The sequelae of chronic hyperglycemia in diabetes of all phenotypes are divided into microvascular and macrovascular complications. The consequences of microvascular disease include loss of vision, renal insufficiency, and neuropathy (distal sensory neuropathy and diabetic autonomic neuropathy [DAN]). Macrovascular complications include myocardial infarction (MI), stroke, and peripheral arterial disease (PAD). The link between glycemic burden and induction of disease-specific complication pathways has been established by four independent biochemical abnormalities: increased polyol pathway flux, increased formation of AGEs, activation of protein kinase C (PKC), and increased hexosamine pathway flux. These seemingly unrelated pathways have an underlying common denominator: an increase in oxidative stress caused by the overproduction of superoxide by the mitochondrial electron transport chain.
• Oxidative Stress
The microvascular and macrovascular complications of diabetes are believed to be caused by oxidative stress. Intracellular oxidative stress occurs when the production of reactive oxygen species (by-products of normal metabolism) exceeds the capacity of the cells’ antioxidants to neutralize them, resulting in cellular dysfunction and damage.
17 Oxidative stress may be minimized by maintaining optimal control of metabolic parameters such as glucose, lipids, and BP. Endothelial cells chronically exposed to oxidative stress activate multiple complication pathways (
Fig. 5-3).
Endothelial cells maintain the barrier between the blood and the vascular wall. Nitric oxide (NO), which is produced within the endothelial cell, regulates vascular tone, while keeping the vessel walls smooth and free of adhesion molecules. Peroxynitrite (PN) (an NO derivative) is formed when NO interacts with superoxide produced within the mitochondria of oxidatively stressed endothelial cells. PN inhibits the endothelial cell’s mitochondrial electron transport system, induces endothelial dysfunction, and activates the expression of endothelial-derived cytokines. These cytokines act like a fuse on a stick of dynamite igniting a series of pathways that, over time will promote the development of microvascular and macrovascular disease.
17,
18
Oxidative stress is triggered more powerfully by postprandial glucose fluctuations than by sustained hyperglycemia.
19 The effects of oxidative stress on long-term diabetes outcomes have important implications in clinical practice. Why do some patients who have “normal” “A1C” levels lower than 6% develop retinopathy, whereas others who have “poorly controlled diabetes” (A1C greater than 9%) remain retinopathy-free their entire lives?
In the DCCT, the diabetic retinopathy (DR) risk at identical sustained levels of A1C was significantly reduced by intensive treatment.
20 For example, in the group of patients who had a sustained A1C of 9% for the entire study duration, the risk of retinopathy was reduced by more than 50% in the intensive control group, even though both the conventional and intensively treated patients had identical A1C levels. Intensively managed patients had less DR due to improved daily glycemic variability when compared with glucose profiles of the conventionally treated patients. This study demonstrates the importance of hyperglycemia, hypoglycemia, and “malglycemia” in promoting complications.
Figure 5-4A,B show a patient with chronic kidney disease and retinopathy whose initial “malglycemia” improved with the addition of a GLP-1 analogue.
Acute glucose fluctuations and hyperglycemia both at fasting and during the postprandial periods result in accelerated advanced glycation and the generation of oxidative stress. Chronic hyperglycemia is best assessed by measuring A1C, whereas acute fluctuations (also known as MAGE—mean amplitude of glycemic excursions) may be determined mathematically by continuous glucose monitoring.
19 Thus, both acute glycemic variability and measures of chronic hyperglycemia (A1C) are important factors in upregulating oxidative stress (
Fig. 5-5). Some experts believe that glucose variability (MAGE) greater than 40 mg per dL, as measured by continuous glucose sensors, should be targeted for intensive intervention to minimize oxidative stress.
21 One should note that oxidative stress is considered the unifying mechanism, which drives all complication pathways related to diabetes.
22
Hyperglycemia, whether acute (postprandial) or chronic, has tissue-damaging effects on cell types such as capillary endothelial cells of the retina, mesangial cells in the renal glomerulus, and peripheral neurons. Why are some cells prone to develop complications, whereas others appear to be immune to the effects of similar exposure to chronic hyperglycemia? The answer lies in a cell’s ability to assimilate the amount of glucose required as an energy source before transporting nonessential glucose out of the cell. Cells (such as neurons and nephrons) that are inefficient interstitial transporters of glucose undergo oxidative stress, which induces endothelial dysfunction, vascular inflammation, and activation of pathways that trigger complications.
17 Other cells [such as those in the gastrointestinal (GI) tract] are more efficient at transporting excessive glucose from inside the cell externally, thereby minimizing the risk of oxidative stress.
Vascular endothelial cells form physical and biologic barriers between the vessel wall and the circulating blood cells, with the endothelium playing an important role in the maintenance of vascular homeostasis. Central to this role is the endothelial production of NO, which is synthesized by the constitutively expressed endothelial isoform of NO synthase. Vascular diseases, including hypertension, diabetes, and atherosclerosis are characterized by impaired endothelium-derived NO bioactivity that may contribute to clinical cardiovascular events. Endothelial cells exposed to oxidative stress generate high levels of reactive oxygen species via their mitochondrial electrontransport chain. Susceptible cells will activate biochemical pathways likely to progress toward longterm microvascular and macrovascular complications unless metabolic stability is restored.
Endothelial dysfunction drives atherosclerosis. Endothelial cell protective mechanisms (e.g., NO and prostacyclin), which are derived vasodilators, favor antiatherogenic mechanisms within the vasculature. Expression of endothelium-derived vasoconstrictors (e.g., endothelin-1 and thromboxane) has been associated with proatherosclerotic events.
23,
24
Just as a town’s department of public works is responsible for repairing potholes that plague city streets, the body has the capacity to form a cellular “patch” over a site of acute endothelial injury. Derived from bone marrow, endothelial progenitor cells (EPCs) are mobilized to the peripheral
circulation in response to tissue ischemia through the release of growth factors and cytokines. The EPCs hone into the ischemic or damaged tissue and stimulate endothelial repair. In addition to traditional cardiovascular risk factors, oxidative stress has been associated with reduction in the number and function of circulating EPCs, whereas an expanded EPC pool decreases cardiovascular mortality.
25
Oxidative stress may even be induced in individuals without diabetes. Using a hyperglycemic clamp, euglycemic subjects exposed to ambient glucose levels greater than 200 mg per dL for just 2 hours were found to have increased levels of urinary F2 isoprostanes (a surrogate marker of oxidative stress).
26 Exposure to blood glucose levels greater than 180 mg per dL results in prolonged endothelial cell dysfunction and vascular inflammation, which persist for 7 days, even once the acute episode of hyperglycemia is reversed.
4 Thus, patients with both acute and chronic hyperglycemia live in a constant state of oxidative stress, a metabolic status that favors progression toward microvascular and macrovascular endpoints. From a clinical perspective, a patient who records a
fasting blood glucose of 200 mg per dL has likely been exposed to activated oxidative stress-related metabolic pathways during their entire resting hours. Failure to recognize and reverse this glycemic burden will put patients at risk for complications that can have a profound effect on their longevity and quality of life.
Table 5-1 lists therapeutic approaches a patient may employ to reduce oxidative stress.
• Advanced Glycosylation
Nonenzymatic glycosylation and oxidation of proteins are natural phenomena of aging that occur very slowly. As glucose becomes incorporated into proteins, AGEs are formed in an irreversible chemical reaction. During this process, reactive oxygen species, such as superoxide and hydrogen peroxide, are also produced. When ambient glucose levels are elevated, the extent of glycosylation increases as sugars become attached to free amino groups on proteins, lipids, and nucleic acids, thereby altering the function and metabolism of these macromolecules. AGE receptors (RAGEs) on macrophages induce monocytes and endothelial cells to increase the production of inflammatory cytokines and adhesion molecules
27 (
Fig. 5-6). The resulting basement membrane thickening can cause symptoms such as joint stiffness and diffuse pain in response to light touch. AGEs can also bind to AGE receptor sites on endothelial cell surfaces, leading to increased inflammatory responses, vascular permeability, and procoagulant activity. The ability to form and detoxify AGE by-products may be genetically predetermined, explaining why some patients who have poor glycemic control
are fortunate to experience no diabetes-related complications, whereas those less fortunate with prediabetes may develop retinopathy or painful diabetic neuropathy (
Fig. 5-1).
• Neuroinflammation
Autoimmune mechanisms may play a role in both the initiation and rate of deterioration of neuropathy. The production of free radicals and superoxide can disrupt the normal neuroprotection achieved by the neurovascular unit.
29 The neurovascular unit consists of a neuron surrounded by astrocytes and microglial cells (
Fig. 5-10A). Astrocytes maintain extracellular ion homeostasis within neurons.
30
Microglial cells (
Fig. 5-10A) are the resident macrophages of the central nervous system.
31 As biologic sensors, these cells continually survey the neurons, making certain that normal neurophysiologic protective mechanisms are active. Microglial cells are capable of mounting both an inflammatory and reparative response when they become “activated.” Once the microglial cells become activated, through physical stress or pharmacologic interference with their protective mechanisms, they produce inflammatory cytokines [interleukin-6 (IL-6)], damage neuronal segments, and alter neurologic activity (
Fig. 5-10B).
31 Opioid use has been found to activate microglial cells, causing them to produce inflammatory cytokines, which result in chronic, disabling pain.
32