+++
Clinical Presentation
++
Diabetes mellitus is a heterogeneous disorder defined by the presence of hyperglycemia. Diagnostic criteria for diabetes include the following: (1) a fasting plasma glucose of 126 mg/dL or more, (2) classic symptoms of hyperglycemia plus a random plasma glucose of 200 mg/dL or more, or (3) a plasma glucose level of 200 mg/dL or more after an oral dose of 75 g of glucose (oral glucose tolerance test, OGTT). More recently, following the establishment of standardized assays, glycated hemoglobin (HbA1C), which correlates with chronic increases in glucose, has been used to diagnose diabetes when HbA1C levels 6.5% or more are documented using an appropriate methodology.
++
Hyperglycemia in all cases is due to a functional deficiency of insulin action. Deficient insulin action can be due to a decrease in insulin secretion by the β cells of the pancreas, a decreased response to insulin by target tissues (insulin resistance), or an increase in the counter-regulatory hormones that oppose the effects of insulin. The relative contributions of these three factors form the basis for the classification of this disorder into subtypes and also helps to explain the characteristic clinical presentations of each subtype (Table 18–3).
++
++
Diabetes prevalence worldwide, which has been increasing over the past few decades, reached 8% in 2011 in those 20 years or older (and a prevalence of 11% in the United States). More than 90% of cases of diabetes mellitus are believed to occur in the context of a genetic predisposition and are classified as either type 1 diabetes mellitus (DM) or type 2 DM (Tables 18–3 and 18–4). Type 1 DM is much less common than type 2 DM, accounting for 5–10% of cases of primary diabetes. Type 1 DM is characterized by autoimmune destruction of pancreatic β cells with resultant severe insulin deficiency. In a minority of patients, the cause of type 1 DM is unknown. The disease commonly affects individuals younger than 30 years; a bimodal peak in incidence occurs around age 5–7 years and at puberty. Although autoimmune destruction of the β cells does not occur acutely, clinical symptoms usually do. Patients present after only days or weeks of polyuria, polydipsia, and weight loss with markedly elevated serum glucose concentrations. Ketone bodies are also increased because of the marked lack of insulin, resulting in severe, life-threatening acidosis (diabetic ketoacidosis). Patients with type 1 DM require treatment with insulin.
++
++
Type 2 DM differs from type 1 DM in several distinct ways (Table 18–4): It accounts for the overwhelming majority of diabetes (90–95%); has a stronger genetic component; occurs most commonly in adults; increases in prevalence with age (ie, 18% of individuals older than 65 years worldwide, or 27% in the United States); occurs more commonly in Native American, Mexican American, and African American populations in the United States; and is associated with increased resistance to the effects of insulin at its sites of action as well as a decrease in insulin secretion by the pancreas. It is often (85% of cases) associated with obesity, an additional factor that increases insulin resistance. Thus, the rising prevalence of diabetes worldwide has been associated with an increasing prevalence of obesity (12%). Insulin resistance is the hallmark of type 2 DM. Because these patients often have varying amounts of residual insulin secretion that prevent severe hyperglycemia or ketosis, they often are asymptomatic and are diagnosed 5–7 years after the actual onset of disease (frank hyperglycemia) by the discovery of an elevated fasting glucose on routine screening tests. Population screening surveys show that a remarkable 30% of cases of type 2 DM in the United States, or 50% of cases worldwide, remain undiagnosed. Additionally, it is estimated that one-third of the adult population in the United States is insulin-resistant and hence in a pre-diabetic (normoglycemic) state. Once diagnosed with type 2 DM, most individuals (70%) are managed with lifestyle modification (eg, diet, exercise, weight management) alone or in combination with medications that (1) enhance endogenous glucose-independent insulin secretion (sulfonylureas), (2) amplify endogenous glucose-dependent insulin secretion (incretins, such as GLP-1), (3) decrease insulin resistance in hepatic or peripheral tissues (eg, metformin or glitazones, respectively), or (4) interfere with intestinal absorption of carbohydrates (eg, intestinal α-glycosidase inhibitors). A new class of drugs inhibiting the transporter responsible for renal glucose reabsorption (sodium-glucose co-transporter 2 [SGLT2]) is also being developed for use in type 2 DM. Type 2 diabetic patients do not usually require insulin treatment for survival. However, some patients with advanced type 2 DM are treated with insulin to achieve optimal glucose control.
++
An epidemic of type 2 DM is occurring worldwide, particularly in non-European populations; it has been estimated that 1 in 3 children born after 2000 will develop diabetes, particularly type 2 DM, in their lifetime. Thus, while type 1 DM remains the most common cause of diabetes in children younger than 10 years (regardless of ethnicity) and in older, non-Hispanic white children, type 2 DM accounts for more than 50% of the diagnoses in older children of Hispanic, African American, Native American, and Asian Pacific Islander ancestry. In all age groups and ethnicities, this increased incidence of type 2 DM is associated with obesity.
++
Other causes of diabetes, accounting for less than 5% of cases, include processes that destroy the pancreas (eg, pancreatitis), specifically inhibit insulin secretion (eg, genetic β-cell defects [MODY]), induce insulin resistance (eg, certain HIV protease inhibitors), or increase counter-regulatory hormones (eg, Cushing syndrome) (Table 18–3, part III). Clinical presentations in these cases depend on the exact nature of the process and are not discussed here.
++
Gestational diabetes mellitus occurs in pregnant women with an incidence ranging from 3–8% in the general population to up to 16% in Native American women (Table 18–3, part IV), may recur with subsequent pregnancies, and tends to resolve at parturition. The prevalence of gestational diabetes mellitus in a population varies in direct proportion to the prevalence of diabetes. Up to 50% of these women with gestational diabetes mellitus eventually progress to diabetes (predominantly type 2 DM). Gestational diabetes usually occurs in the second half of gestation, precipitated by the increasing levels of hormones such as chorionic somatomammotropin, progesterone, cortisol, and prolactin that have counter-regulatory anti-insulin effects. Because of its potential adverse effects on fetal outcome, gestational diabetes in the United States is currently diagnosed or ruled out by routine screening with an oral glucose load at 24 weeks of gestation in those with average risk or at the first prenatal visit in high-risk populations—obese, age older than 25 years, family history of diabetes, or member of an ethnic group with a high prevalence of diabetes.
+++
Type 1 Diabetes Mellitus
++
Type 1 DM is an autoimmune disease caused by the selective destruction of pancreatic β cells by T lymphocytes targeting ill-defined β-cell antigens. The incidence of type 1 DM, while much lower than that for type 2 DM, appears to be increasing worldwide. In early disease, lymphocytic infiltrates of macrophage-activating CD4+ cells and cytokine-secreting, cytotoxic CD8+ cells surround the necrotic β cells. Autoimmune destruction of the β cell occurs gradually over several years until sufficient β-cell mass is lost to cause symptoms of insulin deficiency. At the time of diagnosis, ongoing inflammation is present in some islets, whereas other islets are atrophic and consist only of glucagon-secreting α cells and somatostatin-secreting δ cells. Autoantibodies against islet cells and insulin, while appearing early in the course of disease, are thought to serve as markers, rather than mediators, of β-cell destruction. As such, they have been used to aid in the differential diagnosis of type 1 DM vs. type 2 DM in children (particularly with the rising incidence of type 2 DM in this population) and to assess the probability for development of type 1 DM in first-degree relatives who are at increased risk for type 1 DM (2–6% incidence vs. 0.3% annual incidence in the general population).
++
Islet cell antibodies (ICA), which include those directed against insulin (insulin autoantibody [IAA]), glutamic acid decarboxylase (GAD), a β-cell zinc transporter (ZnT8), and tyrosine phosphatase-IA2 protein (IA2), are each present in 50% of newly diagnosed diabetics and are highly predictive of disease onset in first-degree relatives. Overall, 70% of first-degree relatives positive for at least three of these antibodies develop disease within 5 years. Because the appearance of autoantibodies is followed by progressive impairment of insulin release in response to glucose (Figure 18–7), both criteria have been used with great success to identify at-risk first-degree relatives with the ultimate, but as yet unmet, goal of intervening to prevent diabetes. However, because only 15% of individuals newly diagnosed with type 1 DM have a positive family history, these screening methods cannot be used to identify the vast majority of individuals developing this low-incidence type of diabetes.
++
++
At least 50% of the genetic susceptibility for type 1 DM has been linked to the genes of the major histocompatibility complex (MHC) that encode class II human leukocyte antigens (HLA) molecules (DR, DQ, and DP) expressed on the surface of specific antigen-presenting cells such as macrophages. Class II molecules form a complex with processed foreign antigens or autoantigens, which then activates CD4 T lymphocytes via interaction with the T-cell receptor. Alleles at the HLA-DR or HLA-DQ loci have the strongest influence on the risk of type 1 DM. While 95% of individuals with type 1 DM have either DR3-DQ2 or DR4-DQ8 haplotypes, they share this genotype with 40% of the general population. In addition, only 6% of children with high-risk HLA types will develop diabetes. Thus, identification of HLA haplotypes remains a research tool.
++
While genetic susceptibility clearly plays a role in type 1 DM, the 50% concordance rate in identical twins, as well as the continuing increase in the incidence of type 1 DM since World War II, provides additional evidence that environmental factors may also play a critical role. Evidence suggests that viral infections, such as congenital exposure to rubella, may precipitate disease, particularly in genetically susceptible individuals. It is hypothesized that an immune response to foreign antigens may also incite β-cell destruction if these foreign antigens have some homology with islet cell antigens (molecular mimicry). For example, coxsackievirus infections are also associated to the onset of type 1 DM. One particular coxsackie viral protein shares homology with the islet cell antigen, GAD. Vitamin D deficiency also correlates with a greater risk of type 1 DM, which may partially explain the increased incidence of type 1 DM at higher latitudes.
+++
Type 2 Diabetes Mellitus
++
Given the current obesity-associated epidemic of type 2 DM, environmental factors are clearly critical for the development of this disorder. And yet, the genetic components underlying type 2 DM are even stronger than those associated with type 1 DM. In type 2 DM, in contrast to the absolute lack of insulin in type 1 DM, two metabolic defects are responsible for hyperglycemia: (1) target tissue resistance to the effects of insulin and (2) inadequate pancreatic β-cell insulin secretion in the setting of insulin resistance.
++
Whether the primary lesion in type 2 DM is insulin resistance or defective β-cell insulin secretion continues to be debated. Several decades before the onset of clinical diabetes, insulin resistance and high insulin levels are present. This has led researchers to hypothesize that insulin resistance could be the primary lesion, resulting in a compensatory increase in insulin secretion that ultimately cannot be maintained by the pancreas (Figure 18–7). When the pancreas becomes “exhausted” and cannot keep up with insulin demands, clinical diabetes results.
++
Insulin resistance is the key factor linking obesity and type 2 DM. Nutritional excess from any source ultimately leads to increased free fatty acid (FFA) storage as triglyceride in adipose tissue. The increased release of various factors from adipose, particularly central (visceral) adipose tissue, drives insulin resistance. Critical mediators include the following: (1) toxic effects of excess free fatty acids released from adipose by lipolysis (lipotoxicity); (2) dysregulated secretion of fat-specific proteins (adipokines), such as adiponectin, an insulin-sensitizing hormone and the anti-diabetogenic hormone, leptin that acts centrally to control satiety and enhance insulin sensitivity; and 3) increased production of inflammatory cytokines within adipose tissue. For example, tumor necrosis factor (TNF) secretion from hypertropic adipocytes and macrophages attracted into adipose tissue by other inflammatory adipocyte secretory products (eg, macrophage chemoattractant protein-1 [MCP-1]) is thought to block peroxisome proliferator–activated receptor gamma (PPARδ). PPARδ, whose activity is enhanced by the glitzazone class of diabetes drugs, is an adipose transcription factor that decreases insulin resistance by altering adipokine secretion and decreasing FFA release.
++
Central (visceral) adipose tissue most closely correlates with insulin resistance since it is most susceptible to increased lipolysis due to (1) enhanced sensitivity to the stimulatory effects of counter-regulatory hormones (increased number of β-adrenergic receptors and increased local conversion of inactive cortisone to active cortisol due to high levels of type 1 11β-hydroxysteroid dehydrogenase) and (2) weaker suppressive effect of insulin due to lower insulin receptor affinity. Visceral adipose tissue drains directly into the portal vein, thus exposing the liver to high levels of FFA and altered adipokine levels, resulting in hepatic steatosis and insulin resistance, which manifests as increased hepatic glucose output and elevated fasting glucose levels. Increased FFA flux also results in increased lipid deposition in other insulin-target tissues, such as skeletal muscle, where it is associated with mitochondrial dysfunction and insulin resistance, resulting in impaired insulin-stimulated glucose disposal/transport after a meal due to decreased translocation of GLUT-4. Hyperinsulinemia also contributes to insulin resistance by downregulating insulin receptor levels and desensitizing downstream pathways. Hyperglycemia may lead to increased flux through otherwise minor glucose metabolic pathways that result in products associated with insulin resistance (eg, hexosamines).
++
The importance of obesity in the etiology of type 2 DM (85% of type 2 DM patients are obese) is underscored by the fact that even a 5–10% weight loss in obese individuals with type 2 DM can ameliorate or even terminate the disorder. However, while the majority of obese individuals are hyperinsulinemic and insulin resistant, most do not develop diabetes. Therefore, alternatively or additionally, a primary pancreatic β-cell defect is also postulated to contribute to the pathogenesis of type 2 DM. Beta-cell mass normally increases with obesity. However, in those who develop impaired glucose tolerance and, later, frank diabetes, β-cell apoptosis results in a decline in β-cell mass. Impairment of the acute release of insulin (first phase insulin release) that precedes sustained insulin secretion in response to a meal occurs well before the onset of frank diabetes. Lipid accumulation in β cells is also thought to contribute to impaired β-cell function by various mechanisms, including activation of the pro-apoptotic unfolded protein response (UPR) in the endoplasmic reticulum. Chronic exposure to hyperglycemia and elevated free fatty acids also contribute to impaired β-cell insulin secretion (glucolipotoxicity).
++
In the last 2 decades, a great deal of work has been directed toward identifying the genes that account for the strong genetic component of type 2 DM. Initial efforts targeting specific candidate genes have been followed by genome wide approaches, all of which have yielded useful information, including the identification of a small subset of cases of type 2 DM that are monogenic in origin. One monogenetic form of type 2 DM is maturity-onset diabetes of the young (MODY) (Table 18–3). This autosomal dominant disorder accounts for 1–5% of cases of type 2 DM and is characterized by the onset of mild diabetes in lean individuals before the age of 25 years. MODY is caused by mutations in one of six pancreatic genes, glucokinase, the β-cell glucose sensor, or five different transcription factors. In contrast, the vast majority of cases of type 2 DM are thought to be polygenic in origin, due to the inheritance of an interacting set of susceptibility genes. The list of genes linked to increased risk of type 2 DM is extensive and growing. However, genes associated with defects in insulin secretion account for less than 10% of the genetic risk of type 2 DM.
++
Checkpoint
22. What are the key characteristics of type 1 DM and type 2 DM?
23. What is the role of heredity versus the environment in each of the two major types of diabetes mellitus?
24. What are two possible mechanisms of insulin resistance in type 2 DM?
25. What is the role of obesity in type 2 DM?
+++
Pathology & Pathogenesis
++
No matter what the origin, all types of diabetes result from a relative deficiency of insulin action. In addition, glucagon levels can be inappropriately high. This high glucagon-insulin ratio creates a state similar to that seen in fasting and results in a superfasting milieu that is inappropriate for maintenance of normal fuel homeostasis (Table 18–2; Figure 18–6).
++
The resulting metabolic derangements depend on the degree of loss of insulin action. Adipose tissue is most sensitive to insulin action. Therefore, low insulin activity is capable of suppressing excessive lipolysis and enhancing fat storage. Higher levels of insulin are required to oppose glucagon effects on the liver and block hepatic glucose output. In normal individuals, basal levels of insulin activity are capable of mediating both of these responses, with the liver, in particular, being exquisitely responsive to changes in pancreatic insulin secretion due to its high sensitivity and exposure to elevated levels of insulin in the portal circulation. However, the ability of skeletal muscle to respond to a glucose load with insulin-mediated glucose uptake requires the stimulated secretion of additional insulin from the pancreas.
++
Mild deficiencies in insulin action are, therefore, frequently manifested by an inability of insulin-sensitive tissues (eg, skeletal muscle which is responsible for 85% of postprandial glucose clearance) to clear glucose loads. Clinically, this results in postprandial hyperglycemia (Figure 18–7). Such individuals, most commonly type 2 diabetics with residual insulin secretion but increased insulin resistance, will have abnormal oral glucose tolerance test results and/or high nonfasting (postprandial) glucose levels. However, fasting glucose levels remain normal because sufficient insulin action is present to counterbalance the glucagon-mediated hepatic glucose output that maintains them. When a further loss of insulin action occurs, glucagon’s effects on the liver are not sufficiently counterbalanced. Individuals, therefore, have both postprandial hyperglycemia and fasting hyperglycemia (Figure 18–7). Interestingly, skeletal tissue remains insulin sensitive in some prediabetic individuals who can present instead with isolated increases in hepatic glucose output and fasting glucose levels. Because of the importance of excessive hepatic glucose output in the pathogenesis of type 2 DM (driven by insulin resistance and inappropriately high levels of glucagon), metformin, a drug that specifically targets hepatic glucose output, is used as a first-line treatment in these individuals.
++
Although type 2 diabetics usually have some degree of residual endogenous insulin action, type 1 diabetics have none. Therefore, untreated or inadequately treated type 1 diabetics manifest the most severe signs of insulin deficiency. In addition to fasting and postprandial hyperglycemia, they also develop ketosis because a marked lack or absolute deficiency of insulin allows maximal lipolysis of fat stores to supply substrates for unopposed glucagon stimulation of ketogenesis in the liver.
++
Fatty acids liberated from increased lipolysis, in addition to being metabolized by the liver into ketone bodies, can also be reesterified and packaged into VLDLs. Furthermore, insulin deficiency causes a decrease in lipoprotein lipase, the enzyme responsible for hydrolysis of VLDL triglycerides in preparation for fatty acid storage in adipose tissue, thereby slowing VLDL clearance. Therefore, both type 1 and type 2 diabetics can have hypertriglyceridemia as a result of both an increase in VLDL production and a decrease in VLDL clearance.
++
Because insulin stimulates amino acid uptake and protein synthesis in muscle, the decrease in insulin action in diabetes results in decreased muscle protein synthesis. Marked insulinopenia, such as occurs in type 1 DM, can cause negative nitrogen balance and marked protein wasting. Amino acids not taken up by muscle are instead diverted to the liver where they are used to fuel gluconeogenesis.
++
In type 1 DM or type 2 DM, the superimposition of stress-induced counter-regulatory hormones on what is already an insulinopenic state exacerbates the metabolic manifestations of deficient insulin action. The stress of infection, for example, can, therefore, induce diabetic ketoacidosis in both type 1 and some type 2 diabetics.
++
In addition to the metabolic derangements discussed previously, diabetes causes other chronic complications that are responsible for the high morbidity and mortality rates associated with this disease. Diabetic complications are largely the result of vascular disease affecting both the microvasculature (retinopathy, nephropathy, and some types of neuropathy) and the macrovasculature (coronary artery disease, peripheral vascular disease).
+++
Clinical Manifestations
++
1. Hyperglycemia—When elevated glucose levels exceed the renal threshold for reabsorption of glucose, glucosuria results. This causes an osmotic diuresis manifested clinically by polyuria, including nocturia. Dehydration results, stimulating thirst that results in polydipsia. A significant loss of calories can result from glucosuria, because urinary glucose losses can exceed 75 g/d (75 g × 4 kcal/g = 300 kcal/d). Polyphagia also accompanies uncontrolled hyperglycemia. The three “polys” of diabetes—polyuria, polydipsia, and polyphagia—are common presenting symptoms in both type 1 and symptomatic type 2 patients. Weight loss can also occur as a result of both dehydration and loss of calories in the urine. Severe weight loss is most likely to occur in patients with severe insulinopenia (type 1 DM) and is due to both caloric loss and muscle wasting. Increased protein catabolism also contributes to the growth failure seen in children with type 1 DM.
++
Elevated glucose levels raise plasma osmolality:
++
++
Changes in the water content of the lens of the eye in response to changes in osmolality can cause blurred vision.
++
In women, glucosuria can lead to an increased incidence of candidal vulvovaginitis. In some cases, this may be their only presenting symptom. In uncircumcised men, candidal balanitis (a similar infection of the glans penis) can occur.
++
2. Diabetic ketoacidosis—A profound loss of insulin activity leads not only to increased serum glucose levels because of increased hepatic glucose output and decreased glucose uptake by insulin-sensitive tissues but also to ketogenesis. In the absence of insulin, lipolysis is stimulated, providing fatty acids that are preferentially converted to ketone bodies in the liver by unopposed glucagon action. Typically, profound hyperglycemia and ketosis (diabetic ketoacidosis) occur in type 1 diabetics, individuals who lack endogenous insulin. However, diabetic ketoacidosis can also occur in type 2 DM, particularly during infections, severe trauma, or other causes of stress that increase levels of counter-regulatory hormones, thus producing a state of profound inhibition of insulin action.
++
Severe hyperglycemia with glucose levels reaching an average of 500 mg/dL can occur if compensation for the osmotic diuresis associated with hyperglycemia fails. Initially, when elevated glucose levels cause an increase in osmolality, a shift of water from the intracellular to the extracellular space and increased water intake stimulated by thirst help to maintain intravascular volume. If polyuria continues and these compensatory mechanisms cannot keep pace with fluid losses—particularly decreased intake as a result of the nausea and increased losses resulting from the vomiting that accompany ketoacidosis—the depletion of intravascular volume leads to decreased renal blood flow. The kidney’s ability to excrete glucose is, therefore, reduced. Hypovolemia also stimulates counter-regulatory hormones. Therefore, glucose levels rise acutely owing to increased glucose production stimulated by these hormones and decreased clearance by the kidney, an important source of glucose clearance in the absence of insulin-mediated glucose uptake.
++
In diabetic ketoacidosis, coma occurs in a minority of patients (10%). Hyperosmolality (not acidosis) is the cause of coma. Profound cellular dehydration occurs in response to the marked increase in plasma osmolality. A severe loss of intracellular fluid in the brain leads to coma. Coma occurs when the effective plasma osmolality reaches 330 mOsm/L (normal: 280–295 mOsm/L). Because urea is freely diffusible across cell membranes, blood urea nitrogen is not used to calculate the effective plasma osmolality as:
++
++
The increase in ketogenesis caused by a severe lack of insulin action results in increased serum levels of ketones and ketonuria. Insulinopenia is also thought to decrease the ability of tissues to use ketones, thus contributing to the maintenance of ketosis. Acetoacetate and β-hydroxybutyrate, the chief ketone bodies produced by the liver, are organic acids and, therefore, cause metabolic acidosis, decreasing blood pH and serum bicarbonate (Figure 18–8). Respiration is stimulated, which partially compensates for the metabolic acidosis by reducing PCO2. The presence of unmeasured ketoacid anions in diabetic ketoacidosis (DKA) causes an increased anion gap (the calculated difference between measured cations and anions), which under normal circumstances is primarily due to negatively charged proteins, such as albumin:
++
Anion Gap (mEq/L) = (Na+ + K+) − (Cl− + HCO3−)
++
++
When the pH level is lower than 7.20, characteristic deep, rapid respirations occur (Kussmaul breathing). Although acetone is a minor product of ketogenesis (Figure 18–8), its fruity odor can be detected on the breath during diabetic ketoacidosis. It should be noted that the ketosis of DKA is much more severe than that appropriately occurring with starvation, because in the latter case, residual insulin action can prevent excessive lipolysis and hepatic ketogenesis while still allowing for peripheral ketone utilization.
++
Na+ is lost in addition to water during the osmotic diuresis accompanying diabetic ketoacidosis. Therefore, total body Na+ is depleted. Serum levels of Na+ are usually low owing to the osmotic activity of the elevated glucose, which draws water into the extracellular space and in that way decreases the Na+ concentration (serum Na+ falls approximately 1.6 mmol/L for every 100 mg/dL increase in glucose).
++
Total body stores of K+ are also depleted by diuresis and vomiting. However, acidosis, insulinopenia, and elevated glucose levels cause a shift of K+ out of cells, thus maintaining normal or even elevated serum K+ levels until acidosis and hyperglycemia are corrected. With administration of insulin and correction of acidosis, serum K+ falls as K+ moves back into cells. Without treatment, K+ can fall to dangerously low levels, leading to potentially lethal cardiac arrhythmias. Therefore, K+ supplementation is routinely given in the treatment of diabetic ketoacidosis. Similarly, phosphate depletion accompanies diabetic ketoacidosis, although acidosis and insulinopenia can cause serum phosphorus levels to be normal before treatment. Phosphate replacement is provided only in cases of extreme depletion given the risks of phosphate administration. (Intravenous phosphate may complex with Ca2+, resulting in hypocalcemia and Ca2+ phosphate deposition in soft tissues.)
++
Marked hypertriglyceridemia can also accompany diabetic ketoacidosis because of the increased production and decreased clearance of VLDL that occurs in insulin-deficient states. Increased production is due to: (1) the increased hepatic flux of fatty acids, which, in addition to fueling ketogenesis, can be repackaged and secreted as VLDL; (2) increased hepatic VLDL production due to the loss of inhibitory effects of insulin on proteins required for VLDL assembly (apoB and microsomal triglyceride transfer protein [MTP]); and (3) decreased clearance due to decreased lipoprotein lipase activity. Although serum Na+ levels can be decreased owing to the osmotic effects of glucose, hypertriglyceridemia can interfere with some common procedures used to measure serum Na+. This causes pseudohyponatremia (ie, falsely low serum Na+ values, due to overestimation of actual serum volume).
++
Nausea and vomiting often accompany diabetic ketoacidosis, contributing to further dehydration. Abdominal pain, present in 30% of patients, may be due to gastric stasis and distention. Amylase is frequently elevated (90% of cases), in part because of elevations of salivary amylase, but it is usually not associated with symptoms of pancreatitis. Leukocytosis is frequently present and does not necessarily indicate the presence of infection. However, because infections can precipitate diabetic ketoacidosis in type 1 DM and type 2 DM, other manifestations of infection should be sought, such as fever, a finding that cannot be attributed to diabetic ketoacidosis.
++
Diabetic ketoacidosis is treated by replacement of water and electrolytes (Na+ and K+) and administration of insulin. Both treatment modalities are of great importance, as evidenced historically by the marked decrease in mortality from DKA with the advent of insulin therapy (from 100% to 50%) and the further significant decrease (from 50% to 20%) when the importance of hydration was recognized and instituted. With fluid and electrolyte replacement, renal perfusion is increased, restoring renal clearance of elevated blood glucose, and counter- regulatory hormone production is decreased, thus decreasing hepatic glucose production. Insulin administration also corrects hyperglycemia by restoring insulin-sensitive glucose uptake and inhibiting hepatic glucose output. Rehydration is a critical component of the treatment of hyperosmolality. If insulin is administered in the absence of fluid and electrolyte replacement, water will move from the extracellular space back into the cells with correction of hyperglycemia, leading to vascular collapse. Insulin administration is also required to inhibit further lipolysis, thus eliminating substrates for ketogenesis, and to inhibit hepatic ketogenesis, thereby correcting ketoacidosis.
++
During treatment of diabetic ketoacidosis, measured serum ketones may transiently rise instead of showing a steady decrease. This is an artifact because of the limitations of the nitroprusside test that is often used at the bedside to measure ketones in both serum and urine. Nitroprusside only detects acetoacetate and not β-hydroxybutyrate. During untreated diabetic ketoacidosis, accelerated fatty acid oxidation generates large quantities of NADH in the liver, which favors the formation of β-hydroxybutyrate over acetoacetate (Figure 18–8). With insulin treatment, fatty acid oxidation decreases and the redox potential of the liver shifts back in favor of acetoacetate formation. Therefore, although the absolute amount of hepatic ketone body production is decreasing with treatment of diabetic ketoacidosis, the relative amount of acetoacetate production is increasing, leading to a transient increase in measured serum ketones by the nitroprusside test.
++
3. Hyperosmolar coma—Severe hyperosmolar states in the absence of ketosis can occur in type 2 DM. These episodes are frequently precipitated by decreased fluid intake such as can occur during an intercurrent illness or in older debilitated patients who lack sufficient access to water and have abnormal renal function hindering the clearance of excessive glucose loads. The mechanisms underlying the development of hyperosmolality and hyperosmolar coma are the same as in diabetic ketoacidosis. However, because only minimal levels of insulin activity are required to suppress lipolysis, these individuals have sufficient insulin to prevent the ketogenesis that results from increased fatty acid flux. Because of the absence of ketoacidosis and its symptoms, patients often present later and, therefore, have more profound hyperglycemia and dehydration; glucose levels often range from 800–2400 mg/dL. Therefore, the effective osmolality exceeds 330 mOsm/L more frequently in these patients than in those presenting with diabetic ketoacidosis, resulting in a higher incidence of coma.
++
Although ketosis is absent, mild ketonuria can be present if the patient has not been eating. K+ losses are less severe than in diabetic ketoacidosis. Treatment is similar to that of diabetic ketoacidosis. Mortality is 10 times higher than in diabetic ketoacidosis because the type 2 diabetics who develop hyperosmolar nonketotic states are older and often have other serious precipitating or complicating illnesses. For example, myocardial infarction can precipitate hyperosmolar states or can result from the alterations in vascular blood flow and other stressors that accompany severe dehydration.
++
4. Hypoglycemia—Hypoglycemia is a complication of insulin treatment in both type 1 DM and type 2 DM, but it can also occur with oral hypoglycemic drugs that stimulate glucose-independent insulin secretion (eg, sulfonylureas). Hypoglycemia often occurs during exercise or with fasting, states that normally are characterized by slight elevations in counter-regulatory hormones and depressed insulin levels. Under normal circumstances, low insulin levels in these conditions are permissive for the counter-regulatory hormone-mediated mobilization of fuel substrates, increased hepatic glucose output, and inhibition of glucose disposal in insulin-sensitive tissues. In addition, the fall in insulin secretion by the pancreatic β cell in response to low glucose levels is an important stimulus for increased secretion of glucagon. All of these responses would normally restore blood glucose levels. However, in diabetic patients, all of these responses fail when insulin is maintained at excessive levels (relative to plasma glucose) due to excessive exogenous insulin dosing or endogenous glucose-independent insulin stimulation.
++
The acute response to hypoglycemia is mediated by the counter-regulatory effects of glucagon and catecholamines (Table 18–5). However, the glucagon response can be inadequate in diabetes, increasing the importance of adrenal epinephrine secretion. When counter-regulatory mechanisms fail, initial neurogenic symptoms of hypoglycemia occur secondarily to CNS-mediated sympathoadrenal discharge, resulting in adrenergic (shaking, palpitations, anxiety) and cholinergic (sweating, hunger) responses that encourage carbohydrate-seeking behavior. However, as glucose drops further, neuroglycopenic symptoms also occur from the direct effects of hypoglycemia on CNS function (confusion, coma). A characteristic set of symptoms (night sweats, nightmares, morning headaches) also accompanies hypoglycemic episodes that occur during sleep (nocturnal hypoglycemia).
++
++
With symptomatic episodes occurring several times per week, type 1 diabetics are especially prone to hypoglycemia due to a virtually absent glucagon response to hypoglycemia. Moreover, recent episodes of hypoglycemia reduce the adrenal epinephrine response to subsequent hypoglycemia and cause hypoglycemia unawareness by reducing the sympathoadrenal response and associated neurogenic symptoms via unknown mechanisms. This hypoglycemia-induced autonomic failure, which is distinct from diabetic autonomic neuropathy, is reversed by avoidance of hypoglycemia but exacerbated by exercise or sleep, both of which can similarly decrease the sympathoadrenal response to a given level of hypoglycemia.
++
Acute treatment of hypoglycemia in diabetic individuals consists of rapid oral administration of glucose at the onset of warning symptoms or the administration of exogenous glucagon intramuscularly by others when neuroglycopenic symptoms preclude oral self-treatment. Rebound hyperglycemia can occur after hypoglycemia because of the actions of counter-regulatory hormones (Somogyi phenomenon), an effect that can be aggravated by excessive glucose administration.
+++
Chronic Complications
++
Over time, diabetes results in damage and dysfunction in multiple organ systems (Table 18–6). Vascular disease is a major cause of most of the sequelae of this disease. Both microvascular disease (retinopathy, nephropathy, neuropathy) that is specific to diabetes and macrovascular disease (coronary artery disease, peripheral vascular disease) that occurs with increased frequency in diabetes contribute to the high morbidity and mortality rates associated with this disease. Neuropathy also causes increased morbidity, particularly by virtue of its role in the pathogenesis of foot ulcers.
++
++
Although type 1 DM and type 2 DM both suffer from the complete spectrum of diabetic complications, the incidence varies with each type and with treatment. Macrovascular disease is the major cause of death in type 2 DM. With the advent of intensive glucose control strategies and the use of renin-angiotensin system inhibitors, renal failure secondary to nephropathy is no longer the most common cause of death in individuals with type 1 DM who now, with increased longevity, are increasingly suffering from macrovascular complications. Although blindness occurs in both types, proliferative changes in retinal vessels (proliferative retinopathy) are a major cause of blindness in type 1 DM, whereas macular edema is the most important cause in type 2 DM. Autonomic neuropathy, one of the manifestations of diabetic neuropathy, is more common in type 1 DM.
++
1. Role of glycemic control in preventing complications—A paradigm shift in diabetes treatment occurred in 1993 with publication of the results of the Diabetes Control and Complications Trial (DCCT), the first major trial to examine the effects of attempted glucose normalization (tight or intensive diabetic control) on the incidence of complications. In this study of individuals with type 1 DM, intensive (vs. conventional) treatment reduced microvascular complications (retinopathy, nephropathy, neuropathy) by 60%. A subsequent study in type 2 DM (United Kingdom Prospective Diabetes Study [UKPDS]) demonstrated a 25% decrease in microvascular complications (retinopathy, nephropathy) with improved glycemic control. In contrast, the role of glycemic control in preventing macrovascular disease, the major cause of death in type 2 DM, is less clear. With the publication in 2008 of three major clinical trials demonstrating either no improvement, or indeed an increase (ACCORD trial), in mortality and macrovascular complications with intensive treatment in type 2 DM, discussions regarding the most appropriate treatment goals (e.g., degree of glucose normalization) and modalities (eg, therapeutics that minimize risk of hypoglycemia and/or weight gain) in type 2 DM continue.
++
While the importance of glycemic control in influencing the occurrence of microvascular complications is undisputed, genetic factors also clearly play a role. For example, evidence from a variety of studies suggests that approximately 40% of type 1 diabetics are particularly susceptible to the development of severe microvascular complications. This observation suggests that not all individuals with type 1 DM achieve the same benefits from intensive control regimens, which are both inconvenient and associated with an increased risk of hypoglycemia. The identity of genetic factors associated with microvascular disease risk is the subject of ongoing investigations, which have already identified numerous candidate genes coding for the extracellular matrix, transcription factors, growth factor signaling, and/or erythropoietin.
++
2. Microvascular complications—Consistent with clinical evidence defining the critical role of hyperglycemia in microvascular disease, data indicate that high intracellular levels of glucose in cells that cannot down-regulate glucose entry (endothelium, glomeruli, and nerve cells) result in microvascular damage via four distinct, diabetes-specific pathways that were sequentially discovered (Figure 18–9): (1) increased polyol pathway flux, (2) increased formation of advanced glycation end-product (AGE), (3) activation of protein kinase C (PKC), and (4) increased hexosamine pathway flux. More recent information suggests that increased flux through these four pathways is induced by a common factor, overproduction of mitochondrial-derived reactive oxygen species generated by increased flux of glucose through the TCA cycle (Figure 18–9). The end result of these changes in the microvasculature is an increase in protein accumulation in vessel walls, endothelial cell dysfunction, loss of endothelial cells, and, ultimately, occlusion.
++
++
The polyol pathway has been extensively studied in diabetic nerve cells and is also present in endothelial cells (Figure 18–9). Many cells contain aldose reductase, an enzyme that converts toxic aldehydes to their respective alcohols (polyol pathway). While aldose reductase has a low affinity for glucose, under conditions of intercellular hyperglycemia, this pathway can account for up to one-third of glucose flux, converting glucose to sorbitol. While excess sorbitol was originally thought to cause osmotic damage, more recent data instead suggest that the real culprit is the consumption of NADPH during glucose reduction. As NADPH is required to regenerate reduced glutathione (GSH), a thiol that detoxifies reactive oxygen species, NADPH consumption prevents the clearance of damaging free radicals. While polyol pathway–mediated damage appears to be a prominent feature in nerve cells, its role in the vasculature is less clear.
++
The formation of irreversibly glycated proteins called advanced glycosylation end-products (AGEs) also causes microvascular damage in diabetes (Figure 18–9). When present in high concentrations, glucose can react reversibly and nonenzymatically with protein amino groups to form an unstable intermediate, a Schiff base, which then undergoes an internal rearrangement to form a more stable glycated protein, also known as an early glycosylation product (Amadori product) (Figure 18–10). Such a reaction accounts for the formation of glycated HbA, also known as HbA1c. In diabetics, elevated glucose leads to increased glycation of HbA within red blood cells. Because red blood cells circulate for 120 days, measurement of HbA1c in diabetic patients serves as an index of glycemic control over the preceding months. Early glycosylation products can undergo a further series of chemical reactions and rearrangements, often involving the formation of reactive carbonyl intermediates, leading to the irreversible formation of AGE. Dicarbonyl formation from direct auto-oxidation of glucose also contributes to AGE formation (Figure 18–10). AGE damage the microvasculature via 3 major pathways: (1) intracellular AGE formation from proteins involved in transcription alters endothelial gene expression; (2) irreversible cross linking of AGE adducts formed from matrix proteins results in vascular thickening and stiffness; and (3) binding of extracellular AGE adducts to AGE receptors (RAGE) on macrophages and endothelium stimulates NF-κB-regulated inflammatory cascades and resultant vascular dysfunction.
++
++
Intracellular endothelial hyperglycemia stimulates glycolysis and, with this, an increase in the de novo synthesis of diacylglycerol (DAG) from the glycolytic intermediate, glyceraldehyde-3-phosphate (Figure 18–9). DAG, in turn, activates several isoforms of protein kinase C (PKC) that are present in these cells. This inappropriate activation of PKC alters blood flow and changes endothelial permeability, in part via effects on nitric oxide pathways, and also contributes to thickening of the extracellular matrix.
++
Last, increased shunting of glucose through the hexosamine pathway via diversion of the glycolytic intermediate, fructose-6-phosphate, is also postulated to play a role in microvascular disease (Figure 18–9). The hexosamine pathway contributes to insulin resistance, producing substrates that, when covalently linked to transcription factors, stimulate the expression of proteins, such as transforming growth factor and plasminogen activator inhibitor, that enhance microvascular damage.
++
Evidence suggests that all four of these pathways may actually be linked by a common mechanistic element: hyperglycemia-induced oxidative stress. In particular, the increase in electron donors that results from shunting glucose through the tricarboxylic acid cycle increases mitochondrial membrane potential by pumping proteins across the mitochondrial inner membrane. This increased potential prolongs the half-life of superoxide generating enzymes, thus increasing the conversion of O2 to O2–. These increased reactive oxygen species lead to inhibition of the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GADPH), and a resultant increase in upstream metabolites that can now be preferentially diverted into the four mechanistic pathways (Figure 18–9).
++
a. Retinopathy—Diabetes is a leading cause of blindness in developed countries (vs. untreated cataracts in developing nations). Diabetic retinopathy, present after 20 years in more than 95% with type 1 DM and 60% with type 2 DM, occurs in two distinct stages: nonproliferative and proliferative.
++
Nonproliferative retinopathy has a prevalence of 30% in adults with diabetes in the United States, occurs frequently in both type 1 DM and type 2 DM, and is already present at the time of diagnosis in more than 20% of individuals with type 2 DM. Microaneurysms of the retinal capillaries, appearing as tiny red dots, are the earliest clinically detectable sign of diabetic retinopathy (background retinopathy). These outpouchings in the capillary wall are due to loss of surrounding pericytes that support the capillary walls. Vascular permeability is increased. Fat that has leaked from excessively permeable capillary walls appears as shiny yellow spots with distinct borders (hard exudates) forming a ring around the area of leakage. The appearance of hard exudates in the area of the macula is often associated with macular edema, which is the most common cause of blindness in type 2 DM, occurring in 7% of diabetics. As retinopathy progresses, signs of ischemia appearing as background retinopathy worsen (preproliferative stage). Occlusion of capillaries and terminal arterioles causes areas of retinal ischemia that appear as hazy yellow areas with indistinct borders (cotton wool spots or soft exudates) because of the accumulation of axonoplasmic debris at areas of infarction. Retinal hemorrhages can also occur, and retinal veins develop segmental dilation.
++
Retinopathy can progress to a second, more severe stage characterized by the proliferation of new vessels (proliferative retinopathy). Neovascularization is more prevalent in type 1 DM than in type 2 DM (25% vs. 15% after 20 years) and is a leading cause of blindness in type 1 DM. It is hypothesized that retinal ischemia stimulates the release of growth-promoting factors, resulting in new vessel formation. However, these capillaries are abnormal, and traction between new fibrovascular networks and the vitreous can lead to vitreous hemorrhage or retinal detachment, two potential causes of blindness.
++
b. Nephropathy—Diabetes is the most common cause of end-stage renal disease (ESRD) worldwide. Although ESRD occurs more frequently in type 1 DM than in type 2 DM (35% vs. 20% after 20 years), type 2 DM accounts for more than half of the diabetic population with ESRD because of its greater prevalence. ESRD also occurs more frequently in Native Americans, African Americans, and Hispanic Americans than in non-Hispanic whites with type 2 DM.
++
Diabetic nephropathy results primarily from disordered glomerular function. Histologic changes in glomeruli are indistinguishable in type 1 DM and type 2 DM and occur to some degree in the majority of individuals. Basement membranes of the glomerular capillaries are thickened and can obliterate the vessels; the mesangium surrounding the glomerular vessels is increased owing to the deposition of basement membrane-like material and can encroach on the glomerular vessels; and the afferent and efferent glomerular arteries are also sclerosed. Glomerulosclerosis is usually diffuse but in 50% of cases is associated with nodular sclerosis. This nodular component, called Kimmelstiel-Wilson nodules after the investigators who first described the pathologic changes in diabetic kidneys, is pathognomonic for diabetes but is present in only 30% of patients with microalbuminuria.
++
In type 1 DM patients, glomerular changes are preceded by a phase of hyperfiltration resulting from vasodilation of both the afferent and efferent glomerular arterioles, an effect perhaps mediated by two of the counter-regulatory hormones, glucagon and growth hormone, or by hyperglycemia. It is unclear whether this early hyperfiltration phase occurs in type 2 DM. It has been proposed that the presence of atherosclerotic lesions in older type 2 DM patients may prevent hyperfiltration and thus account for the lower incidence of overt clinical nephropathy in these individuals.
++
Early in the course of the disease, the histologic changes in renal glomeruli are accompanied by microalbuminuria, a urinary loss of albumin that cannot be detected by routine urinalysis dipstick methods (Figure 18–11). Albuminuria is thought to be due to a decrease in the heparan sulfate content of the thickened glomerular capillary basement membrane. Heparan sulfate, a negatively charged proteoglycan, can inhibit the filtration of other negatively charged proteins, such as albumin, through the basement membrane; its loss, therefore, allows for increased albumin filtration.
++
++
If glomerular lesions worsen, proteinuria increases and overt nephropathy develops (Figure 18–11). Diabetic nephropathy is defined clinically by the presence of more than 300 mg of urinary protein per day, an amount that can be detected by routine urinalysis. In diabetic nephropathy (unlike other renal diseases), proteinuria continues to increase as renal function decreases. Therefore, end-stage renal disease is preceded by massive, nephrotic-range proteinuria (>4 g/d). The presence of hypertension speeds this process. Although type 2 DM patients often already have hypertension at the time of diagnosis, type 1 DM patients usually do not develop hypertension until after the onset of nephropathy. In both cases, hypertension worsens as renal function deteriorates. Therefore, control of hypertension is critical in preventing the progression of diabetic nephropathy.
++
Retinopathy, a process that is also worsened by the presence of hypertension, usually precedes the development of nephropathy. Therefore, other causes of proteinuria should be considered in diabetic individuals who present with proteinuria in the absence of retinopathy.
++
c. Neuropathy—Neuropathy (Table 18–6) occurs commonly in about 60% of both type 1 DM and type 2 DM patients and is a major cause of morbidity. Diabetic neuropathy can be divided into three major types: (1) a distal, primarily sensory, symmetric polyneuropathy that is by far the most common (50% incidence); (2) an autonomic neuropathy, occurring frequently in individuals with distal polyneuropathy (>20% incidence); and (3) much less common, transient asymmetric neuropathies involving specific nerves, nerve roots, or plexuses.
++
Symmetric distal polyneuropathy—Demyelination of peripheral nerves, which is a hallmark of diabetic polyneuropathy, affects distal nerves preferentially and is usually manifested clinically by a symmetric sensory loss in the distal lower extremities (stocking distribution) that is preceded by numbness, tingling, and paresthesias. These symptoms, which begin distally and move proximally, can also occur in the hands (glove distribution). Pathologic features of affected peripheral somatic nerves include demyelination and loss of nerve fibers with reduced axonal regeneration accompanied by microvascular lesions, including thickening of basement membranes. Activation of the polyol pathway in nerve cells is thought to play a major role in inducing symmetric distal polyneuropathy in diabetes. In addition, the microvascular disease that accompanies these neural lesions may also contribute to nerve damage. The presence of antibodies to autoantigens in patients with neuropathy also suggests a possible immune component to this disorder. Last, defects in the production or delivery of neurotrophic factors, such as nerve growth factor (NGF), are hypothesized to play a role in the pathogenesis of symmetric distal neuropathy.
++
Autonomic neuropathy—Autonomic neuropathy often accompanies symmetric peripheral neuropathy, occurs more frequently in type 1 DM, and can affect all aspects of autonomic functioning, most notably those involving the cardiovascular, genitourinary, and GI systems. Less information is available regarding the morphologic changes occurring in affected autonomic nerves, but similarities to somatic nerve alterations suggest a common pathogenesis.
++
Fixed, resting tachycardia and orthostatic hypotension are signs of cardiovascular autonomic nervous system damage that can be easily ascertained on physical examination. Orthostatic hypotension can be quite severe. Erectile dysfunction occurs in more than 50% of diabetic men and is due both to neurogenic (parasympathetic control of penile vasodilation) and vascular factors. Sexual dysfunction in diabetic women has not been well studied. Loss of bladder sensation and difficulty emptying the bladder (neurogenic bladder) lead to overflow incontinence and an increased risk of urinary tract infections as a result of residual urine. Motor disturbances can occur throughout the GI tract, resulting in delayed gastric emptying (gastroparesis), constipation, or diarrhea. Anhidrosis in the lower extremities can lead to excessive sweating in the upper body as a means of dissipating heat, including increased sweating in response to eating (gustatory sweating). Autonomic neuropathy can also result in decreased glucagon and epinephrine responses to hypoglycemia.
++
Mononeuropathy and mononeuropathy multiplex—The abrupt, usually painful onset of motor loss in isolated cranial or peripheral nerves (mononeuropathy) or in multiple isolated nerves (mononeuropathy multiplex) occurs much less frequently than does symmetric polyneuropathy or autonomic neuropathy. Vascular occlusion and ischemia are thought to play a central role in the pathogenesis of these asymmetric focal neuropathies, which are usually of limited duration and occur more frequently in type 2 DM. The third cranial nerve is the most frequently involved, causing ipsilateral headache followed by ptosis and ophthalmoplegia with sparing of papillary reactivity. In contrast to the rare occurrence of these vascular neuropathies, symptomatic compression by entrapment of peripheral nerves (eg, ulnar nerve at elbow; median nerve at the wrist) occurs in 30% of diabetics and usually involves both the nerve and surrounding tissues.
++
3. Macrovascular complications—Atherosclerotic macrovascular disease occurs with increased frequency in diabetes, resulting in an increased incidence of myocardial infarction, stroke, and claudication and gangrene of the lower extremities. Although macrovascular disease accounts for significant morbidity and mortality in both types of diabetes, the effects of large-vessel disease are particularly devastating in type 2 DM and are responsible for approximately 75% of deaths. The protective effect of gender is lost in women with diabetes; their risk of atherosclerosis is equal to that of men (Figure 18–12).
++
++
Reasons for the increased risk of atherosclerosis in diabetes are threefold: (1) the incidence of traditional risk factors, such as hypertension and hyperlipidemia, is increased (50% and 30% incidence at diagnosis, respectively); (2) diabetes itself (likely due to both hyperglycemia and insulin resistance) is an independent risk factor for atherosclerosis; and (3) diabetes appears to synergize with other known risk factors to increase atherosclerosis. The elimination of other risk factors, therefore, can greatly reduce the risk of atherosclerosis in diabetes (Figure 18–12).
++
Hypertension associated with increased total body extracellular Na+ content and volume expansion occurs with increased frequency in type 1 DM and type 2 DM and is responsive to targeted inhibition of the renin-angiotensin system. Despite these similar findings, the epidemiology of hypertension in the two subtypes suggests that different pathophysiologic mechanisms may be operative. In type 1 DM, hypertension usually occurs after the onset of nephropathy (40% incidence after 40 years of type 1 DM), when renal insufficiency impairs the ability to excrete water and solutes. In type 2 DM, hypertension is often already present at the time of diagnosis (70% are hypertensive) in these older, obese, insulin-resistant individuals. Indeed, it has been proposed that insulin resistance plays a central role in both diabetes and hypertension. For example, insulin resistance is associated with activation of the renin-angiotensin system, which leads to hypertension, while renin-angiotensin system activation, in turn, decreases insulin sensitivity.
++
In contrast to its central role in microvascular disease, the importance of hyperglycemia as a risk factor for macrovascular disease, which occurs in 40% of 40-year-old individuals with type 1 DM (vs. <10% of controls), remains uncertain. However, insulin resistance, a hallmark of type 2 DM that can also develop in response to hyperglycemia in type 1 or type 2 DM, is clearly an important driver of macrovascular complications in diabetes. Insulin resistance is central to the pathogenesis of two obesity-associated syndromes: (1) prediabetes (impaired fasting glucose or glucose tolerance) and (2) metabolic syndrome (a cluster of metabolic abnormalities, including central obesity, elevated glucose, elevated blood pressure, elevated triglycerides, and low high-density lipoprotein [HDL] cholesterol). Both of these syndromes are associated with increased cardiovascular risk, as well as an increased risk for later development of diabetes. At present in the United States, one-third of the adult population is thought to fall into these high-risk categories. Fortunately, an important clinical trial (Diabetes Prevention Program) has demonstrated that significant risk reductions occur in response to lifestyle interventions in this population.
++
In addition to being a component of metabolic syndrome, hypertriglyceridemia, which is associated with increased risk of cardiovascular disease, is the principal lipid abnormality in poorly controlled type 1 and type 2 DM. Very-low-density lipoprotein-triglyceride (VLDL-TG) levels are increased because of insufficient insulin action in liver and adipose tissue. This results in (1) increased VLDL production due to increased flux of fatty acids from adipose tissue to the liver (ie, increased lipolysis) and loss of insulin suppression of hepatic proteins required for VLDL assembly (ie, loss of phosphoinositide 3-kinase [PI 3-kinase] inhibition of apolipoprotein B [apoB] production and loss of inhibition of the transcription factor FoxO1-induced expression of microsomal triglyceride transfer protein [MTP]); and (2) decreased VLDL clearance as a result of decreased lipoprotein lipase activity. Excessive VLDL levels alter the composition of LDL and HDL, transferring triglycerides to these particles while depleting them of cholesterol, creating small dense LDL particles and low HDL-cholesterol levels, both of which are independent risk factors for cardiovascular disease. LDL cholesterol may also be elevated both because of increased production (VLDL is catabolized to LDL) and decreased clearance (insulin deficiency may reduce LDL receptor activity). Insulin treatment usually corrects lipoprotein abnormalities in type 1 DM. In contrast, treatment of hyperglycemia often does not normalize lipid profiles in obese, insulin-resistant individuals with type 2 DM unless accompanied by weight reduction (ie, by a concomitant reduction in insulin resistance).
++
Possible reasons why diabetes may be an independent risk factor for atherosclerosis and may also act synergistically with other risk factors include the following: (1) alterations in lipoprotein composition in diabetes that make the particles more atherogenic (eg, increased small dense LDL, increased levels of Lp[a], enhanced oxidation and glycation of lipoproteins); (2) the occurrence of a relative procoagulant state in diabetes, including an increase in certain clotting factors and increased platelet aggregation; (3) proatherogenic alterations in the vessel walls caused either by the direct effects of hyperinsulinemia in type 2 DM or by boluses of exogenously administered insulin (vs. hepatic first-pass clearance of endogenously secreted insulin) in type 1 DM, which include promotion of smooth muscle proliferation, alteration of vasomotor tone, and enhancement of foam cell formation (cholesterol-laden cells that characterize atherogenic lesions); (4) proatherogenic alterations in the vessel walls caused by the direct effects of hyperglycemia, including deposition of glycated proteins, just as occurs in the microvasculature; and, importantly, (5) the proinflammatory milieu that is associated with insulin resistance.
++
4. Diabetic foot ulcers—Diabetic foot ulcers occur in 10% of diabetics, can be complicated by osteomyelitis, and result in amputation in 1%, an event that is associated with high mortality (50% by 3 years). Risk factors for ulcer development include (1) increased injuries in insensate feet due to symmetric polyneuropathy (present in 75–90% of diabetics with foot ulcers), which can be detected clinically by decreased vibratory and cutaneous pressure sensation and absence of ankle reflexes; (2) macrovascular disease (present in 30–40% with foot ulcers) and microvascular disease; (3) infections caused by alterations in neutrophil function and vascular insufficiency; and (4) faulty wound healing caused by unknown factors.
5. Infection—Neutrophil chemotaxis and phagocytosis are defective in poorly controlled diabetes. Cell-mediated immunity may also be abnormal. In addition, vascular lesions can hinder blood flow, preventing inflammatory cells from reaching wounds (eg, foot ulcers) or other possible sites of infection. Therefore, individuals with diabetes are more prone to develop infections and may have more severe infections. As a result, certain common infections (eg, candidal infections, periodontal disease) occur more frequently in diabetics. A number of unusual infections also are seen in diabetics (ie, necrotizing papillitis, mucormycosis of the nasal sinuses invading the orbit and cranium, and malignant otitis externa caused by Pseudomonas aeruginosa).
6. Skeletal changes in diabetes—Children with type 1 DM have a much lower bone mass, attributed to loss of the anabolic effects of insulin on bone that stimulate the differentiation of bone-forming osteoblasts, and an associated increased in fragility bone fractures. Adults with type 2 DM have an increased fracture risk, perhaps due to subtle microarchitectural changes (eg, increased cortical porosity) since bone mineral density in these typically obese individuals is normal or increased. Emerging evidence suggests that the interactions between carbohydrate homeostasis and the skeleton are bidirectional. Osteocalcin, an insulin-inducible protein secreted by osteoblasts, increases β-cell mass and insulin secretion while also improving adipose insulin sensitivity by stimulating adiponectin expression. The role of osteocalcin in diabetes pathogenesis and treatment is an area of active investigation.
++
Checkpoint
26. How does type 1 diabetes mellitus result in negative nitrogen balance and protein wasting?
27. What are some acute clinical manifestations of diabetes mellitus?
28. Describe the pathophysiologic mechanisms at work in diabetic ketoacidosis.
29. Explain why ketones may appear to be increasing with appropriate treatment of diabetic ketoacidosis.
30. Explain why hyperosmolar coma without ketosis is a more common presentation than ketoacidosis in type 2 diabetes mellitus.
31. What chronic complication of diabetes mellitus can exacerbate iatrogenic hypoglycemia?
32. What are the most common microvascular and macrovascular complications of long-standing diabetes mellitus, and what are their pathophysiologic mechanisms?
33. What were the major conclusions from DCCT and UKPDS?
34. What pathways activated by oxidative stress are proposed to contribute to the development of complications of diabetes mellitus?
35. What are the characteristics of nonproliferative and proliferative retinopathy in diabetes mellitus?
36. What are the anatomic and physiologic changes observed during the progression of diabetic nephropathy?
37. Does nephropathy usually precede retinopathy in patients with diabetes mellitus?
38. Suggest three reasons for increased risk of atherosclerosis in diabetes mellitus.
39. What are the probable differences in the pathophysiology of hypertension in type 1 versus type 2 diabetes mellitus?
40. What three major types of neuropathy are observed in long-standing diabetes mellitus? What are the common symptoms and signs of each?
41. Which types of infections occur with increased frequency in patients with diabetes mellitus, and why?
+++
Neuroendocrine Islet Cell Tumors of the Pancreas
++
While highly prevalent in individuals with multiple endocrine neoplasia type 1 (MEN-1), neuroendocrine tumors arising from the islet cells are otherwise infrequent and account for only 5% of primary pancreatic neoplasms, most of which instead arise from cells of the exocrine pancreas. However, the clinical manifestations associated with islet cell tumor overproduction of a given hormone are illustrative of their normal physiologic functions (Table 18–7). Those tumors associated with inappropriate secretion of hormones regulating carbohydrate metabolism (insulin, glucagon, somatostatin) are highlighted here.
++
+++
Insulinoma (β-cell tumor)
+++
Clinical Presentation
++
The occurrence of fasting hypoglycemia in an otherwise healthy individual is usually due to an insulin-secreting tumor of the β cells of the islets of Langerhans (insulinoma; Table 18–7). Although insulinoma is the most common islet cell tumor, it is still a rare disorder. Insulinomas occur most frequently in the fourth to seventh decades, although they can occur earlier, particularly when associated with MEN-1, a neoplastic syndrome characterized by tumors of the parathyroids, pituitary, and endocrine pancreas (see Chapter 17). The diagnosis of hypoglycemia is based on the Whipple triad: (1) symptoms and signs of hypoglycemia, (2) an associated low plasma glucose level, and (3) reversibility of symptoms on administration of glucose.
++
In the great majority of cases, insulinomas are benign solitary lesions composed of whorls of insulin-secreting β cells. Multiple tumors, although infrequent (<10%), are seen most often in patients with MEN-1. Fewer than 10% of the tumors are malignant, as determined by the presence of metastases.
+++
Pathology and Pathogenesis
++
Inappropriately high levels of insulin in situations normally characterized by a lowering of insulin secretion (eg, fasting and exercise) result in hypoglycemia. Normally, in the postabsorptive and fasting state, insulin levels decline, leading to an increase in glucagon-stimulated hepatic glucose output and a decrease in insulin-mediated glucose disposal in the periphery, which maintains normal serum glucose levels. With exercise, low insulin allows muscles to use glycogen, glucagon, and other counter-regulatory hormones to increase hepatic glucose output and counter-regulatory hormones to mobilize fatty acids for ketogenesis and fatty acid oxidation by muscle. With an insulinoma, insulin levels remain high during fasting or exercise. In this circumstance, glucagon-mediated hepatic glucose output is suppressed while insulin-mediated peripheral glucose uptake continues, and insulin stimulates hepatic fatty acid synthesis and peripheral fatty acid storage while suppressing fatty acid mobilization and hepatic ketogenesis. The result is fasting or exercise-induced hypoglycemia in the absence of ketosis.
+++
Clinical Manifestations
++
Individuals with insulinomas often are symptomatic for years before diagnosis and are self-treated with frequent food intake. Not all patients experience fasting hypoglycemia in the morning (only 30% of insulinoma patients develop hypoglycemia after a diagnostic 12-hour fast). Often they experience late afternoon hypoglycemia, particularly when precipitated by exercise. Because alcohol, like insulin, inhibits gluconeogenesis, alcohol ingestion can also precipitate symptoms. A high percentage of individuals with insulinoma experience neuroglycopenic as well as autonomic symptoms (Table 18–5). Confusion (80%), loss of consciousness (50%), and seizures (10%) often lead to misdiagnoses of psychiatric or neurologic disorders.
++
Fasting hypoglycemia can be due either to elevated insulin, as occurs in insulinoma, or to non–insulin-mediated effects such as loss of counter-regulatory hormones (eg, loss of cortisol in Addison disease), severe hepatic damage that prevents hepatic glucose production, loss of peripheral stores of substrates for hepatic glucose production (eg, cachexia), or some states of markedly increased glucose utilization (eg, sepsis, cancer). To distinguish insulin-mediated from non–insulin-mediated fasting hypoglycemia, patients suspected of having insulinoma are subjected to a diagnostic fast during which glucose, insulin, and C peptide levels are measured. An inappropriately elevated insulin level in the setting of hypoglycemia is diagnostic of an insulin-mediated cause of hypoglycemia. Causes of insulin-mediated hypoglycemia other than insulinoma include surreptitious injection of insulin, ingestion of oral hypoglycemic medications that stimulate glucose-independent endogenous insulin (sulfonylureas), and the presence of insulin antibodies. Binding of insulin to the antibodies prevents insulin action, but release of the insulin at an inappropriate time can result in hypoglycemia. Surreptitious insulin administration can be ruled out by C peptide measurements. Because insulin and C peptide are cosecreted, insulinomas will cause elevations in both, whereas elevated levels of exogenous insulin will not be matched by elevations of C peptide in surreptitious injections of insulin. Similarly, insulin antibodies do not result in elevated C peptide levels. Because sulfonylurea drugs stimulate endogenous insulin (and, therefore, C peptide) secretion, insulinoma and inappropriate ingestion of these agents can only be differentiated by measuring drug levels.
+++
Glucagonoma (α-cell tumor)
++
Glucagonomas are usually diagnosed by the appearance of a characteristic rash in middle-aged individuals, particularly perimenopausal women, with mild diabetes mellitus (Table 18–7). Glucagon levels are usually increased 10-fold relative to normal values but can even be increased 100-fold.
++
Necrolytic migratory erythema begins as an erythematous rash on the face, abdomen, perineum, or lower extremities. After induration with central blistering develops, the lesions crust over and then resolve, leaving an area of hyperpigmentation. These lesions may be the result of nutritional deficiency, such as the hypoaminoacidemia that occurs from excessive glucagon stimulation of hepatic amino acid uptake and utilization as fuel for gluconeogenesis, rather than the direct effect of glucagon on the skin. Appearance of the rash is a late manifestation of the disease.
++
Diabetes mellitus or glucose intolerance is present in the vast majority of patients as a result of increased stimulation of hepatic glucose output by the inappropriately high glucagon levels. Insulin levels are secondarily increased. Diabetes is, therefore, mild and is not accompanied by glucagon-stimulated ketosis, because sufficient insulin is present to suppress lipolysis, thus limiting potential substrates for ketogenesis.
++
Anemia and a variety of nonspecific GI symptoms related to decreased intestinal motility also can accompany glucagonomas.
++
Although these tumors are solitary and their growth is slow, they are usually large and have often metastasized by the time of diagnosis, making surgical resection difficult. Octreotide, the synthetic somatostatin analog, can be used to ameliorate symptoms via its suppression of glucagon secretion.
+++
Somatostatinoma (δ-cell tumor)
++
Somatostatinomas present with a variety of GI symptoms in individuals with mild diabetes (Table 18–7). However, these extremely rare tumors are almost uniformly found incidentally during operations for cholelithiasis or other abdominal complaints because the presenting symptoms are both nonspecific and common in an adult population. Documentation of elevated somatostatin levels confirms the diagnosis.
++
A classic triad of symptoms frequently occurs with excessive somatostatin secretion: diabetes mellitus, because of its inhibition of insulin and glucagon secretion; cholelithiasis, because of its inhibition of gall-bladder motility; and steatorrhea, because of its inhibition of pancreatic exocrine function. Hypochlorhydria, diarrhea, and anemia can also occur.
++
In type 1 DM and type 2 DM, the effects of insulin insufficiency are aggravated by the occurrence of elevated glucagon levels. In contrast, with somatostatinomas, both insulin and glucagon are suppressed. Therefore, the hyperglycemia resulting from insulinopenia is tempered by the absence of glucagon stimulation of hepatic glucose output. Although low insulin levels are permissive for lipolysis, glucagon deficiency prevents hepatic ketogenesis. The diabetes associated with somatostatinomas is, therefore, mild and not ketosis prone.
++
Although the majority of somatostatinomas occur in the pancreas, a significant number are found in the duodenum or jejunum. Like glucagonomas, somatostatinomas are often solitary and large and have frequently metastasized by the time of diagnosis.