286 1 American Diabetic Association. American Diabetic Association Clinical Practice Recommenda tions. Diabetes Care. January 2011; 34 (suppl 1). y g o o n i r c o d n E Table 9.2 Insulin l Available in 100 U/mL preparations. May be drawn up and injected using special syringes (ma rked in units) or directly injected from preloaded adjustable pen injectors. Five major typ es available for use. Rapid-acting insulin analogs Insulin lispro (Humalog ), insulin aspa rt (NovoLog ), modified to promote rapid absorption, must be injected immediately before o r after eating to cover prandial spike in glucose levels. Dosing schedule: With meals. Shor t-acting insulin Regular insulin , must be injected 15 \200\22330 min before eating. Less c ommonly prescribed given challenges with timing of insulin and onset of insulin action. Int ermediate-acting insulin ( NPH insulin), peak effect at 4 \200\22310 h, effec- tive duratio n is 10 \200\22316 h. Dosing schedule: Twice daily. Long-acting insulin analogs Insulin gla rgine (Lantus ), insulin detemir (Levemir), modified to promote steady absorption and cont inuous cov- erage of glucose levels without peaks. May not be mixed with other types of ins ulin or insulin analogs. Dosing schedule: Once daily (morning or night), although consider twice-daily dosing for total insulin >40 units to ensure absorption of full dose. High conc entration insulin analogs should only be used in cases of extreme insulin resistance. Humul in R U-500 is only available as a regular form of insulin. Peak effect 2 \200\2234 h after administration, duration of action 5 \200\2237 h. Should only be prescribed by a diabetolog ist. Premixed preparations combine intermediate-acting insulin with short-acting insulin or rapid-acting insulin analogs in specified fractions (i.e., 70/30 NPH insulin/regular insul in, 75/25 NPH/insulin lispro). May be used to minimize daily injections. Table 9.3 Insulin regimens used to treat type 1 diabetes General Ideal insulin administration consists of \200\234basal \200\235 coverage for 24 h man- agement of blood glucose and \200\234bolus \200\235 or \200\234prandial \200\235 cov erage to manage blood glucose spikes during meals. Persons with T1DM require exogenous insu lin at all times given insulin deficiency and risk of diabetic ketoacidosis (DKA). Continuo us insulin administration Available through insulin pumps dosed for time of day, meal intak e, and correction of elevated blood glu- cose levels. Insulin cartridges filled with rapid- acting insulin analogs. Two daily injections Comprised of (1) intermediate-acting insulin m ixed with a rapid-acting insulin analog (or short-acting insulin) before breakfast; and (2) intermediate-acting insulin mixed with a rapid-acting insulin analog (or short-acting insu lin) before dinner. Often started by administering two-thirds of the estimated daily dose b efore breakfast and one-third before dinner. Three daily injections Comprised of (1) interm ediate-acting insulin mixed with a rapid-acting insulin analog (or short-acting insulin) be fore breakfast; (2) a rapid-acting insulin analog (or short-acting insulin) before dinner; and (3) intermediate-acting insulin at bedtime. May reduce the frequency and severity of ov ernight hypoglycemia. Four daily injections Comprised of (1 \200\2233) a rapid-acting insul in analog (or short-acting insulin) before breakfast, lunch, and dinner; and (4) a long-act ing insulin analog at bedtime. Preprandial doses of rapid-acting insulin analogs may be adm inistered as fixed doses or may be adjusted to account for (a) estimated grams of carbohydr ate to be eaten or (b) sliding scale correction formulas based on preprandial blood glucose levels. 287 (Continued) Table 9.3 (Continued) Intercurrent illnesses may increase daily insulin requirements despite diminished appetite and reduced caloric intake. During the course of any moderate to severe illness, patients s hould be instructed to (a) maintain caloric intake, (b) drink large volumes of fluids, (c) check blood glucose levels at least four times daily, and (d) check for urine ketones with home dipstick tests if blood glucose levels are noted to be persistently elevated. Insulin doses may need to be transiently increased to prevent the onset of hyperglycemia, volume de pletion, and ketoacidosis. Type 2 diabetes mellitus Definition Clinical syndrome characterized by insulin resistance l eading to endogenous hyperinsulinemia with eventual -cell failure and relative insulin d eficiency. Over time, the combined effects of insulin resistance and inade- quate insulin s ecretion lead to persistent hyperglycemia. Strongly associated with obesity, physical inact ivity, and positive family history. Higher preva- lence among certain ethnic groups includi ng African Americans, Latinos, Native Americans, Asian Americans, and Pacific Islanders. Al though once considered a disease of adults, incidence of confirmed diagnoses of type 2 diab etes mellitus (T2DM) in children and adolescents is increasing with the obesity epidemic. C oncordance is >80% in identical twins. Presentation Highly variable. At one end of the spec trum, patients may present with mild asymptomatic hyperglycemia identified on routine labor a- tory testing. At the other extreme, patients with unsuspected and untreated disease may present in advanced, decompensated, hyperosmolar states. Known as the hyperosmolar hypergly cemic state (HHS), it is characterized by severe hyperglycemia, volume depletion, and menta l status changes. Metabolic syndrome is defined by high-density lipoprotein (HDL) cho- lest erol <40 mg/dL (men) or <50 mg/dL (women), waist circumference >102 cm (men) or >88 cm (wom en), blood pressure (BP) > 130/85 mmHg or active treatment for hypertension, and fasting bl ood glucose >100 mg/dL or active drug treatment for elevated blood glucose.Persons with any three of the five criteria have metabolic syndrome. There is a strong link between the met abolic syndrome and subsequent risk of developing T2DM. Diagnosis Suspected diagnosis. 2 ma y be confirmed on the basis of (1) HbA1c >6.5% in a certified laboratory, (2) a random plas ma glucose >200 mg/dL with associated symptoms (polyuria, polydipsia, weight loss), (3) a f asting plasma glucose >126 mg/dL, or (4) a 75 g oral glucose toler- ance test with a 2 h pl asma glucose >200 mg/dL. Positive results should be verified with repeat testing. \200\234 Pre-diabetes \200\235 may be diagnosed when testing reveals (a) HbA1c 5.7 \200\2236.4%, (b) a fasting plasma of 100 \200\223125 mg/dL glucose (impaired fasting glucose, IFG), or (c) a 2 h plasma glucose of 140 \200\223199 mg/dL (impaired glucose tolerance, IGT). There is g rowing evidence that treatment of prediabetes with lifestyle modification and/or pharmacolo gic therapy may delay or prevent the progression of disease and end-organ damage. Testing i n asymptomatic patients Should be considered in all over- weight adults (body mass index [B MI] >25 kg/m 2 ) and who have one or more additional risk factors for diabetes (metabolic s yndrome, above). Without risk factors, screen adults >45 yrs. 288 Treatment Must be tailored to the state of disease and severity of hyper- glycemia at the t ime of presentation. See Table 9.4. Lifestyle modification All patients, regardless of stag e of T2DM should be extensively counseled modify both diet and lifestyle. Weight loss (7% b ody weight) and exercise (150 min/wk moderate exercise) can restore insulin tolerance. Asym ptomatic patients with mild or intermittent hyperg- lycemia may be managed with comprehensi ve exercise and nutrition therapy targeted to limit glycemic excursions. All patients shoul d receive smoking cessation counseling, if appropriate. Prediabetes (HbA1c 5.7 \200\2236.4% , IFG, IGT) Target weight loss of 7% of body weight, physical activity at least 150 min/wk moderate activity. Consider metformin therapy (see below) in those at high risk for develop - ing diabetes (i.e., HbA1c >6%). Patients with persistent hyperglycemia may need to be sta rted on treatment with oral agents or insulin. Oral agents are preferred as first-line ther apy for those with earlier stage T2DM (HbA1c <9%). Oral medications may be used in differen t combinations to optimize glycemic control. Certain oral agents may be contraindicated in patients with impaired renal or hepatic function. In some cases, patients presenting with s evere hyperglycemia ( \200\234glucotoxic \200\235) initially requiring insulin may be succe ssfully transitioned to oral agents as glucose toxicity subsides and -cell function is r estored. Pharmacotherapy, insulin In time, most patients who are initially main- tained on regimens of oral agents alone eventually require the addition of insulin. Patients presenti ng with later stage T2DM (HbA1c >9%) often require insulin from the outset. With the except ion of metformin (see below), most other oral agents should be discontinued with insulin in i- tiation. Monitoring of blood glucose requires frequent self-measurement. Recommended fre quency may vary depending on intensity of treatment and frequency of changes to the regimen . Clinical guidelines recommend intensifying treatment to target HbA1c levels <7%. This may be difficult to achieve in practice. See Table 9.5. Bariatric surgery May be considered fo r adults with BMI >35 kg/m 2 and T2DM, particularly with disease that is hard to control wi th lifestyle inter- ventions and medications or in those with diabetic complications. Lipid management Measure annual fasting lipid profile.Diet and lifestyle modifications should be implemented for all patients with diabetes. Add statin therapy regardless of lipid panel f or (a) diabetic patients with known cardiovascular disease (CVD), (b) patients >40 without CVD but with CVD risk factors (men >50, women >60 and family history, hypertension, dyslipi demia, smoking, or albuminuria). Goal low-density lipoprotein (LDL) is <70 mg/dL if known C VD. In individuals of any age and at low risk for CVD with diabetes, if LDL >100 mg/dL, add statin therapy.Combination therapy with other lipid-lowering agents may be necessary if hi gh-dose sta- tins do not achieve goals. Antiplatelet agents Consider aspirin therapy (75 \200\223162 mg/d) in patients with T1DM or T2DM at increased CVD risk (men >50, women >60 + one additional CVD risk factor = family history, hypertension, dyslipidemia, smoking, albu minuria). y g o o n i r c o d n E l 289 Table 9.4 Noninsulin agents Eight major classes. Should not be used in T1DM therapy. Sulfonylureas Stimulate insulin se cretion.Effective in patients with early T2DM given medication \200\231s dependence on func tional cells. Commonly prescribed preparations include glipizide (Glucotrol 2.5 \200 \22320 mg/d \200\223bid, Glucotrol XL 5 \200\22310 mg/d), glyburide (DiaBeta , Micronase 1.25 \200\22320 mg/d, Glynase 0.75 \200\22312 mg/d), and glimepiride (Amaryl 1 \200 \2234 mg/d). Often used in combination with biguanides and thiazolidinediones. Glimepiride may be associated with a lower incidence of hypoglycemia. Preparations are available that c ombine metformin with glyburide (Glucovance ) and glip- izide (Metaglip ). side effects ( SE): Hypoglycemia, weight gain, increased risk of CV morality. Contraindications (CI) : DKA , NPO status. Biguanides Suppress hepatic gluconeogenesis. May help to increase insulin sen sitivity in peripheral tissues. Metformin is the only biguanide available for use in the Un ited States. Available in regular and long-acting preparations (Glucophage 500 \200\2231, 000 mg bid, Glucophage XR 1,000 \200\223 2,000 mg qpm). Usually started at a low dose wit h meals and titrated upward every 2 weeks to maximum dose (2,000 mg/d) to prevent side effe cts. Self-limited side effects : May include nausea, abdominal cramping, and diarrhea. May help to promote weight loss. CI : Creatinine >1.5 mg/ dL (men), >1.4 mg/dL (women), metabol ic acidosis including DKA. Must be held for 4 \200\2238 h prior to and following exposure t o IV contrast. Thiazolidinediones PPAR -gamma receptor agonists. Increase insu- lin sens itivity. Available preparations include rosiglitazone (Avandia 4 \200\2238 mg/d) and piog litazone (Actos 15 \200\22345 mg/d). May take 3 \200\2236 wks to see full effect. SE : Tr ansaminase levels should be monitored regularly. May cause weight gain and lower extremity swelling. Rosiglitazone is associated with increased risk of cardiovascular and ischemic ev ents. All thiazolidinediones are associated with bone loss and should be used with caution in patients with osteoporosis. CI : Patients with congestive heart failure (New York Heart Association [NYHA] Class III or IV) or impaired hepatic function. Incretin mimetics GLP-1 a gonists available only in SQ injectable form. Exenatide (Byetta 5 \200\22310 mcg SQ bid) or liraglutide (Victoza 0.6 \200\2231.8 mg/d SQ) should be considered as add-on drugs in T2DM not controlled on 1 \200\2232 oral agents. Should not be used as monotherapy. May prom ote weight loss. Side effects include diarrhea, indigestion, nausea.Reports of pancreatitis . CI : Pancreatitis, DKA. DPP-IV inhibitors Can be used alone or in combination with other oral agents.Can be used in chronic kidney disease, but must be dose-adjusted. Sitagliptin ( Januvia 100 mg/d PO) or saxagliptin (Onglyza 2.5 \200\2235 mg/d PO). Caution with hepat ic disease and history of pancreatitis. SE : Headache, nasopharyngitis, URI. CI : DKA. Megl itinides Rapid-acting insulin secretagogues. Must be taken right before meals. May help to control postprandial hyperglycemia. Available preparations include repaglinide (Prandin 0 .5 \200\2234 mg qac) and nateglinide (Starlix 60 \200\223120 mg qac). SE : Hypoglycemia, diarrhea, nausea. CI : DKA. -Glucosidase inhibitors Limit glycemic excursions by inhibit ing enzy- matic breakdown of carbohydrates. Must be taken with meals. Available preparation s include acarbose (Precose 25 \200\223100 mg qac) and miglitol (Glyset 25 \200\223100 mg qac). SE : Bloating and diarrhea. CI : Should not be used in patients with inflammatory bowel disease, cirrhosis, DKA, or bowel obstruction. Amylin analog Available only as SQ inj ection. Pramlintide (Symlin 60 \200\223120 mcg SQ immediately after meals). Side effects include abdominal pain, nausea, vomiting. CI : Gastroparesis, hypoglycemia. 290 y g o o n i r c o d n E Table 9.5 Insulin regimens used to treat type 2 diabetes l General In long-standing T2DM, ideal insulin administration consists of \200\234basal \200 \235 coverage for 24 h management of blood glucose and \200\234bolus \200\235 or \200\234 prandial \200\235 coverage to manage blood glucose spikes during meals. Additional, sliding -scale insulin may be administered with scheduled prandial doses if premeal blood glucose l evels are elevated. Less aggres- sive management with fewer injections may be possible in e arly disease when pancreas has some endogenous function. Unlike T1DM, persons with T2DM do not necessarily require exogenous insulin at all times. Continuous insulin administration A vailable through insulin pumps dosed for time of day, meal intake, and correction of elevat ed blood glu- cose levels. Insulin cartridges filled with rapid-acting insulin analogs. One daily injection May be added to supplement standing regimens of oral agents. Usually start ed as a fixed dose of (a) intermediate-acting insulin at bedtime and (b) a long-acting insu lin analog at bedtime or before breakfast. Two daily injections May allow for greater flexi bility in making adjust- ments to accommodate variations in blood glucose levels. Doses adm in- istered before breakfast and before dinner may be comprised of (a) intermediate-acting insulin, (b) intermediate-acting insulin mixed with a rapid-acting insulin analog (or short -acting insulin), or (c) premixed preparations combining intermediate-acting insulin with s hort-acting insulin or rapid-acting insulin analogs. Multiple daily injection regimens simi lar to those used to treat patients with T1DM may also be employed to target more intensive con- trol. Total daily insulin requirements tend to be much higher in patients with T2DM. Some patients may require >100 U/d to achieve and main- tain adequate glycemic control. Pat ients with extreme insulin resistance requiring extremely high doses of insulin may benefit from U-500 insulin. This should be prescribed by a diabetologist. 291 Diabetic retinopathy Microvascular complication of T1DM and T2DM secondary to changes in re tinal blood vessels caused by prolonged exposure to elevated blood glucose levels. Affects most patients with T1DM, although manifestations are usually not detectable until 5 yrs aft er initial diagnosis. May be detect- able in up to 25% of patients with T2DM diabetes at ti me of presentation. Diabetes is the leading preventable cause of blindness in adults 20 \200\22374 yrs of age. See Table 9.6. Evaluation Individuals with diabetes require yearly r etinal exams. They should be performed by an experienced provider. Comprehensive evalua- ti on requires pupillary dilation, slit-lamp examination, and indirect ophthal- moscopy. Exami nations limited to direct ophthalmoscopy often miss key findings. Individuals with T1DM sho uld be referred for evaluation within 3 \200\2235 yrs of initial diagnosis and yearly there after. Individuals with T2DM should be referred at the time of presentation and yearly ther eafter. Pregnancy may increase the risk of development or progression of diabetic retinopat hy. Comprehensive evaluation should be performed prior to conception and during the first t rimester. Prevention and treatment Intensive control of blood glucose levels may delay the onset or progression of diabetic retinopathy. Adjunctive treat- ment should target aggressi ve control of hypertension and hyperlipidemia. Table 9.6 Stages of diabetic retinopathy Preretinopathy Subtle dilation of the retinal veins. Nonproliferative retinopathy Also know n as background retinopa- thy. Weakened areas of retinal capillary walls form outpouchings that may be visible as microaneurysms. Bleeding from these weakened areas in the superficia l layer of the retina may produce flame-shaped hemor- rhages. Bleeding in deeper layers may produce dot-blot hemorrhages. Leakage of plasma from retinal capillary may lead to formati on of yel- lowish hard exudates. If leakage occurs near the macula, it may lead to swelling identifiable as macular edema. Preproliferative retinopathy Closure of retinal capillaries leads to focal hypoxia visible as poorly defined soft exudates or cotton wool spots. Retin al veins develop irregular contours. Proliferative retinopathy Neovascularization with grow th of vessels into the vitreous humor. New vessels are weak and prone to rupture. Vitreous hemorrhages may obscure vision. Reabsorption of blood may lead to scarring and traction tha t may cause retinal detachment. Growth of vessels into the anterior chamber may cause a pai nful increase in intraocular pressure. Laser photocoagulation treatment may help arrest identified proliferative retinopathy and m acular edema. Symptoms or signs concerning for vitreous hemorrhage, retinal detachment, or changes in intraocular pressure should prompt urgent referral. Other complications Elevated glucose levels in the aqueous humor may draw fluid out of the lens causing increased stiff ness and myopia. Changes are reversible with improved blood glucose control. Patients with diabetes are more prone to develop cataracts. Diabetic nephropathy Microvascular complication that develops as a result of changes in glo m- erular function secondary to prolonged exposure to elevated blood glu- cose levels. Neph ropathy risk is similar in patients with T1DM and T2DM. Diabetes is the cause of almost 50% of cases of end-stage renal disease requiring renal replacement with dialysis or transplan tation. Progression may be exacerbated by concomitant hypertension or preexisting renal dis - ease. See Table 9.7. 292 Table 9.7 Stages of diabetic nephropathy Stage I Marked by onset of diabetes. Characterized by 30 \200\22340% increase in glomerular filtration rate (GFR) with bilateral enlargement of kidneys. Stage II Normal urinary excre tion of albumin (<30 mg/24 h). Stage III Incipient diabetic nephropathy. Microalbuminuria w ith urinary excretion of 30 \200\223300 mg albumin/24 h. 20% of patients with T1DM who reac h this stage will progress to end-stage renal disease within 10 yrs. Stage IV Overt diabeti c nephropathy. Proteinuria with urinary excretion of >0.5 g protein/24 h. Corresponds to ur inary excretion of >300 mg albumin/24 h. Protein usually detectable on urine dipstick testi ng. Marks beginning of progressive decline in GFR. Stage V End-stage renal disease. Detection Initial evaluation with quantification of urinary excretion of albumin. This can be assessed by measuring the albumin/creatinine ratio in a random urine specimen ( \200\234 spot urine microalbumin \200\235). An albumin/ creatinine ratio >30 mcg/mg has been proven to be a sensitive and specific predictor of microalbuminuria. Results that are consistent w ith microal- buminuria or proteinuria should be confirmed on repeat testing within 3 months . Measure serum creatinine at least annually in all adults with diabe- tes to estimate GFR. Treatment of hypertensive patients In patients with concomitant hypertension, aggressive c ontrol of BP may help to forestall the progressive decline in renal function. Clinical guid elines recommend targeting systolic BPs <130 mm Hg and diastolic BPs <80 mm Hg. Whenever po ssible, an angiotensin-converting enzyme (ACE)-inhibitor or angiotensin receptor blocker (A RB) should be selected as a first-line antihypertensive agent. ACE-inhibitors and ARBs have been proven to effectively reduce urinary protein excretion in patients with T1DM and T2DM . Persistent cough may be a limiting side effect of ACE-inhibitors.Both agents may precipit ate (a) hyperkalemia, which may be particularly severe in patients with hyporenine- mic hyp oaldosteronism and (b) acute kidney injury in patients with renal artery stenosis. Serum po tassium and creatinine levels should be checked 2 \200\2233 wks after starting treatment. A dditional antihypertensive agents may need to be added in a stepwise fashion to achieve tar get levels of BP con- trol. Thiazide diuretics may provide an additive effect in patients w ith pre- served renal function (GFR >50 mL/min). A range of different preparations combinin g ACE-inhibitors and ARBs with thiazide diuretics in varying doses are available. Other cla sses of agents may be used as well, although atten- tion should be paid to potential compli cating side effects ( -blockers may impair recognition of hypoglycemia; -blockers and centrally acting agents may exacerbate orthostatic hypotension). Treatment of normotensive patients In patients with T1DM, con- firmed microalbuminuria, and normal BP, treatment wit h an ACE-inhibitor or ARB may delay the onset of proteinuria marking a progression to overt diabetic nephropathy. Similar benefits may accrue in patients with T2DM. y g o o n i r c o d n E l 293 Diabetic neuropathy Complication that develops as a result of irreversible damage to nerve fibers secondary to prolonged exposure to elevated blood glucose lev- els. Classification s chemes differentiate between peripheral neuropathy and autonomic neuropathy. Peripheral neu ropathy Most common type is distal symmetric poly- neuropathy. Manifestation of progressive damage to sensory and motor nerve fibers that may be detected in up to 30% of patients wit h diabe- tes. Usually begins in distal lower extremities, extending proximally in a stockin g-and-glove distribution. Asymptomatic involvement may be sus- pected when physical examina tion of the feet reveals (1) diminished or absent ankle jerk reflexes (usually the first ma nifestation), (2) diminished proprioception, and/or (3)diminished sensation to light touch with 10 g monofilament testing. Symptomatic involvement may present with pain characterized as paresthesias, hyperesthesias, or burning sensations. May spontaneously resolve or progr ess to a state of numbness. Other variants include focal mononeuropathy (commonly involving oculomotor nerves), radiculopathy (involving thoracic or lumbar nerve roots), and mononeur op- athy multiplex (presenting with asymmetric involvement of multiple periph- eral nerves) . Intensive control of blood glucose levels may delay progression of peripheral neuropathy, although reversal may not be possible. Pain may respond to staged treatment with tricyclic antidepressants ( desipramine or amitriptyline 25 \200\223200 mg qhs), topical capsaicin cream (Zostrix 0.075% cream qi d), gabapentin (Neurontin 300 \200\223600 mg tid), pregabalin (Lyrica 25 \200\223300 mg in 2 \200\2233 divided doses), carbamazepine (Tegretol 200 \200\223600 mg bid), or trama dol (Ultram 50 \200\223100 mg q6h). Autonomic neuropathy Variable manifestations, dependi ng on distribu- tion and extent of disruption in function of sympathetic and parasympa- the tic nerve fibers. Cardiovascular involvement may present with evidence of resting tachycard ia, exercise intolerance, or orthostatic hypotension (defined as a 20 mm Hg drop in systoli c BP or a 10 mm Hg drop in dia- stolic BP after standing for 2 min). Patients with orthosta tic hypotension may report dizziness, weakness, and nausea when standing. Treatment with fl udrocortisone (Florinef 0.05 \200\2230.1 mg/d) or midodrine (ProAmatine 10 mg tid) may help to relieve symptoms by augmenting intravascular volume with the former and increasing vascular tone with the latter. GI involvement may present with variable symptoms of gastrop athy, diarrhea, or constipa- tion. Diabetic gastroparesis is an extreme form of gastropathy that presents with marked dilation and hypotonia of the stomach, with delayed transit of f ood into the small intestine that may lead to early satiety, regurgita- tion of undigested food, and problems with coordination of preprandial insulin injections. Delayed transit may be confirmed on gastric emptying studies.Gastric emptying studies should be performed only when blood glucose is under control, as hyperglycemia may lead to false-positive tests. Pr okinetic agents used to treat persistent diabetic gastroparesis include metoclopramide (Reg lan 5 \200\22320 mg 15 \200\22360 min qac) and erythromycin (50 mg suspension qac). Gastr ic pacemakers have shown some efficacy in cases of extreme gastroparesis. Severe diabetic d iarrhea may respond to treat- ment with clonidine or octreotide . Genitourinary involvement may lead to development of a neurogenic bladder. Urinary retention may respond to treatmen t with bethanechol (Urecholine 10 \200\22350 mg tid). Self-catheterization may be necessa ry in extreme cases. Erectile dysfunction is a common com- plication of diabetes that may b e exacerbated by a range of contributing factors (atherosclerotic disease, hypogonadism, tr eatment with antihyper- tensive agents). Affected patients may respond to treatment with ph ospho- diesterase inhibitors sildenafil (Viagra 25 \200\22350 mg \227 1), vardenafil (Le vitra 2.5 \200\22320 mg \227 1), and tadalafil (Cialis 5 \200\22320 mg \227 1). These agents may be contraindicated in patients with known or suspected orthostatic hypoten- sio n or coronary artery disease. Individuals with T1DM with significant autonomic neuropathy m ay have blunted or absent counterregulatory responses to treatment-induced hypoglycemia, a dangerous complication identified as hypoglycemic unawareness . 294 The diabetic foot The combined effects of (1) distal symmetric polyneuropathy and (2) perip heral vascular disease restricting blood flow to the lower extremi- ties may predispose pat ients to developing significant complications related to foot injuries. Damage to motor ner ve fibers may lead to atrophy and weakness of muscles in the distal lower extremities. Prog ressive changes may lead to deformities that increase the pressure at prominent points on t he soles of the feet. This may lead to development of thick calluses that may ulcerate. To complicate matters, damage to sensory nerve fibers with progressive diabetes may make it di fficult for patients to detect foot ulcers or other traumatic injuries to the joints and so ft tissues in the foot and ankle. If left untreated, foot ulcers may develop polymicrobial celluli- tis, which can progress to osteomyelitis.In many cases, chronic infection is diffi cult to eradicate in devitalized tissue sites exposed to persistently elevated blood glucos e levels. Serious, life-threatening infections in limbs compromised by restricted blood flo w may require treatment with surgical amputation. >60% of lower extremity amputations are performed to treat complications of dia betic foot infections. Prevention Close inspection of the feet should be performed on at le ast an annual basis to check for evidence of diminished sensation, altered periph- eral pul ses, joint deformities, signs of tissue damage, or calluses that may be forming at points o f direct pressure. All patients should be counseled to perform regular self-inspection of t he feet to check for signs of unsuspected trauma or injury. Consider podiatry referral for trimming of toenails to recommended lengths and provision of fitted shoes with adequate sup port without binding or constricting the feet. Treatment Should be undertaken with the assi stance of a podiatric spe- cialist. Superficial diabetic foot ulcers that do not appear to be infected should be treated with aggressive debridement. Air casting may help to promote healing by relieving direct pressure. Deep ulcers may be probed to check for signs of osteo myelitis. Radiographic evaluation with plain films, magnetic resonance imaging (MRI) scanni ng, and tagged white blood cell (WBC) studies may help to confirm a suspected diagnosis. Ce llulitis and osteomyelitis require treatment with bed rest, surgical debridement, and prolo nged courses of IV antibiotics. Bone biopsy is the gold standard to determine the appropria te antibiotic. In cases of chronic wounds compli- cated by peripheral vascular disease, rev ascularization may help to promote resolution and healing. Amputation may be necessary if d eep infections fail to resolve or if a spreading anaerobic infection or gangrene supervenes . y g o o n i r c o d n E l Hypoglycemia Strict definition 3 ( \200\234Whipple \200\231s triad \200\235) based on confi rmation of (1) a plasma glucose level <50 mg/dL, (2) hyperadrenergic or neuroglycopenic sym p- toms that occur at the time the low plasma glucose level is detected, and (3) relief of those symptoms corresponding to an increase in the plasma glucose level after administratio n of oral or IV glucose. Hyperadrenergic symptoms include palpitations, tremulousness, naus ea, diaphoresis, and anxiety. Neuroglycopenic symptoms include dizziness, drowsiness, confu - sion, and dysarthria. Severe neuroglycopenia may result in loss of con- sciousness and se izures. Symptoms may develop in variable combinations and/or sequences. Causes Most common cause of hypoglycemia is iatrogenic (e.g., treatment with insulin or with insulin secretago gues). Correct treatment-induced hypoglycemia with 15 \200\22320 g glucose in conscious pat ient or glucagon injec- tion in the unconscious patient.Individuals should be given a presc ription for and instructions on how to use glucagon pen in case of emergencies. In patients who are not being treated with agents for diabetes, hypoglycemia may be classified as fast ing (occurring at any time of day) or postprandial (occurring reproducibly after meals). Fa sting hypoglycemia Distinction must be made between insulin-mediated and non-insulin-mediat ed mechanisms. Disorders associated with insulin-mediated hypoglycemia include insulinoma, insulin autoantibody production, and factitious administration of insulin or insulin secret agogues. Disorders associated with non-insulin-mediated hypoglycemia include chronic kidney disease, hepatic failure, sepsis, primary adrenal insufficiency, hypopituitarism, neoplasm s that produce insulin-like growth factor 2 (IGF-2), and a range of inherited metabolic def ects. Mechanisms underlying hypoglycemia associated with exposure to specific pharmacologic agents 295 3 Evaluation and management of adult hypoglycemic disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metabol . 2009. (quinolones, quinine, IV pentamidine, aminoglutethimide) are less clear. Investigation of h ypoglycemia usually focuses on sequentially (1) ruling out disorders associated with non-in sulin-mediated hypoglycemia, (2) conduct- ing a monitored fast to confirm insulin-mediated hypoglycemia, and (3) determining whether detectable insulin is endogenously secreted or fa cti- tiously administered. See Table 9.8. Insulinoma Very rare. May develop in the setting of multiple endocrine neoplasia type 1 (MEN-1) syndrome (pituitary tumor, parathyroid hyper - plasia, pancreatic mass). The majority of confirmed insulinomas represent isolated benign neoplasms. <10% prove to be malignant following patho- logic evaluation. Principal treatme nt is surgical enucleation. Preoperative localization may be difficult. Imaging modalities include computed tomog- raphy (CT) scanning, MRI scanning, transabdominal ultrasound, endos copic ultrasound, and octreotide scanning. Measurement of insulin levels drawn from hepatic veins after arterial administration of calcium gluconate may help to localize regions of e xcessive secretion. In cases where imaging fails to identify a suspicious mass, intraoperat ive localization may be attempted through exploration, palpation, and direct ultrasonograph y. Distal or partial pancreatectomy may be considered as an empiric measure when a suspi- c ious mass cannot be localized, although this will likely commit the patient to lifelong ins ulin therapy following surgery. Persistent or malignant disease may require treatment with diazoxide to suppress insulin secretion. Postprandial hypoglycemia Recurrent episodes of hy poglycemia may occur in patients who have undergone upper GI surgical procedures (gastric b anding, Roux-en-Y).This can occur immediately following sur- gery or years after. Transient episodes related to excessive physiologic Table 9.8 Monitored fast May be conducted in any inpatient or outpatient setting that allows for monitoring of intak e and activity. The patient may drink sugar-free and noncaffeinated beverages. Physical act ivity should be encouraged. Protocol Draw blood samples q6h to measure plasma glucose, insu lin, C-peptide, proinsulin, and -hydroxybutyrate. Once plasma glucose drops to <60 mg/dL , increase frequency of blood draws to every 1 \200\2232 h. Terminate the fast once (a) pla sma glucose drops to <45 mg/dL and the patient has signs/symptoms of hypoglycemia, (b) plas ma glucose >45 mg/dL if symptoms present, or (c) 72 h have elapsed without symptoms. At the end of the fast, draw blood samples to measure plasma glucose, insulin, C-peptide, proinsu lin, -hydroxybutyrate, and oral hypoglycemic agents. Then inject 1.0 mg of glucagon IV a nd measure plasma glucose 10, 20, and 30 min later. Interpretation In a blood sample collec ted when plasma glucose is <55 mg/dL, an insulin level >3 U/mL may be considered to be in appropriately elevated. An insulinoma may be suspected when a concomitant C-peptide level i s >0.6 ng/mL with a proinsulin level >5 pmol/L. Plasma glucose levels that increase by >25 mg/dL or less following administration of glucagon and -hydroxybutyrate levels of 2.7 mm ol suggest mediation of hypoglyce- mia by insulin (or IGF-1). Factitious administration of insulin may be suspected when C-peptide and proinsulin levels are lower than these threshol ds. In situations where factitious administration of insulin secre- tagogues may be suspect ed, blood samples can be checked to screen for sulfonylurea exposure. 296 insulin secretion may occur during the initial onset of T2DM. Self-identified \200\234reac tive \200\235 hypoglycemia in otherwise healthy individuals is considered a controversial d iagnosis. Experimental attempts to provoke and correlate symptoms have reported conflicting results. Oral glucose tolerance testing or mixed meal testing has not proven to reliably r eproduce hypoglycemia. Anecdotally, some patients report improvement in symptoms after alte ring diets to increase intake of protein and complex carbohydrates in smaller portions dist ributed throughout the course of the day. y g o o n i r c o d n E l Thyroid function tests Physiology Thyrotropin releasing hormone (TRH) secreted by the hypo- thalamus stimulates secretion of TSH from thyrotroph cells in the ante- rior pituitary. TS H binds to receptors on thyrocytes in the thyroid gland, stimulating (a) uptake of iodine, (b) organification of iodine with thyroid peroxidase and thyroglobulin (TG) to, (c) produce thyroxine (T4) and triiodothyronine (T3), followed by (d) secretion of T4 and T3 from the thyroid gland. See Figure 9.1. Most of the T4 and T3 secreted by the thyroid gland bind to transportation proteins in the circulation. Free (unbound) T4 is converted to T3 by deiodin ase enzymes in peripheral tissues. Free T3 is the active form of thyroid hormone that binds to nuclear receptors to exert different regulatory effects in the target organ. Free T4 an d T3 exert nega- tive regulatory feedback on the secretion of TRH from the hypothalamus and the secretion of TSH from the anterior pituitary. There is a log-linear relationship betwe en thyroid hormone levels and TSH levels. The major- ity of abnormalities of thyroid functi on in the clinical setting stem from disorders that primarily involve the thyroid gland its elf. As such, TSH is an intrinsic assay that provides the most sensitive index of thyroid g land function. See Table 9.9. Table 9.9 Evaluation of suspected hypothyroidism 297 1 Check a TSH level Normal = euthyroid Elevated = likely primary hypothyroidism Low = possible central (seconda ry) hypothyroidism, although rare 1 If the TSH level is elevated, check an unbound (free T4 ) thyroxine \212 \212 \212 level \212 \212 Elevated TSH + low free T4 =primary hypothyroidism Elevated TSH + normal free T4 = subclini cal hypothyroidism 3 If the TSH level is low, check an unbound (free T4) thyroxine level \212 Low TSH + low free T4 = possible central (secondary) hypothyroid- ism (defect in hypothalam us or pituitary) 4 To confirm diagnosis of autoimmune-mediated hypothyroidism (most common, Hashimoto \200 \231s thyroiditis), check antithyroid peroxidase and antithyroglobulin antibody titers \212 Elevated antithyroid peroxidase and/or antithyroglobulin antibody titers = autoimmune thyro iditis. Negative antibody titers do not rule out autoimmune disease. Table 9.10 Evaluation of suspected hyperthyroidism 1 Check a TSH level \212 \212 \212 Normal = euthyroid Low = thyrotoxicosis Elevated = possible central (secondary) hyperthyroi dism 2 If the TSH level is low, check an unbound (free T4) thyroxine level and a total triiodothyronine (T3) level \212 \212 \212 Low TSH + elevated free T4, or T3 = thyrotoxicosis Low TSH + normal free T4, and T3 = subcl inical thyrotoxicosis Elevated TSH + elevated free T4, or T3 = central (secondary) hyper- t hyroidism (defect in hypothalamus or pituitary) 3 Check for findings consistent with manifestations of Graves \200\231 disease (goiter, dermopathy, symptoms and signs of thyroid eye disease)