2 Long-term Complications of Type 2 Diabetes HyperglycemiaDamage to mediumand large blood vesselsDamage to smallblood vesselsMacrovascular DiseaseMicrovascular DiseaseCoronary ArteryDiseaseCerebrovascularPeripheral vasculardiseaseRetinopathyNephropathyNeuropathyPatients with type 2 diabetes face an array of long-term complications that are responsible for the majority of the morbidity and mortality associated with type 2 diabetes. (1) The major long-term complications of type 2 diabetes include:Retinopathy: Damage to the retina of the eyeNephropathy: Damage to the kidneysNeuropathy: Damage to the nervesCardiovascular diseases: Coronary artery disease, cerebrovascular disease, and peripheral vascular disease.High blood glucose levels in type 2 diabetes can contribute to damage of small and large blood vessels throughout the body (2) resulting in microvascular and macrovascular complications. This figure (2) summarizes the development of long-term microvascular and macrovascular complications in patients with type 2 diabetes.Kasper DL, Fauci AS, Longo, DL, et al. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill Companies, Inc., 2005.Price SA, Wilson, LM. Pathophysiology: Clinical Concepts of Disease Processes. St Louis: Mosby, 2003.
3 Selected Glucose Regulatory Hormones InsulinSecreted by beta cells of pancreasDecreases glucose blood levels by facilitating glucose entry into certain cells to be used for energy or energy storageGlucagonSecreted by alpha cells of pancreasIncreases glucose blood levels via gluconeogenesis and glycogenolysis in the liverIncretinsGut hormones, release stimulated by food ingestionGlucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) are the predominant incretinsCortisolAn essential hormone produced by the adrenal glandsLevels rise with stress and lead to an increase in glucose levelsEpinephrine“Fight or flight” hormone produced by the adrenal glandsSomatostatinSecreted by the delta cells of the pancreasInhibits the release of many hormones including insulin, glucagon, and growth hormoneInsulinsecreted by beta-cells of pancreasdecreases glucose blood levels by facilitating glucose entry into certain cells for energy or storageGlucagonsecreted by alpha-cells of pancreasincreases glucose blood levels via hepatic gluconeogenesis in liver and glyogenolysis in liver and muscleIncretinsgut hormones, release stimulated by food ingestionglucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) are the predominant incretinsCortisolAn essential hormone produced by the adrenal glandsLevels rise with stress and lead to an increase in glucose levelsEpinephrine“Fight or flight” hormone produced by the adrenal glandsDorland’s Medical Dictionary WB Saunders.ndzSzdmd_c_57zPzhtmndzSzdmd_e_12zPzhtm3
4 Key Types of Lipids Triglycerides Cholesterol Lipoproteins Most common fat in diet and in the bodyMain role is energy storage in fat cellsComprised of 3 fatty acids and a glycerol moleculeCarried in the blood primarily by VLDLCholesterolFound in foods of animal originUsed to build cell membranes, steroid hormones, and bile saltsCarried in the blood by LDL and HDLLipoproteinsMolecules of lipid (triglycerides and cholesterol) assembled with proteinTransport vehicles for triglycerides and cholesterolLDL - low density lipoproteinHDL - high density lipoproteinVLDL - very low density lipoproteinLipids and Their Role in the BodyLipids, that is, fats, come from foods and are also made by the body (1). Lipids play important roles in the body, one of which is to store energy (2). Fats are used as the building blocks for essential cellular substances such as cell walls (2).Key types of circulating lipids include (2):triglyceridescholesterollipoproteins:. low-density lipoproteins (LDL). very-low-density lipoproteins (VLDL). high-density lipoproteins (HDL)TriglyceridesTriglycerides are the most common fat in our diet and the most common fat in the body (3). Triglycerides are molecules that are made of 3 fatty acids attached to a glycerol molecule backbone, as shown in Figure 4A (3). The main role of triglycerides is energy storage (2). Excess glucose, proteins, and other fats are all converted into triglycerides for storage (1). Triglycerides are primarily stored in fat cells in what is called fat or adipose tissue (2). Excess fat (obesity) is an established risk factor for type 2 diabetes (4). When triglycerides are needed for energy, they are first broken back down into glycerol and 3 fatty acids (2). The fatty acids, now called free fatty acids (FFA).are then transported to where they are needed for energy production (2).fatty acid: any of the saturated or unsaturated organic acids that have a single carboxyl group and usually an even number of carbon atoms; one component of triglycerides glycerol (gliscer-ol): a simple carbohydrate that serves as the backbone for triglycerides; attaches to 3 fatty acids to form a triglyceride adipose tissue (adci-pbs): fat tissuefree fatty acids (FFA): fatty acids that are bound to albumin and are in the bloodCholesterolCholesterol is found in foods such as many meats and egg yolks (1). However, a large proportion of cholesterol is synthesized in the body, primarily in the liver, from fatty acids (2), (1). The main role of cholesterol is to act as the building block of essential cellular substances, such as cell membranes, steroid hormones, and the bile salts that aid in the absorption of fat from the intestines (2). Just as excess triglycerides can be harmful, excess cholesterol can also be harmful. Excess cholesterol can be deposited in blood vessel walls, forming fatty plaques that increase the risk of coronary artery disease (1).LipoproteinsTriglycerides and cholesterol, because they are fats, do not dissolve in water (1). In order for triglycerides and cholesterol to be transported in the water-based blood, they are assembled with proteins called apoproteins (1). Several different apoproteins exist, and they are designated by the letters A, B, C, D, and E (for example, apo E), plus in some cases a number (for example, apo B 100) (1). The combination of lipid (triglyceride and cholesterol) and protein is called a lipoprotein (lipo = lipid, protein = protein) (1). Figure 4B illustrates the basic structure of a lipoprotein. Lipoproteins contain an inner core of triglycerides and cholesterol, and an outer shell of apoproteins and other molecules (1).Tortora GJ, Grabowski SR. Principles of Anatomy and Physiology. 10th ed. New York: John Wiley & Sons, Inc., 2003.Guyton AC, Hall JE. Textbook of Medical Physiology. 10th ed. Philadelphia, PA: W.B. Saunders Company, 2000.Wardlaw GM, Kessel MW. Perspectives in Nutrition. 5th ed. New York: McGraw-Hill Companies, Inc, 2002.Harmel AP, Mathur R. Davidson’s Diabetes Mellitus: Diagnosis and Treatment. 5th ed. Philadelphia, PA: Saunders, 2004.4
5 Lipid MetabolismIngested fats are broken into fatty acids and other compounds in the intestines via lipolysisFatty acids absorbed by the intestines are combined with glycerol to form triglycerides in a process termed lipogenesisOnce in the blood, the triglycerides are broken back down into fatty acids and glycerolFatty acids areused for immediate energy productionORstored in the form of triglycerides for later energy useThe following are key steps in the normal metabolism of lipids. The first steps involve lipids that come from food, but once these lipids enter the bloodstream, they mix with lipids created in the body. In this sequence:Fat is broken down into fatty acids and other compounds in the intestines in a process termed lipolysis (lipo = lipid, lysis = breakdown) (1).Once absorbed through the intestine wall, the fatty acids are combined with glycerol to form triglycerides in a process termed lipogenesis (lipo = lipid, genesis = synthesis) (1).Once in the blood, the triglycerides are broken back down into fatty acids (now called free fatty acids) and glycerol (1).Muscle, fat, liver, and other cells absorb the free fatty acids and either (1):use them for immediate energy productionreform them into triglycerides and store them for later useThe liver has a central role in lipid metabolism, especially in terms of the production of cholesterol and triglycerides, and in transporting these lipids to other sites in the body that need them.The following are key events in this portion of lipid metabolism:The liver packages cholesterol and triglycerides.both those made in the liver and those sent to the liver.into VLDL, which are sent into the bloodstream (1).Triglycerides in the VLDL particles are broken down into fatty acids and glycerol, which are taken up by body cells and either used for energy production or reformed into triglycerides and stored for later use (1).lipolysis (li-polci-sis): the breakdown of lipidslipogenesis (lip-b-jenc_-sis): the synthesis of lipidsWhen VLDL is depleted of triglycerides, it is converted to cholesterol-rich LDL particles (1).LDL binds to receptors on body cells (especially liver cells), is taken into the cell, and is broken down into protein and cholesterol (1).Some LDL is taken up by scavenger cells that then deposit the cholesterol in the walls of blood vessels, forming lipid plaques (1).A final part of the lipid metabolic pathway involves HDL:HDL is produced and secreted by both the liver and the intestine (1)HDL, often referred to as the "good" cholesterol, is important for the transfer of cholesterol from body cells to plasma lipoproteins and the liver for elimination (2), (1).Wardlaw GM, Kessel MW. Perspectives in Nutrition. 5th ed. New York: McGraw-Hill Companies, Inc, 2002.Tortora GJ, Grabowski SR. Principles of Anatomy and Physiology. 10th ed. New York: John Wiley & Sons, Inc., 2003.5
6 Lipoproteins: Major Types LDL - Low-density lipoproteintransports about 75% of the cholesterol in the blood from the liver to the body tissues, where it is used for cell membranes, synthesis of steroid hormonesalso known as "bad cholesterol“ as it may deposit cholesterol in blood vessels, forming plaques that lead to coronary artery diseaseHDL - High-density lipoproteinremoves excess cholesterol from body cells and transports it to the liver for eliminationalso known as "good cholesterol" as it prevents accumulation of cholesterol in blood vessels and is associated with a reduced risk of coronary artery diseaseVLDL – Very Low-density lipoproteinformed in the liver and contain mostly lipids that are made in the bodytransports about 50% of the triglycerides synthesized in the liver to adipose tissue for storageLDLtransports about 75% of the total cholesterol in the blood (1)transports cholesterol from the liver to the body tissues, where it is used for cell membranes, synthesis of steroid hormones, etc (1)also known as "bad cholesterol" because when present in high levels, it deposits its cholesterol in blood vessels, forming plaques that lead to coronary (1)the composition of LDL affects its ability to form lipid plaques; small, dense LDL particles are more atherogenic than large "fluffy" LDL particles (2)HDLremoves excess cholesterol from body cells and transports it to the liver for elimination (1)also known as "good cholesterol" because it prevents accumulation of cholesterol and is associated with a reduced risk of coronary artery disease (1)VLDLformed in the liver and contain mostly lipids that are made in the body (1)transports about 50% of the triglycerides synthesized in the liver to adipose tissue for storage (1)when they deposit some of their triglycerides in adipose tissue, VLDL particles are converted to LDL (1)Tortora GJ, Grabowski SR. Principles of Anatomy and Physiology. 10th ed. New York: John Wiley & Sons, Inc.,American Diabetes Association. Position Statement: Dyslipidemia Management in Adults With Diabetes. Diabetes Care. Jan, 2004; 27(Suppl. 1): S68-S71.6
7 Glucose and Lipid Metabolism: Definitions of Key Terms fat; found almost exclusively in foods of animal origin and continuously synthesized in the bodyLipidthe breakdown of lipids (to produce energy)Lipolysisthe formation of lipids (to store energy)Lipogenesisbreakdown of glycogen to glucose (to produce energy)Glycogenolysisformation of glycogen from glucose (to store energy)Glycogenesisthe main form of carbohydrate storage primarily in the liver and muscle tissue; readily converted to glucose to satisfy its energy needsGlycogenthe breakdown of glucose (to produce energy)Glycolysisthe formation of new glucose from protein or fat (to store energy)Gluconeogenesisthe primary circulating sugar in the blood and the major energy source of the body – used to produce ATPGlucoseGlucose - a simple sugar occurring widely in most plant and animal tissue; the principal circulating sugar in the blood and themajor energy source of the bodygluconeogenesis - formation of new glucose from protein or fatglycolysis the metabolism of glucose to produce energyglycogen molecule that is the main form of carbohydrate storage; occurs primarily in the liver and muscle tissue; readily converted to glucose as needed by the body to satisfy its energy needsglycogenesis formation of glycogen from glucoseglycogenolysis breakdown of glycogen to glucoselipid- -fat; found almost exclusively in foods of animal origin and continuously synthesized in the bodylipogenesis the synthesis of lipidslipolysis - the breakdown of lipids7
8 Protein MetabolismIngested proteins are broken down into amino acids, absorbed into the blood, and taken up by cells of the bodyWithin cells, amino acids are used to synthesize other proteins the body needs.Proteins can be:Converted to fat or glycogen for energy storageBroken down and used to make glucose for energy needs (gluconeogenesis)Proteins fulfill a variety of key roles in the body, ranging from forming the structure of organs and muscles to acting as the enzymes that facilitate the chemical reactions of metabolism (1). When necessary, proteins can also be broken down for energy production (1).Proteins are synthesized from molecules called amino acids (1). Much like beads in a necklace, amino acids are linked together in long chains called peptides (1). Proteins are formed when one or more peptide chains are coiled and folded in configurations specific to each protein (2).Normal protein metabolism consists of the following steps, as shown in Figure 5A:When foods containing proteins (such as meats, fish, chicken, beans, etc) are consumed, the proteins are broken down into amino acids in the digestive tract (1).The process of breaking down proteins is termed proteolysis (proteo = protein, lysis = break down).Amino acids are absorbed into the blood and taken up by muscle and fat cells (1).Within the cells, these amino acids are used to synthesize other proteins that the cells need (1).Excess amino acids can be converted to fat (primarily) or glycogen for storage (1).Proteins can be broken down to amino acids that can be used to produce energy or to build glucose (gluconeogenesis) in the liver (1).Insulin affects protein metabolism by:promoting protein synthesis and storage (1)inhibiting protein breakdown (1)When insulin action is normal and glucose is transported into muscle, fat, and liver cells for energy, proteins are not needed for energy (1). Instead, they are used as enzymes, to form muscles and other organs, and in a variety of other key roles (1).Guyton AC, Hall JE. Textbook of Medical Physiology. 10th ed. Philadelphia, PA: W.B. Saunders Company, 2000.Wardlaw GM, Kessel MW. Perspectives in Nutrition. 5th ed. New York: McGraw-Hill Companies, Inc, 2002.8
9 Progression of Type 2 Diabetes: Nondiabetic State 1. Adequatebeta cellfunction2. Normalinsulinsensitivity3. AdequateplasmainsulinCore Defects in Type 2 DiabetesThe core defects in type 2 diabetes are (1):insulin resistanceinadequate insulin production by the beta-cells of the pancreas These 2 defects work in concert, with the development of diabetes as the result. It is thought that insulin resistance occurs first (2). However, by the time type 2 diabetes is diagnosed, both insulin resistance and inadequate insulin production by the beta-cells often exist. Therefore, it is impossible to say for certain which started the process. Most cases of type 2 diabetes develop gradually and may not be diagnosed for several years (3). The following figures illustrate that insulin resistance and inadequate insulin production progressively result in type 2 diabetes.Normal StateAs shown in Figure 2A:1. People without diabetes have normal glucose levels (termed euglycemia; eu = good, glyc = glucose, emia = blood).2. People without diabetes have adequate insulin levels. This means that their bodies secrete adequate amounts of insulin to facilitate the transport of glucose out of the bloodstream and into muscle, fat, and liver cells, thus keeping blood glucose levels normal.When the body is sensitive to insulin's effects, as opposed to being resistant to insulin's effects, one is considered to have normal insulin sensitivity.American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. Jan, 2005; 28(Suppl. 1): S4-S36.Harmel AP, Mathur R. Davidson’s Diabetes Mellitus: Diagnosis and Treatment. 5th ed. Philadelphia, PA: Saunders, 2004Harris MI, Klein R, Welborn, TA, et al. Onset of NIDDM occurs at Least 4-7 Yr Before Clinical Diagnosis. Diabetes Care. July, 1992; 15(7):4. Normalblood glucoseNormalGlucose LevelsFPG <100 mg/dLTime9
10 Progression of Type 2 Diabetes: Early Abnormalities in Deteriorating Glucose Homeostasis 3. Impaired beta cellfunction2. Hyperinsulinemia1. Decreasedinsulin sensitivity4. NormalInsulin Resistance BeginsFigure 2B shows the early stages of the pathogenesis of type 2 diabetes:1. In individuals who will eventually develop type 2 diabetes, one of the early stages in the development of this disease is that the muscle, fat, and liver cells become less sensitive to (resistant to) the effects of insulin (1). This means that insulin is less effective at facilitating the transport of glucose into muscle, fat, and liver cells. Insulin sensitivity begins to decrease.Because muscle, fat, and liver cells are resistant to the effects of insulin, the beta-cells of the pancreas must produce a greater amount of insulin to keep the blood glucose levels normal (1), (2). Therefore, the amount of insulin in the blood begins to rise (1), (2).Initially, the body responds to the increased amount of insulin and is able to move an appropriate amount of glucose into the cells (1). Thus, blood glucose levels remain relatively normal (1), (2).Harmel AP, Mathur R. Davidson’s Diabetes Mellitus: Diagnosis and Treatment. 5th ed. Philadelphia, PA: Saunders, 2004Kasper DL, Fauci AS, Longo, DL, et al. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw- Hill Companies, Inc., 2005blood glucoseNormalGlucose LevelsFPG <100 mg/dLTime10
11 Progression of Type 2 Diabetes: Prediabetes 2. Compensatoryhyperinsulinemia4. Beta celldysfunction3. Blood glucose rises1. DecreasingPrediabetesAs the disease progresses, insulin resistance worsens. As shown in Figure 2C:1. The body produces more and more insulin.resulting in hyperinsulinemia (hyper = high, insulin = insulin, emia = in the blood) (1).2. However, eventually even the increased insulin is unable to move enough glucose into the cells, and blood glucose levels start to rise above normal range (1). As noted previously, when glucose levels are higher than normal but not yet in the diabetic range, the individual can be described as having prediabetes, which is determined by IFG and IGT (2).3. The strain of producing extra insulin damages the beta-cells, and they start to produce less insulin (1). This decline in insulin production is termed beta-cell failure (1). As beta-cell failure occurs (1):1-the amount of insulin in the blood decreases2-the amount of glucose in the blood increases even moreHarmel AP, Mathur R. Davidson’s Diabetes Mellitus: Diagnosis and Treatment. 5th ed. Philadelphia, PA: Saunders, 2004American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. Jan, 2005; 28(Suppl. 1): S4-S36.insulin sensitivityNormalPrediabetesGlucose LevelsGlucose LevelsFPG <100 mg/dLIFG = FPG = 100 to 125 mg/dLIGT = OGTT = 140 to 199 mg/dLTime11
12 Progression of Type 2 Diabetes: Type 2 Diabetes 1. Hyperglycemia3. Declining insulin levels2. Progressive beta cell failure5. Beta cell failureAt some point, the plasma glucose levels rise above the normal range, resulting in hyperglycemia (Figure 2D) (1). A patient is diagnosed with type 2 diabetes when hyperglycemia reaches (2):1) >126 mg/dL when the glucose is measured as a fasting plasma glucose (FPG)2) >200 mg/dL when the glucose is measured during an oral glucose tolerance testIf left untreated, type 2 diabetes progresses, with greater beta-cell failure, and increasing hyperglycemia (1).Harmel AP, Mathur R. Davidson’s Diabetes Mellitus: Diagnosis and Treatment. 5th ed. Philadelphia, PA: Saunders, 2004American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. Jan, 2005; 28(Suppl. 1): S4-S36.4. Decreasedinsulin sensitivitypersists or worsensNormalPrediabetesDiabetesGlucose LevelsGlucose LevelsGlucose LevelsFPG <100 mg/dLIFG = FPG = 100 to 125 mg/dL- Symptoms plusIGT = OGTT = 140 to 199 mg/dLcasual glucose≥200 mg/dL- FPG ≥126 mg/dL- OGTT ≥200 mg/dLTime12
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