This is a 61-year-old woman who presented with diabetic symptoms and misclassified as having type 1 diabetes with negative autoimmune-related type 1 diabetes antibodies: Tyrosine Phosphatase antibobies:0.3 U/ml (negative < 10) and Glutamic acid Decarboxylase antibodies:0.5 U/ml (negative < 10). She was referred to our center due to uncontrolled diabetes despite the high doses of insulin and the coexistence of severe insulin resistance and decreased body mass index (BMI:19.4 kg/m2). Age of presentation was 29 years and for the following 30 years she was treated with multiple daily insulin injections with high insulin requirements(5 IU/kg/day) together with metformin 2gr/day for 30 years, but constantly displaying poor glycemic control. Dyslipidemia was observed at the age of 35 years with raised cholesterol levels and severe hypertriglyceridemia despite intense lipid lowering therapy which lately consisted of the combination of fenofibrate 145 mg, rosuvastatin 40 mg/day and omega-3 fatty acids/day together with restricted fat intake. Hypertension was observed at the age of 5 years, and lately treated with the combination of nifedipine 120 mg/day, eplerenone 25 mg/day and hydrochlorothiazide 25 mg/day.
She also had micro- and macrovascular complication of diabetes indicating constantly insufficient glycemic control. She presented peripheral diabetic neuropathy, and nephropathy (eGFR: 43 ml/min, albuminuria: 314 mg/24 h). She also suffered from severe cardiovascular disease including peripheral artery disease, and hypertrophic myocardiopathy. Peripheral artery disease presented as intermittent claudication and carotid stenosis, for which she had a right carotid endarterectomy at the age of 52 years old. She was managed with clopidogrel 75 mg /day.
She had menarche at age 11, followed by irregular menstruation and then premature menopause at the age of 38. She also reported polycystic ovarian syndrome and never conceived. She underwent hysterectomy due to fibroids at the age of 54. She was diagnosed with osteoporosis at the age of 58 and has since received alendronate 70 mg/week.
Family History
It has not been possible to conduct genetic family screening. Her mother and her maternal aunt have diabetes from a young age, and both showed early presentation of cardiovascular disease, presenting as ischemic stroke at the age of 45 years old and myocardial infarction at the same age, respectively. Her mother had reproductive problems and six miscarriages. Two out of four sisters and one brother developed hypertension and dyslipidemia in young age.
Genetic Analysis
A genetic screening for lipodystrophy revealed a novel heterozygous mutation in the PPARG gene (c470A > G, p. Glu157Gly, exon3). (The University of Chicago Genetic Services Laboratory). This particular amino acid change has not been described in other patients with PPARG-related disorders, but a different pathogenic sequence change affecting the same amino acid residue (p. Glu157Asp) has been described in a family with PPARG-related lipodystrophy [11].
Examination
Examination revealed clinical signs of lipodystrophy of upper and lower limbs and gluteal area. Facial fat and abdominal prominence were also noted. She also had phlebectasia, hirsutism and cervical acanthosis nigricans. The patient mentioned that this phenotype was present from a young age. Blood pressure was 175/84 mmHg.She was underweighted with a BMI: 19.40 kg/m2 (weight:46 kg, height:154 cm). Muscle weakness, presenting with a weak hand grip and exercise intolerance with pain and frailty were also prominent (Fig. 1A).
To assess the degree of regional fat loss in this case, we compared the total and proportional fat content in defined body regions using Dual-energy x-ray absorptiometry (DXA) with a group of healthy, lean postmenopausal women [12]. The case has a relatively short stature and as a consequence a total lean mass not far from the lower end the 95% confidence interval of the comparators. The total fat mass was drastically lower giving a first indication of a lipodystrophic state. The visceral fat mass was similar to the comparators whilst the proportional fat content in extremities was drastically reduced showing the classic features of peripheral fat loss in partial lipodystrophy (Table 1).
Table 1
Regional body fat content in the case
| Case | Healthy comparator group n = 13 |
Age (years) | 64 | 59 (58–60) |
BMI (kg/m2) | 19.7 | 23.1 (22.7–23.5) |
Height (cm) | 153 | 161 (159–162) |
Total fat mass (kg) | 10.9 | 20.1 (19.2–21.1) |
Total Lean mass (kg) | 34.1 | 36.6 (35.5–37.6) |
Android subcutaneous fat mass (kg) | 0.6 | 1.0 (0.9–1.1) |
Android visceral fat mass (kg) | 0.3 | 0.3 (0.2–0.4) |
Gynoid fat mass (kg) | 1.3 | 4.0 (3.8–4.2) |
Arm fat% | 26.5 | 40 (38–41) |
Leg fat % | 18.7 | 40 (38–41) |
Comparator values are mean (95% confidence interval) |
Biochemical Measurements
At the time of the first evaluation biochemical measurements revealed glycated hemoglobin (HbA1C) of 10%, total cholesterol of 132 mg/dl of which high density lipoprotein (HDL-C) was 25 mg/dl. There was severe hypertriglyceridemia at 2,919 mg/dl. Further tests confirmed chronic kidney disease (blood urea nitrogen:49.6 mg/dl, creatinine: 1.3 mg/dl, eGFR: 43 ml/min) and albuminuria (314 mg/24 h).
We performed glucagon stimulation test which revealed residual insulin secretion (fastingC-peptide:2.09 ng/ml, 6 minutes after 1 mg of glucagon infusionC-peptide:3.13 ng/ml). Plasma leptin concentration was close to zero (0.43 ng/ml).
Imaging Assessment
Abdominal ultrasound confirmed hepatic steatosis and transient elastography (fibroscan) detected liver stiffness of 18 Kpa.Abdominal Magnetic Resonance Imaging (MRI) was unremarkable apart from hepatomegaly with a liver percentage fat fraction of 9.4%, and an enlarged spleen (Fig. 1D). Cardiac MRI revealed left ventricular hypertrophy (maximal wall thickness 17 mm) and myocardial fibrosis in the basal interventricular septum (LGE SCORE 1/48, LGE mass 2%). Two-dimensional echocardiography revealed severe left ventricular hypertrophy, minimal mitral regurgitation, and ejection fraction of 60% (Fig. 1B).
Effect of metreleptin treatment
After noting her poor glycemic control, her antidiabetic treatment was intensified with empagliflozin 10 mg/daily and liraglutide 1.8 mg/daily, but this resulted only in a slight improvement in glycemic control after 3 months (HbA1c: 9.3%), despite additional strict dietetic management, but without any change in insulin management. We did not observe any change in triglyceride (TG) levels.
Metreleptin was then initiated at 5.8 mg once daily on top of the current lipid and diabetes management. Glycemic control and hypertriglyceridemia improved within two months of treatment evidenced by decrease of HbA1C from 10–8.7% and the reduction of TG from a baseline value of 2919 mg/dl to 242 mg/dl. At six months there was further reduction in HbA1C (7.9%) and in TG (198 mg/dl). This improvement was sustained one year after treatment with metreleptin in same dose (HbA1C:8%, TG:185 mg/dl-standard serum determinations are listed in Table 2). Insulin doses were reduced from more than 5 IU/kg/day to 2.22 IU/kg/day. Blood pressure was also better controlled without any change in anti-hypertensive medication.
Table 2
Summary of the results over 12 months of metreleptin therapy
| Baseline | 2 months | 6 months | 12 months |
HbA1C (%) | 10 | 8.7 | 7.9 | 8 |
TG (mg/dl) | 2919 | 242 | 198 | 185 |
Total cholesterol (mg/dl) | 132 | 137 | 115 | 106 |
HDL (mg/dl) | 25 | 25 | 26 | 29 |
LDL (mg/dl) | - | 64 | 49 | 46 |
ALT (mg/dl) | 24 | 24 | 18 | 17 |
AST (mg/dl) | 21 | 27 | 24 | 26 |
BUN (mg/dl) | 49.6 | 56 | 25 | 39 |
Creatinine (mg/dl) | 1.3 | 1.3 | 1.04 | 1.09 |
Liver fat fraction (%) | 9.4 | - | 6.8 | - |
Liver Stiffness (Kpa) | 18 | | 18 | |
BMI (Kg/m2) | 19.40 | - | - | 18.98 |
ALT: alanine aminotransferase, AST: aspartate transaminase, BMI: Body Mass Index, BUN: blood urea nitrogen, HbA1C: glycated hemoglobin, HDL: high-density lipoprotein, LDL: low-density lipoprotein, TG: triglycerides. The biochemical assessment was performed after 8 hours fasting. |
At six months of metreleptin treatment a reduced liver fat content was observed (MRI estimated liver percentage fat fraction was reduced from 9.4–6.8%). However, liver stiffness assessed by transient elastography remained stable. A repeated DXA scan showed unchanged total fat mass content and cardiac MRI revealed no change (Fig. 1C). Reduction in appetite following metreleptin treatment was reported. Metreleptin treatment was well tolerated with no other adverse effects.