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Nonobese, Nonketotic Childhood Onset Diabetes: Look for Lipodystrophies Partha P

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Nonobese, Nonketotic Childhood Onset Diabetes: Look for Lipodystrophies Partha P CASE STUDIES Nonobese, Nonketotic Childhood Onset Diabetes: Look for Lipodystrophies Partha P. Chakraborty,1 Sayantan Ray,2 Subhodip Pramanik,2 Rana Bhattacharjee,2 Sujoy Ghosh,2 and Subhankar Chowdhury2 iabetes in children and youth agnosed as having type 2 diabetes (3). poses a unique diagnostic We describe here two patients with Dand therapeutic challenge. childhood-onset diabetes secondary Although type 1 and type 2 diabetes to congenital lipodystrophies and are undoubtedly the most frequently discuss their clinical and diagnostic encountered forms of diabetes, oth- features. er forms are not uncommon in this Case Presentations age-group. Many young patients with a so-called “specific types of diabetes Case 1 due to other causes” may be misdi- A 6-year-old girl born of a consan- agnosed as having type 1 or type 2 guineous union had been detected diabetes because of a lack of awareness to have diabetes while undergoing of the various diagnostic possibilities evaluation for failure to gain weight. (1). The group of patients with other She was placed on insulin by her pri- forms of diabetes constitutes <5% of mary care physician and referred to all patients diagnosed with diabetes us for unsatisfactory glycemic control before the age of 25 years and in- despite receiving a high dosage of in- cludes a variety of conditions (2). sulin (3.7 units/kg; total daily dose: Lipodystrophy, a group of disor- 52 units). She did not notice osmot- ders characterized by loss or abnormal ic symptoms and had no history of distribution of body fat, is associated hospitalization. Her birth weight was with insulin resistance and resul- 2.1 kg, and she had been unusually tant abnormal glucose homeostasis. thin since birth. Her family history Depending on the extent of the loss was negative for diabetes. of adipose tissue, these rare disorders Clinical examination revealed a are divided into three subgroups: thin-built girl (weight 14.2 kg, height generalized, partial, and localized. 1.03 m, BMI 13.3 kg/m2) with gen- Barring the localized form, the other eralized loss of subcutaneous adipose 1Department of Medicine, Midnapore variants are associated with pro- tissue (Figures 1 and 2). She had hep- Medical College & Hospital, Midnapore, West Bengal, India found metabolic dysfunction. These atomegaly, a small umbilical hernia, disorders can be inherited or can be and prominent muscles and subcuta- 2Department of Endocrinology & Metabolism, IPGME&R/SSKM Hospital, acquired secondary to a number of neous veins, without acanthosis. Her Kolkata, West Bengal, India infectious or immunological diseases breasts were of Tanner stage 1, and Corresponding author: Partha P. and can potentially be associated with she had no clitoromegaly. Results of Chakraborty, [email protected] diabetes. laboratory tests are summarized in https://doi.org/10.2337/cd16-0055 Patients with lipodystrophies are Table 1. Ultrasound of the abdomen often misdiagnosed as having type 2 revealed hepatomegaly with fatty liver ©2017 by the American Diabetes Association. Readers may use this article as long as the work diabetes and occasionally as having and a normal pancreas. MRI scan- is properly cited, the use is educational and not type 1 diabetes. The prevalence of ning showed a loss of subcutaneous for profit, and the work is not altered. See http:// creativecommons.org/licenses/by-nc-nd/3.0 partial lipodystrophy was found to fat from the whole body and bone for details. be 0.79% in patients initially misdi- marrow. A whole-body, dual-energy CLINICAL DIABETES 1 Clinical Diabetes Online Ahead of Print, published online August 30, 2017 CASE STUDIES ■ FIGURE 3. Acanthosis nigricans over nape of the neck (Case 2). diabetes while undergoing evaluation for transaminitis. She had been suffer- ing from right upper-abdominal pain and was found to have hepatomega- ly and deranged liver function tests. There was no history of increased thirst, polyuria, weight loss, or hospi- talization. She had no family history of consanguinity or diabetes in first- or second-degree relatives. Clinical examination revealed an average-built child with prominent acanthosis (Figure 3). She had loss of subcutaneous fat from the arms, legs, and buttocks with prominent veins, but the subcutaneous fat over her face was preserved (Figures 4 and 5). Results of her laboratory tests are summarized in Table 1. Ultrasound of the abdomen revealed hepatomegaly with fatty liver and a normal pancreas. The girl was put on metformin only with satisfactory gly- cemic control. Questions 1. What is lipodystrophy? 2. What are the types of lipodys- trophy? ■ FIGURE 1. Generalized loss of sub- ■ FIGURE 2. Generalized loss of subcu- 3. What are the clinical and cutaneous fat with umbilical hernia taneous fat with prominent musculature biochemical features of (Case 1). and prominent veins (Case 1). lipodystrophy? 4. What is the management of X-ray absorptiometry (DXA) scan ments remained high (4.5 units/kg; lipodystrophy? measured total body fat of 3%. total daily dose: 64 units), but her Commentary blood glucose levels were reasonably The patient was treated with three Adipose tissue is not only a simple controlled after 1 month of therapy. daily injections of short-acting pran- storage depot of lipids that provides dial insulin (human regular insulin) Case 2 energy during prolonged fasting, but and one daily injection of insulin A 5-year-old girl was referred from also plays multiple roles in energy glargine, along with 1.5 g/day of the Department of Hepatology for metabolism. Obesity, a condition of metformin. Her daily insulin require- management of incidentally detected generalized increase in adipose tis- 2 CLINICAL.DIABETESJOURNALS.ORG Clinical Diabetes Online Ahead of Print, published online August 30, 2017 CHAKRABORTY ET AL . TABLE 1. Laboratory Data at Presentation sue mass, is associated with multiple metabolic complications such as di- Case 1 Case 2 abetes, dyslipidemia, hyperuricemia, Fasting plasma glucose (mg/dL) 186 156 and higher cardiovascular morbidity and mortality. Interestingly, the ab- Postmeal plasma glucose (mg/dL) 298 272 sence or inappropriate reduction of adipose tissue is associated with more A1C (%) 9.4 8.1 severe metabolic complications and Fasting insulin (µIU/mL) — 62 early-onset complications (4). Lipodystrophy predisposes pa- Triglycerides (mg/dL) 258 368 tients to insulin resistance and its associated complications such HDL cholesterol (mg/dL) 32 28 as acanthosis nigricans, diabetes, Uric acid (mg/dL) 7. 2 — hypertriglyceridemia, hepatic ste- atosis, and polycystic ovaries. The Alanine transaminase (U/L) — 259 severity of metabolic and other com- plications depends on the extent of Aspartate transaminase (U/L) — 168 fat loss (5). Metabolic abnormalities observed in this group of patients Anti-GAD65 antibody Negative Negative are also encountered in patients with Anti-IA2 antibody Negative Negative metabolic syndrome and type 2 dia- betes. In fact, type 2 diabetes and Anti-insulin antibody Negative Negative the lipodystrophies share a common pathophysiology—a state of defective Postmeal C-peptide (ng/mL) 6.7 8.2 triglyceride storage in adipose tissue IA2, islet antigen 2; GAD, glutamic acid decarboxylase. along with ectopic accumulation of lipid in muscles and liver, resulting in insulin resistance and other com- ponents of the metabolic syndrome. Among the inherited forms of lipodystrophies, the most common variants are congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPL). CGL, or Berardinelli-Seip syndrome, is an autosomal recessive disease in which mutation occurs in one of the four genes encoding AGPAT2, seipin, caveolin-1, or PTRF. All of these genes are involved in the proper function of adipose tissue such as adipocyte maturation, lipid storage, formation and maintenance of lipid droplets, membrane composition, DNA repair efficiency, and insulin signaling (6,7). Seipin mutation is associated with a complete absence of metabolic, bone marrow, and mechanical fat, whereas the other mutations spare the mechanical fat of the orbits, palms, soles, perineum, and periarticular ■ FIGURE 4. Loss of subcutaneous fat ■ FIGURE 5. Preserved subcutaneous regions. Complete absence of subcu- from arm with prominent veins (Case 2). fat over face (Case 2). taneous fat gives rise to an emaciated appearance of face and a muscular CLINICAL DIABETES 3 Clinical Diabetes Online Ahead of Print, published online August 30, 2017 CASE STUDIES appearance of the body. Our patient improvement in deranged metabolic Clinical Pearls in Case 1 presented with a loss of sub- parameters. Proper education, which • Lipodystrophy, a genetically het- cutaneous fat from the entire body, should include both patients and erogeneous group of disorders including her palms and soles, and their families, is of utmost impor- characterized by loss or abnormal probably had a seipin mutation. tance to allay associated stress and distribution of adipose tissue and In the Dunnigan variety of FPL, psychological sequelae. Therapeutic resultant metabolic dysfunction, is lipoatrophy typically involves the lifestyle modification that includes a not uncommon in diabetes clinics. limbs and the trunk, often accom- low-fat diet and regular aerobic phys- • Patients with a working diagnosis panied by increased fat deposition ical exercise is crucial. There are no of type 1 diabetes who do not have in the neck and face, giving rise to guidelines for drug therapy because a suggestive or documented history a Cushingoid
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