Pathophysiology

Diabetes: A Metabolic Disorder

Carbohydrate Metabolism

Carbohydrates (such as those in fruits, breads, cereals, and pasta) consist of one or more sugars. [Wardlaw, 2002] Following ingestion, carbohydrates are broken down into simple sugars. [Wardlaw, 2002] Glucose makes up about 80% of the simple sugars initially produced, and [Tortora, 2003] is the major and preferred fuel used by the body for energy. [Tortora, 2003; Guyton, 2000] Therefore, carbohydrate metabolism essentially refers to glucose metabolism. [Tortora, 2003]

Normal glucose homeostasis is accomplished through highly complex and integrated mechanisms involving interactions between the pancreas (eg, beta and alpha cells), hormones (eg, insulin and glucagon), and end organs (eg, muscle, fat, and liver).

Role of Insulin in Glucose Metabolism: Glucose Transport Into Cells When Glucose Levels Are Rising

Glucose must be transported into insulin-dependent cells to be available for immediate energy needs. Glucose in cells can also be stored in different forms (mainly glycogen) to be used for energy needs later. Glucose uptake into brain cells does not require insulin; however, most cells in the body, including muscle and fat cells, require insulin to facilitate glucose uptake. [Guyton, 2000]

After a meal, when glucose from carbohydrates becomes available and the blood glucose levels begin to rise, the following sequence of molecular events occurs during insulin-facilitated glucose transport (see figure below): [Guyton, 2000]

1. The beta cells of the pancreas produce and secrete insulin.
   
2. Insulin binds to a receptor on the cell surface (eg, muscle, fat, and other cells).
   
3. This binding activates the receptor.
   
4. The activated receptor signals glucose transporters (eg, GLUT4) to move from the interior of the cell (in the cytoplasm) to the cell surface.
   
5. GLUT4 transports glucose into the cell.
   
6. GLUT4 returns to the interior of the cell where it resides until signaled by insulin at a later time.

Insulin and Glucose Transport

As a consequence of these dynamic metabolic interactions, blood glucose levels return to normal, because:

• Insulin has facilitated the movement of glucose out of the blood and into peripheral tissues such as muscle and fat cells
  
• Insulin has inhibited the liver from making more glucose. [Guyton, 2000]

Glucose for Energy and Storage

Once inside the cells, glucose can either be used immediately for the production of energy or be transformed into storage molecules that can be used for energy later. [Guyton, 2000] The figure below illustrates the following 3 paths for utilization of glucose: [Guyton, 2000; Tortora, 2003]

1. If energy is needed immediately, glucose is metabolized to produce energy via glycolysis.
   
2. If more glucose is available than what the cells need immediately for energy, the extra glucose is converted to glycogen via a process called glycogenesis. Glycogenesis occurs primarily in liver cells and, to a limited extent, in muscle cells.
   
3. When glucose is not immediately required for energy and the storage capacity for glycogen is reached in the liver and muscle, additional glucose can be oxidized or converted to fat.

Three Paths for Glucose Utilization

From Guyton AC, Hall JE. Textbook of Medical Physiology. 10th ed. Philadelphia, Pa: WB Saunders Co; 2000:chapter 67.

Role of Glucagon in Glucose Metabolism: Glucose Production When Glucose Levels Are Falling

The figure below shows the following steps of glucose production when blood glucose levels are falling and available glucose has been used up: [Wardlaw, 2002; Guyton, 2000]

1. The alpha cells of the islets of the pancreas secrete glucagon.
2. Glucagon initiates 2 metabolic processes that together increase hepatic glucose production:
   • Glucagon causes the liver to break down glycogen into glucose (glycogenolysis).
   • Glucagon also causes the liver to synthesize new glucose from fats and proteins via gluconeogenesis.
3. This results in the release of glucose and raises blood glucose levels.

Glucose Production

Although glucagon is the main counter-regulatory hormone, catecholamines, growth hormone, and cortisol also protect against hypoglycemia. After meals, the cycle begins once more. Excess glucose is stored as glycogen in the liver, muscle, and fat tissues. However, unlike in the liver, the glycogen in muscle that is broken down into glucose is used for energy only and is not released into the general circulation and, thus, does not contribute to raising blood glucose levels.

Carbohydrate Metabolism in Diabetes

Core defects fundamental to the development of type 2 diabetes are progressive beta cell failure and insulin resistance. With progressive beta cell failure, there is insufficient insulin production from the beta cells to meet the body’s energy needs and blood glucose levels rise. With decreasing insulin sensitivity (or increasing insulin resistance), more insulin is required to transport glucose into cells of the body, and blood glucose levels rise. [Guyton, 2000]

In such situations of insulin insufficiency (ie, when glucose cannot be effectively transported into muscle, fat, and liver cells), the body mistakenly interprets the situation, and thus reacts as if there is a relative insufficiency of glucose available to “feed” these tissues [Guyton, 2000], even though the blood glucose levels are actually elevated. In response to this perceived glucose deficit, glucagon is secreted from the alpha cells of the pancreas to direct the liver to produce even more glucose. Thus, hepatic glucose output can be increased through the following pathways (see figure below): [Guyton, 2000]

1. An increase in glycogenolysis (breaking down glycogen to glucose) in the liver.
2. An increase in gluconeogenesis (synthesis of new glucose) in the liver.
3. A decrease in storage of glucose as glycogen (via glycogenesis) in the liver.
   

Carbohydrate Metabolism in Type 2 Diabetes

From Guyton AC, Hall JE. Textbook of Medical Physiology. 10th ed. Philadelphia, Pa: WB Saunders Co; 2000:chapter 68, 78. Powers AC. Diabetes mellitus. In: Kasper DL et al, eds. Harrison’s Principles of Internal Medicine. New York, NY: McGraw-Hill; 2005:chapter 323.

These dysregulated metabolic processes worsen hyperglycemia, leading to hyperglycemia associated with type 2 diabetes.

Lipid Metabolism

Lipids come from foods and are also synthesized. [Tortora, 2003] Lipids play many important roles in the body, one of which is to store energy. [Guyton, 2000] Key types of circulating lipids include cholesterol and triglycerides. [Guyton, 2000]

Cholesterol

Cholesterol is found in foods such as meat and egg yolks. [Tortora, 2003] However, a large proportion of cholesterol is synthesized in the body, primarily in the liver from fatty acids. [Tortora, 2003; Guyton, 2000] The main role of cholesterol is to act as the building block of essential cellular substances, such as cell membranes, steroid hormones, and bile salts that aid in the absorption of fat from the intestines. [Guyton, 2000]

Excess cholesterol can be deposited in blood vessel walls, forming fatty plaques that increase the risk of atherosclerosis. [Tortora, 2003]

Triglycerides

Triglycerides are the most common fat in the body and in our diet. [Wardlaw, 2002] Triglycerides are molecules that are made of three fatty acids attached to a glycerol molecule backbone (see figure below). [Wardlaw, 2002] The main role of triglycerides is energy storage. [Guyton, 2000] Excess glucose, proteins, and other fats are all converted into triglycerides for storage. [Tortora, 2003] Triglycerides are primarily stored in adipose tissue. [Guyton, 2000] When triglycerides are needed for energy, they are broken down into three fatty acids and glycerol. [Guyton, 2000] These fatty acids are then transported to where they are needed for energy production. [Guyton, 2000]

Triglycerides: Fatty Acids and Glycerol

Lipoproteins

In order for cholesterol and triglycerides to be transported in the blood, they are assembled with proteins into lipoproteins. [Tortora, 2003] The liver plays a central role in lipid metabolism, especially in the production of cholesterol and triglycerides and in facilitating the transport of these lipids to other sites in the body by packaging them as lipoproteins. Three important lipoproteins are:

• Very-low-density lipoprotein (VLDL): The liver packages cholesterol and triglycerides, both those made in the liver and those sent to the liver, into VLDLs, which are sent into the bloodstream. [Wardlaw, 2002; Tortora, 2003] In the blood, triglycerides in the VLDL particles are broken down and taken up by body cells and either used for energy production or reformed into triglycerides and stored for later use. [Wardlaw, 2002] VLDL particles are converted to LDL as some of the triglycerides are deposited in adipose tissue. [Tortora, 2003]

• Low-density lipoprotein (LDL): LDL provides cholesterol to the body tissues (especially liver cells), where it is used for cell membranes and synthesis of steroid hormones. [Tortora, 2003; Wardlaw, 2002] LDL may be taken up by scavenger cells that deposit the cholesterol in the walls of blood vessels, contributing to formation of lipid plaques. [Wardlaw, 2002]; Tortora, 2003]
• High-density lipoprotein (HDL): HDL transfers excess cholesterol from body cells to the liver for elimination. [Tortora, 2003] HDL can prevent accumulation of cholesterol in blood vessels and is associated with a reduced risk of atherosclerosis. [Tortora, 2003]

Overview of Lipid Metabolism

Normal lipid metabolism consists of the following key steps: [Wardlaw, 2002]

• Fat is broken down into fatty acids and other compounds in the intestines in a process termed lipolysis.
• Following absorption through the intestinal wall, the fatty acids are combined with glycerol to form triglycerides (lipogenesis).
• In the blood, the triglycerides are again broken down into fatty acids and glycerol to be absorbed by muscle, fat, liver, and other cells for immediate energy production or repackaged into triglycerides and stored for later use.

Insulin affects lipid metabolism by promoting synthesis of fatty acids in the liver and inhibiting breakdown of fat in adipose tissue. [Kahn, 2005]

Lipid Metabolism in Diabetes

When glucose uptake is reduced in patients with type 2 diabetes, cells turn to other sources of energy, such as free fatty acids and ketones. [Guyton, 2000] In this metabolic pathway: [Guyton, 2000]

• Triglycerides are broken down into free or nonesterified fatty acids and glycerol and are released into the bloodstream.
• Tissues throughout the body metabolize the free fatty acids for energy production.
• Excess fatty acids also trigger the liver to synthesize more triglyceride-rich VLDL and cholesterol-rich LDL.

Excess fat is stored as adipose tissue or in other tissues (eg, muscle) and contributes to obesity. Obesity is a risk factor for type 2 diabetes. [Harmel, 2004] Some research suggests that visceral fat puts patients at higher risk for developing type 2 diabetes and cardiovascular disease than does subcutaneous fat. [Wajchenberg, 2000]

Protein Metabolism

Proteins can: [Guyton, 2000]

• Form the structure of organs and muscles.
• Function as enzymes to facilitate the chemical reactions of metabolism.
• Be broken down for energy production when glucose is not available.

Proteins are synthesized from amino acids. [Guyton, 2000] Amino acids are linked together in long chains called polypeptides. [Guyton, 2000]

Normal protein metabolism consists of the following steps: [Guyton, 2000]

• Following a meal containing proteins (such as meat, fish, chicken, etc), the proteins are broken down into amino acids in the digestive tract (proteolysis).
• The amino acids are absorbed into the blood. After entering the bloodstream, amino acids are taken up by cells of the entire body, especially the liver.
• Within the cells, amino acids are used to synthesize other proteins that the cells need.
• In the liver, amino acids can be used to produce energy or be converted to glucose (gluconeogenesis).

Insulin affects protein metabolism by promoting protein synthesis and storage and inhibiting protein catabolism. [Guyton, 2000]

Protein Metabolism in Diabetes

In type 2 diabetes, glucose cannot be transported readily into muscle, fat, and other cells because of lack of sufficient insulin. These cells must find another source of energy. [Guyton, 2000] While free fatty acids and ketones are usually the next choice for energy production, some cells, particularly muscle cells, turn to amino acids as sources of energy. [Guyton, 2000]

The following steps of protein metabolism in diabetes are shown in the figure below: [Guyton, 2000]

1. When the body needs energy, and glucose and/or fat is not available, the breakdown of proteins for energy results in generation of amino acids.
2. Amino acids can then be used to produce more glucose, thereby contributing to hyperglycemia.
3. Amino acids can also be used directly for energy production.
4. Because insulin levels are not sufficient to promote protein storage, new proteins are not synthesized to replace the ones that are being catabolized into amino acids for energy. Without enough proteins to maintain and rebuild required tissues of the body, cachexia will eventually occur. Before insulin became available for the treatment of type 1 diabetes, profound cachexia was commonly seen in patients with type 1 diabetes and was frequently fatal. While patients with type 2 diabetes are often overweight, patients with uncontrolled type 2 diabetes experiencing progressive beta cell failure can suffer the loss of essential body tissue, leading to profound weight loss.

Protein Metabolism in Diabetes

Understanding the Pathogenesis of Type 2 Diabetes

Normal Islet Cell Physiology

Overview of the Pancreatic Islet

The pancreas is an organ that contains both exocrine and endocrine cells. The exocrine cells secrete digestive enzymes and the endocrine cells produce hormones. Only the endocrine cells are discussed here. The endocrine cells are organized into units called islets of Langerhans (see figure below). The islets of Langerhans contain several types of endocrine cells: alpha (α), beta (β), gamma (γ), and delta (δ) cells.

Pancreatic Islet

Beta and Alpha Cells in Pancreas of Healthy Subjects

The gamma and delta cells make up less than 10% of the endocrine cell mass in the pancreas Bonner-Weir, 2005] and also produce important substances:

• Gamma cells produce the hormone pancreatic polypeptide. Exogenous administration of pancreatic polypeptide reduces gastric acid secretion, mediated by cholecystokinin, and increases transit time in the intestine. [Cleaver, 2005]
• Delta cells produce the hormone somatostatin, which has inhibitory actions. [Ahrén, 2003] Somatostatin inhibits the secretion of growth hormone and thyrotropin at the level of the pituitary. In the pancreas, somatostatin inhibits the release of insulin, glucagon, and pancreatic polypeptide. [Ward, Beard, 1984]

Normal Glucose Homeostasis (Glucose Regulation)

Normal glucose regulation is dependent on a closed-feedback-loop relationship between the liver, peripheral tissue (mainly muscle and adipose), and the pancreatic islet cells that secrete insulin and glucagons. [Porte, 1995; Kahn, 2000] When intact, this delicate metabolic balance allows for periods of fasting without producing hypoglycemia:

• Normally functioning beta and alpha cells in the islets of the pancreas are critical to maintain normal glucose homeostasis (see figures below). Insulin increases and glucagon falls in response to meals in healthy nondiabetic subjects. [Woerle, 2003] Beta cells are poised to release insulin in response to even small increases in glucose. [Buse, 2003] The release of insulin from beta cells also helps suppress the release of glucagon from alpha cells, providing another control for preventing elevated glucose and maintaining glucose homeostasis. [Ahrén, 2003]
• Alpha cells perform the opposite function. They release glucagon when blood glucose levels fall in order to increase glucose output by the liver to help prevent hypoglycemia. [Shah, 2000; Mitrakou, 1992]

The figure below illustrates the following steps in the normalization of glucose when blood glucose levels rise during the fed state:

1. With feeding, glucose enters the bloodstream.
2. A rise in glucose level is detected by the beta cells in the pancreas. Beta cells respond to the rising blood glucose concentration by promptly releasing insulin. [Rhodes, 2005]
3. Insulin promotes glucose uptake to be used as energy or stored for later use. [Woerle, 2003]
4. Insulin also signals the liver to suppress gluconeogenesis.
5. In the fed state, glucagon is suppressed. [Guyton, 2000]
6. The suppression of glucagon contributes to a decrease in hepatic glucose production. [Porte, 1995; Kahn, 2000]
7. The net result is the lowering of blood glucose concentration.

Insulin and Glucagon Regulate Normal Glucose Homeostasis–Fed State

The figure below shows the following steps in the normalization of glucose when blood glucose levels fall during the fasting state:

1. In the fasting state (between meals, after an overnight fast, or in cases of starvation), glucose levels fall.
2. The alpha cells of the pancreas release glucagon. [Unger, 1971; Porte, 1995; Ahrén, 2003]
3. Glucagon directs the liver to convert glycogen into glucose (glycogenolysis) and to increase glucose synthesis (gluconeogenesis) and release this glucose into the bloodstream. Thus, there is an increase in hepatic glucose production.
4. There is also a decrease in insulin secretion by the beta cells of the pancreas.
5. In the fasting state, insulin secretion is suppressed. The suppression of glucose uptake by falling insulin levels contributes to an increase in blood glucose.
6. The net result is the rise of blood glucose concentration.

Insulin and Glucagon Regulate Normal Glucose Homeostasis–Fasting State

Role of Incretins in Glucose Homeostasis

In order for a hormone to qualify as an incretin, it must meet all three of the following established criteria: [Creutzfeldt, 2005]

• It must be released from the intestine in response to ingestion of food, particularly carbohydrates.
• The circulating concentration of the hormone must be sufficiently high in order to stimulate the release of insulin.
• The release of insulin by the physiologic levels of the hormone is glucose-dependent and occurs only at elevated glucose levels.

Two hormones, GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide, originally called gastric inhibitory peptide) fulfill these three criteria and are the incretins that play a major role in glucose homeostasis. [Creutzfeldt, 2005]

Synthesis and Metabolism of GLP-1 and GIP

GLP-1 is a product of the proglucagon gene that codes for several different proteins. As with many hormones, an inactive precursor is secreted and subsequently activated. Proglucagon is the large precursor protein molecule of the following biologically active hormones:

• Glucagon, a counter-regulatory hormone to insulin
• Glucagon-like peptide-1 (GLP-1), an incretin which regulates insulin secretion
• Glucagon-like peptide-2 (GLP-2), an intestinal growth factor which is not an incretin

Interestingly, the proteins that are encoded by the proglucagon gene have contrasting functions in the regulation of glucose metabolism in the fasting state compared with the fed state. Glucagon, which is produced by pancreatic alpha cells and also derived from proglucagon, mobilizes glucose from the liver (ie, hepatic glucose production) in the fasting state to increase blood glucose. When blood glucose levels are elevated, GLP-1 enhances insulin secretion from pancreatic beta cells and suppresses glucagon secretion from pancreatic alpha cells to lower blood glucose. [Kieffer, 1999]

The expression of GLP-1 in the L cells of the distal jejunum and ileum of the small intestine is closely linked to the intake of nutrients, especially glucose. When glucose and other nutrients come into direct contact with cells in the small intestine, hormonal and neural signals stimulate the L cells to secrete GLP-1. GLP-1 has a biphasic release mechanism: [Kieffer, 1999]

• The initial early release of GLP-1 is regulated by hormonal and neural factors. In the 15 to 30 minutes after ingestion of food, circulating levels of GLP-1 increase rapidly.
• The second phase of GLP-1 release, 30 to 60 minutes after food ingestion, appears to be mediated by direct interaction of nutrients with L cells.

GIP is a 42 amino acid protein secreted from the K cells in the duodenum of the small intestine after ingestion of a meal. [Meier, 2004] Active GIP (1-42) is a product of posttranslational processing of the proGIP gene.

The active forms of GLP-1 and GIP have very short biological half-lives. The half-life of GLP-1 is approximately 2 minutes and that of GIP is approximately 5 minutes. As shown in the figure below, the active forms of both the GLP-1 and GIP proteins are rapidly inactivated by the enzyme dipeptidyl peptidase 4 (or DPP-4). DPP-4 cleaves the first two amino acids at the N-terminus of each protein, rendering them inactive. [Meier, 2004; Ahrén, 2003]

GLP-1 and GIP Are Rapidly Metabolized by DPP-4

Although DPP-4 (also known as CD 26) belongs to a family of enzymes that is widely distributed in the body, it has highest activity in the kidney and the intestinal membrane. These sites coincide with the primary sites of secretion of GLP-1 and GIP in the gastrointestinal tract and the site of clearing in the kidney. DPP-4 is active when it is released into the bloodstream. DPP-4 enzymatically cleaves many other proteins (besides GLP-1 and GIP) that have a wide range of functions. [Ahrén, 2003]

Regulation of Insulin and Glucagon by GLP-1 and GIP

GLP-1 and GIP are both recognized as playing a role in maintaining glucose homeostasis. Under fasting conditions, the circulating levels of GLP-1 in the plasma are measurable but very low. Within 10 minutes of the intake of a meal, there is a rapid increase in GLP-1 secretion from the intestinal L cells. [Larsen, 2005]. Both GLP-1 and GIP are dependent on nutrient ingestion for release into the bloodstream. The figure below shows the following sequence of events in the release of gut hormones after meal ingestion. [Drucker, 2003; Ahrén, 2003; Holst, 2002]

1. Within minutes of ingestion of a meal, GLP-1 and GIP are released from the gut.
2. GLP-1 and GIP enhance insulin release from pancreatic beta cells in a glucose-dependent manner.
3. GLP-1, but not GIP, suppresses glucagon release from pancreatic alpha cells in a glucose-dependent manner.
4. An increase in glucose-dependent insulin secretion increases glucose uptake by muscle and other tissues and also decreases hepatic glucose production.
5. A decrease in glucose-dependent glucagon release also results in a decrease in hepatic glucose production.
6. The net result is the lowering of blood glucose levels.

Release of Gut Hormones After Meal Ingestion

The mechanism by which GLP-1 suppresses glucagon release involves both direct and indirect pathways: [Habener, 2005; Pfeifer, 1981]

• The direct pathway involves the interaction of GLP-1 with its receptor on pancreatic alpha cells. Further research in this area is ongoing.
• Indirect pathways include stimulation of insulin secretion (which subsequently suppresses glucagon) and stimulation of somatostatin secretion (by GLP-1 receptor activation on pancreatic delta cells).

A key understanding is that GLP-1 appears to promote an increase in insulin secretion from the beta cells and a decrease in glucagon secretion from the alpha cells when blood glucose levels are high.

Islet Cell Dysfunction

Overview of Beta and Alpha Cell Dysfunction

In type 2 diabetes, dysfunction of the beta cells manifested as impaired insulin secretion and decrease in insulin sensitivity manifested as an increase in insulin resistance contribute to hyperglycemia. [Ward, Bolgiano, 1984; Buse, 2003; Del Prato, Marchetti, 2004] Dysfunction of the alpha cells also occurs in the progression of type 2 diabetes as the ability of glucose to modulate glucagon secretion is impaired. [Del Prato, Marchetti, 2004] Unsuppressed glucagon levels lead to an increase in hepatic glucose production and consequently hyperglycemia. [Del Prato, Marchetti, 2004] With decreased secretion of insulin, there is less uptake of glucose by peripheral tissues (eg, muscle and adipose tissue), also leading to increased blood glucose levels. [Porte, 1995] Thus, the figure below shows that type 2 diabetes results from a progressive insulin secretory defect on the background of insulin resistance.

Pathophysiology of Type 2 Diabetes Includes Islet Cell Dysfunction and Insulin Resistance

In summary, islet cell dysfunction affects insulin secretion, glucose uptake by peripheral tissues, and hepatic glucose production. [DeFronzo, 1999; Porte, Kahn, 1995; DeFronzo, 1992]

Beta Cell Dysfunction

Evidence from clinical studies suggests that dysfunction of beta cells occurs early prior to the development of type 2 diabetes due to progressive beta cell dysfunction and failure. Some degree of beta cell dysfunction is apparent in first-degree relatives of patients with type 2 diabetes before the relatives develop diabetes, suggesting that beta cell dysfunction is integral to the development of type 2 diabetes. [UKPDS, 1995; Weyer, 1999; Del Prato, 2002]

Regarding alpha cell dysfunction, suppression of glucagon secretion is impaired in patients with impaired glucose tolerance (IGT). This, along with impaired insulin secretion (due to beta cell dysfunction), causes increased glucose in the systemic circulation, resulting in hyperglycemia. [Mitrakou, 1992] Lack of glucagon suppression worsens glucose tolerance, contributing to hyperglycemia in the fed state of patients with type 2 diabetes. [Shah, 2000] The concomitant increase in fasting plasma glucagon and impaired suppression of this hormone after ingestion of an oral glucose load or mixed meals are contributors to hyperglycemia in patients with type 2 diabetes. [Del Prato, Marchetti, 2004]

Functional Beta Cell Defects

Type 2 diabetes occurs as a result of absolute or relative insulin deficiency, usually in the presence of insulin resistance. When insulin resistance is present, the pancreas increases insulin output to maintain normal glucose tolerance. The higher levels of insulin production help maintain blood glucose levels in the normal range. Some have hypothesized that the continued high demand on the beta cell for insulin contributes to beta cell failure, but this has not been firmly established. In addition, Butler and colleagues showed that a substantial reduction in islet cell mass can cause insulin resistance in an animal model of diabetes. [Butler, 2004] Other factors such as genetics, glucotoxicity, and lipotoxicity may also contribute to impaired beta cell function. (These factors are discussed later.)

Beta cell dysfunction appears to progress over time even when diabetes is treated. [UKPDS, 1995] Many research methods exist for assessing beta cell function, but useful clinical tests for assessing beta cell function are limited. Some research methods for measuring beta cell function are: [UKPDS, 1995; Ward, 1987; Rhodes, 2005; Hermans, 1999]

• The HOMA (HOmeostasis Model Assessment) test is a method used to estimate beta cell function, insulin resistance, and insulin sensitivity from fasting blood samples. Depending on the specific equations that are used, beta cell function (HOMA %ß), insulin resistance (HOMA-IR), and insulin sensitivity, which is the reciprocal of insulin resistance (HOMA %S), can all be calculated using fasting plasma insulin and fasting plasma glucose values.
• The proinsulin/insulin ratio is indicative of beta cell dysfunction if the ratio is increased.
• The acute response to a glucose bolus during an intravenous glucose tolerance test—known as the acute insulin response to glucose, or AIRg—is among the simpler methods used to assess beta cell function in larger-scale clinical or epidemiologic studies.

Patients with type 2 diabetes whose glucose levels were intensively controlled in the United Kingdom Prospective Diabetes Study (UKPDS)—one of the largest prospective studies of patients with type 2 diabetes—still experienced a gradual deterioration in glycemic control and a rise in hemoglobin A1C (or A1C). When beta cell function was estimated by HOMA %ß, it was also found that progressively increasing hyperglycemia was associated with decreasing beta cell function regardless of the therapy given (see figure below). [UKPDS, 1998; UKPDS, 1995]

Progressive Impairment in Beta Cell Function Underlies Deterioration in Glucose Control

In the gradual transition to type 2 diabetes, many patients initially have normal glucose tolerance, which deteriorates progressively over several years. Often, insulin resistance is present but is generally not sufficient by itself to cause IGT, IFG, or type 2 diabetes. Many people with insulin resistance never develop diabetes. Many researchers believe the progression to type 2 diabetes requires beta cell failure; beta cells cannot secrete enough insulin to compensate for the degree of insulin resistance. In the figure below, the dramatic decline in beta cell function continuously through the progression to type 2 diabetes is contrasted with the depiction of insulin resistance, which tends to worsen only modestly over the same time period. Insulin resistance may exist alone without leading to type 2 diabetes, whereas beta cell dysfunction is essential to the development of type 2 diabetes. [Weyer, 1999; Del Prato, Marchetti, 2002; Saad, 1991; Cavaghan, 2000; Lillioja, 1993]

Beta Cell Dysfunction Is Integral to Development of Type 2 Diabetes

Thus, beta cell dysfunction is demonstrated to occur early prior to the development of type 2 diabetes and worsen after diagnosis, not necessarily following the pattern of change in insulin resistance.

In some studies, it has been shown that beta cell function continues to decline after diagnosis of type 2 diabetes, while insulin sensitivity remains relatively stable. [Levy, 1998] Evidence of the evolution of type 2 diabetes comes from the Belfast Diet Study. This was a prospective study of the natural history of type 2 diabetes in newly diagnosed patients. Patients who had failed diet therapy after 5 to 7 years are displayed in the figure below. The criteria for failure of diet therapy were: [Levy, 1998]

• Persistent weight loss below average weight accompanied by a fasting plasma glucose greater than 270 mg/dL. These patients were placed on insulin.
• Patients with or without symptoms at or above average weight with fasting plasma glucose greater than 198 mg/dL. These patients were placed on either tolbutamide 500 mg or metformin 500 mg twice daily.

The study demonstrated that there was a decline in beta cell function during the first 6 years of follow-up after diagnosis despite intensive dietary management, whereas insulin sensitivity remained relatively constant or declined only modestly. [Levy, 1998]

Beta Cell Function Declines After Diagnosis While Insulin Sensitivity Remains Relatively Stable

Beta cells in patients with type 2 diabetes exhibit both functional secretory defects and altered cell survival. [Marchetti, 2004; Buchanan, 2003; Deng, 2004; Rhodes, 2005] Functional beta cell changes in patients with type 2 diabetes include:

• Defective patterns of insulin release: Studies of patients with type 2 diabetes have demonstrated abnormal pulsatility of insulin response. Normally, insulin is released in pulses and oscillations. [Buchanan, 2003]
• Decreased insulin production: Histological studies of islets isolated from the pancreas of patients with type 2 diabetes showed reduced insulin content, decreased amount of mature insulin granules, and reduced insulin mRNA expression in beta cells. [Marchetti, 2004; Deng, 2004]
• Defects in beta cell responsiveness to hyperglycemia: In patients with type 2 diabetes, there is a reduction in the amount of insulin released in response to varying levels of blood glucose.
• Altered rates of conversion of the inactive form of insulin to the active form: Insulin is initially synthesized inside the cell in the form of proinsulin, a precursor of the hormone. Proinsulin is then cleaved at two different sites to form active insulin and C-peptide (see figure below). The proinsulin/insulin ratio is thought to be a measure of beta cell function; either conversion from proinsulin to insulin is impaired or secretion is so rapid that more proinsulin is released into the circulation before it can be converted. A resulting high proinsulin/insulin ratio suggests beta cell dysfunction, reflecting a defect in insulin processing. [Buchanan, 2003; Rhodes, 2005; Pfutzner, 2004]

Conversion of Proinsulin to Insulin and C-Peptide

Altered Beta Cell Survival

In addition to adequate beta cell function, adequate beta cell mass is also essential for normal glucose homeostasis. Beta cell mass is generally reduced in patients with long-standing type 2 diabetes, as opposed to an increased beta cell mass suggested in some research in obese patients without diabetes. Beta cell loss exceeds beta cell replacement (either by new cell production [ie, neogenesis] or cell proliferation [ie, division]) in the progression towards type 2 diabetes. [Butler, 2003]

Furthermore, there is secretion and extracellular deposition of the protein amyloid in the islets of the pancreas. The prevalence of amyloid in the pancreas has been noted to increase over time with the progression of diabetes as the beta cell mass declines [Butler, 2003]. The presence of these protein deposits in the pancreas serves as a marker for progressive beta cell dysfunction; [Butler, 2003] the role of amyloid is still under investigation. As a result of the loss of beta cell mass, there is a relative apparent increase in alpha cell mass in type 2 diabetes. [Del Prato, Marchetti, 2004]

Factors That Contribute to Beta Cell Dysfunction

There are multiple contributing factors to beta cell dysfunction in type 2 diabetes.

Environment

High caloric intake has been shown to increase oxidative tone and oxyradical-mediated injury, suggesting that it may induce beta cell damage. [Ramesh, 1996] In patients with type 2 diabetes, a sedentary lifestyle may be associated with lower beta cell function than a lifestyle that incorporates physical training; this has been demonstrated in patients who have a moderately reduced insulin secretory capacity but not those whose secretory capacity is already low. [Dela, 2004]

Aging

Aging is associated with a continuous decline in basal insulin secretion. A 25% decrease in fasting posthepatic insulin delivery rate has been observed between the ages of 18 and 85 years. Although body mass, insulin sensitivity, and other modifiable factors may help to sustain insulin release, they may also exacerbate the burden on beta-cell function and so increase the risk of beta-cell exhaustion. [Iozzo, 1999]

Genetics

There is a strong familial risk of developing type 2 diabetes. However, a single genetic cause of most cases of type 2 diabetes is unknown. With the exception of patients with known rare genetic mutations, it is unlikely that only one gene defect causes type 2 diabetes; rather, there are many genes involved (this is called polygenic etiology). Certain genetic backgrounds may be more susceptible to environmental triggers that initiate the progression from mild insulin resistance to glucose intolerance to the development of type 2 diabetes. [Buse, 2003] Some key findings in the genetics of type 2 diabetes are:

• Insulin response is diminished in first-degree relatives of patients with type 2 diabetes, suggesting that beta cell dysfunction may be genetically determined. First-degree relatives of patients with type 2 diabetes showed evidence of insulin resistance before they developed diabetes. [Buse, 2003]
• Maturity Onset Diabetes of the Young (MODY) is a specific subset of type 2 diabetes with onset at a younger age (usually before 25 years); this type of diabetes is not prone to develop ketosis. The genetic mutations that cause MODY affect various functions of the beta cells by causing changes in the expression of critical genes required for normal beta cell function, thus resulting in expression of type 2 diabetes at a younger age. [Hinke, 2004; Buse, 2003]

Glucotoxicity

In the short term, glucose stimulates an increase in the production and release of insulin. However, after chronic continuous exposure to hyperglycemia, insulin secretion can be inhibited. Normally, glucose is rapidly metabolized in cells, but prolonged exposure to high glucose levels appears to be associated with oxidative stress, which impairs the ability of these cells to tolerate and recover from the high glucose levels. Sustained hyperglycemia can turn off genes that protect the cell from death. [Steppel, 2004] Some specific mechanisms have been elucidated:

• Chronic hyperglycemia increases oxidative stress inside the cell and can shut down new insulin production. [Del Prato, 2004]
• Beta cells may be particularly susceptible to glucotoxicity due to a low level of activity of antioxidant enzymes in these cells. [Del Prato, 2004]
• Glucotoxicity may affect the expression of genes that are critical for making the components of the insulin secretory granules. Replenishment of the granules is critical for maintaining the insulin-secretory capacity of the beta cells. [Hinke, 2004]

Lipotoxicity

Lipotoxicity (i.e., hyperlipidemia or high fat levels in the blood) has been shown to cause reduced secretion of insulin in animals after prolonged exposure. [Steppel, 2004] Lipotoxicity also alters the proinsulin/insulin ratio, a measure of beta cell function. A high proinsulin/insulin ratio suggests beta cell dysfunction, reflecting a defect in insulin processing (biosynthesis) and secretion. Accumulation of lipids inside beta cells contributes to beta cell death since certain types of fatty acids can disrupt normal cell signaling. [Rhodes, 2005]

Lipotoxicity may act synergistically with glucotoxicity to diminish beta cell function, reduce insulin secretion, and promote cell death. [Rhodes, 2005]

Anatomic and Histopathologic Changes

There are several structural abnormalities in the islets of the pancreas that can be seen in type 2 diabetes. These include decreased beta cell mass [Butler, 2003; [Donath, 2004] and accumulation of interstitial amyloid deposits. Normally, beta cell mass is regulated by a balance between the formation and division of new cells and natural cell death. [Steppel, 2004] In type 2 diabetes, there is an imbalance between beta cell production and beta cell loss, resulting in greater destruction than production of beta cells. [Butler, 2003]

Abnormalities of Beta Cell Function in Type 2 Diabetes

Normal Insulin Dynamics

In individuals without type 2 diabetes (and who have normal-functioning beta cells), there are 2 distinct phases of insulin secretion, as demonstrated by the biphasic insulin response to an intravenous (IV) glucose load (see figure below). The first (early) phase consists of a rapid increase in insulin secretion that occurs immediately after exposure of the beta cells to IV glucose. This phase is brief and is followed by a return to near-basal levels within approximately 10 minutes. A second (late) phase consists of a sustained increase in insulin secretion that begins 10 to 20 minutes after exposure to glucose. This phase can last for several hours. It is partially due to the release of preformed insulin and partly a result of new insulin production or biosynthesis. [Pfeiffer, 1981; [Pratley, 2001]

Insulin Response to Intravenous Glucose Is Biphasic in Subjects Without Type 2 Diabetes

In people without diabetes, basal insulin is released in regular pulses every 8 to 15 minutes between meals and these pulses are superimposed on much longer oscillations. In patients with type 2 diabetes, the pulsatile pattern of insulin is disrupted, and the pulses are irregular and last for a shorter period of time. [Buchanan, 2003] Furthermore, the insulin pulses are not timed to follow the small changes in glucose levels as closely as they do in normal subjects. [Buse, 2003]

Abnormal Insulin Dynamics

Abnormalities in First-Phase Insulin Response

In patients with established type 2 diabetes, the first-phase insulin response is lost. In one study, the release of insulin from beta cells was measured after nondiabetic subjects and patients with type 2 diabetes were given intravenous injections of glucose (see figure below). Normal subjects showed a sharp first-phase insulin response. However, patients with type 2 diabetes showed an absent first-phase response, with preservation of the second-phase insulin response. [Ward, 1984 (1); [Pfeifer, 1981]

Insulin Response to Intravenous Glucose: First-Phase Insulin Response Is Lost in Type 2 Diabetes

First and Second Phase Insulin Responses to Incretins

In healthy subjects without diabetes, ingestion of a meal results in the rapid release of GLP-1 and GIP, a subsequent increase in glucose-dependent insulin secretion, and a decrease in blood glucose levels. [Quddusi, 2003; Vilsbøll, 2002] Furthermore, both the first and second phases of insulin secretion have been shown to be enhanced in studies in which healthy subjects without diabetes were administered an injection of GLP-1 or GIP. [Vilsbøll, 2002]

In patients with type 2 diabetes, GLP-1 and GIP infusions have been demonstrated to enhance the first phase of insulin secretion. However, in a study of 6 patients with type 2 diabetes, total insulin secretion was still lower than that of healthy subjects (see figure below). [Vilsbøll, 2002]

Effect of GLP-1 and GIP on First Phase Insulin Response

The timing of GLP-1 infusion can also affect the first phase insulin secretion. In a study of 9 subjects without diabetes and 9 patients with type 2 diabetes, pre-infusion of GLP-1 for three hours before the administration of glucose enhanced the insulin response in both groups, [Quddusi, 2003] and the GLP-1–stimulated increase in insulin secretion was significantly higher for the first phase insulin secretion.

In a study of 6 patients with type 2 diabetes, GLP-1, unlike GIP, also affected the second phase insulin response (see figure below).

Thus, pharmacologic doses of GLP-1 have been demonstrated experimentally to have a positive effect on both the first and second phases of insulin secretion. The ability of patients with type 2 diabetes to respond to the insulinotropic actions of GLP-1 appears to persist, although it may be diminished. [Nauck, 1993]

Effect of GLP-1 on Second Phase Insulin Response

Also shown in the figure above, infusion of GIP in this study did not have a significant effect on the second phase insulin response. This defective response to GIP could contribute to the pathogenesis of type 2 diabetes and may possibly be one of the defects in insulin secretion in these patients. [Vilsbøll, 2002] These data suggest that infusion of GIP has been demonstrated to improve the first phase insulin response but not the second phase insulin response.

Alteration in Proinsulin/Insulin Ratio

An increase in the proinsulin/insulin ratio is understood to be indicative of beta cell dysfunction (see figure below). The increased need for insulin appears to force the dysfunctional beta cells to release insulin molecules before they have been properly processed in an attempt to keep up with the increased need. [Ward, 1987]

Patients with Type 2 Diabetes Have Increased Ratio of Proinsulin to Insulin During Fasting

Decreased Beta Cell Responsiveness to Glucose

Insulin from the beta cells normally helps the body to store the excess glucose, thus keeping the glucose levels within normal limits. In type 2 diabetes, the insulin secretion from the beta cells is inadequate for the body’s needs, allowing blood glucose levels to rise after meals. In studies of subjects without diabetes but with relatives with type 2 diabetes or degrees of abnormal glucose tolerance where insulin sensitivity was similar, a number of insulin-secretory defects can be detected. A reduction in first-phase insulin responsiveness to IV glucose showed lower secretory response, demonstrating a progressive shifting of the glucose dose-response curve as glucose tolerance declines (see figure below). Insulin response profiles across extended time periods of oscillating IV glucose infusions showed impaired responsiveness to glucose in terms of magnitude, timing, and alignment of response. Thus, there is an impairment of the ability of the beta cells in patients with type 2 diabetes to detect and appropriately respond to IV glucose administration, which indicates decreased beta cell responsiveness to glucose. [Byrne, 1996] In one study, patients with type 2 diabetes secreted much less insulin than control subjects when the glucose infusion was adjusted to achieve a glucose concentration range between 90 mg/dL and 162 mg/dL. [Byrne, 1996]

Dose-Response Relationships Between Glucose and Insulin Secretory Rate
(Conceptual Schematic)

Glucagon/Insulin Dynamics

In healthy individuals, insulin levels rise and glucagon levels fall after a meal (see figure below). Insulin and glucagon are normally regulated such that when insulin levels rise, glucagon is suppressed.

Insulin Increases and Glucagon Falls in Response to Meals in Healthy Individuals

However, in individuals with type 2 diabetes, insulin and glucagon dynamics are abnormal (see figure below) [Müller, 1970; Del Prato, 2003]

• Glucose levels rise after a meal in both normal individuals and patients with type 2 diabetes, although the glucose levels are higher and the peaks, temporally delayed, are more sustained peaks in patients with type 2 diabetes. [Müller, 1970]
• The insulin responses to a meal are delayed and decreased in magnitude in patients with type 2 diabetes. [Del Prato, 2003; [Müller, 1970]
• Glucagon levels fall after a meal in normal individuals; however, glucagon levels fail to suppress in patients with type 2 diabetes. [Müller, 1970]

Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in Type 2 Diabetes

Thus, insulin secretion from beta cells is decreased and glucagon secretion from the alpha cells is not suppressed (and is increased) in type 2 diabetes.

Abnormalities in Alpha Cell Dysfunction and Impact of Unsuppressed Glucagon Levels

In type 2 diabetes, the loss of the first-phase insulin secretion plays a role in preventing normal suppression of glucagon; thus, the production of glucose in the liver continues unrestrained, further contributing to hyperglycemia after a meal. [Shah, 2000] Furthermore, the lowered levels of overnight secretion of insulin also allow glucagon activity to increase, allowing nighttime glucose levels to rise and contribute to fasting hyperglycemia. [Del Prato, 2004] In some studies, patients with type 2 diabetes have been shown to have higher glucagon concentrations not only postprandially, but also in the fasting state (see figure below). [Toft-Nielsen, 2001]

Fasting and Postprandial Glucagon Levels Are Elevated in Patients With Impaired Glucose Intolerance and Type 2 Diabetes

Insulin Resistance

Insulin resistance is widely accepted as an important contributor to the development of type 2 diabetes. However, according to our current understanding, insulin resistance alone is not sufficient to produce IGT, IFG, or type 2 diabetes. It is well established that people with insulin resistance, or obesity and insulin resistance, may never develop diabetes. Thus, the current understanding is that type 2 diabetes develops in the setting of insulin resistance only when some degree of beta cell failure is also present.

What Is Insulin Resistance?

The term insulin resistance indicates that the insulin produced results in a smaller-than-expected biologic response. [Kahn CR, 2005] The body’s response to the action of insulin is impaired and, thus, the body cannot use available insulin effectively. [Buse, 2003] Various kinds of tissue, such as muscle, liver, and fat, can express varying degrees of insulin resistance. Patients with insulin resistance require a higher-than-normal concentration of insulin to maintain normal glucose levels. The human pancreas normally secretes about 30 to 40 units of insulin each day. [Rosenthal, 1992] Patients with type 2 diabetes and marked insulin resistance may use doses of insulin that far exceed the amount of insulin secreted in healthy individuals without insulin resistance. [Rosenthal, 1992]

Beta cell response to hyperglycemia may contribute to insulin resistance by inducing continuous elevated basal secretion of insulin (hyperinsulinemia), which may desensitize insulin signaling pathways and may impair glucose disposal, particularly through glycogen synthesis. [Buse, 2003]

Hyperglycemia may contribute to a vicious circle whereby insulin secretion is increased but insulin resistance is also increased. The actual amount of insulin secreted can be elevated above levels observed in lean individuals without diabetes, but may not still be high enough to counteract hyperglycemia in type 2 diabetes. [DeFronzo, 1999]

Beta cell function is closely related to loss of insulin sensitivity. [Steppel, 2004; Kahn SE, 1993] The relationship between insulin sensitivity and beta cell function is illustrated as a conceptual schematic in the figure below. Note that the first-phase insulin response is used as a measure of beta cell function. The solid line (50th percentile) in the figure depicts the best-fit relationship, demonstrating that any change in insulin sensitivity is balanced by a reciprocal and proportionate change in beta cell function to maintain normoglycemia. [Kahn SE, 2003; Kahn SE, 1993] When insulin sensitivity is low (marked as A in the figure below), meaning that there is an increase in insulin resistance, increased amounts of insulin are required to bring glucose levels back to the normal range. [Steppel, 2004] The alternative is true when insulin sensitivity is high (marked as B in figure below). As their bodies work to keep glucose levels normal, people with low insulin sensitivity experience larger changes in insulin secretion than those with high sensitivity. The normal compensation for insulin resistance is an increase in insulin secretion by the beta cells. [Kahn SE, 1993] However, as beta cell dysfunction increases in people with low insulin sensitivity (or high insulin resistance), beta cells cannot keep up with the increased demand for insulin. [Steppel, 2004] Subjects below the 50th percentile demonstrate decreased beta cell function for the degree of insulin sensitivity. Subjects with increased beta cell function to respond are represented above the 50th percentile.

Relationship between Beta Cell Function and Insulin Sensitivity
(Conceptual Schematic)

Molecular Causes of Insulin Resistance

Insulin resistance is currently understood to be primarily a defect of glucose transport into cells. [Kahn BB, 2000] The number of glucose transporters is believed to be normal; however, movement of these transporters from the interior of the cell to the cell surface appears to be defective. [Kahn BB, 2000] There are also defects in insulin-signaling pathways and other factors controlling glucose and insulin responses, [DeFronzo, 1999] including reduced number and activity of insulin receptors and decreased activity of certain enzymes involved in glucose metabolism. [Kahn BB, 2000]; [Kahn CR, 2005] A full understanding of this complex physiology requires ongoing research.

Factors That Influence Insulin Resistance

Studies suggest that insulin resistance is influenced by a combination of factors such as genetics, ethnicity, age, obesity, lipotoxicity, high caloric diet, physical inactivity, and glucotoxicity. [Buse, 2003]

Genetics

Most patients with type 2 diabetes have some degree of insulin resistance, [Bogardus, 2002] but not all patients with insulin resistance have type 2 diabetes. [Kahn SE, 2003] Genetics is a factor that can influence insulin resistance, although the details of the mechanisms are not fully understood.

The Pima Indians of Arizona have the highest reported prevalence and incidence rates of type 2 diabetes in the world. [Bogardus, 2002] Pima Indians have been studied extensively by the National Institutes of Health since 1963, [DeMouy, 2005] and much of what we understand about the development of type 2 diabetes came from these studies. Insulin resistance is a predictor of the development of type 2 diabetes independent of other factors, and the most insulin-resistant Pima Indians are at the greatest risk of type 2 diabetes. [Bogardus, 2002] Defects in both insulin secretion and insulin action have been demonstrated in the progression from normal glucose tolerance to impaired glucose tolerance to type 2 diabetes in a longitudinal study of Pima Indians, indicating that both insulin secretion and insulin action are affected early in the development of type 2 diabetes. [Buse, 2003; [Weyer, 1999]

Obesity

Obesity, a significant contributor to insulin resistance, is influenced by both genetics and environment. [Kahn SE, 2003; Ravussin, 2000] One reason that obesity may be closely linked with type 2 diabetes is that obesity itself can promote insulin resistance [ADA Diagnosis, 2004; Harmel, 2004] through lipotoxicity and cytokine and hormonal activity of adipose tissue. Interestingly, studies have shown that patients can help reverse insulin resistance and improve control of their blood glucose levels by restricting caloric intake and increasing physical activity. [ADA Standards, 2005]

Recent evidence suggests that adipose tissue secretes a variety of mediators (e.g., cytokines and hormones) and expresses functionally active receptors (i.e., adrenergic and cholinergic). [Wajchenberg, 2000; Kahn CR, 2005] Some of these mediators may adversely affect insulin signaling, lipid accumulation, and insulin resistance. [Schinner, 2005] Cytokines such as adiponectin, leptin, and resistin are secreted by adipose tissues, and are often called adipocytokines (or adipokines) because they are cytokines secreted by adipocytes. Each of the cytokines mentioned is the object of much active research:

• Adiponectin is thought to be a protective cytokine hormone which enhances insulin sensitivity and increases clearance of fatty acids. [Dushay, 2005] Decreased levels of this hormone are associated with obesity and insulin resistance. [Hawkins, 2005] Conversely, high levels of adiponectin are associated with a decreased risk for the development of type 2 diabetes.
• Leptin is a cytokine that acts to inhibit food intake and enhance energy utilization. [Kahn CR, 2005]
• Resistin is a newly identified peptide hormone produced by adipocytes in rodents. Its role, if any, in maintenance of blood glucose levels and insulin action in humans is currently being explored. [Kahn CR, 2005]

A peptide hormone called ghrelin, which is secreted principally by the stomach, appears to exert effects opposite to those of leptin, including stimulation of appetite. In humans, obesity is associated with reduced ghrelin levels, suggesting that ghrelin helps regulate the neuroendocrine and metabolic response to starvation. [Muccioli, 2002; [Tschöp, 2001]

Visceral fat is thought to be more metabolically active than subcutaneous fat. [Collins, 2005] Visceral adipose depots also seem to have a particularly adverse role in lipid metabolism. They secrete a variety of inflammatory cytokines whose levels are increased in obesity. These inflammatory mediators are thought to contribute to insulin resistance and accelerate the complications of type 2 diabetes and atherosclerosis. [Hawkins, 2005] ; Dushay, 2005] These mediators include tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), transforming growth factor beta (TFG-β), C-reactive protein, platelet-activating factor, angiotensinogen, and resistin.

Lipotoxicity

Some evidence suggests that excess fat tissues and elevated fatty acids can further exacerbate carbohydrate metabolic abnormalities of type 2 diabetes. [Powers, 2005] This concept has been termed lipotoxicity. [Powers, 2005] Adipose tissue is not only a storage site for energy, but is also a metabolically active organ. Increased amounts of adipose tissues, as seen in obesity, release increased amounts of fatty acids. [Dushay, 2005] Excess fatty acids may increase hyperglycemia by:

• Interfering with glucose transport into the cell [Wajchenberg, 2000; [Roden, 1996]
• Increasing hepatic glucose production (by both glycogenolysis and gluconeogenesis) [Roden, 2000; Powers, 2005]
• Inhibiting insulin secretion by beta cells [Poitout, 2002; Powers, 2005]

Physical Inactivity

A sedentary lifestyle is a risk factor for insulin resistance [Rathmann, 2005] and type 2 diabetes. An effective way to improve insulin resistance is exercise, which has been shown to reduce insulin resistance in both animals and humans. Exercise addresses the primary defect of insulin resistance by enhancing the movement of glucose transporters from the interior of the cell to the cell surface. [Buse, 2003] The Diabetes Prevention Program Study showed that a combination of restricted caloric intake and increased physical activity can delay the progression to type 2 diabetes in those at risk. [Buse, 2003]

Glucotoxicity

Tissue dysfunction resulting from chronic hyperglycemia is a phenomenon termed glucotoxicity. [Leahy, 2005] Glucotoxicity can worsen insulin resistance and impair beta cell function. [Ruderman, 2005; [Kahn SE, 2003] Persistent hyperglycemia contributes to insulin resistance by [Ruderman, 2005]:

• Inhibiting insulin-dependent glucose transport into the cells
• Inhibiting glycogen synthesis
• Inhibiting glucose-dependent insulin secretion

Dysregulated Hepatic Glucose Production

Contribution of Glucagon to Normal Glucose Homeostasis

The liver is a major generator and storehouse of glucose. New glucose is made in the liver by enzymes that convert smaller carbon-containing molecules into glucose. Glucose can leave the liver as glucose or be converted into the storage form—glycogen. [Buse, 2003] By some estimates, during the 6-hour interval after a meal, approximately 45% of ingested glucose is stored in the liver as glycogen, whereas about 66% is metabolized for energy. [Woerle, 2003]

To maintain glucose homeostasis between meals, the glucose removed from the circulation by the body’s various tissues is replenished by the liver, either through glycogenolysis or gluconeogenesis. Regulation of these 2 processes requires the coordinated effects of insulin and glucagon. These processes allow the individual to eat intermittently and still maintain normoglycemia. The figure below depicts the role of glucagon in glucose homeostasis. [Jiang, 2003]

Role of Glucagon in Glucose Homeostasis

Normally, release of glucose by the liver is reduced by 80% during the postprandial period (which lasts up to 4 to 5 hours after a meal). During this postprandial period, the insulin/glucagon ratio is relatively high. (The ratio of insulin to glucagon is related to the metabolic state—and is influenced by the composition of the antecedent diet.). [Gerich, 2000; Unger, 1972]

The insulin/glucagon ratio changes depending on the availability of ingested glucose (see figure below [Unger, 1971; Müller, 1971]:

• During starvation, the ratio is very low because more glucagon is needed to increase glucose production in the liver.
• The insulin/glucagon ratio on a low carbohydrate diet is higher than that in a starvation state. The ratio more than doubles with a balanced diet.
• During a glucose infusion, there is a several-fold increase in the insulin/glucagon ratio compared with a balanced diet, indicating a strong demand for insulin and decreased demand for glucagons. [Unger, 1971]

Insulin/Glucagon Ratio Falls as the Need for Endogenous Glucose Production Increases

The term endogenous glucose production refers to hepatic and renal glucose production. The majority of the endogenous glucose production is derived from the liver. [Gerich, 2001; Ekberg, 1999]

Endogenous Glucose Production

In some physiological studies, the first-phase insulin secretion was shown to play a major role in the suppression of hepatic glucose production [Steppel, 2004]:

• Insulin directly acts on the liver to suppress glucose production.
• Glucose uptake in other tissues is increased.
• Glucagon release is suppressed by insulin, further decreasing hepatic glucose production.

What Is Dysregulated Hepatic Glucose Production?

Hepatic glucose production provides a rapid supply of glucose to the body to prevent the development of hypoglycemia, such as with an overnight fast. Unfortunately, excessive hepatic glucose production has been observed in a number of settings of type 2 diabetes, thus contributing to worsening of the hyperglycemia. Factors involved in this dysregulation of hepatic glucose production include:

• Delayed and diminished insulin secretion (both first phase and second phase) inadequate for glucose loads.
• Excessive glucagon production which is not suppressed postprandially and has higher levels in the basal state.
• Impairment of glucose uptake/disposal in the splanchnic circulation, allowing more glucose into the general circulation.
• Impaired suppression of glucose production in the liver, caused by circulating glucose and insulin.

Factors That Influence Excessive Hepatic Glucose Production

In type 2 diabetes, hyperglycemia and decreased insulin secretion reduce the uptake of glucose in muscle and also allow unsuppressed glucagon to increase the production of glucose by the liver. [Buse, 2003; Basu, 2004] As early as the prediabetes stage, a decrease in insulin secretion and an increase in glucagon can cause an increase in hepatic glucose output. [Mitrakou, 1992] The reduced first-phase insulin secretion allows up to 50% more glucose production by the liver than would normally occur. [Mitrakou, 1992]

In type 2 diabetes, the insulin/glucagon ratio is decreased relative to healthy subjects, indicating a loss in the ability of insulin to suppress glucagon secretion. [Del Prato, 2004] Hepatic tissue appears to be more sensitive than normal to glucagon in type 2 diabetes, further exacerbating the increase in hepatic glucose production. [Del Prato, 2004]

Fasting hepatic glucose production is increased in type 2 diabetes. Also, hepatic glucose production fails to suppress postprandially, resulting in increased hepatic glucose production (see figure below). [Kelley, 1994]

Fasting Hepatic Glucose Output Is Increased in Type 2 Diabetes and Hepatic
Glucose Production Fails to Suppress Postprandially

The figure below shows increased hepatic glucose production in patients with type 2 diabetes. Ingestion of a meal by subjects without diabetes resulted in the inhibition of hepatic glucose output by 44% in the first 30 minutes and by 74% at 4 hours. [Pehling, 1984] By comparison, patients with type 2 diabetes have very little suppression of hepatic glucose production at either time point. [Pehling, 1984] Increased hepatic glucose production contributes to postprandial hyperglycemia in type 2 diabetes. Hepatic glucose overproduction may contribute more to postprandial hyperglycemia than insulin resistance. [Del Prato, 2004]

Hepatic Glucose Production Is Elevated in Type 2 Diabetes

Pathophysiologic Evolution of Type 2 Diabetes

Although still evolving, the following concepts are important to our scientific understanding of the complex and multifaceted pathogenesis of type 2 diabetes.

• Beta cell failure is an early, progressive, and fundamental component in the pathophysiologic evolution of type 2 diabetes. By the time of diagnosis of diabetes, substantial amounts of beta cell function have been lost. In long-standing type 2 diabetes, beta cell mass is decreased. Decline in beta cell function is seen early in the disease process, including in prediabetes. Beta cell function includes altered secretion of insulin and loss of first-phase insulin response. Molecular and cellular mechanisms underlying this decline are being studied.
• Insulin resistance is another component in the pathogenesis of type 2 diabetes. The body’s need for insulin may vary over time, such as in insulin-resistant states. Impaired beta cell function may not be able to keep up with the increased demand for insulin secretion, and hyperglycemia may result.
• In addition, there are changes in glucagon secretion, resulting in dysregulated hepatic glucose production. Suppression of glucagon secretion by glucose and insulin, both basal and postprandial, is altered in type 2 diabetes as part of the pathogenesis. Increasing research in the area of glucagon and hepatic glucose output is helping us to better understand the importance of these pathophysiologic and hormonal factors in type 2 diabetes.

• Nondiabetic state.
• Early abnormalities in deteriorating glucose homeostasis.
• Prediabetes.
• Type 2 diabetes.

Nondiabetic State

The following characteristics of the nondiabetic state are shown in the figure below:

1. The beta cells are functioning normally, producing appropriate amounts of insulin.
2. Sensitivity to insulin is normal, and insulin effectively facilitates transport of glucose into cells (e.g., muscle, fat, and other cells).
3. There is an adequate level of insulin production to meet the body’s needs.
4. Glucose levels are normal (euglycemia).

Nondiabetic State (Conceptual Schematic)

Early Abnormalities in Deteriorating Glucose Homeostasis

There is considerable debate regarding the sequence of the development of early abnormalities in deteriorating glucose homeostasis, and they are presented here without regard to the sequence in individuals who will eventually develop type 2 diabetes (see the figure below):

1. One of the early changes that occurs in the pathophysiology in the long evolution towards type 2 diabetes is that the muscle, fat, and other cells become less sensitive to (and more resistant to) the effects of insulin. [Harmel, 2004] This means that insulin is less effective at facilitating the transport of glucose into muscle, fat, and liver cells; insulin sensitivity begins to decrease.
2. Because muscle, fat, and liver cells are somewhat 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. The amount of insulin in the blood begins to rise, resulting in hyperinsulinemia. [Harmel, 2004; Powers, 2005] Clinically, this stage can be recognized as metabolic syndrome.
3. The demand on beta cells pushes them to increase the production of insulin. Some degree of impairment of beta cell function or secretory reserve may be present.
4. At this phase, the body successfully responds with increased amounts of insulin and is able to move an appropriate amount of glucose into the cells. Thus, blood glucose levels remain relatively normal. [Harmel, 2004; Powers, 2005]

Early Abnormalities in Deteriorating Glucose Homeostasis (Conceptual Schematic)

Prediabetes

The following progression to prediabetes is shown in the figure below:

1. Insulin sensitivity continues to worsen (i.e., insulin sensitivity decreases); insulin resistance increases.
2. The beta cells are incessantly called upon to produce more and more insulin, resulting in increasing hyperinsulinemia.
3. However, the beta cells now cannot increase supply to compensate for the demand for insulin production. The available insulin is insufficient to move enough glucose into the cells, and blood glucose levels start to rise above the normal range. [Harmel, 2004] Hepatic glucose production also increases, contributing to increased glucose levels. When glucose levels are higher than normal but not yet in the range for a diagnosis of diabetes, the individual can be described as having prediabetes. Prediabetes is defined by impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). [ADA Standards, 2005]
4. Prediabetes becomes evident as beta cell dysfunction progresses. Beta cell dysfunction is considered fundamental to the eventual development of type 2 diabetes.

Prediabetes (Conceptual Schematic)

Type 2 Diabetes

As beta cell health further declines, less insulin is available than is required to maintain normal glucose homeostasis. This decline in insulin production reflects progressive beta cell failure. [Harmel, 2004]

Finally, when the plasma glucose levels rise above the prediabetic range, type 2 diabetes is diagnosed. [Harmel, 2004] The figure below shows the following defects of type 2 diabetes:

1. 1. Plasma glucose levels rise above the normal range, resulting in increasing hyperglycemia. A patient is diagnosed with type 2 diabetes when hyperglycemia reaches [ADA Standards, 2005]:
   • ≥200 mg/dL when glucose is measured by a casual plasma glucose and accompanied with symptoms of diabetes (polyuria, polydipsia, and unexplained weight loss), OR
   • ≥126 mg/dL when the glucose is measured as a fasting plasma glucose (FPG), OR
   • ≥200 mg/dL when the glucose is measured 2 hours after an oral glucose load (75 g).
2. Progressive beta cell failure occurs over time.
3. The insulin-secretory capacity of the beta cell steadily declines.
4. Loss of insulin sensitivity persists or may worsen (i.e., insulin resistance persists or worsens).
5. As diabetes persists over time, complete beta cell failure may occur, in which case, patients will become insulin deficient and require insulin therapy.

Type 2 Diabetes (Conceptual Schematic)

References

Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2004;27(suppl 1):S5–S10.

American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28(suppl 1):S4–S36.

Basu A, Shah P, Nielsen M, Basu R, Rizza RA. Effects of type 2 diabetes on the regulation of hepatic glucose metabolism. J Invest Med. 2004;52:366–374.

Bogardus C, Tataranni PA. Reduced early insulin secretion in the etiology of type 2 diabetes mellitus in Pima Indians. Diabetes. 2002;51(suppl 1):S262–S264.

Bonner-Weir S. Islets of Langerhans: morphology and postnatal growth. In: Kahn CR, Weir GC, King GL, et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lea & Febiger; 2005: 41–51.

Buchanan TA. Pancreatic beta-cell loss and preservation in type 2 diabetes. Clin Ther. 2003;25(suppl B):B32–B46.

Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia, Pa: WB Saunders; 2003;1427–1483.

Butler AE, Jang J, Gurlo T, Carty MD, Soeller WC, Butler PC. Diabetes due to a progressive defect in ß-cell mass in rats transgenic for human islet amyloid polypeptide (HIP rat). Diabetes. 2004;53:1509–1516.

Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza R, Butler PC. ß-Cell deficit and increased ß-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–110.

Byrne MM, Sturis J, Sobel RJ, Polonsky KS. Elevated plasma glucose 2 h post challenge predicts defects in ß-cell function. Am J Physiol Endocrinol Metab. 1996;270:E572–E579.

Cavaghan MK, Ehrmann DA, Polonsky KS. Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. J Clin Invest. 2000;106:329–333.

Cleaver O, Melton DA. Development of the endocrine pancreas. In: Kahn CR, Weir GC, King GL, et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lea & Febiger; 2005:21–39.

Collins S, Ahima RS, Kahn BB. Biology of adipose tissue. In: Kahn CR, Weir GC, King GL, et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lea & Febiger; 2005: 207–226.

Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91.

Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH₂-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1985;30(3): 154-167.

DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: metabolic and molecular implications for identifying diabetes genes. Diabetes Reviews. 1997;5:177–269.

DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303.

DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM: a. A balanced overview. Diabetes Care. 1992;15:318–368.

Dela F, von Linstow ME, Mikines KJ, Galbo H. Physical training may enhance beta-cell function in type 2 diabetes. Am J Physiol Endocrinol Metab. 2004;287:E1024–E1031.

Del Prato S. Loss of early insulin secretion leads to postprandial hyperglycemia. Diabetologia. 2003;46(suppl 1):M2–M8.

Del Prato S, Marchetti P. Beta and alpha cell dysfunction in type 2 diabetes. Horm Metab Res. 2004;36:775–781.

Del Prato S, Marchetti P, Bonadonna RC. Phasic insulin release and metabolic regulation in type 2 diabetes. Diabetes. 2002:51(suppl 1):S109–S116.

DeMouy J. The Pima Indians: Pathfinders for Health. National Institute for Diabetes and Digestive and Kidney Diseases. May 2002. Available at: http://diabetes.niddk.nih.gov/dm/pubs/pima/pathfind/pathfind.htm. Accessed on September 8, 2006.

Deng S, Vatamaniuk M, Huang X, et al. Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes. 2004;53:624–632.

Donath MY, Halban PA. Decreased beta-cell mass in diabetes: significance, mechanisms and therapeutic implications. Diabetologia. 2004;47:581–589.

Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940.

Dushay J, Abrahamson MJ. Insulin resistance and type 2 diabetes: a comprehensive review. A CME activity released April 8, 2005; valid for credit through April 8, 2006. Available at www.medscape.com/viewprogram/3942. Accessed November 7, 2005.

Ekberg K, Landau BR, Wajngot A, et al. Contributions by kidney and liver to glucose production in the post absorptive state and after 60h of fasting. Diabetes. 1999;48:292–298.

Eriksson J, Franssila-Kallunki A, Ekstrand A, et al. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med. 1989;321:337–343.

Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes. 1985;34:222–234.

Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab. 2000;2345–350.

Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: its. Its importance in human glucose homeostasis. Diabetes Care. 2001;24:382–391.

Guyton AC, Hall JE. Textbook of Medical Physiology. 10th ed. Philadelphia, Pa: WB Saunders; 2000.

Habener JF, Kieffer TJ. Glucagon and glucagon-like peptides. In: Kahn CR, Weir GC, King GL, et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lea & Febiger; 2005: 180–193.

Harmel AP, Mathur R. Davidson’s Diabetes Mellitus: Diagnosis and Treatment. Philadelphia, Pa: Saunders; 2004.

Hawkins M, Rossetti L. Insulin resistance and its role in the pathogenesis of type 2 diabetes. In: Kahn CR, Weir GC, King GL, et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lea & Febiger; 2005:425–448.

Hermans MP, Levy JC, Morris RJ, Turner RC. Comparison of tests of ß-cell function across a range of glucose tolerance from normal to diabetes. Diabetes. 1999;48:1779–1786.

Hinke SA, Hellemans K, Schuit FC. Plasticity of the ß cell insulin secretory competence: preparing the pancreatic ß cell for the next meal. J Physiol. 2004;558.2:369–380.

Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430–441.

Iozzo P, Beck-Nielsen H, Laakso M, Smith U, Yki-Jarvinen H, Ferrannini E, for the European Group for the Study of Insulin Resistance. Independent influence of age on basal insulin secretion in nondiabetic humans. J Clin Endocrinol Metab. 1999;84:863–868.

Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab. 2003;284:E671–E78.

Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106:473–481.

Kahn CR, Saltiel AR. The molecular mechanism of insulin action and the regulation of glucose and lipid metabolism. In: Kahn CR, Weir GC, King GL, et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lea & Febiger; 2005:chapter 9, 145–168.

Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia. 2003;46:3–19.

Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993:42:1663–1672.

Kahn SE, Verchere CB, Addrikopoulos S, et al. Reduced amylin release is a characteristic of impaired glucose tolerance and type 2 diabetes in Japanese Americans. Diabetes. 1998;47:640–645.

Kelley D, Mokan M, Veneman T. Impaired postprandial glucose utilization in non-insulin-dependent diabetes mellitus. Metabolism. 1994;43:1549–1557.

Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20:876–913.

Larsen PJ, Holst JJ. Glucagon-related peptide 1 (GLP-1): hormone and neurotransmitter. Regul Pept. 2005;128:97–107.

Leahy JL. ?-cell dysfunction in type 2 diabetes. In: Kahn CR, Weir GC, King GL, et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lea & Febiger; 2005:449–461.

Lebovitz HE, Kendall DM, Blonde L. Gastrointestinal hormones: emerging players in metabolic regulation. Changing the Course of Disease: Gastrointestinal Hormones and Tomorrow’s Treatment of Type 2 Diabetes. CME presentation released on November 30, 2004. Slide 9.

Levy J, Atkinson AB, Bell PM, McCance DR, Hadden DR. Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study. Diabet Med. 1998;15:290–296.

Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med. 1993;329:1988–1992.

Marchetti P, Del Guerra S, Marselli L, et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab. 2004;89:5535–5541.

Meier JJ, Nauck MA. Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.

Mitrakou A, Kelley D, Mokan M, et al. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med. 1992;326:22–29.

Muccioli G, Tschöp M, Papotti M, Deghenghi R, Heiman M, Ghigo E. Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Eur J Pharmacol. 2002;440:235–254.

Müller WA, Faloona GR, Aguilar-Parada E, Unger RH. Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med. 1970;283:109–115.

Müller WA, Faloona GR, Unger RH. The influence of the antecedent diet upon glucagon and insulin secretion. N Engl J Med. 1971;285:1450–1454.

Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagons-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301–307.

Pehling G, Tessari P, Gerich JE, Haymond MW, Service FJ, Rizza RA. Abnormal meal carbohydrate disposition in insulin-dependent diabetes. Relative contributions of endogenous glucose production and initial splanchnic uptake and effect of intensive insulin therapy. J Clin Invest. 1984;74:985–991.

Pfeifer MA, Halter JB, Porte D Jr. Insulin secretion in diabetes. Am J Med. 1981;70:579–588.

Pfützner A, Kunt T, Hohberg C, et al. Fasting intact proinsulin is a highly specific predictor of insulin resistance in type 2 diabetes. Diabetes Care. 2004;27:682–687.

Pimenta W, Korytkowski M, Mitrakou A, et al. Pancreatic beta cell dysfunction as the primary genetic lesion in NIDDM JAMA. 1995;273:1855–1861.

Poitout V, Robertson RP. Minireview: secondary ß-cell failure in type 2 diabetes—a convergence of glucotoxicity and lipotoxicity. Endocrinology. 2002;143:339–342.

Porte D Jr, Kahn SE. The key role of islet dysfunction in type II diabetes mellitus Clin Invest. Med. 1995;18:247–254

Powers AC. Diabetes mellitus. In: Kasper DL, Fauci AS, Longo DL, et al, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2005.

Pratley RE, Weyer C. The role of impaired early insulin secretion in the pathogenesis of type II diabetes mellitus. Diabetologia. 2001;44:929–945.

Quddusi S, Vahl TP, Hanson K, Prigeon RL, D’Alessio DA. Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans. Diabetes Care. 2003;26:791–798.

Ramesh B. Dietary management of pancreatic beta-cell homeostasis and control of diabetes . Med Hypotheses. 1996;46:357–361.

Rathmann W, Haastert B, Icks A, et al. The diabetes epidemic in the elderly population in Western Europe: data from population-based studies. Gesundheitswesen. 2005;67:S110–S114.

Ravussin E, Bogardus C. Energy balance and weight regulation: genetics versus environment. Br J Nutrition. 2000;83(suppl 1):S17–S20.

Roden M, Price TB, Perseghin G, et al. Mechanism of free fatty acid–induced insulin resistance in humans. J Clin Invest. 1996;97:2859–2865.

Roden M, Stingl H, Chandramouli V, et al. Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans. Diabetes. 2000;49:701–707.

Rhodes CJ. Type 2 diabetes—a matter of ß-cell life and death? Science. 2005;307:380–384.

Rhodes CJ, Shoelson SE, Halban PA. Insulin biosynthesis, processing, and chemistry. In: Kahn CR, Weir GC, King GL, et al, eds. Joslin’s Diabetes Mellitus. 14th13th ed. Philadelphia, Pa: Lea & Febiger; 2005:65–82.

Rosenthal TC. Combining insulin and oral agents in diabetes: indications and controversies. Am Fam Physician. 1992;46:1721–1727.

Ruderman NB, Myers MG Jr, Chipkin SR, Tornheim K. Hormone–fuel interrelationships: fed state, starvation, and diabetes mellitus. In: Kahn CR, Weir GC, King GL, et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lea & Febiger; 2005:127–144

Saad MF, Kahn SE, Nelson RG, et al. Disproportionately elevated proinsulin in Pima Indians with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1990;70:1247–1253.

Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Charles MA, Bennett PH. A two-step model for development of non-insulin-dependent diabetes. Am J Med. 1991;90:229–235.

Schinner S, Scherbaum WA, Bornstein SR, Barthel A. Molecular mechanisms of insulin resistance. Diabet Med. 2005;22:674–682.

Shah P, Vella A, Basu A, et al. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2000;85:4053–4059.

Steppel JH, Horton ES. Beta-cell failure in the pathogenesis of type 2 diabetes mellitus. Curr Diab Rep. 2004;4:169–175.

Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86:3717–3723.

Tortora GJ, Grabowski SR. Principles of Anatomy and Physiology. 10th ed. New York, NY: John Wiley & Sons, Inc.; 2003.

Tscöhp M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes. 2001;50:707–709.

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–853.

UK Prospective Diabetes Study (UKPDS) Group. Overview of 6 years’ therapy of type II diabetes: a progressive disease (UKPDS 16). Diabetes. 1995;44:1249–1258.

Unger RH. Glucagon and the insulin: glucagon ratio in diabetes and other catabolic illnesses. Diabetes. 1971;20:834–838.

Unger RH. Insulin-glucagon ratio. IsrJ Med Sci. 1972;8:252–257.

Vilsböll T, Knop FK, Krarup T, et al. The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide—regardless of etiology and phenotype. J Clin Endocrinol Metab. 2003;88:4897–4903.

Vilsböll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia. 2002;45:1111–1119.

Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocrine Reviews. 2000;21:697–738.

Ward WK, Beard JC, Halter JF, Pfeifer MA, Porte D Jr. Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus. Diabetes Care. 1984;7:491–592.

Ward WK, LaCava EC, Paquette TL, Beard JC, Wallum BJ, Porte D Jr. Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia. 1987;30:698–702.

Wardlaw GM, Kessel MW. Perspectives in Nutrition. 5th ed. New York, NY: McGraw-Hill; 2002.

Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104:787–794.

Woerle HJ, Meyer C, Dostou JM, et al. Pathways for glucose disposal after meal ingestion in humans. Am J Physiol Endocrinol Metab. 2003;284:E716–E725.

Copyright ©2001-2009 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.

20652106(1)-11/07-EBS-PHY