Screening and Treatment of Pre-Diabetes in Primary Care

CASE STUDIES

Case Study: Screening and Treatment of Pre-Diabetes in Primary Care

Richard J. Shrot, MD; Frances M. Sahebzamani, PhD, ARNP; and H. James Brownlee, Jr., MD

Presentation in the United States, affecting an esti- mittee on the Diagnosis and Classifica- J.M., a 48-year-old Hispanic man, was mated 16 million Americans. A pro- tion of Diabetes Mellitus.5 (This report is seen in the primary care clinic for rou- dromal phase of this disease, in which reprinted in full in this issue starting on tine follow-up of hypertension, for patients manifest impaired glucose p. 71.) The committee recognized that which he had been treated for the past 8 metabolism, has recently been identified IGT was more common in most popula- years. His only medication was lisino- as “pre-diabetes” by the U.S. Secretary tions by the older criteria. Lowering the pril, 20 mg/day. Home blood pressure of Health and Human Services.1 Pre- impaired fasting level to 100 mg/dl monitoring averaged 128/82 mmHg. He diabetes is also a major health care bur- should make the predictive value of had a family history for hypertension, den estimated to affect at least an addi- future diabetes more concordant, regard- type 2 diabetes, and coronary artery dis- tional 16 million Americans,2 and possi- less of whether IFG or IGT is used. ease. J.M. reported a 20-lb weight gain bly as many as 43 million with the new With the favorable results of the Dia- over the past year, along with a seden- criteria for impaired fasting glucose betes Prevention Program for Type 2 tary lifestyle with no regular exercise (IFG) being reduced to 100 mg/dl.3 Pre- Diabetes (DPP) published in 2002,6 a routine. Other medical history was nega- diabetes is highly associated with con- recent position statement of the American tive, including symptoms of fatigue, comitant cardiovascular risk factors and Diabetes Association proposes screening polyuria, or polydipsia. He denied past has been found to confer an increased recommendations for pre-diabetes to be or current tobacco use. risk of cardiovascular complications done as part of a health care visit and J.M. presented with a waist size of including myocardial infarction, stroke, suggests screening in individuals age ≥ 42 inches, BMI of 34 kg/m2, and blood and death.1 45 years, especially those who are over- pressure of 125/80 mmHg. A subse- Pre-diabetes is clinically defined by weight (BMI ≥ 25 kg/m2)1 (Table 2). quent lipoprotein profile demonstrated either an IFG between 100 and 125 Screening should also be considered in the common pattern associated with mg/dl or by a 2-hour oral glucose toler- individuals who are < 45 years old and pre-diabetes, including a low HDL cho- ance test (OGTT) result of 140–199 overweight in the presence of other risk lesterol (30 mg/dl) and a high triglyc- mg/dl, indicating impaired glucose toler- factors, such as a first-degree relative eride level (185 mg/dl). The LDL was ance (IGT), or both4 (Table 1). The nor- with diabetes, history of gestational dia- mildly elevated (132 mg/dl), and total mal fasting glucose level was recently betes, high-risk ethnicity, hypertension, cholesterol was 199 mg/dl. His fasting adjusted downward from 110 to 100 or dyslipidemia. Asian Americans may glucose was 111 mg/dl, with a repeat mg/dl, after analysis by the Expert Com- be screened at a lower BMI (≥ 23 kg/m2). value of 115 mg/dl one week later. Table 1. Definition of Pre-Diabetes Questions 1. Does this patient have pre-diabetes? Fasting Plasma Glucose 2-hour Plasma Glucose 2. When should patients be screened for (mg/dl) (mg/dl) pre-diabetes? Impaired fasting glucose (IFG) 100–125 3. How should pre-diabetes be treated Impaired glucose tolerance (IGT) 140–199 in primary care settings? Normal < 100 < 140 Diabetes ≥ 126 ≥ 200 Commentary Type 2 diabetes is a significant cause of The diagnosis of pre-diabetes is made by a positive finding of IFG or IGT or both, and test death, disability, and health care burden results should be confirmed on a different day.

98 Volume 22, Number 2, 2004 • CLINICAL DIABETES CASE STUDIES

Table 2. Routine Screening Recommendations for Pre-Diabetes gression to diabetes. Studies of selected angiotensin-converting enzyme • Age ≥ 45 years, especially with a BMI ≥ 25 kg/m2 (Asian Americans at BMI of inhibitors (ramipril) and statins (pravas- ≥ 23 kg/m2) tatin) have suggested that these drugs • Age < 45 years with BMI ≥ 25 kg/m2 plus additional risk factors for type 2 may delay the progression of pre- 10,11 diabetes (hypertension, history of gestational diabetes, baby weighing > 9 lb, diabetes to diabetes. Results of stud- high-risk ethnic group, HDL < 35 mg/dl, triglycerides > 250 mg/dl, first-degree ies such as the Diabetes Reduction relative with diabetes, history of vascular disease, habitual inactivity, polycystic Assessment with Ramipril and Rosiglita- ovary syndrome) zone Medications (DREAM) trial are • Either FPG or 2-hour OGTT can be used, with positive results confirmed on needed to confirm these findings. J.M.’s another day blood pressure was well controlled with • Done as part of a health care office visit lisinopril, 20 mg/day. A statin was added • Rescreening in 3 years to treat his dyslipidemia. Both of these interventions may help to delay the pro- Based on these screening recommen- delaying progression to diabetes, many gression to diabetes. Aspirin therapy was dations, J.M. was a candidate for screen- questions, including that of cost-effec- initiated to reduce cardiovascular risk. ing with age, ethnicity, BMI, dyslipi- tiveness, persist in the translation of The use of the insulin sensitizers— demia, family history, sedentary these interventions into primary care set- metformin and the thiazolidinediones lifestyle, and hypertension as prevailing tings. Based on the DPP and the Finnish (TZDs)—has been shown to be benefi- risk factors. His low HDL, high triglyc- study,9 successful treatment of pre- cial in delaying the progression from eride level, waist circumference, and diabetes requires thorough patient educa- pre-diabetes to diabetes.6,12 In the DPP, hypertension made him a likely candi- tion, counseling, and support in lifestyle metformin, 850 mg twice daily, reduced date for the diagnosis of pre-diabetes. changes targeting a 5–7% reduction in the relative risk of progression to type 2 These four risk factors, along with total body weight and an exercise goal of diabetes by 31%. Metformin may addi- impairment of glucose tolerance, were 150 minutes/week. J.M. was provided tionally improve outcomes by inducing established as clinical markers for with the necessary counseling for dietary weight loss. Although conducted in insulin resistance by the National Cho- intervention, and, following a pre-exer- women with a history of gestational dia- lesterol Education Program, Adult Treat- cise treadmill stress test, a titrated exer- betes, the Troglitazone in the Prevention ment Panel III, and are used to confirm a cise program was initiated. of Diabetes (TRIPOD) study demon- diagnosis of the metabolic syndrome7 Aggressive management of J.M.’s strated a 56% reduction in relative risk in (Table 3). comorbidities may also help slow pro- progression of pre-diabetes to diabetes. J.M.’s fasting glucose results of 111 Although treatment was discontinued Table 3. Definition of Metabolic and 115 mg/dl confirmed the diagnosis because of the withdrawal of troglita- Syndrome from National of pre-diabetes. To exclude a diagnosis zone from the U.S. market, persistent Cholesterol Education Program of diabetes, a 2-hour OGTT was protective treatment effects were Adult Treatment Panel III ordered. Its result of 173 mg/dl indicated observed more than 8 months after dis- that J.M. had IGT in addition to IFG. A continuation. Long-term clinical trial Risk Factor Defining Level recent analysis of glucose progression data are not yet available for the newer over several decades in the Baltimore Abdominal obesity TZDs, but there is a reasonable expecta- Longitudinal Study of Aging suggests (waist circumference) tion that the currently available medica- that IFG and IGT may represent differ- Men > 102 cm (> 40 in) tions in this drug class may provide simi- ent phenotypes in the natural history of Women > 88 cm (> 35 in) lar benefits. Until further clinical trial 8 progression to type 2 diabetes. This sug- Triglycerides ≥ 150 mg/dl data become available, clinician judg- gestion, however, was based on the older ment–based individualized patient char- definition of IFG. HDL cholesterol acteristics will determine the use of The results of recent clinical trials to Men < 40 mg/dl insulin sensitizers in pre-diabetes. How- prevent or delay progression to type 2 Women < 50 mg/dl ever, lifestyle modifications are first-line diabetes demonstrate the benefit of iden- Blood Pressure ≥ 130/≥ 85 mmHg treatment for pre-diabetes (Table 4). tifying patients at risk and implementing J.M. met with a dietitian and a physi- early aggressive intervention. Although Fasting glucose ≥ 110 mg/dl cal therapist for initial instruction. Brisk intensive lifestyle and selected pharma- walking was the starting baseline exer- Diagnosis is made when three of the five cological interventions have demonstrat- cise for 30 minutes each day, 5 days per criteria are present. ed effective outcomes in preventing or week, with the use of a pedometer to

CLINICAL DIABETES • Volume 22, Number 2, 2004 99 CASE STUDIES

additional risk factors such as hyper- Panel on Detection, Evaluation and Treatment of Table 4. Successful Treatment of High Blood Cholesterol in Adults (Adult Treat- Pre-Diabetes tension or dyslipidemia. ment Panel III). JAMA 285:2486–2497, 2001 • A dyslipidemic pattern of low HDL 8Meigs J, Muller D, Natha D, Blake D, Method Reference cholesterol and high triglycerides, in Andres R: The natural history of progression addition to hypertension and large from normal glucose tolerance to type 2 diabetes Lifestyle The Finnish Study9 in the Baltimore Longitudinal Study of Aging. waist size, are clinical markers for Modification Diabetes 52:1475–1484, 2003 (first-line) insulin resistance and impaired glu- 9Tuomilehto J, Lindstrom J, Eriksson JG, 6 cose metabolism. Valle TT, Hamalainen H, Ilanne-Parikka P, Keina- • 5–7% loss body weight DPP Trial nen-Kiukaanniemi S, Laakso M, Louheranta A, • 150 min/week exercise • Aggressive management of concomi- Rastas M, Salminem V, Uusitupa M: Prevention tant comorbidities, such as hyperten- of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. Pharmacological Therapy sion and dyslipidemia, may delay pro- N Engl J Med 344:1343–1350, 2001 6 Metformin DPP Trial gression of pre-diabetes to diabetes. 10 12 The Heart Outcomes Prevention Evaluation Troglitazone TRIPOD Study • Aggressive lifestyle modification has Study Investigators: Effects of an angiotensin- 13 Acarbose STOP-NIDDM Trial delayed the progression of diabetes by converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J about 60%, while medications such as Med 342:145–153, 2000 measure distances. Calorie counting and metformin have reduced progression 11Freeman DJ, Norrie J, Sattar N, Neely RD, knowledge of healthy choices from the by about 30%. Cobbe SM, Ford I, Isles C, Lorimer AR, Macfar- lane PW, McKillop JH, Packard CJ, Shepherd J, food pyramid were discussed, but the • Efforts should be made to secure Gaw A: Pravastatin and the development of dia- intensive case management approach, as insurance reimbursement for intensive betes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary used in the DPP, was not possible lifestyle modification, including class- Prevention Study. Circulation 103:357–362, 2001 es and case managers such as those because of insurance reimbursement 12Buchanan TA, Xiang AH, Peters RK, Kjos issues and a lack of availability of indi- used in the DPP. SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP: Preservation vidual case managers. of pancreatic (beta)-cell function and prevention After a 6-month trial of diet and exer- REFERENCES of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic cise, J.M. was only able to exercise for 20 1American Diabetes Association and National women. Diabetes 51:2796–2803, 2002 minutes or less each week, had gained 7 Institute of Diabetes and Digestive and Kidney 13 Diseases: The prevention of delay of type 2 dia- Chiasson JL, Josse RG, Gomis R, Hanefeld lb, and had an increase in fasting glucose betes (Position Statement). Diabetes Care 27 M, Karasik A, Laakso M: Acarbose for prevention to 117 mg/dl. Although not approved by (Suppl. 1):S47–S54, 2004 of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 359:2072–2077, 2002 the Food and Drug Administration for 2Saydah SH, Byrd-Holt D, Harris MI: Pro- this indication or recommended by the jected impact of implementing the results of the Diabetes Prevention Program in the U.S. popula- American Diabetes Association, met- tion. Diabetes Care 25:1940–1945, 2002 Richard J. Schrot, MD, CDE, is an asso- formin remains an alternative. 3Davidson M, Landsman P, Alexander C: ciate professor, Frances M. Sahebza- Lowering the criterion for impaired fasting glu- mani, PhD, ARNP, is an assistant profes- cose will not provide clinical benefit. Diabetes Clinical Pearls Care 26:3329–3330, 2003 sor, and H. James Brownlee, Jr., MD, is • Pre-diabetes is diagnosed by a fasting 4American Diabetes Association: Diagnosis a professor and chairman in the Depart- glucose between 100 and 125 mg/dl and classification of diabetes mellitus. Diabetes ment of Family Medicine at the Universi- (IFG) or a 2-hour OGTT result Care 27 (Suppl. 1):S5–S10, 2004 ty of South Florida (USF) School of between 140 and 199 mg/dl (IGT), or 5The Expert Committee on the Diagnosis of Medicine in Tampa, Fla. Dr. Schrot is a Diabetes Mellitus: Follow-up report on the diag- both, confirmed. nosis of diabetes mellitus. Diabetes Care member of the research working group, • The onset of type 2 diabetes can be 26:3160–3167, 2003 and Dr. Sahebzamani and Dr. Brownlee prevented or delayed. 6The Diabetes Prevention Research Group: are co-directors of the USF Pre-Dia- • Screening for pre-diabetes should be Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J betes Treatment and Research Center. considered for patients at age 45 Med 346:393–403, 2002 Dr. Schrot has been director of the years, especially for overweight or 7Expert Panel on Detection, Evaluation and Ambulatory Care Diabetes Clinic at the obese patients, and earlier for patients Treatment of High Blood Cholesterol in Adults: James A. Haley VA Hospital in Tampa, 2 Executive summary of the third report of the with a BMI of 25 kg/m or more with National Cholesterol Education Program Expert Fla.

100 Volume 22, Number 2, 2004 • CLINICAL DIABETES CASE STUDIES

Case Study: Hemachromatosis in Type 2 Diabetes

Peter Capell, MD

Presentation merase chain restriction assay demon- tissue damage. Liver function abnor- G.O. is a 50-year-old white man referred strated homozygosity for the C282Y malities are the most frequent finding for help in managing his diabetes. Two chromosome. Referral to the hepatology leading to a diagnosis. Other important years before his visit, diabetes was diag- clinic resulted in a liver biopsy, which organ systems usually involved include nosed during a routine exam. He was identified increased iron stores and early the pancreas (diabetes), skin (hyper- started on oral hypoglycemic agents. He periportal fibrosis. pigmentation), joints (arthralgias and initially responded to this treatment, but Following confirmation of a diagno- arthritis), heart (arrhythmias), and over the ensuing 2 years, his medication sis of hemochromatosis, he was started gonads (hypogonadism). doses were slowly raised until he was on on phlebotomy therapy. Family screen- Approximately 50% of patients diag- 15 mg glyburide and 2,000 mg met- ing was encouraged and resulted in the nosed with hemochromatosis will have formin. At the time of referral, his fast- finding of asymptomatic diabetes associ- either type 1 or type 2 diabetes. The like- ing blood glucose levels were in the ated with hemochromatosis in his broth- lihood of finding hemochromatosis in range of 150 mg/dl and his hemoglobin er. His medication doses have not the adult population of diabetic patients A1c (A1C) was 8%. He requested a con- changed, nor have his fasting glucose is reportedly between 1–2%. Diabetes is sultation when he was advised to start level or A1C results after 4 months of not uncommonly the only apparent man- on insulin therapy. phlebotomies. ifestation of hemochromatosis in unrec- His medical history was significant ognized cases. for heavy alcohol intake and hepatitis B Questions Early recognition of the presence of with full recovery. Family history was 1. What is the prevalence of hemochro- hemochromatosis is extremely impor- negative for diabetes and hemochromatosis in the general and diabetic tant. Prompt therapy can prevent cirrho- matosis. His review of systems was posi- population? sis of the liver, development of a tive for joint discomfort in his hands and 2. What is the effect of treatment on hepatoma, joint and gonadal damage, erectile dysfunction. diabetic control in patients with and the development of diabetes. In Physical exam revealed normal vital hemochromatosis? addition, as in this case, it can lead to signs and no retinopathy or other signs 3. Should all people with diabetes over early recognition of the disease in family of diabetic complications. His hand age 30 be screened for hemochro- members. Unrecognized, advanced joints showed mild swelling and tender- matosis? hemochromatosis carries a high risk for ness over the proximal interphalangeal premature death. joints, and his skin was slightly, diffusely Commentary Development of diabetes in hyperpigmented. Hereditary hemochromatosis is an auto- hemochromatosis is likely multifactorial. Lab data included a random glucose somal recessive genetic disorder caused Selective -cell damage, due to uptake of 253 mg/dl, A1C of 7.9%, normal cre- by a mutation in the HFE gene located of iron, leads to impaired insulin synthe- atinine and electrolytes, aspartate amino- on the short arm of chromosome 6. This sis and release. -Cell function is not transferase (GOT) of 66 units/l (normal mutation results in increased intestinal impaired. In addition, liver fibrosis leads < 44), alanine aminotransferase (ALT) of absorption of iron and eventually to iron to insulin resistance and contributes to 133 units/l (normal < 31 units/l), normal overload. About 10% of the white popu- some patients requiring large amounts of bilirubin and alkaline phosphatase levels, lation in the United States is heterozy- insulin to obtain optimal blood glucose normal testosterone level, and negative gote, with the frequency for homozygos- control. A family history of diabetes is hepatitis antigen screen. His iron level ity at 0.2–0.5%. Heterozygote individu- observed in 25% of patients with was 306 g/dl (normal < 155) with an als are gene carriers but are not medical- hemochromatosis who develop diabetes. iron-binding capacity of 315 g/dl (nor- ly affected. In contrast, only 4% of those with mal < 400) and percent saturation of Onset of symptoms is seldom hemochromatosis who fail to develop 97% (normal < 50%). Serum ferritin was apparent before age 40 because it takes diabetes have a positive family history. 2,920 g/l (normal < 160). The poly- years to build up enough iron to cause Therefore, it is likely that all three fac-

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tors—-cell damage, insulin resistance, some reports indicate no increased risk effective. However, screening patients and underlying genetic tendencies—play of hemochromatosis in an adult diabetic with a family history of iron overload a causal role in patients with hemochro- population. Furthermore, an elevated disease, abnormal liver enzymes, or matosis developing diabetes. transferrin level is nonspecific, and a arthritis seems prudent. Phlebotomy therapy has a variable positive result will lead to many unnec- impact on diabetes control. In a large essary evaluations being performed. SUGGESTED READINGS study exploring the effect of therapy on Certainly type 2 diabetes and abnormal Ellervik C, Mandrup-Poulsen T, Nordestgaard diabetes control, 40% of 72 patients on liver tests (as in this case), arthritis, or a BG, Larsen LE, Appleyard M, Frandsen M, insulin or oral agents showed improved family history of iron overload disease Peteresen P, Schlichting P, Saermark T, Tybjaerg- Hansen A, Birgens H: Prevalence of hereditary glucose control following phlebotomy (as seen with this patient’s brother) haemochromatosis in late-onset type 1 diabetes therapy. This same study reported that should trigger an order for a transferrin mellitus: a retrospective study. Lancet 358:1405–1409, 2001 6% of patients were able to stop insulin level. Dymock IW, Cassar J, Pyke DA, Oakley WG, therapy during phlebotomy therapy, but Williams R: Observations on the pathogenesis, 12% of the study group required Clinical Pearls omplications and treatment of diabetes in 115 cases of haemochromatosis. Amer J Med increased medication to achieve good • Hemochromatosis is present in 1–2% 52:203–210, 1972 glycemic control. The majority of dia- of all diabetic patients, and diabetes Bomford A, Williams R: Long term results of betic patients will experience no change is often the first clinical manifestation venesection in idiopathic haemochromatosis. or a progressive worsening in their dia- of the disease. QJM 45:611–623, 1976 betes management despite phlebotomy • Early recognition and treatment is imperative to prevent fatal liver or treatment. Peter Capell, MD, is a clinical professor heart abnormalities and can prevent The issue of screening all diabetic of medicine in the Division of the onset of diabetes or improve dia- patients for hemochromatosis is current- Endocrinology and Metabolism at the betes control. ly debated. Screening by transferrin sat- University of Washington School of Med- • Screening all diabetic patients for uration using a level of > 50% is reason- icine in Seattle, Wash. ably inexpensive. The dilemma is that hemochromatosis may not be cost-

Case Study: An 82-Year-Old Woman Presents With Severe Hypoglycemia Induced by an Insulinoma

Saleemah Yasmeen Fahmi, MD, and Philip Raskin, MD

Presentation the patient was reassured. As she was nificant for a glucose level of 36 mg/dl. I.H. is an 82-year-old white woman who waiting for check-out, she developed She was completely asymptomatic upon presented to her primary care physician confusion, a capillary blood glucose test presentation and was thus placed on a with a 10-year history of episodic confu- was performed, and she was noted to fasting protocol. Subsequent laboratory sion and somnolence. The episodes have a plasma glucose level of 28 mg/dl. results are listed in Table 1. occurred about twice a year, typically in She was given juice and her symptoms In this case (as is true in most cen- the morning, just after waking. They resolved after a few moments. ters), the serum insulin, serum C-pep- lasted minutes and were relieved when The patient was subsequently admit- tide, and sulfonylurea levels were not she ate her breakfast or had juice. Over ted to the hospital for further work up. readily available. Therefore, the fasting the 8–10 months before presentation, the On exam, I.H. was found to be a protocol was continued until she became patient noted that the episodes were well-nourished woman in no apparent symptomatic. The subsequent lab results increasing in frequency as well as occur- distress. Her vital signs were significant were consistent with the suspected diag- ring throughout the day. only for mild hypertension. Her physical nosis of an insulin secreting tumor. To When I.H. presented to her primary and neurological exams were unremark- localize the tumor, I.H. had an abdomi- care doctor with the above complaints, able. Her admission lab values were sig- nal CT with contrast, which revealed an

102 Volume 22, Number 2, 2004 • CLINICAL DIABETES CASE STUDIES

Table 1. Laboratory Results for Patient I.H. on Fasting Protocol tinued once the patient becomes symptomatic and the serum glucose falls below Time Serum Glucose Serum Insulin Serum C-peptide Sulfonylurea 45 mg/dl. A final set of labs should be (mg/dl) (U/ml) (ng/dl) drawn. The patient should then be given juice and monitored for resolution of 0957 36 13.6 2.3 NEG symptoms. (Of note in patient I.H., the 1150 50 20.6 2.6 NEG finding of a serum glucose of 36 mg/dl 1330 34 10.7 2.0 NEG and evidence of insulin secretion proba- 1430 34 6.9 1.3 NEG bly would have sufficed.) The fast should be continued for 72 hours if enhancing mass in the pancreatic head cal disorder before the true diagnosis of symptomatic hypoglycemia does not suggestive of an insulinoma (Figure 1). insulinoma was made.4 occur. Diagnosis of insulinoma is estab- Insulinoma patients have a tendency Questions lished by demonstrating inappropriately to develop hypoglycemia early during a 1. What are the clinical signs and symp- high serum levels of endogenous insulin fasting period, typically in the first toms of insulinomas? in the setting of hypoglycemia.5 10–12 hours.7 The change of insulin rel- 2. How is the diagnosis of insulinoma Decrease in plasma glucose level occurs ative to glucose is inappropriate; thus, made? during fasting under normal physiologi- the insulin-to-glucose ratio increases 3. What imaging studies are best for cal conditions. However, the fall in plas- rather than decreases as it does in normal localizing insulinomas? ma glucose is accompanied by a concur- subjects.7 A serum insulin concentration 4. What are the treatment options for rent fall in plasma insulin levels.6 In of ≥ 6 U/ml when the serum glucose insulinoma? cases where the diagnosis of insulinoma concentration is < 45 mg/dl indicates is suspected and the patient is observed inappropriate secretion of insulin, con- Commentary with symptoms of hypoglycemia, the sistent with insulinoma.8 Insulinomas are almost always islet cell serum blood glucose, C-peptide, insulin, It is also very important to measure tumors of the pancreas and occur as and sulfonylurea levels should be drawn C-peptide concentrations, which should single or multiple tumors. They are typ- immediately before intervention. be inappropriately normal or high in the ically benign, although malignant In patients who present for diagnos- case of insulinoma. Proinsulin is the tumors have been reported as well.1 tic work-up, a brief, observed fast should immediate precursor to insulin and is Insulinomas present with the neurogly- be performed in which the above lab val- stored in the -cell. Insulin is formed copenic and sympathoadrenal symp- ues are measured every 4–6 hours initial- when the connecting peptide (C-peptide) toms induced by hypoglycemia.2 I.H. ly and then every 1–2 hours after the is cleaved from the proinsulin presented with confusion, which is typi- patient’s serum blood glucose level falls molecule. This occurs at the time of cal of insulinoma. Other symptoms to < 60 mg/dl. The fast should be discon- insulin secretion, and thus both insulin include visual changes, unusual behav- ior, palpitations, diaphoresis, and tremulousness.3 Interestingly, I.H. had none of the sympathoadrenal symptoms. This phe- nomenon is known as “hypoglycemia unawareness” and is seen most often in type 1 diabetic patients who experience frequent episodes of hypoglycemia. This occurs because the set point for cate- cholamine secretion in response to hypoglycemia is lowered. I.H. did not have weight gain, which is noted in about 18% of insulinoma cases according to one study.4 Misdiagnosis of insulinoma is common. In one study, as many as 20% of patients had been misdiagnosed with a Figure 1. Contrasted abdominal CT scan illustrating enhancing mass at the head psychiatric, seizure, or other neurologi- of the pancreas.

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and C-peptide are released into the circu- distal pancreatectomy, enucleation of the • Imaging and localization of insulino- lation.9 insulinoma and partial pancreatectomy, a ma is typically obtained by CT In a patient with a low or unde- Whipple procedure (removal of the head scan. If undetected and the clinical tectable level of serum C-peptide in the of the pancreas, gastrectomy, duodenec- suspicion is still high, then arteriogra- setting of hyperinsulinemia, self-induced tomy, and splenectomy), and total pan- phy, ultrasonography (transabdominal, hypoglycemia secondary to the adminis- createctomy have all been reported. Enu- endoscopic, and intraoperative), or tration of insulin should be suspected cleation of the tumor is the most 111-In-penteotreotide or octreotide and evaluated. Self-induced hypo- common surgical procedure. Pathology scintigraphy may be pursued. glycemia may present in a similar way to revealed a 1.3-cm insulin-secreting • First-line treatment of insulinoma is that of insulinoma and is typically endocrine neoplasm that was likely surgical resection. However, medical achieved by administering insulin or oral benign. therapy may be initiated if the patient secretagogues such as sulfonylurea. For patients who are not good surgi- is not a good surgical candidate or the Findings, however, in these cases do not cal candidates, who refuse surgery, or tumor is unresectable. typically correlate with food ingestion, whose insulinoma was missed during because the agent is administered irregu- surgery, as well as for patients with REFERENCES larly.9 Patients presenting with self- metastatic disease, medical therapy 1Service FJ: Insulinoma. In UpToDate. Rose, induced hypoglycemia typically have should be attempted. The goal of med- BD, Ed. Wellesley, Mass., UpToDate, 2003. Avail- access to hypoglycemic agents either ical therapy is to prevent symptomatic able online at http://www.uptodate.com/index.asp through their work or through hypoglycemia. Medications that have 2Rizza RA, Haymond MW, Verdonk CA, Mandarino LJ, Miles JM, Service FJ, Gerich, JE: relatives. Factitious hypoglycemia been used for this purpose include dia- Pathogenesis of hypoglycemia in insulinoma induced by sulfonylurea administration zoxide, verapamil, phenytoin, and patients: suppression of hepatic glucose produc- has a laboratory presentation similar to octreotide. Diazoxide diminishes insulin tion by insulin. Diabetes 30:377–381, 1981 that of insulinoma. The insulin and C- secretion and is the most effective drug 3Dizon AM, Kowalyk S, Hoogwerf BJ: Neu- roglycopenic and other symptoms in patients with peptide levels will both be elevated; thus, for controlling hypoglycemia. insulinomas. Am J Med 106:307–310, 1999 it is imperative that the sulfonylurea lev- Octreotide, the somatostatin analog, is 4Service FJ, Dale AJ, Elveback LR, Jiang NS: el is measured as well. also a common treatment for patients Insulinoma: clinical and diagnostic features of 60 1 consecutive cases. Mayo Clin Proc 51:417–429, Imaging and localization of insulino- with unresectable tumors. 1976 mas may be done by spiral CT, arteriog- Postoperatively, I.H.’s glucose levels 5Fajans SS, Floyd JC, Jr.: Fasting hypo- raphy, ultrasonography (transabdominal, stabilized to the low 100s after an initial glycemia in adults. N Engl J Med 294:766–772, endoscopic, and intraoperative), or 111- short period of hyperglycemia. Her post- 1976 In-penteotreotide or octreotide scintigra- operative course was complicated only 6Merimee TJ, Tyson JE: Stabilization of plas- 10 ma glucose during fasting. N Engl J Med phy. I.H., in addition to a CT scan, had by an ileus that resolved on postopera- 291:1275–1277, 1974 an octreotide scan, which aided in char- tive day 11. The patient was discharged 7Merimee TJ, Tyson JE: Hypoglycemia in acterizing the tumor’s secretory nature on a regular diet and has done well. man: pathologic and physiologic variants. Dia- and function. It illustrated a small focus betes 26:161–165, 1977 of mildly increased activity in the upper Clinical Pearls 8Service FJ: Diagnostic approach to hypoglycemia. In UpToDate Rose BD, Ed. Wellesley, abdominal region between the upper • Insulinoma should be suspected in Mass., UpToDate, 2003. Available online at portion of the kidney just to the right of patients who present with symptoms http://www.uptodate.com/index.asp midline, placing it in the region of the of neuroglycopenic and sympathoad- 9Kennedy AL, Merimee TJ: The evaluation of pancreas. Self-induced hypoglycemia is renal symptoms induced by hypo- hypoglycemia. Comprehens Ther 6(8):62–67, 1980 often seen in patients seeking the atten- glycemia. 10Modlin IM, Tang LH: Approaches to the tion of family and medical professionals • If the patient is symptomatic, a capil- diagnosis of gut neuroendocrine tumors: the last or some other form of secondary gain. lary blood glucose level should be word (today). Gastroenterol 112:583–590, 1997 I.H. had an open laparotomy with measured immediately. If noted to be intraoperative ultrasound and enucleation low, then serum glucose, serum of a 1.1-by-1.2 cm discrete, firm nodule insulin, C-peptide, and sulfonylurea Saleemah Yasmeen Fahmi, MD, is a in the center of the pancreatic head iden- levels should be measured before third-year resident, and Philip Raskin, tified by palpation and ultrasound. Pan- intervention. MD, is a professor of medicine in the creatojejunostomy in Roux-en-Y fashion • Factitious hypoglycemia should be Department of Internal Medicine and a was performed in case of operative pan- suspected in patients who have Clifton and Betsy Robinson Chair in creatic ductal injury. Surgical resection is access to insulin or antidiabetic sec- Biomedical Research at the University of the treatment of choice for insulinoma. retagogue drugs through work or Texas Southwestern Medical Center in Enucleation of the insulinoma, partial relatives. Dallas, Tex.

104 Volume 22, Number 2, 2004 • CLINICAL DIABETES