Ashford University Physiology And Metabolism Clinical Exercise Paper

Ashford University Physiology And Metabolism Clinical Exercise Paper Ashford University Physiology And Metabolism Clinical Exercise Paper I need help answering these physiology questions – progression of type 2 diabetes from the below article the questions Over Defronzo article, stop at “Disharmonius quartet”) Ashford University Physiology And Metabolism Clinical Exercise Paper questions_.docx defronzo_ban Question 11 pts What would you expect to see first in the earliest phase of the onset and progression of type 2 diabetes (long before diabetes is diagnosed)? Group of answer choices High blood glucose Low blood glucose High blood insulin Low blood insulin Flag this Question Question 23 pts Which 3 tissues of the body are pathological in type 2 diabetes (Choose 3; aka: the triumvirate) Group of answer choices Bone Central nervous system Pancreas Skeletal muscle Skin Small intestine Thyroid gland Adrenal gland Liver Flag this Question Question 31 pts If the liver is not responding to insulin like it is supposed to after a meal what will it do? Group of answer choices Stop releasing glucose into the blood Start making glycogen Start breaking down fat Release amino acids into the blood Continue releasing glucose into the blood Flag this Question Question 41 pts What part of the body releases insulin? Group of answer choices Beta cells of the pancreas Alpha cells of the pancreas Beta cells of the liver Alpha cells of the liver Beta cells of the adrenal gland Flag this Question Question 51 pts By the time that diabetes is diagnosed how much of the function of the cells that make and release insulin (in #4) is left? Write the percentage: Paragraph: Question 61 pts Which organ is responsible for maintaining blood glucose levels for the brain during fasting by releasing the right amount of glucose into the blood? Group of answer choices Pancreas Liver Muscle Brain Stomach Question 71 pts Type 2 diabetes is a disease in which genetics do not play a role and the whole development of the disease can be linked to lifestyle. Group of answer choices True False Question 81 pts When working properly what effect is insulin supposed to have (after binding to a cell membrane) on endothelial nitric oxide synthase (eNOS: the enzyme that makes nitric oxide)? Paragraph: BANTING LECTURE From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus Ralph A. DeFronzo I nsulin resistance in muscle and liver and ?-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the ?-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/nearmaximally insulin resistant and have lost over 80% of their ?-cell function. In addition to the muscle, liver, and ?-cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), ?-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3) therapy must be started early to prevent/slow the progressive ?-cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiatherogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves ?-cell function, and exerts antiatherogenic effects), and exenatide (which preserves ?-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of ?-cell function. NATURAL HISTORY OF TYPE 2 DIABETES The natural history of type 2 diabetes has been well described in multiple populations (1–16) (rev. in 17,18). Ashford University Physiology And Metabolism Clinical Exercise Paper ORDER NOW FOR CUSTOMIZED AND ORIGINAL NURSING PAPERS Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin (1,16,19 –24). In liver, the insulin resistance is manifested by an overproduction of glucose during the basal state despite the presence of fasting hyperinsulinemia (25) and an impaired suppression of hepatic glucose production (HGP) in response to insulin (26), as occurs following a meal (27). In muscle (19,26,28,29), the insulin resistance is manifest by imFrom the Diabetes Division, University of Texas Health Science Center, San Antonio, Texas. Corresponding author: Ralph A. DeFronzo, [email protected]. DOI: 10.2337/db09-9028 © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See -nc-nd/3.0/ for details. DIABETES, VOL. 58, APRIL 2009 paired glucose uptake following ingestion of a carbohydrate meal and results in postprandial hyperglycemia (27). Although the origins of the insulin resistance can be traced to their genetic background (17,20), the epidemic of diabetes that has enveloped westernized countries is related to the epidemic of obesity and physical inactivity (30). Both obesity (31) and decreased physical activity (32) are insulin-resistant states and, when added to the genetic burden of the insulin resistance, place a major stress on the pancreatic ?-cells to augment their secretion of insulin to offset the defect in insulin action (1,17). As long as the ?-cells are able to augment their secretion of insulin sufficiently to offset the insulin resistance, glucose tolerance remains normal (33). However, with time the ?-cells begin to fail and initially the postprandial plasma glucose levels and subsequently the fasting plasma glucose concentration begin to rise, leading to the onset of overt diabetes (1– 4,12,17,18,34). Collectively, the insulin resistance in muscle and liver and ?-cell failure have been referred to as the triumvirate (1) (Fig. 1). The resultant hyperglycemia and poor metabolic control may cause a further decline in insulin sensitivity, but it is the progressive ?-cell failure that determines the rate of disease progression. The natural history of type 2 diabetes described above (1) is depicted by a prospective study carried out by Felber and colleagues in Lausanne, Switzerland (35) (Fig. 2). Although the study was originally cross-sectional in nature, subjects were followed up for 6 years and shown to progress from one category of glucose intolerance to the next. All subjects had a euglycemic insulin clamp to measure tissue sensitivity to insulin and an oral glucose tolerance test (OGTT) to provide an overall measure of glucose homeostasis and ?-cell function. In lean subjects with normal glucose tolerance (NGT), the mean plasma glucose and insulin concentrations during the OGTT were 115 mg/dl and 62 ?U/ml, while the mean rate of insulinstimulated glucose disposal (measured with a 40 mU/m2 per min euglycemic insulin clamp) was 265 mg/m2 per min. Obesity was associated with a 29% decline in insulin sensitivity, but glucose tolerance remained perfectly normal because of the compensatory increase in insulin secretion. With time the obese NGT individuals progressed to IGT in association with a further 28% reduction in insulin sensitivity (total decrease ? 57% from NGT to IGT). However, the rise in plasma glucose concentration was quite modest because of a further compensatory increase in insulin secretion. However, people with IGT are in a very precarious position. They are maximally or nearmaximally insulin resistant, and their ?-cells are functioning at less than maximum capacity. With time the ?-cells cannot continue to produce these very large amounts of insulin and the obese IGT individual progresses to overt diabetes. The decline in glucose tolerance is associated with a marked decrease in insulin secretion without 773 BANTING LECTURE FIG. 1. Pathogenesis of type 2 diabetes: the triumvirate. Insulin resistance in muscle and liver and impaired insulin secretion represent the core defects in type 2 diabetes (1). See text for a more detailed explanation. further change in insulin sensitivity (Fig. 2). This characteristic rise in insulin response to insulin resistance and hyperglycemia, followed by a subsequent decline, has been referred to as Starling’s curve of the pancreas (1). This natural history of type 2 diabetes has been demonstrated in many prospective studies carried out in many diverse ethnic populations (1–18,36,37). Although the relative contributions of insulin resistance and ?-cell failure to the development of type 2 diabetes may differ in different ethnic groups (38), the onset and pace of ?-cell failure determines the rate of progression of hyperglycemia. ?-CELL FUNCTION Although the plasma insulin response to the development of insulin resistance typically is increased during the natural history of type 2 diabetes (Fig. 2), this does not mean that the ?-cell is functioning normally. To the contrary, recent studies from our group have demonstrated that the onset of ?-cell failure occurs much earlier and is more severe than previously appreciated. In the San Antonio Metabolism (SAM) study and the Veterans Administration Genetic Epidemiology Study (VAGES), we examined a large number of subjects with NGT (n ? 318), IGT (n ? 259), and type 2 diabetes (n ? 201) (39 – 42). All subjects had an OGTT with plasma glucose and insulin concentrations measured every 15 min to evaluate overall FIG. 2. Natural history of type 2 diabetes. The plasma insulin response (E) depicts the classic Starling’s curve of the pancreas (1). See text for a more detailed explanation. F, insulin-mediated glucose uptake (top panel). 774 FIG. 3. Insulin secretion/insulin resistance (disposition) index (?I/ ?G ? IR) in individuals with NGT, IGT, and type 2 diabetes (T2DM) as a function of the 2-h plasma glucose (PG) concentration in lean and obese subjects (39 – 42). glucose tolerance and ?-cell function and a euglycemic insulin clamp to measure insulin sensitivity. It now is recognized that simply measuring the plasma insulin response to a glucose challenge does not provide a valid index of ?-cell function (43). The ?-cell responds to an increment in glucose (?G) with an increment in insulin (?I) (43). Thus, a better measure of ?-cell function is ?I/?G. However, the ?-cell also is keenly aware of the body’s sensitivity to insulin and adjusts its secretion of insulin to maintain normoglycemia (33,43– 45). Thus, the gold standard for measuring ?-cell function is the insulin secretion/insulin resistance (?I/?G ÷ IR), or so called disposition, index. Note that insulin resistance is the inverse of insulin sensitivity. Supplemental Fig. A1 (available in an online appendix at cgi/content/full/db09-9028/DC1) displays the glucose area under the curve (AUC) and insulin AUC in NGT, IGT, and type 2 diabetic subjects who participated in VAGES and SAM. In the right panel, the typical inverted U-shaped or Starling’s curve of the pancreas for the plasma insulin response is evident. Although subjects with IGT have an increase in the absolute plasma insulin concentration, this should not be interpreted to mean that the ?-cells in these individuals are functioning normally. Ashford University Physiology And Metabolism Clinical Exercise Paper Figure 3 depicts the insulin secretion/insulin resistance index (?I/?G ÷ IR) in NGT, IGT, and type 2 diabetic subjects as a function of the 2-h plasma glucose concentration during the OGTT. If a 2-h plasma glucose ?140 mg/dl is considered to represent “normal” glucose tolerance, subjects in the upper tertile (2-h PG ? 120 –139 mg/dl) have lost two-thirds of their ?-cell function (see arrow in Fig. 3). Most disturbingly, subjects in the upper tertile of IGT (2-h PG ? 180 –199 mg/dl) have lost 80 – 85% of their ?-cell function (see second arrow in Fig. 3). Although not commented upon, similar conclusions can be reached from data in previous publications (2,3,7,15). The therapeutic implications of these findings are readily evident. By the time that the diagnosis of diabetes is made, the patient has lost over 80% of his/her ?-cell function, and it is essential that the physician intervene aggressively with therapies known to correct known pathophysiological disturbances in ?-cell function. In biomedical phenomena, most reactions take place as a log function. Figure 4 depicts the natural log of the 2-h plasma glucose concentration during the OGTT as a function of the natural log of the insulin secretion/insulin resistance (?-cell function) index. These two variables are DIABETES, VOL. 58, APRIL 2009 R.A. DEFRONZO In summary, individuals with IGT are maximally or nearmaximally insulin resistant, they have lost 80% of their ?-cell function, and they have an approximate 10% incidence of diabetic retinopathy. By both pathophysiological and clinical standpoints, these pre-diabetic individuals with IGT should be considered to have type 2 diabetes. The clinical implications of these findings for the treatment of type 2 diabetes are that the physician must intervene early, at the stage of IGT or IFG, with interventions that target pathogenic mechanisms known to promote ?-cell failure. PATHOGENESIS OF ?-CELL FAILURE (SUPPLEMENTAL FIG. A2) FIG. 4. Natural log of the 2-h plasma glucose (PG) concentration versus natural log of the insulin secretion/insulin resistance index (measure of ?-cell function) (39 – 42). T2DM, type 2 diabetes. strongly and linearly related with an r value of 0.91 (P ? 0.00001). There are no cut points that distinguish NGT from IGT from type 2 diabetes. Rather, glucose intolerance is a continuum, and subjects simply move up and down this curve as a function of the insulin secretion/insulin resistance index. Therefore, the current diagnostic criteria (46) for IGT and type 2 diabetes are quite arbitrary and, like plasma cholesterol, glucose tolerance should be viewed as a continuum of risk. The higher the 2-h plasma glucose concentration, even within the range of IGT, the greater is the risk for microvascular complications (see subsequent discussion). Even more ominous are the observations of Butler et al. (47). In a postmortem analysis, these investigators quantitated relative ?-cell volume and related it to the fasting plasma glucose concentration. As individuals progressed from NGT to impaired fasting glucose (IFG), there was a 50% decline in ?-cell volume, suggesting a significant loss of ?-cell mass long before the onset of type 2 diabetes. With the progression to overt diabetes, there was a further and significant loss of ?-cell volume. Although ?-cell volume should not be viewed to be synonymous with ?-cell mass, these results suggest that significant loss of ?-cell mass occurs long before the onset of type 2 diabetes, according to current diagnostic criteria (46). In summary, our findings (40 – 42) demonstrate that, at the stage of IGT, individuals have lost over 80% of their ?-cell function, while the results of Butler et al. (47) suggest that subjects with “pre-diabetes” have lost approximately half of their ?-cell volume. “PRE-DIABETES” The recently published results of the Diabetes Prevention Program (DPP) (48) have raised further concern about the clinical implications of the term “pre-diabetes.” In the DPP, individuals who entered with a diagnosis of IGT and still had IGT 3 years later had a 7.9% incidence of background diabetic retinopathy at the time of study end. Individuals who entered the DPP with IGT but who progressed to diabetes after 3 years had a 12.6% incidence of diabetic retinopathy at the time of study end. Moreover, these IGT individuals developed diabetic retinopathy with an A1C of 5.9 and 6.1%, respectively, values much less than the current American Diabetes Association (ADA) treatment goal of 7% (49). Peripheral neuropathy also is a common finding in IGT, occurring in as many as 5–10% individuals (50,51). DIABETES, VOL. 58, APRIL 2009 Age. Ashford University Physiology And Metabolism Clinical Exercise Paper Advancing age plays an important role in the progressive ?-cell failure that characterizes type 2 diabetes. Numerous studies (52–54) have demonstrated a progressive age-related decline in ?-cell function. This is consistent with the well-established observation that the incidence of diabetes increases progressively with advancing age. Genes. ?-Cell failure also clusters in families, and studies in first-degree relatives of type 2 diabetic parents and in twins have provided strong evidence for the genetic basis of the ?-cell dysfunction (55–58). Impaired insulin secretion has been shown to be an inherited trait in Finnish families with type 2 diabetes with evidence for a susceptibility locus on chromosome 12 (59). Most recently, a number of genes associated with ?-cell dysfunction in type 2 diabetic individuals have been described (20,60 – 62). Of these genes, the transcription factor TCF7L2 is best established (60,61). Studies by Groop and colleagues (63) have shown that the T-allele of single nucleotide polymorphism rs7903146 of the TCF7L2 gene is associated with impaired insulin secretion in vivo and reduced responsiveness to glucagon-like peptide 1 (GLP-1). Both the CT and TT genotypes predict type 2 diabetes in multiple ethnic groups (64). In both the Malmo and Botnia studies, presence of either the CT or TT genotype was associated with a significant reduction in the diabetes-free survival time, with odds ratios of 1.58 and 1.61, respectively (63). TCF7L2 encodes for a transcription factor involved in Wnt signaling, which plays a central role in the regulation of ?-cell proliferation and insulin secretion (65). Unfortunately, at present there are no known therapeutic interventions that can reverse either the age-related decline or genetic-related factors responsible for impaired insulin secretion. However, there are a number of causes of ?-cell failure that can be reversed or ameliorated. Insulin resistance. Insulin resistance, by placing an increased demand on the ?-cell to hypersecrete insulin, also plays an important role in the progressive ?-cell failure of type 2 diabetes. Therefore, interventions aimed at enhancing insulin sensitivity are of paramount importance. The precise mechanism(s) via which insulin resistance leads to ?-cell failure remain(s) unknown. It commonly is stated that the ?-cell, by being forced to continuously hypersecrete insulin, eventually wears out. Although simplistic in nature, this explanation lacks a mechanistic cause. An alternate hypothesis, for which considerable evidence exists, is that the cause of the insulin resistance is also directly responsible for the ?-cell failure. Thus, just as excess deposition of fat (LC-fatty acyl CoAs, diacylglycerol, and ceramide) in liver and muscle has been shown to cause insulin resistance in these 775 BANTING LECTURE FIG. 5. Effect of physiological elevation (48 h) in the plasma FFA concentration (brought about by lipid infusion) on plasma C-peptide concentration (left) and insulin secretory response (deconvolution of the palsma C-peptide curve) (right) in offspring of two type 2 diabetic parents (24). organs, i.e., lipotoxicity, deposition of fat in the ?-cell leads to impaired insulin secretion and ?-cell failure (see subsequent discussion). Similarly, hypersecretion of islet amyloid polypeptide (IAPP), which is co-secreted in a one-to-one ratio with insulin, can lead to progressive ?-cell failure (see subsequent discussion). Lipotoxicity. Elevated plasma free fatty acid (FFA) levels impair insulin secretion, and this has been referred to as lipotoxicity (66,67). Studies from our laboratory (24) have shown that a physiological elevation of the plasma FFA concentration for …Ashford University Physiology And Metabolism Clinical Exercise Paper Get a 10 % discount on an order above $ 100 Use the following coupon code : NURSING10

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