Although both insulin resistance and impaired insulin secretion precede the development of postprandial hyperglycemia and the subsequent type 2 diabetic phenotype, insulin resistance is more prominent in the prediabetic state and plays an important role in the pathogenesis of macrovascular disease. Insulin resistance is commonly the earliest manifestation in the development of type 2 diabetes, typically originating 5-10 years before postprandial glucose levels in the diabetic range (200 mg/dL). As long as the P cell is able to compensate by increased insulin production, normal glucose tolerance is maintained. Thus, not all patients with insulin resistance will develop diabetes (8).
Insulin resistance can be worsened by genetic factors, elevated free fatty acids, hyperglycemia, pregnancy, obesity, sedentary lifestyle, aging, and various medications (i.e., steroids, cw-retinoic acid, estrogens, nicotinic acid, oral contraceptives, phenothiazines, and antipsychotic agents). Insulin resistance is characterized by impaired responses to the physiologic effects of this hormone on glucose, lipid, and protein metabolism, and by affecting vascular endothelial function. The endogenous insulin that is secreted is inefficiently capable of suppressing hepatic gluconeogenesis or stimulating glucose use in the muscle and fat (9).
Increases in plasma glucose concentrations by 50-100 mg/dL for as little as 24 hours can cause downregulation of the glucose transport system in the muscle (GLUT4), significantly increasing insulin resistance. Over time, insulin resistance peaks and then plateaus as increases in plasma insulin compensate to maintain the glycemic state.
Fasting hepatic glucose production is increased in both obese and nonobese diabetic patients, compared with normal individuals and those with impaired glucose tolerance that have not met the criteria for diabetes. This increase in hepatic glucose output, owing to increases in glycogenolysis and gluconeogenesis, results in fasting hyperglycemia in type 2 diabetic patients. At some point, usually approximately 10 years after insulin resistance and hyperinsulinemia develop, postprandial hyperglycemia begins to develop, resulting from P-cell dysfunction and/or depletion. Postprandial hyperglycemia is characterized by a delay in first-phase insulin release and blunted second-phase output. This first-phase response plays an important role in the suppression of hepatic glucose production. This progressive deterioration leads to fasting hyperglycemia when insulin levels begin to decline although insulin resistance remains elevated. The progressive nature of the disease and the progressive lack of glycemic control are predominantly caused by this ongoing deterioration of P-cell function with subsequent decreased production of insulin (10).
There is a small subset of patients with type 2 diabetes in whom P-cell dysfunction develops with minimal insulin resistance, but the progressive hyperglycemia induces subsequent insulin resistance. Even those individuals with absolute increases of serum insulin (i.e., higher than normal) have a relative insulin deficiency given their levels of hyperglycemia and severity of insulin resistance.
Although the triple disturbance of insulin resistance, increased hepatic glucose production, and impaired insulin secretion critical to the development of type 2 diabetes has received a great deal of attention in research, the etiological sequence of events resulting in the diabetic state is also of compelling interest . Accelerated hepatic gluconeogenesis and glycogenolysis do not seem to exist in the state of impaired glucose tolerance, where insulin resistance and impaired insulin secretion predominate; in fact, these two abnormalities precede the onset of hyperglycemia in the diabetic type 2 phenotype. Prediabetic individuals have severe insulin resistance, whereas insulin secretion tends to be normal or increased in the prediabetic or impaired glucose tolerant state, including first-phase insulin responses to intravenous challenges. Thus, the type 2 diabetic phenotype evolves from the individual with impaired glucose tolerance and insulin resistance. Although the genetic factors previously mentioned play a key role, acquired factors are also important in susceptible individuals, including sedentary lifestyle, high-fat diet, central visceral obesity, and progressive aging (5).
The body's response to insulin resistance is to enhance the P cell's secretion of insulin to maintain normal glucose tolerance. The development of type 2 diabetes from the impaired glucose-tolerant state occurs as the result of an organized sequence of events.
Initially, hepatic glycogenolysis and gluconeogenesis increase, resulting in enhanced basal hepatic glucose production. This is common in all type 2 diabetic patients with fasting hyperglycemia. Insulin resistance tends to become more severe and peak when fasting hyperglycemia develops, because of the degree of glycemic load, aging, sedentary life style, obesity, and any other concomitant factors that can affect insulin sensitivity and resistance. Normalization of hepatic glucose production and improvement in insulin resistance can be achieved through antidiabetic treatment, resulting in significant amelioration of this particular state. The final sequence of events is a progressive deterioration in P-cell function with subsequent decline in insulin-secreting ability (11).
350 300 250 200 150 100
250 % 200 Relative 150 to Normal 100 50 0
250 % 200 Relative 150 to Normal 100 50 0
Fig. 1. Natural history of type 2 diabetes.
Several factors can be involved in the deterioration in P-cell function, including progressive P-cell exhaustion owing to dietary indiscretion, prolonged glucose toxicity, and preprogrammed genetic abnormalities in P-cell function. Nonetheless, it is the progressive P-cell deterioration that results in a worsening of the hyperglycemic state in the type 2 diabetic patient. The majority of type 2 diabetic patients are overweight and hyperinsulinemic at the time of diagnosis. The subsequent conversion from the impaired glucose-tolerant state to type 2 diabetes is influenced by concomitant medical conditions, distributions of body fat, degree of obesity, ethnicity, sedentary lifestyle, and aging. Thus, one can see that the type 2 diabetic patient is at the end of a progressive triad of metabolic defects whose interrelationships directly affect the natural history and progress of the disease (see Fig. 1) (12).
The impaired glucose-tolerant state is characterized by mild postprandial hyperglycemia, compensatory hyperinsulinemia, and insulin resistance. Clearly, insulin resistance can be present for many years before an individual becomes diabetic. Even at these stages, blood sugar levels are not necessarily elevated.
Understanding the natural history of the disease is important both for the early identification of patients at risk for developing diabetes, and for developing an effective treatment plan including diet and exercise with weight reduction to prevent or delay the development of the disease. Additionally, because insulin resistance is one of the major factors in the prediabetic state and persists in the frankly diabetic individual, improvements in insulin sensitivity with medications like thiazolidinediones and biguanides may be invaluable as first-line agents in early treatment. As we will see in Chapter 6, the glitazones can be invaluable not only in preserving P-cell function but also in regenerating P-cell tissue (13).
Early recognition and treatment is of tremendous advantage because macrovascular disease begins with impaired glucose tolerance and microvascular disease begins with diabetic levels of hyperglycemia. Clearly, patients will die from their macrovascular disease but suffer from their microvascular disease.
Of critical importance is an understanding of how damaging the hyperglycemic state is at the tissue level. At the cellular level, various critical and damaging signaling pathways can be affected by abnormal glucose tolerance. These damaging pathways can be activated by the direct toxic effects of the hyperglycemic state, or by the metabolic derivatives of the hyperglycemic state and their by-products, or by the continuous effects on special signaling pathways at the cellular level caused by glucose metabolites.
Several of these pathways have been characterized. They include the following:
1. Increased formation of advanced glycation endproducts (AGE).
2. Accelerated oxidative stress resulting from reactive oxygen intermediates.
3. Activation of protein kinase C (PKC) isoforms.
4. Increases in the polyol pathway flux.
6. Increased flow through the hexosamine pathway, because of overproduction of superoxide anions induced by the electron transport chain in the mitochondria.
Aldose reductase is an enzyme that causes accumulation of sorbitol at the cellular level in various diabetic conditions. Sorbitol accumulation directly leads to tissue damage and promotes the macro- and microvascular complications of diabetes because excess intracellular sorbitol levels decrease the concentration of various protective organic osmolytes. This is seen in the animal model of cataracts that contain decreased levels of taurine, a potent antioxidant and free-radical scavenger. Interestingly, inhibitors of aldose reductase have restored levels of protective osmolites and prevented diabetic complications by diminishing sorbitol reduction (13).
In many cellular models, progressive elevations of intracellular sorbitol disrupt the signal transduction in related cellular functions, and the elevations are usually associated with the depletion of protective osmolytes, such as taurine and myoinositol. A deficiency of myoinositol correlates with the clinical neuropathy responsible for the impaired nerve fiber regeneration and neurological damage associated with diabetes. Myoinositol deficiencies impair prostaglandin metabolism and nitric oxide synthetase, disrupting cyclo-oxygenase pathways and nitric oxide production, and resulting in various defects in the peripheral nerves, the ganglia, and the endoneurium. Some myo-inositol deficiencies have been improved with the addition of prostaglandin E1 analogs and other substances.
Sorbitol accumulation may also destroy pericytes, thereby accelerating retinopathy and neuropathy. The destruction of the pericytes in the nervous tissue and the retina alters the microcirculation, resulting in tissue ischemia and increased capillary permeability, which decreases the ability of the tissues to produce vasodilatory nitric oxide, which enhances angiotensin II production, increases acetylcholine release, and augments sympathetic tone. This diminution in nitric oxide, with enhanced polyol pathway flux, slows nerve conduction, diminishes blood flow within the endoneurium, and depletes protective intracellular osmolytes (14).
Nitric oxide maintains sodium-potassium adenosine triphosphatase activity, which is critical to nerve metabolism and impulse transmission and to taurine and myoinositol uptake. Thus, disruption in nitric oxide production contributes to many vascular and metabolic defects in the peripheral nerves, endoneurium, and sympathetic ganglia.
Aldose reductase inhibitors prevent many of the microvascular complications of disease and preserve nerve conduction velocity in animals. However, they have not been effective in treating or preventing microvascular disease in humans or in relieving symptoms. Therefore, mere suppression of aldose reductase pathway flux may be inadequate, perhaps because of the many avenues of hyperglycemic tissue damage.
The modification or the glycation of lipoproteins or proteins by sugars result in the formation of AGE. Intracellular and extracellular AGE are primarily the result of intracellular hyperglycemia. AGE are formed by the intracellular oxidation of glucose, the fragmentation of phosphate compounds, and the decomposition of glucose-derived deoxyfructose lysine adducts (Amadori product), which react with amino groups from various cellular proteins. This irreversible formation of AGE accelerates with aging and with the diabetic state (15).
Impaired cellular function seen in the various diabetic complications results from the crosslinkage and covalent modification of proteins by intracellular glucose, enhancing abnormal matrix-cell interactions, which reduce neurite outgrowth and impair endothelial cell adhesion, decreasing vascular elasticity.
The glycosylated hemoglobin commonly measured to indicate the average blood sugar over 60 days is the best-known example of an AGE. Enhanced atherogenicity and accelerated atherosclerosis in diabetes is related to the glycosylation of low-density lipoproteins (LDL), phospholipids, and apolipoprotein B. This glycation decreases the clearance of LDL and enhances its deposition within the intima of the blood vessels. The formation of intracellular and extracellular AGE products is promoted by intracellular hyperglycemia (16). These end products are irreversibly formed and tend to accumulate with aging as the result of the auto-oxidation of glucose to form glyoxal in association with fragmentation of various phosphate compounds, which subsequently react with the amino groups of various cellular proteins.
Impaired cellular functioning in diabetes results in alteration of intracellular proteins and abnormal reactions between various matrix components within the cell. This results in false linkages and covalent modification of proteins.
The critical phenomenon of extracellular matrix-cell impairment can explain the Depuytren contractures found in patients with diabetes and other disorders. These contractures result from adhesive capsulitis and the stiffening of periarticular structures with impairment in full extension associated with flexion contractures and the "prayer sign" in advanced diabetes.
Advanced glycosylation end products are also responsible for enhanced permeability of the renal glomerular basement membrane. This permeability results in microalbuminuria and then macroalbuminuria. Inflammatory responses, apoptosis, and mediators of various immune functions are also enhanced by the glycosylation end products, which bind to their receptor for advanced glycation endproducts (RAGE). The binding of AGE to their receptor sites enhances the expression of proinflammatory and procoagulant molecules, enhancing vascular adhesion and thrombogenesis. This could explain the impaired wound healing and enhanced susceptibility to infection that is prominent in diabetic patients (17).
Various AGE inhibitors and RAGE blockade substances have been successful in inhibiting many of the detrimental effects of these substances, including diminished arterial elasticity, decreased nerve conduction velocity, enhanced urinary albumin excretion, and periodontal inflammation.
The hyperglycemic state induces the formation of harmful free radicals, increasing oxidative stress through nonenzymatic reactions and enzymatic processes. This oxidative stress results from a chemical imbalance between the reactive oxygen species known as free radicals and the endogenous cellular defenses against them. The presence of oxidative stress enhances diabetic vascular disease by inhibiting barrier function within the endothelium, promoting leukocytic adhesion, and reducing circulating levels of nitric oxide. The subsequent accelerated production of prothrombin by the hyperglycemic state helps to explain diabetic hypercoagulation (18).
Free radicals are produced within the mitochondria by oxidative phosphorylation, synthesizing adenosine triphosphate during glucose metabolism and subsequent oxidation. This generates free radicals that can exist independently and contain at least one unpaired electron. These free radicals can combine with hydrogen, forming a hydroxy radical, contributing to the atherogenic process by initiating lipid peroxidation and subsequent foam cell formation. Unless these free radicals are neutralized by antioxidants, they can cause direct cellular damage by oxidation of intracellular mitochondrial DNA, lipids, proteins, and vital cellular structures. These radicals can wreak havoc by indirectly activating the signaling pathways that increase the expression of various gene products responsible for the diabetic microvascular complications of retinopathy, neph-ropathy, and neuropathy.
By diminishing the bioavailable nitric oxide, oxidative stress enhances inflammatory cell adhesion to the endothelial surface, impairing endothelial barrier function and enhancing diabetic and arteriosclerotic vascular disease and endothelial dysfunction (19).
Eating foods high in AGE and various lipid peroxides enhances a predisposition to postprandial hyperglycemia, impairing endothelial function, increasing lipid peroxidation, and decreasing radical trapping activity. Thus, increased levels of oxidized LDL and decreased levels of antioxidant vitamins, such as C and E, are present in diabetic patients, predisposing these patients to macrovascular disease.
The PKC family is a group of phospholipid-dependent protein kinases. These substances mediate various cellular responses to hormones, neurotransmitters, and growth factors; thus, play a key role in regulating vasodilator release, in endothelial activation and in other important cellular functions. The hyperglycemic state increases PKC levels to pathological ranges, increasing the PKC levels directly and enhancing the production of diacylglycerol (20).
PKC is a proinflammatory substance that stimulates the release of growth factors such as vascular endothelial growth factor (VEGF) which enhances endothelial permeability. The activation of PKC contributes to cardiovascular complications by activating nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidases, accelerating the production of plasminogen activator inhibitor-1. Inhibitors of PKC have reversed or prevented impaired angiogenesis in diabetic retinopathy but the responses seemed to vary depending on the patient's genetic background.
PKC-activated NF-kB (a nuclear transcription factor) is responsible for signal transduction, thereby exerting proinflammatory effects. The protein kinase family also induces the transcription of various growth factors including the following:
1. Platelet-derived growth factor-P, which induces vascular wall growth.
2. Transforming growth factor, which promotes matrix expansion.
3. Endothelin 1, which is a vasoconstrictor.
4. VEGF, which increases endothelial permeability and may increase neovascularization.
Tissue damage in the diabetic state also involves a shunting of excess intracellular glucose by the hexosamine pathway (3). This diverts fructose phosphate from glycolysis to provide substrates for the formation of 0-linked glycoproteins and syntheses of various proteoglycans. Pancreatic P cells may be especially sensitive to activation of the hexosamine pathway, resulting in increased intracellular hydrogen peroxide levels impairing insulin release and promoting P-cell dysfunction. N-acetyl-L-cysteine, an antioxidant, suppresses many of the pathological changes associated with activation of the hexosamine pathway.
The hyperglycemic state is also responsible for the overproduction of superoxide anions by the electron transport system in the mitochondria. This may be the central mechanism that underlies all of the destructive pathways responsible for the diabetic paradigm. This central mechanism has been offered by some as an explanation underlying the mechanism whereby retinopathy may continue to progress long after normo-glycemia has been regained. Hyperglycemia can induce mitochondrial DNA mutations resulting from monocyte adhesion and inhibition of peroxisome proliferator-activated receptor activation. The subsequently defective subunits in the electron transport system caused by these mutations may be responsible for increases in the superoxide anion production, continuing to activate tissue damage despite normoglycemic states (18).
Aberrant regulation of the well-studied NF-kB pathway is associated with arteriosclerosis and diabetes and may be among the initial mechanisms in the tissue damage seen in these states. Bovine endothelial cell data have demonstrated that this pathway regulates numerous genes, including those that express VEGF and RAGE.
When abnormally stimulated, this system can generate an ongoing cycle of dys-regulatory metabolic derangements.
Diabetic patients may be prone to an enhanced effect of glucosamine on the plasminogen activator inhibitor-1 promoter, which subsequently activates PKC isoforms. Because of this potential complication, patients with type 2 diabetes should be cautioned about using glucosamine. The activation of the hexosamine pathway decreases insulin resistance and promotes P-cell dysfunction, increasing the stress on pancreatic P cells.
Other kinase pathways in the body enhance insulin resistance, worsening hypergly-cemia and related tissue damage, and subsequently resulting in a vicious cycle of worsening hyperglycemia and enhanced insulin-activity resistance. Inhibition of various detrimental kinase pathways has been experimentally reversed with the antioxidant a-lipoic acid. In some studies, this has lowered fructosamine levels in patients with type 2 diabetes. The subsequent activation of these various detrimental biochemical pathways is responsible for the cellular damage and the systemic disease characterized by type 2 diabetes (10).
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