2. Long-term Complications of Type 2 Diabetes
Hyperglycemia
Damage to medium
and large blood vessels
Damage to small
blood vessels
Macrovascular Disease
Microvascular Disease
Coronary Artery
Disease
Cerebrovascular
Peripheral vascular
disease
Retinopathy
Nephropathy
Neuropathy
Patients 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 eye
Nephropathy: Damage to the kidneys
Neuropathy: Damage to the nerves
Cardiovascular 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
Insulin
Secreted by beta cells of pancreas
Decreases glucose blood levels by facilitating glucose entry into certain cells to be used for energy or energy storage
Glucagon
Secreted by alpha cells of pancreas
Increases glucose blood levels via gluconeogenesis and glycogenolysis in the liver
Incretins
Gut hormones, release stimulated by food ingestion
Glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) are the predominant incretins
Cortisol
An essential hormone produced by the adrenal glands
Levels rise with stress and lead to an increase in glucose levels
Epinephrine
“Fight or flight” hormone produced by the adrenal glands
Somatostatin
Secreted by the delta cells of the pancreas
Inhibits the release of many hormones including insulin, glucagon, and growth hormone
Insulin
secreted by beta-cells of pancreas
decreases glucose blood levels by facilitating glucose entry into certain cells for energy or storage
Glucagon
secreted by alpha-cells of pancreas
increases glucose blood levels via hepatic gluconeogenesis in liver and glyogenolysis in liver and muscle
Incretins
gut hormones, release stimulated by food ingestion
glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) are the predominant incretins
Cortisol
An essential hormone produced by the adrenal glands
Levels rise with stress and lead to an increase in glucose levels
Epinephrine
“Fight or flight” hormone produced by the adrenal glands
Dorland’s Medical Dictionary WB Saunders.
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4. Key Types of Lipids Triglycerides Cholesterol Lipoproteins
Most common fat in diet and in the body
Main role is energy storage in fat cells
Comprised of 3 fatty acids and a glycerol molecule
Carried in the blood primarily by VLDL
Cholesterol
Found in foods of animal origin
Used to build cell membranes, steroid hormones, and bile salts
Carried in the blood by LDL and HDL
Lipoproteins
Molecules of lipid (triglycerides and cholesterol) assembled with protein
Transport vehicles for triglycerides and cholesterol
LDL - low density lipoprotein
HDL - high density lipoprotein
VLDL - very low density lipoprotein
Lipids and Their Role in the Body
Lipids, 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):
triglycerides
cholesterol
lipoproteins:
. low-density lipoproteins (LDL)
. very-low-density lipoproteins (VLDL)
. high-density lipoproteins (HDL)
Triglycerides
Triglycerides 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 tissue
free fatty acids (FFA): fatty acids that are bound to albumin and are in the blood
Cholesterol
Cholesterol 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).
Lipoproteins
Triglycerides 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 Metabolism
Ingested fats are broken into fatty acids and other compounds in the intestines via lipolysis
Fatty acids absorbed by the intestines are combined with glycerol to form triglycerides in a process termed lipogenesis
Once in the blood, the triglycerides are broken back down into fatty acids and glycerol
Fatty acids are
used for immediate energy production OR
stored in the form of triglycerides for later energy use
The 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 production
reform them into triglycerides and store them for later use
The 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 lipids
lipogenesis (lip-b-jenc_-sis): the synthesis of lipids
When 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 lipoprotein
transports 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 hormones
also known as "bad cholesterol“ as it may deposit cholesterol in blood vessels, forming plaques that lead to coronary artery disease
HDL - High-density lipoprotein
removes excess cholesterol from body cells and transports it to the liver for elimination
also known as "good cholesterol" as it prevents accumulation of cholesterol in blood vessels and is associated with a reduced risk of coronary artery disease
VLDL – Very Low-density lipoprotein
formed in the liver and contain mostly lipids that are made in the body
transports about 50% of the triglycerides synthesized in the liver to adipose tissue for storage
LDL
transports 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)
HDL
removes 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)
VLDL
formed 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 body
Lipid
the breakdown of lipids (to produce energy)‏
Lipolysis
the formation of lipids (to store energy)‏
Lipogenesis
breakdown of glycogen to glucose (to produce energy)‏
Glycogenolysis
formation of glycogen from glucose (to store energy)‏
Glycogenesis
the main form of carbohydrate storage primarily in the liver and muscle tissue; readily converted to glucose to satisfy its energy needs
Glycogen
the breakdown of glucose (to produce energy)‏
Glycolysis
the formation of new glucose from protein or fat (to store energy)‏
Gluconeogenesis
the primary circulating sugar in the blood and the major energy source of the body – used to produce ATP
Glucose
Glucose - a simple sugar occurring widely in most plant and animal tissue; the principal circulating sugar in the blood and the
major energy source of the body
gluconeogenesis - formation of new glucose from protein or fat
glycolysis the metabolism of glucose to produce energy
glycogen 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 needs
glycogenesis formation of glycogen from glucose
glycogenolysis breakdown of glycogen to glucose
lipid- -fat; found almost exclusively in foods of animal origin and continuously synthesized in the body
lipogenesis the synthesis of lipids
lipolysis - the breakdown of lipids 7

8. Protein Metabolism
Ingested proteins are broken down into amino acids, absorbed into the blood, and taken up by cells of the body
Within cells, amino acids are used to synthesize other proteins the body needs.
Proteins can be:
Converted to fat or glycogen for energy storage
Broken 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. Adequate
beta cell
function
2. Normal
insulin
sensitivity
3. Adequate
plasma
insulin
Core Defects in Type 2 Diabetes
The core defects in type 2 diabetes are (1):
insulin resistance
inadequate 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 State
As 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, 2004
Harris 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. Normal
blood glucose
Normal
Glucose Levels
FPG <100 mg/dL
Time 9

10. Progression of Type 2 Diabetes: Early Abnormalities in Deteriorating Glucose Homeostasis
3. Impaired beta cell
function
2. Hyperinsulinemia
1. Decreased
insulin sensitivity
4. Normal
Insulin Resistance Begins
Figure 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, 2004
Kasper DL, Fauci AS, Longo, DL, et al. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw- Hill Companies, Inc., 2005
blood glucose
Normal
Glucose Levels
FPG <100 mg/dL
Time 10

11. Progression of Type 2 Diabetes: Prediabetes
2. Compensatory
hyperinsulinemia
4. Beta cell
dysfunction
3. Blood glucose rises
1. Decreasing
Prediabetes
As 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 decreases
2-the amount of glucose in the blood increases even more
Harmel AP, Mathur R. Davidson’s Diabetes Mellitus: Diagnosis and Treatment. 5th ed. Philadelphia, PA: Saunders, 2004
American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. Jan, 2005; 28(Suppl. 1): S4-S36.
insulin sensitivity
Normal
Prediabetes
Glucose Levels
Glucose Levels
FPG <100 mg/dL
IFG = FPG = 100 to 125 mg/dL
IGT = OGTT = 140 to 199 mg/dL
Time 11

12. Progression of Type 2 Diabetes: Type 2 Diabetes
1. Hyperglycemia
3. Declining insulin levels
2. Progressive beta cell failure
5. Beta cell failure
At 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 test
If 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, 2004
American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. Jan, 2005; 28(Suppl. 1): S4-S36.
4. Decreased
insulin sensitivity
persists or worsens
Normal
Prediabetes
Diabetes
Glucose Levels
Glucose Levels
Glucose Levels
FPG <100 mg/dL
IFG = FPG = 100 to 125 mg/dL
- Symptoms plus
IGT = OGTT = 140 to 199 mg/dL
casual glucose
≥200 mg/dL
- FPG ≥126 mg/dL
- OGTT ≥200 mg/dL
Time 12