Life threatening acute complications of diabetes mellitus

COMPLICATIONS

Complications of diabetes can be divided into acute and chronic. The acute complications include hypoglycemia (see the section on Diabetes Mellitus earlier in this chapter), diabetic ketoacidosis, and the hyperosmolar hyperglycemic syndrome. Chronic complications include microvascular and macrovascular disease. Patients with diabetic ketoacidosis generally present with metabolic acidosis with blood glucose below 500 mg/dl, whereas patients with nonketotic hyperglycemia coma present with a blood glucose level of over 1000 mg/dl with no acidosis. The pathophysiology of both disorders is related to the physiological response to stress. Infection (which is the most common cause of diabetic ketoacidosis), trauma, ischemia (cerebrovascular accident, myocardial infarction), or volume depletion can induce signals to increase catecholamines, cortisol, growth hormone, and glucagon (insulin counterregulatory hormones that increase gluconeogenesis) and cause an imbalance of glucose metabolism. These stress hormones increase blood glucose and osmolarity while decreasing cellular insulin. The lack of insulin results in ketone production by the liver and the development of an anion gap metabolic acidosis. Diabetic ketoacidosis also presents with nausea, vomiting, abdominal pain, polyurea, polydipsia, weight loss, diplopia, delirium, or coma. Objective laboratory studies reveal a metabolic acidosis, pseudohyperkalemia, glucosuria, and both serum and urine β-hydroxybuterate and acetoacetate (ketones). Due to the rapid onset of acidosis and good renal clearance in the younger patient population with type 1 diabetes, the blood glucose level rarely exceeds 800 mg/dl.

Diabetic ketoacidosis is the most commonly observed acute complication of type 1 diabetes. Patients with type 2 diabetes may also develop diabetic ketoacidosis, but this is not common. The second most common cause of diabetic ketoacidosis is patient noncompliance with insulin.

As demonstrated by the Diabetes Control Clinical Trial (DCCT) strict glycemic control is the single most important factor in preventing and/or delaying the long-term complications of diabetes. However, patients will also need appropriate blood pressure and serum cholesterol management to reduce the associated cardiovascular risk factors. ACE inhibitors are particularly beneficial in diabetic persons—not only for blood pressure control but also for their ability to delay diabetic nephropathy. Patients may also benefit from cholesterollowering medications such as the HMG CoA reductase inhibitors to achieve low-density lipoprotein levels of less than 110 mg/dl. Yearly ophthalmological examinations should be conducted for early diagnosis and management of diabetic retinopathy. Routine foot care is essential for the detection of foot ulcers secondary to diabetic peripheral neuropathy. A low-fat diet, exercise, and weight loss have been show, to decrease the severity of insulin resistance in type 2 diabetes.

Autophagy and Diabetes Complications

Complications of diabetes represent the major causes of morbidity and mortality that are associated with this chronic metabolic disorder84. Specifically, cardiovascular disease is the leading cause of mortality in subjects with diabetes, which represents the major cause of end stage renal disease, blindness and limb amputations in developed and many developing societies. Broadly speaking, diabetes complications can be categorized as macrovascular, which are those affecting large and medium size blood vessels and microvascular complications, which involve small blood vessels such as small arterioles. Macrovascular complications include accelerated atherosclerosis, leading to increased coronary artery disease, increased cerebrovascular disease and stroke, and increased peripheral arterial disease that contributes to critical limb ischemia. There is also strong evidence that diabetes leads to direct adverse effects in the heart that leads to diabetic cardiomyopathy85. Microvascular impairment leads to the complications of diabetic retinopathy, diabetic nephropathy and diabetic neuropathy. The pathogenesis of these diverse complications of diabetes is complex, is only partially understood and has been the subject of many reviews. Only recently has attention turned to the potential contribution of changes in autophagy due to the complications of diabetes.

As reviewed in other chapters, autophagy may serve a protective role in cells where it promotes cellular survival by removing damaged organelles such as mitochondria. Therefore in these contexts, a decrease in autophagy could contribute to cellular dysfunction that occurs on the basis of accumulation of dysfunctional organelles or irreversibly damaged cellular substructures. Conversely, excessive levels of autophagy can contribute to cell death. Thus a challenge in elucidating the contribution of autophagy to diabetes complications rests in the difficulty in discerning if any observed change in autophagic flux represents an adaptation or a maladaptation that is contributing to tissue injury or to its preservation in the context of the abnormal metabolic milieu that characterizes diabetes. Thus, although descriptions of changes in autophagy in diabetes complications are of interest, interpretation of the significance of the direction of the changes observed is more challenging. Ultimately, the most robust interpretations will be made when autophagy is independently manipulated in the context of a diabetes complication and a determination made of the impact of this manipulation on the progression of the particular complication in question.

Prior to summarizing what is known thus far regarding potential contributions of autophagy to diabetes complications, it will be of value to summarize mechanisms that may regulate autophagy in susceptible tissues in the diabetic milieu. Diabetes is characterized by hyperglycemia, hyperlipidemia, hypoinsulinemia (in the case of poorly controlled Type 1 diabetes) and hyperinsulinemia and insulin resistance in the case of type 2 diabetes. In addition, there might be increased concentrations of circulating cytokines, advanced glycation end products and systemic oxidative stress. Each of the components of the altered metabolic milieu could potentially influence autophagic signaling. Glucose enters cells via facilitative glucose transporters86. In most tissues, hyperglycemia will therefore be associated with increased cellular glucose uptake, increased glycolysis and the activation of metabolic pathways that originate from glycolytic intermediates such as the hexosamine biosynthesis pathway, the pentose phosphate shunt and the polyol pathway. Byproducts of these metabolic pathways can activate signaling mechanisms that may contribute to tissue injury in the context of diabetes87. A variety of studies that will be described later, in the context of specific complications, clearly indicate that exposure of cells to increased glucose concentrations can modulate autophagy in various ways. On the one hand it is clear that glucose deprivation is a potent activator of autophagy acting via mechanisms that include activation of AMPK, and activation of Sirt188, 89. However, increased delivery of glucose to cells does not necessarily result in a suppression of autophagy but may activate autophagy via mechanisms that involve increased oxidative stress that arise from mitochondrial ROS overproduction, ER stress or the repression of inhibitors of autophagy such as GATA490-93. Advanced glycation end products have also been shown to promote autophagy via mechanisms that are incompletely understood94.

In many cell types, activation of Class 1A PI3K leading to activation of mTOR is a potent repressor of autophagy95. Thus it is plausible that reduced or defective insulin signaling could lead to increased autophagy in the context of diabetes. Whether or not this represents a dominant mechanism or is superseded by other metabolic regulators of autophagy in respective tissues is incompletely understood. Other potential regulators of autophagy that could be at play in the context of diabetes include consequences of increased FA uptake and delivery, and signaling via inflammatory cytokines. Additional key signaling regulators of autophagy such AMPK, Sirt1, FOXO are altered by the diabetic milieu and as such could potentially influence autophagic flux in susceptible tissues and organs.

Complications

Complications of diabetes can be divided into acute and chronic. The acute complications include hypoglycemia (see the Diabetes Mellitus section), diabetic ketoacidosis, and hyperosmolar hyperglycemic syndrome. Chronic complications include microvascular and macrovascular disease (see the Diabetes Mellitus section). Patients with diabetic ketoacidosis generally present with metabolic acidosis and a blood glucose level below 500 mg/dl, whereas patients with nonketotic hyperglycemia coma present with a blood glucose level above 1,000 mg/dl with no acidosis. The pathophysiology of both disorders is related to the physiologic response to stress. Acute insulin deficiency (due to lack of compliance, pump blockage, brittle diabetes), infection (the most common cause of diabetic ketoacidosis), trauma, ischemia (cerebrovascular accident, myocardial infarction), or volume depletion can induce signals to increase catecholamines, cortisol, growth hormone, and glucagon (insulin counterregulatory hormones that increase gluconeogenesis), resulting in an imbalance of glucose metabolism. These stress hormones increase blood glucose and osmolarity while decreasing cellular insulin. The lack of insulin results in ketone production by the liver and the development of an anion gap metabolic acidosis. Diabetic ketoacidosis also presents with nausea, vomiting, abdominal pain, polyuria, polydipsia, weight loss, diplopia, delirium, or coma. Objective laboratory studies reveal a metabolic acidosis, pseu­dohyperkalemia, glucosuria, and both serum and urine β-hydroxybutyrate and acetoacetate (ketones). Due to the rapid onset of acidosis and good renal clearance in younger patients with type 1 diabetes, the blood glucose level rarely exceeds 800 mg/dl.

Diabetic ketoacidosis is the most commonly observed acute complication of type 1 diabetes. Patients with type 2 diabetes may also develop diabetic ketoacidosis, but it is not common. The second most common cause of diabetic ketoacidosis is patient noncompliance with insulin.

COMPLICATIONS

The complications of diabetes may be divided into early, which are frequently encountered in children, and late, which are uncommonly seen in the pediatric age group. The most common early complications of diabetes are directly attributable to insulin deficiency or excess. DKA, which may occur either as an initial presentation of diabetes or in the setting of intercurrent illness or poor glycemic control, is discussed earlier.

The most common early complication of diabetes, related to insulin treatment, is hypoglycemia. Mild hypoglycemic reactions, consisting of headache, tremors, abdominal pain, or mood changes, are considered a part of tight control. More severe hypoglycemia, however, may lead to severe alterations in consciousness, coma, seizures, and even death. Particularly in children, the chronic effects of repeated episodes of hypoglycemia on cognitive development are worrisome, thus limiting the extent to which the goals of intensive control can be applied to children. Electroencephalographic abnormalities may be documented in the majority of diabetic children with a history of severe hypoglycemia, and also in a significant percentage of diabetic children with only mild hypoglycemia. School performance and tests of neuropsychological functioning are lower in diabetic children compared with controls, particularly in children with diabetes onset before 5 years of age. Additionally, episodes of hypoglycemia may predispose to more hypoglycemia, by blunting the counterregulatory hormones glucagon and epinephrine. This hypoglycemia unawareness syndrome is extremely common in adults with diabetes but may also be seen in older children and adolescents with longer duration of diabetes. Younger children may be considered to have “functional” hypoglycemia unawareness because of limited ability to recognize and/or communicate their symptoms.

Another early complication of diabetes is lipohypertrophy, which results from the repeated subcutaneous injections of insulin into the same area, rather than rotating the sites of injections. Lipohypertrophy appears as a firm, rubbery mass in the subcutaneous space, but the problem is more than cosmetic: absorption of insulin from areas of lipohypertrophy is poor and erratic, resulting in decreasing effectiveness of insulin doses and unpredictable hypoglycemia.

Early complications of diabetes specific to childhood are delayed growth and puberty, secondary to chronic insulin deficiency and poor metabolic control. The Mauriac syndrome, or diabetic dwarfism, consisting of short stature, delayed growth and pubertal development, pallor, hepatomegaly, and thickened skin, is rarely seen in children today and is readily treatable with improved diabetes control.

Late complications of diabetes, related mainly to chronic microvascular and macrovascular disease, are the major causes of diabetes-related mortality and morbidity. The etiology and pathogenesis of microvascular disease are still under investigation but certainly involve a combination of factors, including thickening and weakening of capillary basement membranes by nonenzymatic protein glycosylation, accumulation of sorbitol and other sugar alcohols in tissues, and alterations in the paracrine/autocrine expression and action of growth factors such as insulin-like growth factor-I and transforming growth factor-β in target tissues. Risk of microvascular complications, however, is not solely related to metabolic control; the risk of development of microvascular disease is almost certainly also related to differential genetic susceptibility to the metabolic effects of diabetes, although specific susceptibility genes have yet to be identified. Hypercholesterolemia, hypertriglyceridemia, alterations in lipoproteins, and hypertension all contribute to the development of macrovascular disease.

Retinopathy is the most common microvascular complication of diabetes, and diabetic retinopathy is the leading cause of blindness in the United States. The earliest lesion is nonproliferative retinopathy, which consists of microaneurysms. More severe forms of this background retinopathy include the development of exudates and venous beading. Background retinopathy eventually develops in almost all diabetics but is not sight threatening. Proliferative retinopathy, characterized by fibrous proliferation, new blood vessel formation, and macular edema, is associated with progressive loss of vision. Proliferative retinopathy occurs in about 50% of diabetics after a disease duration of 20 years but is almost never seen in children before the age of 15. The development of retinopathy in children appears to be related not only to the duration of diabetes but also the pubertal stage; less retinopathy is seen in prepubertal children than in pubertal children with the same disease duration.

Kidney failure is one of the most common causes of death in patients with diabetes, and diabetic nephropathy is the most common cause of renal failure in the United States. Diabetic nephropathy may be divided into five stages. Glomerular hyperfiltration and renal enlargement are the earliest changes, associated with an increase in glomerular filtration rate. Hyperfiltration is correlated with hyperglycemia but is present even in patients with good metabolic control. In the second stage, which occurs 18 to 24 months after the onset of T1DM, thickening of the glomerular basement membrane and expansion of the mesangial matrix occur. Microalbuminuria (urinary albumin excretion rate of 30-300 mg/24 hr or 20-200 μg/min) may be seen but is not persistent. Persistent microalbuminuria is the hallmark of the third stage, which develops in about 25% of patients within 10 years of diagnosis. The progression to frank proteinuria, stage four, (urinary albumin excretion > 300 mg/24 hr or 200 μg/min), nephrotic syndrome, and end-stage renal disease (stage 5) occurs in about 30% to 40% of patients with diabetes of 30 years' duration. Overt nephropathy is uncommon in children, but earlier stages of the disease may be seen in the pediatric diabetes population. The prevalence of microalbuminuria in children and adolescents is about 20% to 30% and, as in retinopathy, appears to depend on not only the duration of diabetes but also the number of years postpuberty.

Diabetic neuropathy develops in about 50% of diabetics within 10 years of disease diagnosis, although clinically evident diabetic neuropathy is extremely rare in children. However, decreased vibration and light touch sensation as well as decreased nerve conduction velocity, indicative of peripheral neuropathy, may be detected in children using sensitive techniques. Autonomic neuropathy is also extremely rare in children with diabetes, although abnormal cardiac autonomic testing may be demonstrated. Autonomic dysfunction in diabetics has been implicated in increased risk of hypoglycemia unawareness and sudden death (“dead-in-bed” syndrome).

Macrovascular disease and atherosclerosis are the major causes of death in adults with T1DM. Hypercholesterolemia and hyperlipidemia are frequently seen even in pediatric patients with T1DM, the extent of which is inversely proportional to the degree of metabolic control.

Diabetic Kidney Disease (DKD)

Renal complications of diabetes, including microalbuminuria, overt proteinuria, and nephrotic syndrome, manifests with HTG and low HDL-C. Plasma levels of apoB and apoC-III often are elevated (Thomas et al., 2015). Hyperglycemia, hyperlipidemia, abdominal obesity, hypertension, and smoking are risk factors for microalbuminuria in patients with diabetes (Rutledge et al., 2010). Dyslipidemia promotes progression of renal insufficiency through glomerular and tubulointerstitial injury with concomitant accelerated atherosclerosis (Shoji et al., 2001). CVD risk factors such as elevated levels of circulating cell-adhesion molecules and systemic inflammatory markers are found in the early stages of both DKD and nondiabetic chronic kidney disease (Thomas et al., 2015). Macroalbuminuria has been associated with an increase in oxidized LDL levels (Jandeleit-Dahm et al., 1999), and HDL may lose antiinflammatory and antioxidant properties in DKD (Thomas et al., 2015). HDL3-C, sphingolipid, and TG-enrichment of HDL have been suggested as potential contributors to DKD (Thomas et al., 2015).

Publisher Summary

The complications of diabetes still produce devastating consequences. An obvious path to prevention of complications is some form of b-cell replacement therapy. A b-cell is defined as a cell with the phenotype of a mature insulin-producing cell found in pancreatic islets. It is possible to have insulin-producing cells that are immature and lack the full phenotype of a true b-cell. Some of these are b-cell precursors that, at some point, can be called young b-cells. However, there are cells containing insulin that will never become b-cells, such as those identified in the thymus, brain, retina, liver, and yolk sac. The introduction of the Edmonton protocol provided better results, the improvement being due to better islet preparations, transplantation of more islets, and improved immunosuppression. Islets are introduced into the liver through the portal vein via transhepatic angiography. These important studies provide proof-of-principle for the concept of cellular transplants as a treatment for diabetes. All new insulin-producing cells originate from precursor cells, which are not necessarily true stem cells. Stem cells can be defined as precursor cells capable of indefinite self-renewal. An embryonic stem cell (ESC) is pluripotent: able to differentiate into the three embryonic germ layers, ectoderm, endoderm, and mesoderm, and then any cell type of the body. Facultative progenitor cells also include pancreatic duct cells that can form pancreatic acini and islets. Rapid improvements in the understanding of the mechanisms of cellular development and a wide array of potential stem or precursor cell candidates provide fuel for optimism that adult cells could solve.

8.14.3.6 Diabetes Complications

Rates of diabetes complications have declined in the past decades in many countries. However, a substantial proportion of people with longstanding diabetes still develop complications that have a significant adverse effect on quality of life. The three most common microvascular complications are neuropathy, retinopathy and nephropathy. Neuropathy is occurring in around 50% of individuals with diabetes. Common symptoms of diabetic peripheral neuropathy (DPN) include burning, numbness, tingling, pain and/or weakness starting in the distal lower extremities. These symptoms may progress into more extreme symptoms of neuropathic pain in around 10%–30% of affected individuals. DPN is the strongest initiating risk factor for diabetic foot ulceration, which may necessitate an amputation. In addition, retinopathy is the leading cause of blindness, affecting 4% to 23% globally, dependent on the country and level of severity. Nephropathy affects about roughly 40% of people with diabetes globally and can lead to a high risk of having to go on dialysis. Concerns about developing diabetes complications are a major cause of distress for many. This is partly dependent on risk awareness. A systematic review in type 2 diabetes (18 studies), revealed low risk awareness overall and an optimistic bias regarding future risk of diabetes-related complication, particularly in people from ethnic minorities (Rouyard et al., 2017). In one study, up to 70% of people with type 2 diabetes were not aware of the link between type 2 diabetes and risk for cardiovascular disease. Accurate risk perception, beliefs about seriousness and concerns are key components in motivating behavioral change (see 5).

With all the information and treatment accessible today, developing complications may be perceived by the affected person as “having failed” and induce feelings of guilt and self-blame, sometimes exacerbated by healthcare professionals linking the onset to complications to “not having followed their recommendations”.

Acute complications

Acute complications of DM may represent a medical emergency or life-or-death situation. Any symptom even remotely suggestive of acute complications must be addressed immediately.

Major Complications of Diabetes

Cardiovascular disease

Hypertension

Retinopathy

Renal disease

Neuropathy

Amputations

Periodontal disease

Pain

Depression

Autoimmune disorders

Hypoglycemia: in T1DM, occurs from taking too much insulin, missing a meal, or overexercising; with “brittle” type 1; or in any diabetic on insulin or sulfonylurea who neglects monitoring. Daytime hypoglycemic symptoms: sweating, nervousness, tremor, and hunger. Nighttime hypoglycemia may be asymptomatic or may cause night sweats, unpleasant dreams, or early morning headache. Earliest autonomic symptom of hypoglycemia is hunger when glucose is below 65 to 70 mg/dL. Other symptoms: irritability, anxiety, heart palpitations, pallor, and sweating. Neuroglycopenic symptoms, when the brain becomes starved of glucose: blurry vision, headache, fatigue, abnormal behavior, slurred speech, unconsciousness, and seizures. Treatment of hypoglycemia follows the 15 to 15 rule: ingest 15 g of starch or sugar source and recheck glucose in 15 minutes. If glucose is still below 80 mg/dL, ingest another 15 g of carbohydrate and recheck glucose in an hour. If glucose sinks below 55 mg/dL, the patient will need help from another person. When it is below 20 mg/dL, seizure is likely and glucagon should be injected. The patient should record any hypoglycemic events and report them to the physician.

DKA: most commonly seen in patients with newly diagnosed T1DM when they have infections, when they have deliberately or accidentally omitted their insulin, and under other circumstances—trauma, myocardial infarction or stroke, surgery, dental abscess, and other physiologic stress. Lack of insulin leads to extremely high blood glucose and a buildup of acidic ketone molecules as fat stores are burned to provide energy. If progressive, ketoacidosis can lead to metabolic problems, coma, or death. Ketoacidosis is a medical emergency; prompt recognition is imperative. Instruct patients to check for ketones in urine or blood when glucose is above 250 mg/dL for more than a few hours, if they are feverish or have an infection, if they feel unwell, and regularly during pregnancy, because DKA is usually fatal to the fetus. Symptoms of DKA: fruity breath, disorientation, abdominal tenderness, polyuria and polydipsia, hyperventilation, and signs of dehydration. Treatment of DKA depends on severity of the situation and glucose level—it can require injecting insulin, eating, or referral to an emergency department.

Nonketogenic hyperosmolar hyperglycemia: in T2DM with some insulin production or in T1DM on inadequate insulin for acute situation. It evolves over days with severe dehydration and electrolyte (sodium, potassium) disturbance. If patient is comatose, mortality rate is greater than 50%. Cause is profound dehydration from deficient fluid intake or precipitating events (pneumonia, burns, stroke, recent surgery, certain drugs [phenytoin, diazoxide, glucocorticoids, and diuretics]). Onset is insidious over period of days or weeks; symptoms include weakness, polyuria and thirst, and worsening signs of dehydration (weight loss, loss of skin elasticity, dry mucous membranes, tachycardia, hypotension). This condition is completely preventable by regular monitoring during illness or stress.

Hyperosmolar hyperglycemic state (HHS): occurs mostly in older T2DM patients, usually in seventh decade of life. It develops gradually over days to weeks. There is no ketoacidosis in HHS, but it has a higher mortality because it occurs in patients with other serious problems—acute illness, recent surgery, congestive heart failure, renal dysfunction, or cardiovascular disease—or who are taking certain drugs, are victims of elder abuse or neglect, or are noncompliant with diabetic therapy. Diagnostic criteria: glucose level above 600 mg/dL, profound dehydration, other changes in pH, and some alteration in consciousness. Symptoms: drowsiness, coma, visual changes, sensory deficits, and even paralysis or seizures. HHS is a medical emergency; transport patient to emergency department. Injecting insulin can cause severe complications; hospital care is best.

Classic pathways

General studies of diabetes complications have identified several well known metabolic and structural alterations linked to end organ damage. Neuropathy has been attributed to similar mechanisms. Thus, these intensively evaluated classic abnormalities in DM are important to consider but none offers satisfying or complete explanations. One major drawback of this work is that it has often lacked a neurosciences perspective. For example, many investigations along these lines have not considered or addressed loss of distal sensory terminals, selective sensory targeting and other facets of DPN. Overall there is an extensive literature and substantial controversy on the role of classic diabetic pathways in the pathogenesis of DPN. Additional chapters in this volume highlight some of these varying interpretations.

Excessive flux of polyols (sugar alcohols) especially sorbitol, through the aldose reductase pathway has been linked to depletions of nerve myo-inositol, changes in PKC subunits and dysfunction of nerve Na/K ATPase that contribute to slowing of nerve conduction velocity, a cardinal feature of DPN (Greene et al., 1987; Sima et al., 1987; Schmidt et al., 1989; Borghini et al., 1994; Cherian et al., 1996; Mizisin et al., 1997; Roberts and McLean, 1997). Aldose reductase is expressed by SCs and perineuronal satellite cells, however, and the impact of this pathway on neurons may therefore be secondary (Jiang et al., 2006). Aldose reductase inhibitors (ARIs) or PKC inhibitors that interrupt polyol flux have been studied in several therapeutic trials. Many trials have only demonstrated limited benefits with toxicity and in some instances there has been poor endoneurial penetration. More promising benefits have emerged in later trials (Judzewitsch et al., 1983; Sima et al., 1988; Zenon et al., 1990). Although ARIs appear to be effective in reversing conduction velocity slowing, their impact on axonal degeneration is uncertain. The linkage between excessive polyol flux and neurodegeneration therefore remains unclear.

Diabetic microangiopathy refers to functional alterations followed by structural damage of small nutrient blood vessels. These changes, together with rises in blood viscosity and oxygen release, may lead to ischemic damage of neurons and axons in diabetes. Microangiopathy has been a particularly popular concept of DPN pathogenesis. The structural changes in nerve microvessels or vasa nervorum are extensively documented in humans and described in some DPN models (Williams et al., 1980; Tuck et al., 1984; Dyck et al., 1985, 1986a, b; Timperley et al., 1985; Johnson et al., 1986; Yasuda and Dyck, 1987; Malik et al., 1989, 1993; Yasuda et al., 1989). Epidemiologic linkages between DPN and vascular risk factors have added support to the concept that vascular disease is responsible its development (Tesfaye et al., 2005). Despite the evidence cited, there are significant difficulties with this hypothesis that are briefly summarized here. For example, several rigorously conducted studies of nerve blood flow in experimental diabetes models have not demonstrated reductions that can account for neuropathy; vascular caliber is increased rather than reduced in experimental models; approaches that “correct” nerve blood flow and improve neuropathy may not be specific; interventions and transgenic models that do not target microvessels can correct cardinal features of experimental DPN. In humans with mild DPN enrolled in a clinical trial, direct measurements of nerve blood flow were not reduced (Theriault et al., 1997). We have suggested that microangiopathy contributes to DPN, especially in later disease, but that it is not its primary trigger (Zochodne et al., 1996; Theriault et al., 1997; Zochodne and Nguyen, 1999; see our review, Zochodne, 2002).

Free radical oxidative and nitrergic stress (Ceriello and Giugliano, 1997; Low et al., 1997; Lyons and Jenkins, 1997; Zalba et al., 2000) and impaired antioxidant defenses may contribute to diabetic neuron damage (West, 2000). This hypothesis is considered in this volume in detail in the chapter by Fernyhough (Ch. 25). Our laboratory identified rises in nitric oxide synthase activity in ganglia and nerve (Zochodne et al., 2000). Nitrotyrosine immunoreactivity, a footprint of peroxynitrite toxicity in ganglia, has also been identified (Cheng and Zochodne, 2003). Similarly, rises in nitrotyrosine in nerves from a short-term rat model of experimental diabetes were identified but are of uncertain localization (Negi et al., 2010). Approaches that attenuate oxidative stress have improved features of experimental diabetic neuropathy (Obrosova et al., 2000; Drel et al., 2007; Vareniuk et al., 2008). How oxidative stress might selectively target distal terminals, particularly of sensory axons, requires clarity. Recent evidence of direct axon targeting by oxidative stress, however, has been identified by in vitro studies of the adult diabetic sensory neuron (Zherebitskaya et al., 2009).

When to Adjust Treatment

To avoid the complications of diabetes, we should avoid clinician inertia and monitor therapy every 2–3 months. Effectiveness of therapy is evaluated with assessment of A1c, logbook data for SMBG records, documented and suspected hypoglycemia, and other potential adverse events (weight gain, fluid retention, and hepatic, renal, or cardiac disease) as well as monitoring of comorbidities. Regimen must be modified until the goal for pre- and post-meals as well as A1c level has been achieved. It is important to recognize that, in some circumstances, some patients may not achieve the desired goals of treatment. When this situation arises, reevaluating the treatment regimen may require assessment of barriers including income, health literacy, diabetes distress, depression, and competing demands, including those related to family responsibilities and dynamics. Corrective strategies may include change in pharmacological therapy; reinforcement of lifestyle interventions, especially the relationship between food and blood sugar; frequent contact with the patient; referral to a social worker or mental health professional; or utilization of Continuous Glucose monitoring device to better evaluate glycemia. For patients on insulin or on short-acting repaglinide, providing an algorithm for self-titration based on SMBG may be appropriate.

After augmenting her metformin and adding the second agent, the effectiveness of Linda's new regimen will be evaluated in 2–3 months with a repeat A1c, as well as the assessment of her logbook data showing results of both pre- and post-meals. If her A1c is not at target, a third agent could be considered, based on the AACE algorithm. Using this approach, the third agent can be a TZD, glinide, or sulfonylurea, recommended in that order to minimize the risk of hypoglycemia. Additionally, the combination of metformin, and incretin mimetic, may partially help to counteract the possible weight gain associated with these three new agents.37