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Partial lipodystrophy of the limbs in a diabetes clinic setting
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Contents lists available at ScienceDirect
Primary Care Diabetes journal homepage: http://www.elsevier.com/locate/pcd
Original research
Partial lipodystrophy of the limbs in a diabetes clinic setting Tevfik Demir a,1, Baris Akinci a,∗,1, Leyla Demir b, Canan Altay c, Tahir Atik d, Umit Cavdar a , Mustafa Secil c , Abdurrahman Comlekci a a
Dokuz Eylul University, Division of Endocrinology, Izmir, Turkey Ataturk Training Hospital, Department of Biochemistry, Izmir, Turkey c Dokuz Eylul University, Department of Radiology, Izmir, Turkey d Ege University, Department of Pediatric Genetics, Izmir, Turkey b
a r t i c l e
i n f o
a b s t r a c t
Article history:
Objective: Partial lipodystrophy of the limbs (PLL) is a newly described form of lipodystrophy
Received 14 September 2015
that is characterized by symmetrical distal lipoatrophy of the limbs and insulin resistant
Received in revised form
diabetes.
23 November 2015
Research design and methods: In this study, we prospectively screened our patients with type
Accepted 12 December 2015
2 diabetes for the presence of PLL phenotype. Metabolic parameters of PLL patients were
Available online xxx
compared to those with type 2 diabetes who applied to our diabetes clinic during the same period of time.
Keywords:
Results: Between Sep 2013 and Mar 2015, 2020 patients with type 2 diabetes were evaluated for
Diabetes clinic
the presence of PLL. PLL was confirmed in 16 patients. The prevalence of PLL was calculated
Insulin resistance
as 0.79% in our diabetes clinic. The most common phenotypic presentations were loss of
Lipodystrophy
subcutaneous fat in the forearms, calves and thighs, and loss of fat in forearms and calves.
Lipids
Patients with PLL had poor metabolic control and marked insulin resistance compared to
Type 2 diabetes
subjects with type 2 diabetes. Diabetes had been diagnosed at a younger age in patients with PLL. Patients with PLL also had more atherogenic lipid profiles. Conclusions: Our data suggests that PLL is a relatively common form of lipodystrophy in diabetes clinics, which is associated with poor metabolic control and marked insulin resistance. The recognition of PLL in patients with type 2 diabetes can help better clinical management by alerting the physician to these associated co-morbidities. © 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Lipodystrophies are a heterogeneous group of disorders characterized by impaired adipose tissue distribution and
∗
1
metabolism [1]. Fat is near-totally absent in patients with generalized lipodystrophies, whilst the lack of fat is selective in patients partial lipodystrophies. Several genes have been identified for congenital generalized lipodystrophy (CGL) [2–6] and familial partial lipodystrophy (FPL) [7–10]. On the other hand,
Corresponding author. Tel.: +90 232 4123747; fax: +90 232 2792267. E-mail address: [email protected] (B. Akinci). These two authors contributed equally to this work.
http://dx.doi.org/10.1016/j.pcd.2015.12.006 1751-9918/© 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: T. Demir, et al., Partial lipodystrophy of the limbs in a diabetes clinic setting, Prim. Care Diab. (2015), http://dx.doi.org/10.1016/j.pcd.2015.12.006
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fat loss has no genetic basis in acquired generalized lipodystrophy (AGL) and acquired partial lipodystrophy (APL) [1]. Lipodystrophies are commonly associated with metabolic abnormalities. Poorly controlled diabetes, severe hypertriglyceridemia and hepatic steatosis may be observed in patients with lipodystrophy as a result of marked insulin resistance which is believed to be secondary to fat tissue dysfunction [11]. Recently, Strickland et al. [12] has described a novel form of lipodystrophy, partial lipodystrophy of the limbs (PLL), which is characterized by symmetrical distal lipodystrophy of the limbs and insulin resistant diabetes. Using hyperinsulinemic clamp studies, they showed that insulin resistance was more prominent in patients with PLL compared to patients with type 2 diabetes. When compared to other non-HIV related forms of lipodystrophy, which have very rarely been reported in the literature, the authors proposed that this novel lipodystrophy subtype would affect larger number of patients in the real life. To determine the prevalence of PLL in a diabetes clinic, we prospectively screened our patients with type 2 diabetes for the presence of PLL phenotype. Whole body MRI was used to confirm the diagnosis. Metabolic parameters of PLL patients were compared to those with type diabetes who applied to our clinic during the same period of time.
2.
Patients and methods
A total of 2020 patients with type 2 diabetes, who were admitted to our diabetes clinic between Sep 2013 and Mar 2015, were screened for PLL. The study was approved by the Dokuz Eylul University Ethics Review Panel. PLL was clinically diagnosed based on characteristic fat loss pattern and supporting clinical findings associated with insulin resistance. Patients were considered as PLL if (I) lipodystrophy primarily involved the distal extremities (forearms or forearms plus calves), (II) the lipodystrophy pattern was symmetrical, and (III) the signs of insulin resistance were evident such as acanthosis nigricans, polycystic ovaries, insulin resistant diabetes, hypertriglyceridemia and hepatic steatosis. Fat distribution was assessed by whole body magnetic resonance imaging (WB MRI). The WB MRI was performed by using a 1.5-T MR device (Gyroscan Intera, release 8.1; Philips Medical Systems, Best, the Netherlands) with a 6 multichannel body coil. MR images of all patients were interpreted by 2 radiologists (M.S. and C.A.) with consensus. After the MRI study, patients were excluded if (I) increased visceral or subcutaneous fat was observed, but no lipoatrophy can be visualized in the distal extremities, (II) the lipodystrophy pattern was not symmetrical, (III) there was some lipoatrophy on the extremities, but no distal involvement was observed, and (IV) there was gluteal or anterior thorax involvement. Mutation analysis of the genes LMNA, LMNB2, PPARG, CAV1, PLIN1, AKT2, and CIDEC were carried out by direct automated DNA sequencing from the patients’ genomic DNA based on the clinical features. PCR primers used in order to amplify the regions of interests could be sent upon request.
Sequencing was performed with Miseq V2 chemistry on MiSeq instrument (Illumina California, USA). Analysis was performed with IGV software. All patients underwent detailed physical examination, full biochemistry and urinalysis for protein content. In patients with PLL, fasting insulin, C-peptide, leptin and adiponectin levels were measured. Hepatic steatosis was evaluated by high resolution ultrasound (US), conventional MRI and MR spectroscopy (MRS). The US was obtained with convex transducers (frequency bandwidth 3–6 MHz). Conventional MRI and MRS were performed by using a 1.5-T MR device (Gyroscan Intera, release 8.1; Philips Medical Systems, Best, the Netherlands) with a phased-array coil. Glucose, HbA1c, triglyceride and cholesterol levels were measured by standardized methods with appropriate quality control and quality assurance procedures. Insulin levels were measured by a chemiluminescent method. Homeostasis model assessment (HOMA-IR) score was calculated as fasting serum insulin (IU/mL) × fasting plasma glucose (mg/dL)/405. Fasting C-peptide levels were measured by a chemiluminescent immunoassay. Leptin and adiponectin levels were measured with enzyme-linked immunosorbant assay (ELISA) according to the manufacturer’s instructions (Boster, Pleasanton, CA, USA; Leptin: EK0439, sensitivity: <8 pg/mL; Adiponectin: EK0595, sensitivity: <60 pg/mL). Statistical analysis was performed using Statistical Package of Social Science (SPSS Inc, Chicago, IL, USA), version 15.0 for Windows. Data was expressed as median (25–75 percentiles). Mann Whitey-U test was used for comparison of scale parameters. Categorical variables were compared by the chi-square test. A p-value less than 0.05 was accepted as statistically significant.
3.
Results
Of 2020 patients with type 2 diabetes, 22 patients were candidates for PLL after physical examination. PLL was confirmed in 16 patients when WB MRI procedures were completed. Other 6 patients were considered as false positive cases. The prevalence of PLL was calculated as 0.79% in our diabetes clinic. Table 1 shows clinical characteristics of 16 patients with PLL. The median age was 51 (25–75 percentiles: 48–59). The age range was 41–66 years. 14 patients (87.5%) were women. Patients reported a median age of starting fat loss of 39 years (25–75 percentiles: 31–46). The BMI ranged from 25 kg/m2 to 45.1 kg/m2 . The lipodystrophy pattern was symmetrical in all patients and only the limbs were affected. Loss of subcutaneous fat in the forearms, calves and thighs (6 patients, Fig. 1) and forearms and calves (5 patients) were the most common presentations, with lipodystrophy involving calves in three patients and calves and thighs in two patients. Intraabdominal fat was increased. Fat accumulation was noticed in the scapular/neck area. None of the PLL patients had any mutation on genes which has been shown to cause partial lipodystrophy. The laboratory data of patients with PLL is presented in Table 2. Fourteen patients (87.5%) had poorly controlled diabetes (HbA1c > 7%). Nine patients (56.2%) were on insulin. The average insulin dose was 113 units/day. Eleven patients (68.7%) had hypertriglyceridemia, and 11 (68.7%) patients had
Please cite this article in press as: T. Demir, et al., Partial lipodystrophy of the limbs in a diabetes clinic setting, Prim. Care Diab. (2015), http://dx.doi.org/10.1016/j.pcd.2015.12.006
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Table 1 – The clinical characteristics of patients with PLL. Patient 1
Patient 2
Patient 3
Current age Gender The age when fat loss was first noticed (years) Lipodystrophy pattern
54 F 45
52 F 22
49 F 30
46 F 45
52 F 50
66 F 35
60 M 57
59 F 57
Forearms, calves
Forearms, calves
Calves
Forearms, calves
Calves
Forearms, calves, thighs
The age when PLL was first diagnosed (years) Diabetes status Diabetes duration (years) BMI (kg/m2 ) Hyper-triglyceridemia Low HDL Hypertension Acanthosis Hepatosteatosis Macrovascular complications Microvascular complications Current treatment
53
50
Forearms, calves, thighs 48
45
50
65
59
Forearms, calves, thighs 59
+ 3
+ 25
+ 5
+ 20
+ 15
+ 1
+ 10
+ 23
45.1 − + − − + −
30.1 + + + + + +
25 + + − + + −
37 − − + + + −
25.2 − − + − + −
34.2 + + + + + −
33.6 + + + + + −
30.8 − + + − + −
−
−
−
+
−
+
+
+
Metformin, insulin
Metformin, insulin, ramipril
Metformin, gliclazide
Metformin, insulin, perindopril
Metformin, insulin perindopril
Metformin, gliclazide, lisinopril
Gliclazide, metformin, fenofibrate, candesartan,
118
178
NA
112
46
NA
NA
Pioglitazone, acarbose, vildagliptin metformin, losartan NA
Insulin dose (per day)
Patient 9
Patient 4
Patient 5
Patient 6
Patient 7
Patient 8
Patient 10
Patient 11
Patient 12
Patient 13
Patient 14
Patient 15
Patient 16
45 F 44 Forearms, calves, thighs
50 F 32 Forearms, calves
47 M 37 Calves, thighs
60 F 40 Forearms, calves
48 F 46 Calves
49 + 17 28.1 + + − − + − + Metformin, insulin
57 F 30 Forearms, calves, thighs 56 + 18 36 + + + + + − − Metformin, losartan, HCT
41 F 30 Calves, thighs
44 IFG, IGT NA 25.3 + − − + + − − Metformin, levo-thyroxine
49 F 34 Forearms, calves, thighs 47 + 15 30.5 + + + + + − − Insulin, irbesartan
41 + 2 28.4 − − + + + − − Metformin
47 + 6 32 + − − + + − − Insulin, metformin
48 + 6 28.3 + + + + + − + Insulin, metformin, vildagiptin, irbesartan
NA
100
128
NA
NA
140
59 + 15 35.1 + + + + + − − Insulin, metformin, sitagliptin, metoprolol, HCT 102
96
BMI: body mass index, HDL: high density lipoprotein, HCT: hydrochlorothiazide, IFG: impaired fasting glucose, IGT: impaired glucose tolerance, NA: not applicable, PLL: partial lipodystrophy of the limbs.
low HDL cholesterol. Eleven patients (68.7%) were hypertensive. All patients had hepatic steatosis. Acanthosis nigricans was visible in 12 patients (75%). Six patients had micro(37.5%) and 1 patient (6.3%) had macro-vascular complications of diabetes. Complements 3 and 4 levels were normal
in all patients. Leptin and adiponectin levels were shown in Table 2. The metabolic parameters of 16 PLL patients were compared to 2004 PLL negative patients with type 2 diabetes. BMI values were comparable. Diabetes was diagnosed at a
Please cite this article in press as: T. Demir, et al., Partial lipodystrophy of the limbs in a diabetes clinic setting, Prim. Care Diab. (2015), http://dx.doi.org/10.1016/j.pcd.2015.12.006
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Fig. 1 – MR images and MR spectroscopy findings of controls and patients with PLL. (A) Female control, (B) male control, (C) patient 3 (female patient with PLL), (D) patient 7 (male patient with PLL). Whole body T1 WI (I), axial T1 WIs at the level of abdomen (II), forearm (III), thigh (IV), legs (V) reveal fat distribution of the body and extremities. Dual phase T1 WIs (VI and VII) show signal loss on out of phase images in affected patients which is in consistent with variable degree of hepatosteatosis. MRS spectra of affected patients indicate the variable degree of hepatosteatosis (VIII, arrows).
younger age in patients with PLL. Compared to subjects with type 2 diabetes, glycemic control was poor in patients with PLL. Hypertension was more common in patients with PLL. Patients with PLL had increased triglyceride, total- and LDL cholesterol levels, and decreased HDL levels (Table 3). Leptin and adiponectin levels were measured in 16 age-, genderand BMI-matched PLL negative subjects with type 2 diabetes. Patients with PLL had reduced levels of leptin and adiponectin compared to those with type 2 diabetes; however the differences between two groups were not statistically significant (12.57 ng/mL, 25–75 percentiles: 8–27.18 ng/mL vs. 20.72 ng/mL, 25–75 percentiles: 12.58–27.48 ng/mL, p = 0.216 for leptin; 15.23 pg/mL, 25–75 percentiles: 8.81–23.68 pg/mL vs. 22.75 pg/mL, 25–75 percentiles: 15.99–30.15 pg/mL, p = 0.066 for adiponectin).
4.
Discussion
PLL is a recently described form of lipodystrophy which is associated with marked insulin resistance and type 2 diabetes. It is unknown if the entity is a form of acquired fat loss which is seen in the course of insulin resistant diabetes. It is very well established that truncal adipose tissue accumulation is associated with insulin resistance and poor metabolic control in diabetic patients [13]. Similarly, patients with PLL exhibit signs of marked insulin resistance, and they mostly have poor metabolic control. The fat loss in PLL is somewhat similar to which is reported in FPL, particularly Kobberling variety. Visceral fat was increased and fat accumulation was noticed in the scapular/neck area; however these observation need to be
Please cite this article in press as: T. Demir, et al., Partial lipodystrophy of the limbs in a diabetes clinic setting, Prim. Care Diab. (2015), http://dx.doi.org/10.1016/j.pcd.2015.12.006
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ARTICLE IN PRESS ALT: alanine aminotransferase, C3: complement component-3, C4: complement component-4, GGT: Gamma-glutamyl transferase, HDL: high density lipoprotein, HOMA: homeostatic model assessment, LDL: low density lipoprotein, NA: not applicable, PLL: partial lipodystrophy of the limbs.
11.76 9.4 79.2 7.14 3.64 0.88 4.21 39.78 108 178 92 139.9 27.1 309.26 23.31 0.89 11.38 25.25 14.15 10.1 86.9 4.16 1.94 1.24 2.04 81.33 99 81 38 146.7 28.4 29.35 18.26 1.17 31.71 17.70 5.66 7.1 54.1 4.08 1.82 1.19 2.07 65.42 39 39 <5 129.6 24.7 169.87 6.16 1.64 4.47 8.73 9.38 8 63.9 6.91 1.69 1.60 4.52 54.81 66 59 <5 160.6 34.5 78.06 4.59 1.06 25.42 29.33 10.65 8.6 70.5 4.76 1.78 1.21 2.71 50.39 27 36 <5 185 28.2 288.15 19.67 0.58 47.89 23.68 10.04 9.1 76.0 4.95 3.81 0.96 2.27 61.88 35 28 10 165.6 38.1 199.18 12.82 1.29 27.18 12.01 8.88 13.3 121.9 5.51 3.66 0.96 2.87 38.01 15 27 140 133 36.3 267.52 15.2 0.45 12.57 4.29 5.83 5.5 36.6 7.42 3.07 1.60 4.42 58.34 36 51 6 158.9 34.8 49.72 1.81 1.14 7.01 7.85 13.98 8.7 71.6 5.90 1.97 1.27 4.08 65.41 13 15 <5 113.3 35.3 46.18 2.25 0.55 8.0 12.99 8.10 8.4 68.3 5.27 3.43 0.85 3.57 137.02 25 49 64 125 24 56.60 2.88 2.10 7.12 15.23 5.32 6.2 44.3 4.78 1.83 1.03 2.92 85.75 20 16 40 155.4 32.4 157.23 2.25 1.52 35.16 28.26 10.38 9.3 78.1 5.48 1.37 1.40 3.46 44.2 16 17 11 137 27.2 157.23 10.16 0.63 12.45 23.06 17.32 9.3 78.1 5.15 1.18 1.45 3.15 67.18 22 15 8 139.1 54.3 305.44 33.88 0.45 12.77 19.21 9.60 9.1 76.0 7.65 3.67 1.01 4.96 100.78 54 39 20 172 31.4 30.14 1.71 1.03 10.61 13.8 19.87 11.9 106.6 7.91 10.12 0.78 3.36 69.83 8 26 21 182 36.4 180.71 23 0.41 17.15 8.81 10.82 8.9 73.8 4.89 1.39 0.88 3.36 69.83 11 17 26 NA NA NA NA NA NA NA Fasting glucose (mmol/L) HbA1c (%) HbA1c (mmol/mol) Total cholesterol (mmol/L) Triglyceride (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Creatinin (mol/L) ALT (U/L) GGT (U/L) Protein excretion (mg/L) C3 (mg/dL) C4 (mg/dL) Fasting insulin (pmol/L) HOMA Fasting C-peptid (nmol/L) Fasting leptin (ng/mL) Adiponectin (pg/mL)
Patient 3 Patient 2 Patient 1
Table 2 – The laboratory levels of patients with PLL.
Patient 4
Patient 5
Patient 6
Patient 7
Patient 8
Patient 9
Patient 10
Patient 11
Patient 12
Patient 13
Patient 14
Patient 15
Patient 16
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confirmed in further studies. Both conditions mainly affect women. Lipodystrophy consistently involves the limbs and predominantly gluteal regions in the Kobberling variety of FPL, whilst fat loss is limited to the distal parts of the limbs in PLL. Mutations in the LMNA gene have been associated with Dunnigan variety, the most common subtype of FPL [11]. Several other genes are also involved in FPL [7–10]. However, none of the subjects with PLL in our study had any of the mutations associated with FPL. The late onset of fat loss and the lack of family history in PLL may also suggest that this entity accounts for an acquired form of lipodystrophy. Our study reports a prevalence of 0.79% for PLL in our diabetes clinic which is apparently higher than other types of non-HIV related lipodystrophies. In fact, there are no established incidence and prevalence data reported on any type of lipodystrophies. However, it is reported that CGL has an estimated prevalence of 1 in 10 million [14], which might be slightly higher in Turkey as result of increased number of in family marriages. There are around 250 patients with APL reported elsewhere [15,16]. As far as FPL is concerned, the prevalence seems to be higher. Several studies have also indicated that FPL may have a greater prevalence than previously thought due to lack of recognition of subtle forms [17,18]. The same pattern also stands for PLL. It is quite possible that most patients with PLL remain unrecognized as the fat loss has a very slow progression rate and truncal obesity along with thin limbs is a relatively common finding that is expected in some patients with type 2 diabetes. However, as clearly shown previously [12], patients PLL are more insulin resistant than PLL negative patients with type 2 diabetes. Similarly, subjects with PLL had poor metabolic control and marked insulin resistance in our study. We suggest that clinicians should keep in mind that PLL is a relatively common entity in diabetes clinics, and they should consider screening their patients with type 2 diabetes for PLL if they have poorly controlled diabetes along with the signs of marked insulin resistance. Metreleptin, a recombinant human leptin analog, has recently been approved for the treatment of patients with generalized lipodystrophy [19]. It has been demonstrated to improve metabolic abnormalities associated insulin resistance such as hyperglycemia and hepatic steatosis [20]. Metreleptin would be a potential treatment to improve metabolic abnormalities in patients with PLL. Several studies have suggested that metreleptin treatment might be beneficial on metabolic abnormalities in partial lipodystrophies; however, the effect was not as robust as it was observed in generalized lipodystrophies [21,22]. Unlike generalized lipodystrophy patients with consistently very low levels of leptin, partial lipodystrophies demonstrate varying levels of leptin from severe hypoleptinemia to normal levels [23]. Further work is needed to investigate if metreleptin treatment is beneficial in PLL. In conclusion, our data emphasizes that PLL is a relatively common subtype of lipodystrophy in patients with type 2 diabetes, which is associated with poor metabolic control and marked insulin resistance. It is uncertain if the recognition of this new entity in diabetes clinics would help improve metabolic control in patients with type 2 diabetes. However, the simple clinical suspicion of PLL based on physical examination marks patients with more severe hepatic steatosis,
Please cite this article in press as: T. Demir, et al., Partial lipodystrophy of the limbs in a diabetes clinic setting, Prim. Care Diab. (2015), http://dx.doi.org/10.1016/j.pcd.2015.12.006
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Table 3 – Comparison of metabolic parameters of patients with PLL and subjects with type 2 diabetes. PLL (n = 16) Age BMI The age when diabetes was diagnosed (years) Hypertension Fasting glucose (mmol/L) HbA1c (%) HbA1c (mmol/mol) Total cholesterol (mmol/L) Triglyceride (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Creatinin (mol/L) ALT (U/L)
51 (48–59) 30.65 (28.2–34.9) 42 (34–45) 11 (68.8%) 10.545 (9.10–13.99) 8.9 (8.2–9.3) 73.8 (66.1–78.1) 5.43 (4.89–7.08) 2.09 (1.47–3.67) 4.96 (0.88–1.37) 3.41 (2.89–4.19) 63.65 (51.27–78.68) 24 (15–50)
Type 2 diabetes (n = 2004)
p Value
58 (49–67) 30 (27–35) 50 (41–57) 784 (39.1%) 6.44 (5.22–8.60) 7.1 (6.3–8.1) 54.1 (45.4–65) 4.89 (4.13–5.69) 1.55 (1.08–2.17) 1.24 (1.06–1.47) 2.92 (2.33–3.54) 71.60 (60.99–84.86) 20 (15–29)
0.066 0.699 0.005 0.002 <0.001 0.001 0.001 0.007 0.004 0.047 0.025 0.074 0.381
ALT: alanine aminotransferase, BMI: body mass index, HDL: high density lipoprotein, LDL: low density lipoprotein, NA: not applicable, PLL: partial lipodystrophy of the limbs.
hypertension, and dyslipidemia. Thus, the recognition can aid in better overall clinical management by alerting the physician to these associated co-morbidities.
Conflict of interest [4]
There are no relevant conflicts of interest to disclose. Dr. Tevfik Demir is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The study was funded locally.
[5]
Author contributions T.D. wrote the manuscript and researched data. B.A. wrote the manuscript and researched data. L.D. researched data, performed biochemical studies. C.A. researched data, performed radiological studies. T.A. researched data and performed genetic studies. U.C. researched data. M.S. performed radiological studies. A.C. reviewed/edited the manuscript.
[6]
[7]
Acknowledgements [8]
None.
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Contents lists available at ScienceDirect
Primary Care Diabetes journal homepage: http://www.elsevier.com/locate/pcd
Original research
Partial lipodystrophy of the limbs in a diabetes clinic setting Tevfik Demir a,1, Baris Akinci a,∗,1, Leyla Demir b, Canan Altay c, Tahir Atik d, Umit Cavdar a , Mustafa Secil c , Abdurrahman Comlekci a a
Dokuz Eylul University, Division of Endocrinology, Izmir, Turkey Ataturk Training Hospital, Department of Biochemistry, Izmir, Turkey c Dokuz Eylul University, Department of Radiology, Izmir, Turkey d Ege University, Department of Pediatric Genetics, Izmir, Turkey b
a r t i c l e
i n f o
a b s t r a c t
Article history:
Objective: Partial lipodystrophy of the limbs (PLL) is a newly described form of lipodystrophy
Received 14 September 2015
that is characterized by symmetrical distal lipoatrophy of the limbs and insulin resistant
Received in revised form
diabetes.
23 November 2015
Research design and methods: In this study, we prospectively screened our patients with type
Accepted 12 December 2015
2 diabetes for the presence of PLL phenotype. Metabolic parameters of PLL patients were
Available online xxx
compared to those with type 2 diabetes who applied to our diabetes clinic during the same period of time.
Keywords:
Results: Between Sep 2013 and Mar 2015, 2020 patients with type 2 diabetes were evaluated for
Diabetes clinic
the presence of PLL. PLL was confirmed in 16 patients. The prevalence of PLL was calculated
Insulin resistance
as 0.79% in our diabetes clinic. The most common phenotypic presentations were loss of
Lipodystrophy
subcutaneous fat in the forearms, calves and thighs, and loss of fat in forearms and calves.
Lipids
Patients with PLL had poor metabolic control and marked insulin resistance compared to
Type 2 diabetes
subjects with type 2 diabetes. Diabetes had been diagnosed at a younger age in patients with PLL. Patients with PLL also had more atherogenic lipid profiles. Conclusions: Our data suggests that PLL is a relatively common form of lipodystrophy in diabetes clinics, which is associated with poor metabolic control and marked insulin resistance. The recognition of PLL in patients with type 2 diabetes can help better clinical management by alerting the physician to these associated co-morbidities. © 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Lipodystrophies are a heterogeneous group of disorders characterized by impaired adipose tissue distribution and
∗
1
metabolism [1]. Fat is near-totally absent in patients with generalized lipodystrophies, whilst the lack of fat is selective in patients partial lipodystrophies. Several genes have been identified for congenital generalized lipodystrophy (CGL) [2–6] and familial partial lipodystrophy (FPL) [7–10]. On the other hand,
Corresponding author. Tel.: +90 232 4123747; fax: +90 232 2792267. E-mail address: [email protected] (B. Akinci). These two authors contributed equally to this work.
http://dx.doi.org/10.1016/j.pcd.2015.12.006 1751-9918/© 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
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fat loss has no genetic basis in acquired generalized lipodystrophy (AGL) and acquired partial lipodystrophy (APL) [1]. Lipodystrophies are commonly associated with metabolic abnormalities. Poorly controlled diabetes, severe hypertriglyceridemia and hepatic steatosis may be observed in patients with lipodystrophy as a result of marked insulin resistance which is believed to be secondary to fat tissue dysfunction [11]. Recently, Strickland et al. [12] has described a novel form of lipodystrophy, partial lipodystrophy of the limbs (PLL), which is characterized by symmetrical distal lipodystrophy of the limbs and insulin resistant diabetes. Using hyperinsulinemic clamp studies, they showed that insulin resistance was more prominent in patients with PLL compared to patients with type 2 diabetes. When compared to other non-HIV related forms of lipodystrophy, which have very rarely been reported in the literature, the authors proposed that this novel lipodystrophy subtype would affect larger number of patients in the real life. To determine the prevalence of PLL in a diabetes clinic, we prospectively screened our patients with type 2 diabetes for the presence of PLL phenotype. Whole body MRI was used to confirm the diagnosis. Metabolic parameters of PLL patients were compared to those with type diabetes who applied to our clinic during the same period of time.
2.
Patients and methods
A total of 2020 patients with type 2 diabetes, who were admitted to our diabetes clinic between Sep 2013 and Mar 2015, were screened for PLL. The study was approved by the Dokuz Eylul University Ethics Review Panel. PLL was clinically diagnosed based on characteristic fat loss pattern and supporting clinical findings associated with insulin resistance. Patients were considered as PLL if (I) lipodystrophy primarily involved the distal extremities (forearms or forearms plus calves), (II) the lipodystrophy pattern was symmetrical, and (III) the signs of insulin resistance were evident such as acanthosis nigricans, polycystic ovaries, insulin resistant diabetes, hypertriglyceridemia and hepatic steatosis. Fat distribution was assessed by whole body magnetic resonance imaging (WB MRI). The WB MRI was performed by using a 1.5-T MR device (Gyroscan Intera, release 8.1; Philips Medical Systems, Best, the Netherlands) with a 6 multichannel body coil. MR images of all patients were interpreted by 2 radiologists (M.S. and C.A.) with consensus. After the MRI study, patients were excluded if (I) increased visceral or subcutaneous fat was observed, but no lipoatrophy can be visualized in the distal extremities, (II) the lipodystrophy pattern was not symmetrical, (III) there was some lipoatrophy on the extremities, but no distal involvement was observed, and (IV) there was gluteal or anterior thorax involvement. Mutation analysis of the genes LMNA, LMNB2, PPARG, CAV1, PLIN1, AKT2, and CIDEC were carried out by direct automated DNA sequencing from the patients’ genomic DNA based on the clinical features. PCR primers used in order to amplify the regions of interests could be sent upon request.
Sequencing was performed with Miseq V2 chemistry on MiSeq instrument (Illumina California, USA). Analysis was performed with IGV software. All patients underwent detailed physical examination, full biochemistry and urinalysis for protein content. In patients with PLL, fasting insulin, C-peptide, leptin and adiponectin levels were measured. Hepatic steatosis was evaluated by high resolution ultrasound (US), conventional MRI and MR spectroscopy (MRS). The US was obtained with convex transducers (frequency bandwidth 3–6 MHz). Conventional MRI and MRS were performed by using a 1.5-T MR device (Gyroscan Intera, release 8.1; Philips Medical Systems, Best, the Netherlands) with a phased-array coil. Glucose, HbA1c, triglyceride and cholesterol levels were measured by standardized methods with appropriate quality control and quality assurance procedures. Insulin levels were measured by a chemiluminescent method. Homeostasis model assessment (HOMA-IR) score was calculated as fasting serum insulin (IU/mL) × fasting plasma glucose (mg/dL)/405. Fasting C-peptide levels were measured by a chemiluminescent immunoassay. Leptin and adiponectin levels were measured with enzyme-linked immunosorbant assay (ELISA) according to the manufacturer’s instructions (Boster, Pleasanton, CA, USA; Leptin: EK0439, sensitivity: <8 pg/mL; Adiponectin: EK0595, sensitivity: <60 pg/mL). Statistical analysis was performed using Statistical Package of Social Science (SPSS Inc, Chicago, IL, USA), version 15.0 for Windows. Data was expressed as median (25–75 percentiles). Mann Whitey-U test was used for comparison of scale parameters. Categorical variables were compared by the chi-square test. A p-value less than 0.05 was accepted as statistically significant.
3.
Results
Of 2020 patients with type 2 diabetes, 22 patients were candidates for PLL after physical examination. PLL was confirmed in 16 patients when WB MRI procedures were completed. Other 6 patients were considered as false positive cases. The prevalence of PLL was calculated as 0.79% in our diabetes clinic. Table 1 shows clinical characteristics of 16 patients with PLL. The median age was 51 (25–75 percentiles: 48–59). The age range was 41–66 years. 14 patients (87.5%) were women. Patients reported a median age of starting fat loss of 39 years (25–75 percentiles: 31–46). The BMI ranged from 25 kg/m2 to 45.1 kg/m2 . The lipodystrophy pattern was symmetrical in all patients and only the limbs were affected. Loss of subcutaneous fat in the forearms, calves and thighs (6 patients, Fig. 1) and forearms and calves (5 patients) were the most common presentations, with lipodystrophy involving calves in three patients and calves and thighs in two patients. Intraabdominal fat was increased. Fat accumulation was noticed in the scapular/neck area. None of the PLL patients had any mutation on genes which has been shown to cause partial lipodystrophy. The laboratory data of patients with PLL is presented in Table 2. Fourteen patients (87.5%) had poorly controlled diabetes (HbA1c > 7%). Nine patients (56.2%) were on insulin. The average insulin dose was 113 units/day. Eleven patients (68.7%) had hypertriglyceridemia, and 11 (68.7%) patients had
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Table 1 – The clinical characteristics of patients with PLL. Patient 1
Patient 2
Patient 3
Current age Gender The age when fat loss was first noticed (years) Lipodystrophy pattern
54 F 45
52 F 22
49 F 30
46 F 45
52 F 50
66 F 35
60 M 57
59 F 57
Forearms, calves
Forearms, calves
Calves
Forearms, calves
Calves
Forearms, calves, thighs
The age when PLL was first diagnosed (years) Diabetes status Diabetes duration (years) BMI (kg/m2 ) Hyper-triglyceridemia Low HDL Hypertension Acanthosis Hepatosteatosis Macrovascular complications Microvascular complications Current treatment
53
50
Forearms, calves, thighs 48
45
50
65
59
Forearms, calves, thighs 59
+ 3
+ 25
+ 5
+ 20
+ 15
+ 1
+ 10
+ 23
45.1 − + − − + −
30.1 + + + + + +
25 + + − + + −
37 − − + + + −
25.2 − − + − + −
34.2 + + + + + −
33.6 + + + + + −
30.8 − + + − + −
−
−
−
+
−
+
+
+
Metformin, insulin
Metformin, insulin, ramipril
Metformin, gliclazide
Metformin, insulin, perindopril
Metformin, insulin perindopril
Metformin, gliclazide, lisinopril
Gliclazide, metformin, fenofibrate, candesartan,
118
178
NA
112
46
NA
NA
Pioglitazone, acarbose, vildagliptin metformin, losartan NA
Insulin dose (per day)
Patient 9
Patient 4
Patient 5
Patient 6
Patient 7
Patient 8
Patient 10
Patient 11
Patient 12
Patient 13
Patient 14
Patient 15
Patient 16
45 F 44 Forearms, calves, thighs
50 F 32 Forearms, calves
47 M 37 Calves, thighs
60 F 40 Forearms, calves
48 F 46 Calves
49 + 17 28.1 + + − − + − + Metformin, insulin
57 F 30 Forearms, calves, thighs 56 + 18 36 + + + + + − − Metformin, losartan, HCT
41 F 30 Calves, thighs
44 IFG, IGT NA 25.3 + − − + + − − Metformin, levo-thyroxine
49 F 34 Forearms, calves, thighs 47 + 15 30.5 + + + + + − − Insulin, irbesartan
41 + 2 28.4 − − + + + − − Metformin
47 + 6 32 + − − + + − − Insulin, metformin
48 + 6 28.3 + + + + + − + Insulin, metformin, vildagiptin, irbesartan
NA
100
128
NA
NA
140
59 + 15 35.1 + + + + + − − Insulin, metformin, sitagliptin, metoprolol, HCT 102
96
BMI: body mass index, HDL: high density lipoprotein, HCT: hydrochlorothiazide, IFG: impaired fasting glucose, IGT: impaired glucose tolerance, NA: not applicable, PLL: partial lipodystrophy of the limbs.
low HDL cholesterol. Eleven patients (68.7%) were hypertensive. All patients had hepatic steatosis. Acanthosis nigricans was visible in 12 patients (75%). Six patients had micro(37.5%) and 1 patient (6.3%) had macro-vascular complications of diabetes. Complements 3 and 4 levels were normal
in all patients. Leptin and adiponectin levels were shown in Table 2. The metabolic parameters of 16 PLL patients were compared to 2004 PLL negative patients with type 2 diabetes. BMI values were comparable. Diabetes was diagnosed at a
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Fig. 1 – MR images and MR spectroscopy findings of controls and patients with PLL. (A) Female control, (B) male control, (C) patient 3 (female patient with PLL), (D) patient 7 (male patient with PLL). Whole body T1 WI (I), axial T1 WIs at the level of abdomen (II), forearm (III), thigh (IV), legs (V) reveal fat distribution of the body and extremities. Dual phase T1 WIs (VI and VII) show signal loss on out of phase images in affected patients which is in consistent with variable degree of hepatosteatosis. MRS spectra of affected patients indicate the variable degree of hepatosteatosis (VIII, arrows).
younger age in patients with PLL. Compared to subjects with type 2 diabetes, glycemic control was poor in patients with PLL. Hypertension was more common in patients with PLL. Patients with PLL had increased triglyceride, total- and LDL cholesterol levels, and decreased HDL levels (Table 3). Leptin and adiponectin levels were measured in 16 age-, genderand BMI-matched PLL negative subjects with type 2 diabetes. Patients with PLL had reduced levels of leptin and adiponectin compared to those with type 2 diabetes; however the differences between two groups were not statistically significant (12.57 ng/mL, 25–75 percentiles: 8–27.18 ng/mL vs. 20.72 ng/mL, 25–75 percentiles: 12.58–27.48 ng/mL, p = 0.216 for leptin; 15.23 pg/mL, 25–75 percentiles: 8.81–23.68 pg/mL vs. 22.75 pg/mL, 25–75 percentiles: 15.99–30.15 pg/mL, p = 0.066 for adiponectin).
4.
Discussion
PLL is a recently described form of lipodystrophy which is associated with marked insulin resistance and type 2 diabetes. It is unknown if the entity is a form of acquired fat loss which is seen in the course of insulin resistant diabetes. It is very well established that truncal adipose tissue accumulation is associated with insulin resistance and poor metabolic control in diabetic patients [13]. Similarly, patients with PLL exhibit signs of marked insulin resistance, and they mostly have poor metabolic control. The fat loss in PLL is somewhat similar to which is reported in FPL, particularly Kobberling variety. Visceral fat was increased and fat accumulation was noticed in the scapular/neck area; however these observation need to be
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ARTICLE IN PRESS ALT: alanine aminotransferase, C3: complement component-3, C4: complement component-4, GGT: Gamma-glutamyl transferase, HDL: high density lipoprotein, HOMA: homeostatic model assessment, LDL: low density lipoprotein, NA: not applicable, PLL: partial lipodystrophy of the limbs.
11.76 9.4 79.2 7.14 3.64 0.88 4.21 39.78 108 178 92 139.9 27.1 309.26 23.31 0.89 11.38 25.25 14.15 10.1 86.9 4.16 1.94 1.24 2.04 81.33 99 81 38 146.7 28.4 29.35 18.26 1.17 31.71 17.70 5.66 7.1 54.1 4.08 1.82 1.19 2.07 65.42 39 39 <5 129.6 24.7 169.87 6.16 1.64 4.47 8.73 9.38 8 63.9 6.91 1.69 1.60 4.52 54.81 66 59 <5 160.6 34.5 78.06 4.59 1.06 25.42 29.33 10.65 8.6 70.5 4.76 1.78 1.21 2.71 50.39 27 36 <5 185 28.2 288.15 19.67 0.58 47.89 23.68 10.04 9.1 76.0 4.95 3.81 0.96 2.27 61.88 35 28 10 165.6 38.1 199.18 12.82 1.29 27.18 12.01 8.88 13.3 121.9 5.51 3.66 0.96 2.87 38.01 15 27 140 133 36.3 267.52 15.2 0.45 12.57 4.29 5.83 5.5 36.6 7.42 3.07 1.60 4.42 58.34 36 51 6 158.9 34.8 49.72 1.81 1.14 7.01 7.85 13.98 8.7 71.6 5.90 1.97 1.27 4.08 65.41 13 15 <5 113.3 35.3 46.18 2.25 0.55 8.0 12.99 8.10 8.4 68.3 5.27 3.43 0.85 3.57 137.02 25 49 64 125 24 56.60 2.88 2.10 7.12 15.23 5.32 6.2 44.3 4.78 1.83 1.03 2.92 85.75 20 16 40 155.4 32.4 157.23 2.25 1.52 35.16 28.26 10.38 9.3 78.1 5.48 1.37 1.40 3.46 44.2 16 17 11 137 27.2 157.23 10.16 0.63 12.45 23.06 17.32 9.3 78.1 5.15 1.18 1.45 3.15 67.18 22 15 8 139.1 54.3 305.44 33.88 0.45 12.77 19.21 9.60 9.1 76.0 7.65 3.67 1.01 4.96 100.78 54 39 20 172 31.4 30.14 1.71 1.03 10.61 13.8 19.87 11.9 106.6 7.91 10.12 0.78 3.36 69.83 8 26 21 182 36.4 180.71 23 0.41 17.15 8.81 10.82 8.9 73.8 4.89 1.39 0.88 3.36 69.83 11 17 26 NA NA NA NA NA NA NA Fasting glucose (mmol/L) HbA1c (%) HbA1c (mmol/mol) Total cholesterol (mmol/L) Triglyceride (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Creatinin (mol/L) ALT (U/L) GGT (U/L) Protein excretion (mg/L) C3 (mg/dL) C4 (mg/dL) Fasting insulin (pmol/L) HOMA Fasting C-peptid (nmol/L) Fasting leptin (ng/mL) Adiponectin (pg/mL)
Patient 3 Patient 2 Patient 1
Table 2 – The laboratory levels of patients with PLL.
Patient 4
Patient 5
Patient 6
Patient 7
Patient 8
Patient 9
Patient 10
Patient 11
Patient 12
Patient 13
Patient 14
Patient 15
Patient 16
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confirmed in further studies. Both conditions mainly affect women. Lipodystrophy consistently involves the limbs and predominantly gluteal regions in the Kobberling variety of FPL, whilst fat loss is limited to the distal parts of the limbs in PLL. Mutations in the LMNA gene have been associated with Dunnigan variety, the most common subtype of FPL [11]. Several other genes are also involved in FPL [7–10]. However, none of the subjects with PLL in our study had any of the mutations associated with FPL. The late onset of fat loss and the lack of family history in PLL may also suggest that this entity accounts for an acquired form of lipodystrophy. Our study reports a prevalence of 0.79% for PLL in our diabetes clinic which is apparently higher than other types of non-HIV related lipodystrophies. In fact, there are no established incidence and prevalence data reported on any type of lipodystrophies. However, it is reported that CGL has an estimated prevalence of 1 in 10 million [14], which might be slightly higher in Turkey as result of increased number of in family marriages. There are around 250 patients with APL reported elsewhere [15,16]. As far as FPL is concerned, the prevalence seems to be higher. Several studies have also indicated that FPL may have a greater prevalence than previously thought due to lack of recognition of subtle forms [17,18]. The same pattern also stands for PLL. It is quite possible that most patients with PLL remain unrecognized as the fat loss has a very slow progression rate and truncal obesity along with thin limbs is a relatively common finding that is expected in some patients with type 2 diabetes. However, as clearly shown previously [12], patients PLL are more insulin resistant than PLL negative patients with type 2 diabetes. Similarly, subjects with PLL had poor metabolic control and marked insulin resistance in our study. We suggest that clinicians should keep in mind that PLL is a relatively common entity in diabetes clinics, and they should consider screening their patients with type 2 diabetes for PLL if they have poorly controlled diabetes along with the signs of marked insulin resistance. Metreleptin, a recombinant human leptin analog, has recently been approved for the treatment of patients with generalized lipodystrophy [19]. It has been demonstrated to improve metabolic abnormalities associated insulin resistance such as hyperglycemia and hepatic steatosis [20]. Metreleptin would be a potential treatment to improve metabolic abnormalities in patients with PLL. Several studies have suggested that metreleptin treatment might be beneficial on metabolic abnormalities in partial lipodystrophies; however, the effect was not as robust as it was observed in generalized lipodystrophies [21,22]. Unlike generalized lipodystrophy patients with consistently very low levels of leptin, partial lipodystrophies demonstrate varying levels of leptin from severe hypoleptinemia to normal levels [23]. Further work is needed to investigate if metreleptin treatment is beneficial in PLL. In conclusion, our data emphasizes that PLL is a relatively common subtype of lipodystrophy in patients with type 2 diabetes, which is associated with poor metabolic control and marked insulin resistance. It is uncertain if the recognition of this new entity in diabetes clinics would help improve metabolic control in patients with type 2 diabetes. However, the simple clinical suspicion of PLL based on physical examination marks patients with more severe hepatic steatosis,
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Table 3 – Comparison of metabolic parameters of patients with PLL and subjects with type 2 diabetes. PLL (n = 16) Age BMI The age when diabetes was diagnosed (years) Hypertension Fasting glucose (mmol/L) HbA1c (%) HbA1c (mmol/mol) Total cholesterol (mmol/L) Triglyceride (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Creatinin (mol/L) ALT (U/L)
51 (48–59) 30.65 (28.2–34.9) 42 (34–45) 11 (68.8%) 10.545 (9.10–13.99) 8.9 (8.2–9.3) 73.8 (66.1–78.1) 5.43 (4.89–7.08) 2.09 (1.47–3.67) 4.96 (0.88–1.37) 3.41 (2.89–4.19) 63.65 (51.27–78.68) 24 (15–50)
Type 2 diabetes (n = 2004)
p Value
58 (49–67) 30 (27–35) 50 (41–57) 784 (39.1%) 6.44 (5.22–8.60) 7.1 (6.3–8.1) 54.1 (45.4–65) 4.89 (4.13–5.69) 1.55 (1.08–2.17) 1.24 (1.06–1.47) 2.92 (2.33–3.54) 71.60 (60.99–84.86) 20 (15–29)
0.066 0.699 0.005 0.002 <0.001 0.001 0.001 0.007 0.004 0.047 0.025 0.074 0.381
ALT: alanine aminotransferase, BMI: body mass index, HDL: high density lipoprotein, LDL: low density lipoprotein, NA: not applicable, PLL: partial lipodystrophy of the limbs.
hypertension, and dyslipidemia. Thus, the recognition can aid in better overall clinical management by alerting the physician to these associated co-morbidities.
Conflict of interest [4]
There are no relevant conflicts of interest to disclose. Dr. Tevfik Demir is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The study was funded locally.
[5]
Author contributions T.D. wrote the manuscript and researched data. B.A. wrote the manuscript and researched data. L.D. researched data, performed biochemical studies. C.A. researched data, performed radiological studies. T.A. researched data and performed genetic studies. U.C. researched data. M.S. performed radiological studies. A.C. reviewed/edited the manuscript.
[6]
[7]
Acknowledgements [8]
None.
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