Endocrine Journal 2004, 51 (3), 279–286

Lipoatrophic in an Elderly Woman: Clinical Course and Serum Adipocytokine Concentrations

PEDRO IGLESIAS, PILAR ALVAREZ FIDALGO*, ROSA CODOCEO* AND JUAN J. DÍEZ**

Department of Endocrinology, Hospital General, Segovia, Spain *Department of Biochemistry, Hospital La Paz, Madrid, Spain **Department of Endocrinology, Hospital Ramón y Cajal, Madrid, Spain

Abstract. Generalized is a rare disorder of adipose tissue, whose etiology remains unknown. Pathophysiology of this disorder is characterized by generalized loss of body fat associated with an infrequent form of diabetes mellitus (lipoatrophic diabetes). Main features of this form of diabetes mellitus are the severe resistance and the absence of ketoacidosis. Lipodystrophy can be congenital or acquired. In the acquired form, metabolic disturbances usually begin in the first years of life and the response to conventional treatment is very poor. Some alterations in serum adipocytokines have been described in this disease. We report the case of a 74-year-old woman with acquired generalized lipodystrophy who presented with low-normal serum concentrations of leptin, low adiponectin and resistin levels, and high serum levels of TNF. Patient was initially treated with fenofibrate, metformin and high doses of subcutaneous insulin achieving an adequate metabolic control. During this period, serum adipocytokines were periodically measured. We comment on the different etiopathogenic mechanisms and the therapeutic modalities of this rare syndrome.

Key words: Lipoatrophic diabetes, Leptin, Adiponectin, Resistin, TNF (Endocrine Journal 51: 279–286, 2004)

LIPOATROPHIC DIABETES (LD) is a well known, have been reported [6]. The age of onset of the disease although highly uncommon, form of diabetes mellitus occurs during the childhood, adolescence or early [1, 2]. LD refers to a group of extremely infrequent adult life and diabetes usually occurs after the onset of disorders of unknown etiology characterized by the as- the lipoatrophy [7]. The onset of the disease in the sociation of nonketotic diabetes mellitus with severe elderly is an exceptional event. It is generally refrac- and loss of adipose tissue (lipo- tory to conservative treatment although it has been re- dystrophy) [2–4]. This lipodystrophy may be either cently reported that leptin-replacement therapy may be partial or generalized. Generalized lipodystrophy (GL) effective. To date only 36 patients with AGL have may be congenital (CGL) or acquired (AGL). The been reported [8]. congenital form, also called Berardinelli-Seip syndrome, Adipose tissue is currently considered as an hor- is an autosomal recessive condition in which total lack monally active system which produces several adipo- of both subcutaneous and visceral fat commonly be- cytokines such as leptin, tumor necrosis factor- gins at birth [2, 3]. The acquired form, initially report- (TNF), interleukin, adiponectin, and resistin. All of ed by Ziegler in 1928 [5] and, subsequently, described them are involved in the control of metabolism. Lep- in detail by Lawrence in 1946 (Lawrence syndrome) tin is considered to be a fundamental signal of satiety [4], is usually sporadic although some familial cases to the brain [9]. Overproduction of TNF by adipose tissue is involved in insulin resistance in obesity [10]. Received: October 7, 2003 Adiponectin is a recently discovered adipocytokine Accepted: January 15, 2004 with antiatherogenic [11] and anti-inflammatory [12] Correspondence to: Pedro IGLESIAS, M.D., Department of Endo- properties. Finally, resistin has been identified as a crinology, Hospital General, Ctra Avila s/n, 40002-Segovia, Spain novel adipose-specific cysteine-rich protein with ca- 280 IGLESIAS et al. pacity to impair insulin sensitivity and glucose toler- ischemic cerebrovascular accident (CVA) of the right ance [13]. Severe lipodystrophy caused by deficiency cerebral media artery with a slight residual left hemi- or destruction of adipose cells is characterized by low paresis as sequela. Six months before CVA a diag- leptin and adiponectin levels [14–16]. The effect of nosis of mellitus was established and the absence of adipose tissue in AGL on serum con- oral hypoglycemic agent therapy was started. After 5 centrations of other adipocytokines, such as TNF months, therapy with oral agents was substituted by and resistin, is not completely known. subcutaneously administered insulin therapy because We report the case of a 74-year-old woman with an of poor metabolic control. She had ingested alcohol AGL who developed lipoatrophy and diabetes mellitus in excess for 10 years, but she completely stopped during old age. We measured serum concentrations of drinking about 8 years before. The patient was known adipocytokines at diagnosis and during one year of to have colonic diverticulosis, nontoxic multinodular combined therapy with metformin and high doses of goiter, depressive syndrome, mixed hyperlipemia, insulin. Clinical course, therapeutic aspects and patho- lithiasis of the left kidney, and reiterative urinary tract genic implications of these adipocytokines of this rare infections. There was no history of hypertension. Her entity are reviewed. father had suffered from arterial hypertension and died of CVA. The rest of the family history was unremark- able. The patient’s medications comprised lispro in- Case Report sulin analog (196 U/day), alprazolam (2 mg daily), and acetylsalicylic acid (300 mg daily). A 74-year-old woman was admitted to the hospital The patient presented with asthenia and progressive because of poor metabolic control of her diabetes. The weight loss, more pronounced in the last three years, patient was in good general state of health until ap- associated with adequate food ingestion and appetite proximately two years earlier, when she developed an (Fig. 1). These symptoms were accompanied by a

Fig. 1. Photographs taken over 30 years of the patient. Note the progressive change in facial appearance due to the marked loss of facial subcutaneous adipose tissue fundamentally in the last 3 years. LIPOATROPHIC DIABETES IN AN ELDERLY WOMAN 281 continuing worsening of her metabolic control (HbA1c 6.4 g/dl (6.4–8.3), calcium 9.0 mg/dl (8.5–10.4) and values of 9–10.5%), in spite of high doses of subcuta- circulating free fatty acids 0.9 mmol/l (0.1–0.6). He- neous insulin (196 U/day of lispro insulin; 4.4 U/kg/ matocrit was 37.1%, white-cell count 5.35 × 109/l, day). There was also a persistent elevation of liver platelet count 150 × 109/l, and erythrocyte sedimenta- enzymes, as well as severe proteinuria (4.1 g/day). tion rate 13 mm/hour. Urine gave 2+ test for gluco- Her temperature was 36ºC, pulse 76 bpm, weight suria and ketonuria was negative; the sediment 45.5 kg, body mass index 18.5 kg/m2, triceps skinfold contained 10–15 white cells, 3–6 red cells per high- 5.8 mm, and muscle arm circumference 19.2 cm. The power field. Plasma sodium was 134 mmol/l (135– patient was cachectic with a firm skin and a general- 145) and potassium was 4.2 mmol/l (3.5–5.0). Pro- ized loss of subcutaneous body fat. Head and neck thrombin activity was 80% and partial thromboplastin were normal except for a minimal multinodular goiter time 42.6 seconds. Glycosylated hemoglobin (HbA1c) and a residual left central facial paralysis. Lungs were was 8.8%. Creatinine clearance was 50 ml/min and clear and the heart was normal. Breasts were normal. the 24 hour quantified proteinuria was 5.2 g. Serum Abdomen was soft with normal bowel sounds; the liv- immunoglobulins (IgG 1090 mg/dl [694–1618], IgA er edge descended 3 cm below the right costal margin, 356 mg/dl [68–378], and IgM 154 mg/dl [60–263]) with a vertical span of 9 cm; the spleen was not pal- were normal, and the complement components C3 and pated. No abdominal or pelvic masses were found. C4 were 113 mg/dl (88–201) and 14 mg/dl (16–47), No ascitic fluid was present. The lower extremities respectively. Serologic testing was negative for anti- showed signs of muscular hypertrophy exhibiting mitochondrial antibodies, antinuclear antibodies (ANA), prominent superficial veins and muscles (Fig. 2). On insulin autoantibodies, IgA antigliadin antibodies, IgA neurologic examination there was a residual left hemi- antitransglutaminase antibodies, anti-topoisomerase I paresis. (anti-Scl-70) antibodies, anti-LKM autoantibodies, Biochemical examinations showed glucose 359 mg/ rheumatic factor, and cryoglobulins. Tumor markers dl (75–110), creatinine 0.9 mg/dl (0.5–1.0), cholesterol (carcinoembryonic antigen; CEA), alpha-fetoprotein, 229 mg/dl (50–200), triglycerides 1449 mg/dl (50– chromogranin A, neuron specific enolasa (NSE), CA 200), uric acid 2.6 mg/dl (2.4–5.7), aspartate amino- 19.9, and CA 125) were also negative. Infectious transferase (ASAT) 75 U/l (<32), alanine amino- serology (tests for human immunodeficiency virus transferase (ALAT) 128 U/l (<31), gamma-glutamyl (HIV), hepatitis B and C antibodies) was negative. transpeptidase (GGTP) 164 U/l (5–36), lactic dehydro- Serum hormonal study showed C peptide 8.3 ng/ml genase (LDH) 323 U/l (240–480), alkaline phos- (0.7–4.0), insulin 145.3 U/ml (5–25), glucagon phatase 178 U/l (91–240), total bilirubin 0.1 mg/dl 150 pg/ml (59–177), thyrotropin (TSH) 2.1 U/ml (0.3–1.1), albumin 3.4 g/dl (3.5–5.0), total protein (0.4–5.0), insulin-like growth factor type 1 (IGF 1) 120 ng/ml (61–102), dehydroepindrosterone sulfate (DHEA-S) <0.1 g/ml (0.1–3.3), and androstenedione 0.7 ng/ml (0.2–3.1). Baseline serum concentrations of leptin, adiponectin, and resistin were 2.6 ng/ml (1.0–7.8), 1.8 g/ml (8–62), and 3 ng/ml (5.3–11.4), respectively. On the contrary, serum concentrations of TNF were markedly elevated [38.1 pg/ml (<20)] (Table 1). X-ray film of the chest was normal. Electrocardio- gram showed a normal rhythm at a rate of 70 bpm, with left electric axis and negative T-waves in V2-V6. Echocardiogram revealed a moderate concentric hyper- trophy of the left ventricle, with reduction of the dias- tolic function. Ultrasonographic examination of the Fig. 2. Detail of the lower extremities of the patient. Note the abdomen was normal without signs of portal hyper- loss of subcutaneous adipose tissue and the muscular tension. Ultrasonographic examination of pelvis showed hypertrophy. an atrophic genital apparatus. CT scan of the abdomen 282 IGLESIAS et al.

Table 1. Evolution of the clinical and analytical data of the patient

Basal 2 months 4 months 12 months Clinical data Weight (kg) 44.2 48 48.5 48 Body mass index (kg/m2) 18.5 20.2 20.4 20.2 Biochemical data Glucose (mg/dl) 359 190 132 206 Cholesterol (mg/dl) 229 168 200 166 Triglycerides (mg/dl) 1449 374 273 228 HbA1c (%) 8.8 6.9 6.5 5.8 Hormonal data Fig. 3. Plasma glucose level 24 hour profiles during the Leptin (ng/ml) 2.6 1.2 3.6 1.7 intravenous infusion of 4 different doses of regular TNF (pg/ml) 38.1 47.0 41.5 49.0 insulin. Note the severe insulin resistance of the patient. Resistin (ng/ml) 3 3.8 6.5 2.8

Adiponectin ( g/ml) 1.8 2.3 0.2 1.5 tention to improve insulin sensitivity. Lipid-lowering Therapy therapy with fenofibrate (200 mg/day) was temporari- Diet (kcal/day) 2000 2000 2000 2000 ly used to control hyperlipemia, and consequently in- Insulin U-500 (U/day) 500 300 305 250 creasing the sensitivity to exogenous insulin. This Metformin (mg/day) 1700 1700 1700 1700 drug was employed only for a month due to the fact Fenofibrate (mg/day) 200 – – – the patient suffered hepatic cirrhosis. With this thera- peutic regime preprandial blood glucose levels were revealed lithiasis of the left kidney. Gastroscopy adequately controlled (100–160 mg/dl), by means of a showed a small hiatus hernia with some small antral significant lower dose of insulin (285 U/day). In these ulcers, whereas pylorus, duodenal bulb, and second conditions a partial recovery of weight (47.3 kg) was portion of the duodenum were normal. A test for evident after a month of hospitalization. H. pylori in- Helicobacter pylori was positive. Colonoscopy fection was treated with amoxicillin and omeprazole, revealed colon diverticula. Contrast examination of and enalapril (5 mg/day) was initiated in order to im- the small intestine was also normal. Funduscopy study prove proteinuria. During the following 12 months of the eye did not show signs of . after discharge, the patient maintained a good meta- Biopsy specimen of the gastric mucosa showed bolic control of her diabetes with values of HbA1c chronic active gastritis, whereas biopsy of the small ranging between 5.8–6.9% and her body weight was intestine was normal. Liver biopsy revealed a histo- stabilized at 48 kg. There were no significant changes in logic image of cirrhosis with signs of steatohepatitis. serum leptin, adiponectin and resistin concentrations, Fat excretion in the feces was 15 g (normal <6 g/day). and TNF levels remained elevated (Table 1). During her hospitalization, the patient was initially treated with a 2500 kcal diet with dietary supplementa- tion with -3 fatty acid-rich fish oil, and intravenous Discussion regular insulin therapy with the objective of improving her nutritional status and glycemic control. However, The patient here reported shows the association of in spite of employing high doses of intravenous insulin a recent onset generalized lack of body fat with non- (>100 U/day), her blood glucose levels were not ketotic diabetes mellitus with severe insulin resistance controlled and her corporal body weight continued (hyperinsulinism, increase in serum C peptide levels, decreasing until 44.2 kg (Fig. 3). For these reasons, and high resistance to exogenous insulin administra- the patient was started on a low fat 2000 kcal diet with tion), hyperlipidemia (hypertriglyceridemia with high dietary supplementation of medium-chain triglyceride serum levels of fatty acids), hepatomegaly (cirrhosis (MCT) oil, and subcutaneous U-500 regular insulin with signs of steatohepatitis with immunologic study (Actrapid, human U-500; 500 U/day). At this moment, and infectious serology negative), nephrotic proteinuria, metformin was prescribed (850 mg/b.i.d.) with the in- muscle hypertrophy and hypertrophy of left ventricle LIPOATROPHIC DIABETES IN AN ELDERLY WOMAN 283 without hypertension. All these findings were compat- to consider the present case as a form of type 3, idio- ible with the clinical diagnosis of AGL (Lawrence pathic AGL with LD. syndrome). AGL is an extremely infrequent syndrome Serum leptin concentrations reflect the amount of with less than 40 cases reported to date [4, 6, 7, 8, 15, body fat being reduced in patients with AGL [15]. Our 17–20]. The present case represents an unexpected patient showed low-normal leptin levels indicating a and exceptional form of clinical presentation of this reduction of body fat content. Adiponectin levels are syndrome due to the age of onset of both lipoatrophy decreased in some insulin-resistant states, such as obe- and diabetes. sity, type 2 diabetes, and in patients with lipodystro- Different viral infections, thryoid dysfunction, and phies [15, 16, 26]. The present case also showed low pregnancy have been implicated in the etiology of adiponectin levels with no changes after metformin AGL [7, 23]. In our patient there were no clear precip- therapy. This hypoadiponectinemia might be related itating factors. The possible etiopathogenic role of to extremely reduced body fat content and the associa- excessive amount of alcohol ingested during 10 years tion with severe insulin resistance reported in AGL. and/or reiterative bacterial infections is unclear. Al- Resistin is a recently identified cytokine whose func- though H. pylori infection is associated with an tions have been related to insulin resistance [27]. It increased production of cytokines such as TNF, has been hypothesized that resistin might represent an interleukin-1, -6, and -8 that can alter the glycemic adipocyte derived substance which would act as a control in diabetic patients, TNF levels were elevated mediator between obesity and insulin resistance [13]. from the diagnosis and they did not modify with The patient reported here showed low serum concen- appropriate therapy and after that 13C-urea breath trations of resistin at diagnosis indicating that the insu- test became negative. Several inflammatory and/or lin resistance associated to LD is not mediated by this autoimmune mechanisms in the pathogenesis of loss of adipocytokine. Finally, it has been suggested that adipose tissue have been proposed [20, 24]. Some TNF could be in relation to metabolic disturbances patients show the presence of panniculitis, although and weight loss described in generalized lipodystrophy this finding has not been uniformly found [7, 14, 25]. [16, 23]. TNF induces weight loss in experimental Other patients have other associated autoimmune dis- animals by several mechanisms including suppression orders [7]. Hubler et al. [20] reported the presence of of food intake, suppression of lipoprotein lipase, and autoantibodies against adipocyte membranes in one catabolic effects on energy storage tissues [28]. More- patient. Recently, it has been proposed a new classifi- over, TNF produces insulin resistance probably acting cation of AGL according to possible etiopathogenic through insulin receptor diminishing insulin signaling mechanisms [8]. Three types of AGL have been dis- into the cell [29]. TNF appears to play a general role tinguished: type 1, AGL with panniculitis; type 2, in reducing adipose tissue mass promoting apoptosis AGL with accompanying autoimmune disease; and of both preadipocytes and mature adipocytes [30]. type 3, idiopathic AGL. Our patient did not have any Lastly, patients with HIV-associated lipodystrophy clinical evidence of panniculitis or autoimmune dis- show high levels of TNF which are negatively corre- ease. There were no other associated autoimmune lated with plasma adiponectin suggesting an inhibitory clinical diseases, all the serological and immunlogical effect of TNF on adiponectin levels [16]. Our patient investigations were negative. Although we did not de- also showed high serum TNF levels, approximately 2 termine insulin receptor antibodies and autoantibodies times over the normal range. The extremely elevated against adipocyte membranes, the absence of other concentrations of TNF suggest that this cytokine serum autoantibodies makes the possibility of an im- might have played a role not only in the loss of body mune etiology very improbable. Moreover, endocri- weight, but also in the reduced concentrations of nological investigations, including thyroid function adiponectin and insulin resistance found in this patient. tests, were normal, except for the serum concentrations Several therapeutic modalities have been investi- of insulin and C peptide, which were elevated, thus gated in the management of AGL showing different indicating a severe insulin resistance. The negative clinical results. The optimal diet for AGL is unknown. result of the serum tumor markers, as well as the nor- In order to improve glycemic control and/or hypertri- mal morphologic study, excluded the possibility of a glyceridemia several diet modifications have been paraneoplastic syndrome. These observations led us suggested. Among them are dietary fat restriction [7], 284 IGLESIAS et al. dietary supplementation with -3 fatty acid-rich fish patient the use of lispro insulin analog did not show oil [30, 31] or substitution of long-chain fatty acids therapeutical advantages with respect to regular insu- with medium chain triglyceride (MCT) oil [32], and lin. With the aim of improving lipid profile we initial- calorie restriction [33]. In our patient, initial dietary ly used fenofibrate for a limited period of time due to supplementation with -3 fatty acid-rich fish oil asso- the presence of histologically demonstrated hepatic ciated with a moderate high calorie diet was not cirrhosis. At the same time, metformin, an anti-hyper- effective in improving body weight; however, an iso- glycemic and insulin-sensitizing agent, was initiated to caloric, low-fat (2000 kcal/day, fat percentage 35%, reduce blood glucose levels by means of improving ~78 g) with medium-chain triglyceride (MCT) oil insulin-mediated suppression of hepatic glucose pro- enriched diet was beneficial to increase body weight duction and enhancing insulin-stimulated glucose and to improve glycemic and lipid profiles. The die- disposal in skeletal muscle. This combined therapy tetic supplementation with MCT oil was made with the (metformin and fenofibrate) associated with high doses aim of reducing the fat excretion in the feces for of insulin was accompanied by a biochemical and clin- improving her nutritional status. ical improvement that was evident at the first month Severe insulin resistance has been managed with of therapy. After observing that both glycemic and very high doses of insulin and drugs that improve lipid profile continued improving only with dietetic insulin sensitivity, especially metformin [7] and tro- measures combined with metformin and insulin therapy, glitazone [21]. The therapeutic role of the new thiazo- and that this treatment was associated with a progres- lidinediones, rosiglitazone and pioglitazone, in AGL is sive reduction in insulin needs, it was decided to avoid not known. It was recently reported that there are the use of fenofibrate again. Since that moment, a partial beneficial therapeutical effects of lispro insulin progressive reduction in serum triglyceride levels was analog in this disease. The addition of subcutaneous observed (Table 1). This fact could explain, at least preprandial administration of lispro insulin analog to in part, the decrease of the exogenous insulin needs metformin and intraperitoneal insulin therapy reduced and the improvement of glycemic control, as shown by peritoneal insulin requirements and improved glycemic the progressive reduction of HbA1c levels during one control [18]. Control of hypertriglyceridemia with year of follow-up. It is possible that after the initial lipid-lowering therapy with bezafibrate may improve control of hypertriglyceridemia induced by fenofibrate glucose tolerance in these patients [19]. More recently and, thereafter, the improvement of insulin resistance, the beneficial metabolic effects with the use of recom- the long term effect of metformin would contribute to binant human leptin (rh-leptin) have been reported in improve the insulin sensitivity and the metabolic con- these patients [35–37]. The administration of subcuta- trol of the patient. In summary, this case suggests that neous rh-leptin twice a day for four months improved low adiponectin and high TNF serum levels might glycemic control and decreased triglyceride levels and act in the pathogenesis of the insulin resistance of liver volume with an adequate tolerance [35, 37]. the LD in AGL. Moreover, combined therapy with Moreover, insulin resistance was completely reversed fenofibrate, metformin, and high doses of regular insu- in lipoatrophic mice by the combined therapy of phys- lin may be a useful therapeutic tool in some cases of iological doses of leptin and adiponectin [38]. In our this disorder.

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