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Open access

Baris Akinci, Rasimcan Meral, Diana Rus, Rita Hench, Adam H Neidert, Frank DiPaola, Maria Westerhoff, Simeon I Taylor and Elif A Oral

Summary

A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients.

Learning points:

  • A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years.
  • Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed.
  • The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin.
  • Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite.
  • Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.
Open access

Peter Novodvorsky, Emma Walkinshaw, Waliur Rahman, Valerie Gordon, Karen Towse, Sarah Mitchell, Dinesh Selvarajah, Priya Madhuvrata and Alia Munir

Summary

Bariatric surgery is an effective therapy for obesity but is associated with long-term complications such as dumping syndromes and nutritional deficiencies. We report a case of a 26-year-old caucasian female, with history of morbid obesity and gestational diabetes (GDM), who became pregnant 4 months after Roux-en-Y bypass surgery. She developed GDM during subsequent pregnancy, which was initially managed with metformin and insulin. Nocturnal hypoglycaemia causing sleep disturbance and daytime somnolence occured at 19 weeks of pregnancy (19/40). Treatment with rapid-acting carbohydrates precipitated further hypoglycaemia. Laboratory investigations confirmed hypoglycaemia at 2.2 mmol/L with appropriately low insulin and C-peptide, intact HPA axis and negative IgG insulin antibodies. The patient was seen regularly by the bariatric dietetic team but concerns about compliance persisted. A FreeStyle Libre system was used from 21/40 enabling the patient a real-time feedback of changes in interstitial glucose following high or low GI index food intake. The patient declined a trial of acarbose but consented to an intraveneous dextrose infusion overnight resulting in improvement but not complete abolishment of nocturnal hypoglycaemia. Hypoglycaemias subsided at 34/40 and metformin and insulin had to be re-introduced due to high post-prandial blood glucose readings. An emergency C-section was indicated at 35 + 1/40 and a small-for-gestational-age female was delivered. There have been no further episodes of hypoglycaemia following delivery. This case illustrates challenges in the management of pregnancy following bariatric surgery. To our knowledge, this is the first use of FreeStyle Libre in dumping syndrome in pregnancy following bariatric surgery with troublesome nocturnal hypoglycaemia.

Learning points:

  • Bariatric surgery represents the most effective treatment modality in cases of severe obesity. With increasing prevalence of obesity, more people are likely to undergo bariatric procedures, many of which are women of childbearing age.
  • Fertility generally improves after bariatric surgery due to weight reduction, but pregnancy is not recommended for at least 12–24 months after surgery. If pregnancy occurs, there are currently little evidence-based guidelines available on how to manage complications such as dumping syndromes or gestational diabetes (GDM) in women with history of bariatric surgery.
  • Diagnosis of GDM relies on the use of a 75 g oral glucose tolerance test (OGTT). The use of this test in pregnant women is not recommended due to its potential to precipitate dumping syndrome. Capillary glucose monitoring profiles or continuous glucose monitoring (CGM) is being currently discussed as alternative testing modalities.
  • As the CGM technology becomes more available, including the recently introduced FreeStyle Libre Flash glucose monitoring system, more pregnant women, including those after bariatric surgery, will have access to this technology. We suggest urgent development of guidelines regarding the use of CGM and flash glucose monitoring tools in these circumstances and in the interim recommend careful consideration of their use on a case-to-case basis.
Open access

Athanasios Fountas, Zoe Giotaki, Evangelia Dounousi, George Liapis, Alexandra Bargiota, Agathocles Tsatsoulis and Stelios Tigas

Summary

Proteinuric renal disease is prevalent in congenital or acquired forms of generalized lipodystrophy. In contrast, an association between familial partial lipodystrophy (FPLD) and renal disease has been documented in very few cases. A 22-year-old female patient presented with impaired glucose tolerance, hyperinsulinemia, hirsutism and oligomenorrhea. On examination, there was partial loss of subcutaneous adipose tissue in the face, upper and lower limbs, bird-like facies with micrognathia and low set ears and mild acanthosis nigricans. Laboratory investigations revealed hyperandrogenism, hyperlipidemia, elevated serum creatine kinase and mild proteinuria. A clinical diagnosis of FPLD of the non-Dunnigan variety was made; genetic testing revealed a heterozygous c.1045C > T mutation in exon 6 of the LMNA gene, predicted to result in an abnormal LMNA protein (p.R349W). Electromyography and muscle biopsy were suggestive of non-specific myopathy. Treatment with metformin and later with pioglitazone was initiated. Due to worsening proteinuria, a renal biopsy was performed; histological findings were consistent with mild focal glomerular mesangioproliferative changes, and the patient was started on angiotensin-converting enzyme inhibitor therapy. This is the fourth report of FPLD associated with the c.1045C > T missense LMNA mutation and the second with co-existent proteinuric renal disease. Patients carrying this specific mutation may exhibit a phenotype that includes partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy.

Learning points:

  • Lipodystrophy is a rare disorder characterized by the complete or partial loss of subcutaneous adipose tissue, insulin resistance, diabetes mellitus and hyperlipidemia.
  • Proteinuric renal disease is a prevalent feature of generalized lipodystrophy but rare in familial partial lipodystrophy.
  • Patients carrying the c.1045C > T missense LMNA mutation (p.R349W) may present with familial partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy.