generate energy by oxido-reduction reactions and proton translocation derived from carbohydrates (TCA cycle), amino acids and fatty acids (?-oxidation). For this purpose, oxygen is consumed to generate water, heat and adenosine triphosphate (ATP). The inner membrane invaginations of the mitochondria, called cristae, contain all transmembrane proteins of the electron transfer system (ETS) and the ATP synthase (Benard and Rossignol, 2008, Vonck and Schafer, 2009).
All components of the TCA cycle and ?-oxidation pathway are located inside the mitochondrial matrix. Oxidation of substrates generates reduced nicotinamide adenine dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH2) that will provide electrons to the ETS. Electrons flow from donors (NADH at complex I and FADH2 at complex II) to an oxygen molecule forming H2O at complex IV. There is a parallel translocation of protons to the intermembrane space from the matrix that creates an electrochemical gradient used by ATP synthase in a coupled manner to generate ATP.
This electrochemical gradient can also dissipate through uncoupling proteins (UCPs) using a non-ATPase-coupled proton leak and generating heat in a process called thermogenesis. The high electronegative potential generated can also drive the entry of calcium into the matrix. Mitochondrial biogenesis and dynamicsMitochondrial biogenesis is defined as the generation of more mitochondrial mass and takes place in response to increased energy demand.
It has been recently established that mitochondrial fission and fusion contribute to multiple essential functions including calcium handling, ROS production and energy output (Chen and Chan, 2005, Parone et al., 2008, Soubannier and McBride, 2009). The relevance of these events in mitochondrial and cell physiology has been partially unraveled and observed that the disruption of such processes results in mitochondrial heterogeneity and dysfunction (Zorzano et al., 2009, Chan, 2006). Therefore, a fine-tune regulation of mitochondrial biogenesis and dynamics is necessary to obtain and maintain functional mitochondria.Mitochondrial biogenesis is a complex process that requires the expression of a large number of proteins encoded by both nuclear and mitochondrial genomes. The mitochondrial genome encodes only 13 proteins, which are essential subunits of the respiratory complexes. This genome also provides the 22 tRNAs and 2 rRNAs necessary for the translation of these mitochondrial-encoded proteins.
In contrast, transcription of the mitochondrial genome is encoded by the nuclear genome, which is under the control of a single transcription factor named TFAM.
Therefore, fine-tuned coordination is required between the mitochondrial and the nuclear genomes to orchestrate the expression of proteins necessary for a successful mitochondrial biogenesis.
This coordination is achieved by complex regulatory mechanisms that involve the action of a relatively small number of nuclear transcription factors, which are discussed in detail below.
These transcription factors are in turn regulated by cofactors that integrate physiological signals with the activity of the transcription factors to regulate mitochondrial biogenesis in response to environmental stimuli. Nuclear transcription factors involved in mitochondrial biogenesisThrough their DNA-binding domain, transcription factors bind to specific sequences in the gene promoter region to regulate transcription of a subset of genes.
Several transcription factors have been shown to regulate expression of genes involved in the respiratory chain and mitochondrial metabolism, however only a few are considered the major transcription factors crucial for mitochondrial biogenesis.
Nuclear Respiratory Factor 1 (NRF-1)NRF-1 has a fundamental role in coordinating nuclear and mitochondrial transcription. It induces expression of TFAM, TFB1M and TFB2M (Virbasius and Scarpulla, 1994, Gleyzer et al., 2005), which are essential proteins for the transcription of the mitochondrial genome, and also TOMM20, a key protein required for the transport of nuclear-encoded proteins into the mitochondria. It has also been shown to regulate multiple subunits of the respiratory chain as well as other proteins involved in other mitochondrial functions. This respiratory factor was named NRF-2 and was subsequently identified as the human homolog of the mouse GABP (Virbasius et al., 1993).
Similarly to NRF-1, disruption of the NRF-2 gene also produces a lethal phenotype (Ristevski et al., 2004).
Instead, it is a member of a family of orphan nuclear receptors that also include ERRbeta and ERRgamma. Unlike NRF-1 and NRF-2 where gene knockout proves lethal, disruption of ERRalpha results in a viable phenotype showing decreased body weight and adipose depot size (Luo et al., 2003).
This mouse shows normal energy expenditure with no major decrease in mitochondrial proteins.
Other transcription factorsWhile not directly involved in transcription of mitochondrial biogenesis or respiratory chain genes, other transcription factors including PPARalpha, PPARdelta, and YY1 are also important for providing other mitochondrial proteins. PGC-1 coactivator familyWhile the transcription factors discussed above are part of the transcriptional machinery necessary for mitochondrial biogenesis, the members of the PGC-1 coactivator family provide the integration of physiological stimuli with the transcription factors to adapt mitochondrial biogenesis to changes in the environment. PGC-1 coactivators lack a DNA-binding domain, but they are able to interact with and activate several transcription factors by recruiting other cofactors with chromatin-remodeling activities (Monsalve et al., 2000).
PPARgamma coactivator 1alpha (PGC-1alpha), the founding member of the PGC-1 family, was first identified by its ability to activate PPARgamma in brown adipocytes (Puigserver et al., 1998). PGC-1beta and PRC where subsequently identified based on their structural similarity with PGC-1alpha (Lin et al., 2002a, Andersson and Scarpulla, 2001).
It is this regulatory capacity that allows PGC-1alpha to respond to physiological stimuli and activate the mechanisms leading to increased mitochondrial biogenesis.
Physical exercise has also been recognized as a main activator of mitochondrial biogenesis.
In the muscle cell, the AMP-dependent protein kinase (AMPK) responds to low energy levels (increase in AMP content) by inducing a signaling cascade that results in the activation of catabolic pathways and inhibition of anabolic pathways in an attempt to restore energy levels. Therefore, AMPK has been recognized as a key mediator in the physiological and metabolic adaptation to physical exercise. Interestingly, AMPK can directly phosphorylate PGC-1alpha and activate its transcriptional activity regulating expression of mitochondrial genes (Jager et al., 2007).
Mitochondrial dysfunction as a potential mechanism underlying skeletal muscle insulin resistanceMitochondrial adaptations (biogenesis and dynamics) and function largely affect muscle metabolism and have a significant impact on whole-body metabolism (Patti et al., 2010).
As mentioned before, metabolic flexibility is defined as the ability to rapidly modulate substrate oxidation as a function of environmental, hormonal and different energy conditions (Storlien et al., 2004). Defects in pathways controlling glucose and energy homeostasis in skeletal muscle have been shown to impair these adaptations, leading to metabolic inflexibility. For the purposes of this chapter, we will define mitochondrial dysfunction as both the reduction in mitochondrial oxidative activity and in mitochondrial adenosine triphosphate (ATP) synthesis. Early evidences relating insulin resistance and skeletal muscle mitochondrial dysfunctionSeveral key studies published between 1999 and 2005 laid the foundation for understanding the underlying mechanisms between mitochondrial dysfunction and subsequent insulin resistance in skeletal muscle and development of T2DM. Dysregulation of skeletal muscle fat oxidation in obesityThe first studies that identified a relationship between alterations in muscle metabolism and insulin resistance did not mention any link with mitochondrial dysfunction (Kelley et al., 1999).
However, research performed by Kelley and co-workers addressed why the pattern of fatty acid utilization in skeletal muscle during fasting conditions might be associated with obesity-related insulin resistance, which is relevant for the scope of this chapter.
The study included 16 lean and 40 obese volunteers with leg balance measurements of glucose and free fatty acid uptake. Indirect calorimetry across the leg was also measured in order to determine substrate oxidation during fasting and insulin-stimulated conditions. This study demonstrated that fatty acids were the predominant substrate oxidized by skeletal muscle during fasting conditions in lean subjects. However, rates of fatty acid oxidation during fasting were significantly lower in obese subjects, even though rates of fatty acid uptake were similar to those of lean subjects. Furthermore, the respiratory quotient values across the leg showed a reduced reliance on lipid oxidation in obese subjects. What it is also important is that weight loss only partially improved these patterns; the leg respiratory quotient in obese subjects was unchanged between pre- and post-weight loss, so the reliance of skeletal muscle in fat oxidation during fasting conditions was not improved. The authors suggested that their data pointed to these defects as primary impairments leading to obesity, rather than resulting from obesity. Muscle mitochondria in obesity and type 2 diabetesIn this study, Kelley and co-workers provided early evidence that mitochondrial dysfunction in human skeletal muscle contributes to the development of insulin resistance and progression to T2DM (Kelley et al., 2002b). Previous work by the same group demonstrated that the severity of skeletal muscle insulin resistance in T2DM and obesity is related to diminished activity of oxidative enzymes (Simoneau and Kelley, 1997). Furthermore, triglyceride accumulation in skeletal muscle is also correlated with the severity of insulin resistance and with diminished oxidative enzyme activity. Because it was known that skeletal muscle depends on oxidative phosphorylation to produce energy and that insulin resistance in T2DM and obesity involves altered oxidation of carbohydrates and lipids, the authors attempted to elucidate the potential contribution of mitochondrial dysfunction to skeletal muscle insulin resistance in humans. For this purpose vastus lateralis muscle samples from lean controls without T2DM, obese subjects with or without T2DM were obtained. An assessment of the activity of the mitochondrial OXPHOS system and a quantitative study of the mitochondria morphology by transmission electron microscopy was performed in the different muscle biopsies.
Creatine kinase and citrate synthase activities were measured as markers of muscle fiber content and mitochondrial content, respectively.
Results showed that skeletal muscle mitochondria structure and functional capacity were impaired in T2DM subjects and, to a lesser degree, in obese subjects. Mitochondrial respiratory complex I activity was reduced by 40% in skeletal muscle from subjects with T2DM when compared to lean controls without diabetes. Moreover, skeletal muscle mitochondrial area and size were smaller in obesity and T2DM and, in some instances, particularly in T2DM, severely damaged.
Although age can affect the size of mitochondria, in this case aging did not account for the ~30% reduction in size in obesity and T2DM.Based on their results, authors proposed a potential mechanism that could explain how impaired mitochondrial function leads to insulin resistance in skeletal muscle, which would be lipid accumulation within myocytes.
This was not a new finding, as previous studies (Kelley et al., 2002a) from the same group had shown that increased lipid accumulation in skeletal muscle is associated with insulin resistance and, in turn, lipid accumulation in skeletal muscle in obesity and T2DM is related to a reduced oxidative enzyme activity.
Downregulation of oxidative metabolism genes in humans with insulin resistance and diabetesPatti and colleagues addressed how gene regulation was modulated by T2DM (Patti et al., 2003). The results showed that skeletal muscle from subjects with prediabetes and T2DM had decreased expression of oxidative phosphorylation genes, many of which are regulated by nuclear respiratory factor (NRF)-dependent transcription. A decreased expression of the co-activators PGC-1alpha and PGC-1beta, both of which induce NRF-dependent transcription, was also found. Therefore, subjects with insulin resistance and T2DM have a reduced expression of multiple (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesThis study extended the results obtained by Patti and colleagues (Patti et al., 2003). Mootha and co-workers used Gene Set Enrichment Analysis, designed to detect modest but coordinated changes in the expression of groups of functionally related genes to study differential expression among healthy individuals, impaired glucose tolerance subjects, and subjects with T2DM (Mootha et al., 2003). They named OXPHOS-CR to a subset of genes, which include about two-thirds of the OXPHOS genes, strongly expressed in skeletal muscle, heart and brown adipose tissue.
No relationship was found between body mass index (BMI) or waist-to-hip ratio and OXPHOS-CR expression, and neither between quantitative measures of fiber types and OXPHOS-CR. However, expression of OXPHOS-CR correlated positively with the aerobic capacity of the individuals under study and negatively to diabetes. In summary, a set of genes involved in oxidative phosphorylation, whose expression was coordinately decreased in skeletal muscle of T2DM subjects, were identified. Thus, authors hypothesized that the decreased expression of OXPHOS-CR genes might contribute to T2DM. Impaired mitochondrial activity in insulin-resistant offspring of subjects with T2DMIn this study Petersen and co-workers aimed to determine the potential mechanism for the intra-myocellular accumulation of lipids leading to insulin resistance (Petersen et al., 2004). Young and lean insulin-resistant offspring of subjects with T2DM and insulin-sensitive subjects were studied.
To test their hypotheses, authors utilized hyperinsulinemic-euglycemic clamps in these subjects to measured intra-myocellular lipid and intrahepatic triglyceride content, assessed whole-body and subcutaneous fat lipolysis rates and determined mitochondrial oxidative-phosphorylation activity in muscle by magnetic resonance spectroscopy. The insulin-stimulated rate of glucose uptake was 60% lower in the insulin-resistant subjects, which could be explained by a 70% reduction in insulin-stimulated non-oxidative muscle glucose metabolism.
They also observed an 80% increase in intra-myocellular lipid content and a 30% reduction in mitochondrial oxidative phosphorylation, suggesting that subjects with T2DM have an inherited reduction in mitochondrial content in muscle, which in turn may be responsible for the reduced rates of mitochondrial oxidative phosphorylation. Putting the pieces together, the link between mitochondrial dysfunction and T2DMIn the year 2005 Drs.
Lowell and Shulman wrote a viewpoint where they hypothesized that insulin resistance and hyperglycemia could be caused by a primary mitochondrial dysfunction (Lowell and Shulman, 2005).
Insulin resistance occurs due to the accumulation of intracellular fatty acyl CoA and diacylglycerol, which in turn activate critical signal transduction pathways, leading to suppression of the insulin signaling pathway. DAG would then activate the phosphorylation of serines and threonines of the insulin receptor susbtrate 1 (IRS-1) through enzymes such as protein kinases C (PKC). PKCs activate the serine kinase cascade and increase the IRS-1 serine (Ser, S) phosphorylation of the the insulin receptor susbtrate 1 (IRS-1).
The phosphorylation of serines located in critical sites leads to a blockage of the IRS-1 tyrosines (Tyr, Y) phosphorylation by the insulin receptor, inhibiting insulin-induced phosphatidyl inositol 3-kinase activity (PI3-kinase) resulting in a decreased insulin-stimulated Akt activity. Akt reduced activity fails to activate the translocation of GLUT4 to the membrane, diminishing the insulin-induced glucose uptake and impairing the removing of glucose from blood.It is still uncertain whether skeletal muscle mitochondrial dysfunction is a cause or rather a consequence of the metabolic derangements that contribute to insulin resistance in T2DM, including lipid accummulation, pro-inflammatory signals or endoplasmic reticulum stress. However, given its complex pathophysiology, establishing causality has proved difficult and the mechanisms leading to insulin resistance remain elusive.7. These features, together with impaired energy substrate utilization and the observation that these deleterious effects are not restricted to skeletal muscle, led to the hypothesis that mitochondrial dysfunction plays a major role in T2DM etiology (Lowell and Shulman, 2005). Since the publication of this hypothesis, there has been a growing interest in further assessing the potential implication of mitochondrial function in the etiology of this metabolic disease. One of the first attempts to clearly prove this hypothesis used transgenic mice with defective mitochondria in order to observe whether they would develop T2DM (Pospisilik et al., 2007). Earlier reports from this same group have shown that conditional deletion of apoptosis inducing factor (AIF) provokes OXPHOS dysfunction (Vahsen et al., 2004). Initially, AIF was considered as a mitochondrial protein involved in signaling events leading to cell death.
Subsequent studies have demonstrated that the primary physiological role of AIF is the maintenance of an efficient mitochondrial respiratory system.
Studies assessing whole body glucose homeostasis and diet-induced obesity and diabetes either in tissue specific (liver and skeletal muscle) AIF knockout mice or in mice with ubiquitous OXPHOS defects showed that these mice were more insulin sensitive and were protected against diet-induced obesity and diabetes, in contrast with previous hypotheses (Pospisilik et al., 2007).
Recently, this observation has been confirmed in another study using rats fed with an iron-deficient diet, which provokes a reduction in the iron containing proteins of OXPHOS (Han et al., 2011). Controversy about the effects of high fat diet feeding in skeletal muscle oxidative capacityIn 2007, two different studies were published addressing whether a high fat diet (HFD) decreases or improves skeletal muscle mitochondrial oxidative capacity. In one (Garcia-Roves et al., 2007), rats were fed with a HFD during 4 weeks in order to raise circulating fatty acids and therefore to study the mechanisms that regulate the already reported improved fatty acid oxidation capacity of glycolytic skeletal muscle. Rats fed with the HFD regime showed higher fatty acids content, increased skeletal muscle fatty acid oxidative capacity in the epitrochlearis (glycolytic muscle), increased expression of enzymes of the fatty acid oxidation pathway and increased protein content of carboxylic acid cycle and OXPHOS system markers. Furthermore, this study showed that this metabolic adaptation occurs through activation of the peroxisome proliferated activated receptor delta (PPARdelta), a nuclear receptor responsible for regulating transcription of enzymes that belong to the fatty acid oxidation pathway and mitochondrial biogenesis process.
Fatty acids, mostly unsaturated, are ligands and activators of PPARs, which explain the metabolic regulations observed in this study (Garcia-Roves et al., 2007).
Similar results were published, almost simultaneously, by Cooney and colleagues in mice (Turner et al., 2007). In both periods of time HFD mice showed an increased capacity to oxidize fatty acid in skeletal muscle, concomitantly with an increased enzymatic activity of key proteins in the fatty acid oxidation pathway and higher protein content of different mitochondrial markers. Most importantly, these improvements in fatty acid handling and mitochondrial respiration in fat-fed mice occurred at the time these animals showed skeletal muscle insulin resistance and impaired whole body glucose handling (Turner et al., 2007).




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