Obese Young Girl With Acanthosis Nigricans and Vaginal Yeast Infection

PATIENT PROFILE:

A 12-year-old African American girl comes to youroffice for a well-child checkup. She is tall for herage (height above the 95th percentile) and obese(body mass index [BMI] above the 95th percentile).Physical examination reveals acanthosisnigricans on her neck, axilla, and upper abdominalregion

(Figure)

and a vaginal yeast infection.Routine urinalysis reveals a glucose level ofgreater than 1000 mg/dL, with negative proteinand ketones. A random blood glucose test, obtainedbecause of the glucosuria, is 249 mg/dL.Both of the girl's parents are obese; themother had gestational diabetes with her last 2pregnancies. The maternal grandmother andgrandfather both have type 2 diabetes, as do severalmaternal and paternal aunts and uncles. Thematernal grandfather had a myocardial infarctionat age 48 and has hypertension and hypercholesterolemia.The patient's father had coronarybypass surgery at age 42.

WHAT WOULD YOU DO NOW?

A.

Test for autoantibodies to glutamic aciddecarboxylase, islet cells, insulinoma associatedantigen-2 (IA-2), and insulin to exclude adiagnosis of type 1 diabetes.

B.

Determine C-peptide levels.

C.

Hospitalize the patient.THE CONSULTANT'S CHOICE
This child's clinical presentation and family historysuggest type 2 diabetes. Although numbers vary at centersthroughout the United States, most pediatric endocrinologistsreport that among patients identified as having truetype 2 diabetes, nearly 100% have a BMI of greater than85%; also, 90% to 95% have acanthosis nigricans--a cutaneousmanifestation of insulin resistance characterized byvelvety, hyperpigmented skin, most often in intertriginousareas.

¹

With the current epidemic of obesity, up to 24% of children who present with type 1 diabetes are overweightat diagnosis; this indicates that weight alone cannot beused to differentiate type 1 from type 2 diabetes.Unlike those with type 1 diabetes, most children withtype 2 diabetes have glucosuria at presentation, with mildor absent polyuria and polydipsia and little to no recentweight loss. Type 2 diabetes is usually not associated withthe development of diabetic ketoacidosis (DKA) becausethis disease process is one of relative, rather than absolute,insulin deficiency (in contrast to type 1 diabetes). However,insulinopenia caused by beta-cell dysfunction from glucosetoxicity can result in DKA in patients with type 2 diabetes;thus, the presence of DKA does not rule out type 2 diabetes.Up to 40% of patients with newly diagnosed type 2diabetes may have ketonuria. In addition, in one study of43 consecutive patients who presented with DKA, type 2diabetes was subsequently diagnosed in 7 (16%).

²

Family history may be helpful: between 74% and100% of children with type 2 diabetes have a first- or second-degree relative with type 2 disease.

³

Occasionally, thediagnosis will only be clarified by observing the disease'sclinical course and by testing for the presence of autoantibodiesto islet cells, glutamic acid decarboxylase, insulin,and IA-2. Autoantibodies are rare in children with type 2diabetes. In addition, unlike in type 1 diabetes, there areno specific genetic associations (eg, HLA) in patients withtype 2 disease.Some have advocated measuring C-peptide levels ifthere is uncertainty about whether a child has type 1 or type2 diabetes. However, C-peptide levels may be low in childrenwith type 2 diabetes at diagnosis because of glucosetoxicity to the beta cells. Thus, C-peptide levels (Choice

B

)should not be measured immediately at presentation.This patient had a candidal yeast infection, which is notuncommonly found at diagnosis or in patients with poorlycontrolled diabetes. The infection was treated with a singledose of oral fluconazole. She had an HbA

_1c

value of 7.7%.Because the patient appeared well hydrated andthere was no evidence of DKA, we felt she did not need tobe hospitalized (Choice

C

). Outpatient diabetes education with a certified diabetes educator and nutritionist was initiated.The child admitted to having 2 or 3 servings at eachmeal and to drinking around 64 oz of soda and juice perday. She was advised to exercise 30 min/d, 5 days perweek, and to cut back on portion sizes and on sugar-ladendrinks by substituting water or diet soda. She was counseledto check her blood sugar level before and 2 hoursafter meals (3 or 4 times daily). Target levels for fastingblood sugar and postprandial blood sugar were less than120 mg/dL and 180 mg/dL, respectively.Therefore, the most appropriate answer at this stagewould be determining the presence of autoantibodies(Choice

A

) to exclude type 1 diabetes.After type 2 diabetes was diagnosed, this patient wasplaced on a weight-reducing diet and exercise program.She monitored fasting and 2-hour postprandial bloodsugar at home 2 or 3 times per day and reported fastingblood glucose values of 120 mg/dL to 160 mg/dL, andpostprandial blood sugars of 200 mg/dL to 250 mg/dL.

Follow-up.

Despite the dietary restrictions and exercise,the patient's HbA

_1c

had increased to 8% after 3months, and her weight had increased by 0.6 kg.

WHAT WOULD YOU DO NOW?

A.

Continue the diet and exercise program.

B.

Initiate insulin therapy.

C.

Start a thiazolidinedione.

D.

Begin metformin therapy.THE CONSULTANT'S CHOICE
Treatment varies depending on the individual child'sclinical presentation. Nevertheless, the goals of treatmentare the same for all children with diabetes: to maintain normallevels of blood glucose, blood pressure, and lipids; toavoid acute complications, such as DKA; and to preventlong-term microvascular and macrovascular complications.Weight management through diet and exercise is thecornerstone of treatment for all children (Choice A). However,successful diabetes management without pharmacotherapyoccurs in fewer than 10% of patients over time.

⁴

Successful treatment of type 2 diabetes is definedas cessation of excessive weight gain with normal lineargrowth, fasting blood glucose levels of less than 120mg/dL, and an HbA

_1c

of less than 7%. If lifestyle modificationfails to achieve treatment goals, pharmacotherapymust be initiated. A recent survey of North American cliniciansshowed that 48% of all children with type 2 diabeteswere treated with insulin and that 44% were treatedwith 1 or more oral hypoglycemic agents.

⁵

Among oralagents, metformin was the most frequently prescribed(71%), followed by sulfonylureas (46%), thiazolidinediones(9%), and a meglitinide (4%).While insulin therapy (Choice

B

) is a very effectivemethod of normalizing blood glucose levels, it must begiven as an injection and it may lead to hypoglycemia.Also, it increases weight (an especially undesirable effectin children with type 2 diabetes).

• Sulfonylureas, which increase insulin secretion and sensitivity,may result in hypoglycemia and weight gain.
• α-Glucosidase inhibitors work by slowing hydrolysis andabsorption of complex carbohydrates and, thus, must betaken with each meal. These agents work best in childrenwho have postprandial hyperglycemia in the absence of fasting hyperglycemia.

The Scope of the Diabetes Problem

I

n 1992, type 2 diabetes represented2% to 4% of all newly diagnosedcases of diabetes in children. By1994, 16% of new cases of diabetesin urban areas were type 2 diabetes.By 1999, up to 45% of all newdiabetes cases in children were type2 disease.

⁹

Certain ethnic groups aredisproportionately affected: mostchildren with type 2 diabetes areAfrican American, Mexican American,or Native American. In one center,up to 75% of patients with type 2diabetes were African American children--a finding that has been replicatedin other centers.

¹⁰

While the higher incidence oftype 2 diabetes in these ethnicgroups is partially the consequenceof high rates of obesity seen in thesepopulations, there also seems to be agenetic basis for this finding. AfricanAmericans have more insulin resistanceat puberty and have a greaterinsulin response to glucose challenge,which may indicate insulin resistance.In addition, resting metabolicrate is lower in African Americanchildren than in white children.

¹¹

The incidence of type 2 diabetesin children has paralleled therise in childhood obesity. The definitionof obesity in children is a BMIof greater than 95%; overweight isdefined as a BMI of greater than85%. At least 20% of, or 6 million,American children under 19 years are now overweight or obese.The incidence of childhood obesityhas more than doubled over thepast 20 years.

¹²

The National LongitudinalSurvey of Youth--a prospectivecohort study conducted from 1986 to1998 among 8270 children 4 to 12years old--showed a prevalence ofobesity of 21.5% among AfricanAmerican youths, of 21.8% amongHispanics, and of 12.3% among non-Hispanic whites by 1998.

¹³

There are several well-defined,well-studied genetic causes of childhoodobesity, such as leptin deficiencyand Prader-Willi syndrome. Nevertheless,the rise in childhood obesityin the United States is primarily theresult of environmental factors. Childrenare leading sedentary lifestyles;watching more television; and eatinghigh-calorie, high-fat foods more frequentlythan children did 20 yearsago. A study of snacking habits between1977 to 1978 and 1994 to 1996showed that children are snacking14% more per day and consuming 23%of total calories per day from snacks.

¹⁴

The American food dollar spent oneating out has increased from 20% to38% since the 1970s, and fast-foodrestaurants have grown at a rate of 7%per year. Portion sizes in restaurantmeals, take-out foods, and snackshave increased more than 100%.The complications of obesity includesleep apnea, orthopedic abnormalities, abnormalities,gallstones, and psychologicalproblems, as well as the metabolicsyndrome, which includes hypertension,dyslipidemia, elevated prothromboticsubstances, insulinresistance, polycystic ovarian disease,and type 2 diabetes.Current estimations are that16 million Americans have insulinresistance, or prediabetes secondaryto obesity, and that 17 millionAmericans have type 2 diabetes.The postulated mechanismby which obesity leads to insulin resistanceis characterized by excessivefilling of cells with fat--an energeticallyrich substance that subsequentlyrestricts further nutrient(glucose) uptake into cells and thatleads to hyperglycemia and compensatoryhyperinsulinemia.

¹⁵

Thedevelopment of glucose intoleranceis delayed by the pancreatic responseto the defect in peripheralaction of insulin of increased insulinproduction and secretion. Overtime, however, the pancreatic secretionof insulin becomes inadequatefor the degree of insulin resistance,and the levels of postprandial andthen fasting glucose rise; onset offrank hyperglycemia is the result.Hyperglycemia leads to structuraland functional damage to thebeta cell through glucose toxicity,which reduces beta-cell functionand survival.

^16,17

• The thiazolidinediones (Choice C)--which are not FDAapprovedfor use in children--increase peripheral insulinsensitivity and have beneficial effects on lipids (they lowerLDL and increase HDL cholesterol levels). They also increaselevels of cardioprotective hormones, such asadiponectin, and are therefore cardioprotective.
• Metformin (Choice D)--the most commonly prescribedoral hypoglycemic agent in adults as well as children--decreaseshepatic glucose output and increases peripheralinsulin sensitivity; it also can result in weight loss.

Our preferred choice of pharmacotherapy for thischild, therefore, would be metformin.

Follow-up.

The patient began taking 500 mg/d ofmetformin. She was instructed to monitor blood sugar levelsbefore each meal and before bed (2 hours after dinner).One month after the initial visit, she had lost 0.6 kgand reportedly had decreased her soda and juice intake to8 oz/d. However, many of her fasting and postprandialblood sugar levels remained outside the target range. HerHbA1c was now 8.1%. Accordingly, the metformin dosagewas increased to 500 mg bid; the girl's parents were instructedto increase the dosage by 500 mg weekly to amaximum of 1000 mg bid if most blood sugar levels werestill outside the target range.Three months later, the patient's weight had increasedby 1.2 kg and her HbA

_1c

had risen to 10%. Shenow reported polyuria and polydipsia. Her urine was positivefor glucose and ketones. She admitted that she hadnot taken the metformin for over 2 months because ofnausea and abdominal cramps from the drug. She hadalso stopped checking her blood sugar levels since shewas not taking the medication. Her parents were unawareof her noncompliance. (This scenario is fairly typical:many children do not comply with therapy and lie to theirparents about taking medications and measuring theirblood glucose levels.)

WHAT WOULD YOU DO NOW?

A.

Encourage the patient to take metformin asprescribed.

B.

Start a different oral hypoglycemic agent,such as a thiazolidinedione.

C.

Start insulin therapy and encourage thepatient to take metformin as prescribed.THE CONSULTANT'S CHOICE
Metformin is not uncommonly associated with GIdistress, including nausea; occasional vomiting; and loose,frequent bowel movements or diarrhea. Not surprisingly,this commonly leads to poor compliance. However, evenwhen patients do comply with their prescribed treatmentregimen, oral monotherapy becomes ineffective over timein the majority of those with type 2 diabetes. Studies inadults show that monotherapy may provide adequateglycemic control for 5 to 10 years.

⁶

The United KingdomProspective Diabetes Study (UKPDS) of intensive therapyin adults with type 2 diabetes showed that 44% of the patientstreated with a sulfonylurea at the beginning of thestudy required additional pharmacotherapy after 6 years.This translates to an annual failure rate of 7%.

⁷

Thus,choices

A

and

B

are not the best options.When pharmacotherapy with maximum doses of asingle agent is no longer effective, many clinicians trycombination oral therapy (eg, metformin with another oralagent; other combinations, such as a thiazolidinedioneplus a sulfonylurea; or even triple combinations). However,the more complicated the oral hypoglycemic regimenbecomes, the higher the rate of noncompliance.

⁸

Whenoral therapy is unsuccessful, either because of patient noncomplianceor failure of medications to normalize bloodglucose values, insulin can be added to the oral regimenor introduced as monotherapy.

Follow-up.

Because of this patient's deterioratingmetabolic control and noncompliance with her oral regimen,it was felt that she would benefit from the addition ofinsulin to her regimen (Choice

C

).The major reason to initiate insulin therapy is deteriorationof metabolic control despite optimal oral hypoglycemicregimens. Also, insulin therapy should be institutedif patients have drug intolerance or contraindications to 1or more oral agents, or if they do not comply with oralregimens. Occasionally, temporary insulin therapy maybe indicated--such as during acute intercurrent illness,surgery, or concomitant corticosteroid therapy.WRAP-UP
The epidemic of obesity among children in Americahas resulted in an epidemic of childhood-onset type 2 diabetes.The early development of obesity and insulin resistanceconfers a greater and considerable risk of early morbidityand mortality.Although there are medications to help control thecomorbidities of obesity and insulin resistance, diet andexercise remain at the forefront of both prevention andtreatment of these conditions. Every physician who caresfor children needs to emphasize the need for a healthydiet and regular exercise as part of anticipatory guidance;such guidance may help curtail this burgeoning epidemic.In addition, physicians need to be aware of which childrenare at increased risk for type 2 diabetes and to screenthem for a possible early diagnosis.We recommend screening all children who are overweight(BMI greater than 85% for age) and who fulfill any2 of the following criteria:

• Are African American, Mexican American, or NativeAmerican.
• Have acanthosis nigricans.
• Have a family history of type 2 diabetes.

These children should be screened with a fastingblood sugar every 2 years starting at age 10 years or atthe onset of puberty.

References:

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