Ilgin Yildirim Simsir

Natural History of Congenital Generalized Lipodystrophy: A Nationwide Study From Turkey

CONTEXT Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near-total lack of body fat. OBJECTIVE We aimed to study natural history and disease burden of various subtypes of CGL. DESIGN We attempted to ascertain nearly all patients with CGL in Turkey. SETTING This was a nationwide study. PATIENTS OR OTHER PARTICIPANTS Participants included 33 patients (22 families) with CGL and 30 healthy controls. MAIN OUTCOME MEASURE(S) We wanted to ascertain genotypes by sequencing of the known genes. Whole-body magnetic resonance imaging was used to investigate the extent of fat loss. Metabolic abnormalities and end-organ complications were measured on prospective follow-up. RESULTS Analysis of the AGPAT2 gene revealed four previously reported and four novel mutations (CGL1; c.144C>A, c.667_705delinsCTGCG, c.268delC, and c.316+1G>T). Analysis of the BSCL2 gene revealed four different homozygous and one compound heterozygous possible disease-causing mutations (CGL2), including four novel mutations (c.280C>T, c.631delG, c.62A>T, and c.465-468delGACT). Two homozygous PTRF mutations (c.481-482insGTGA and c.259C>T) were identified (CGL4). Patients with CGL1 had preservation of adipose tissue in the palms, soles, scalp, and orbital region, and had relatively lower serum adiponectin levels as compared to CGL2 patients. CGL4 patients had myopathy and other distinct clinical features. All patients developed various metabolic abnormalities associated with insulin resistance. Hepatic involvement was more severe in CGL2. End-organ complications were observed at young ages. Two patients died at age 62 years from cardiovascular events. CONCLUSIONS CGL patients from Turkey had both previously reported and novel mutations of the AGPAT2, BSCL2, and PTRF genes. Our study highlights the early onset of severe metabolic abnormalities and increased risk of end-organ complications in patients with CGL.

Acquired partial lipodystrophy is associated with increased risk for developing metabolic abnormalities

OBJECTIVE Acquired partial lipodystrophy (APL) is a rare disorder characterized by progressive selective fat loss. In previous studies, metabolic abnormalities were reported to be relatively rare in APL, whilst they were quite common in other types of lipodystrophy syndromes. METHODS In this nationwide cohort study, we evaluated 21 Turkish patients with APL who were enrolled in a prospective follow-up protocol. Subjects were investigated for metabolic abnormalities. Fat distribution was assessed by whole body MRI. Hepatic steatosis was evaluated by ultrasound, MRI and MR spectroscopy. Patients with diabetes underwent a mix meal stimulated C-peptide/insulin test to investigate pancreatic beta cell functions. Leptin and adiponectin levels were measured. RESULTS Fifteen individuals (71.4%) had at least one metabolic abnormality. Six patients (28.6%) had diabetes, 12 (57.1%) hypertrigylceridemia, 10 (47.6%) low HDL cholesterol, and 11 (52.4%) hepatic steatosis. Steatohepatitis was further confirmed in 2 patients with liver biopsy. Anti-GAD was negative in all APL patients with diabetes. APL patients with diabetes had lower leptin and adiponectin levels compared to patients with type 2 diabetes and healthy controls. However, contrary to what we observed in patients with congenital generalized lipodystrophy (CGL), we did not detect consistently very low leptin levels in APL patients. The mix meal test suggested that APL patients with diabetes had a significant amount of functional pancreatic beta cells, and their diabetes was apparently associated with insulin resistance. CONCLUSIONS Our results show that APL is associated with increased risk for developing metabolic abnormalities. We suggest that close long-term follow-up is required to identify and manage metabolic abnormalities in APL.

Insulin Resistance in Brain and Possible Therapeutic Approaches

Although the brain has long been considered an insulin-independent organ, recent research has shown that insulin has significant effects on the brain, where it plays a role in maintaining glucose and energy homeostasis. To avoid peripheral insulin resistance, the brain may act via hypoinsulinemic responses, maintaining glucose metabolism and insulin sensitivity within its own confines; however, brain insulin resistance may develop due to environmental factors. Insulin has two important functions in the brain: controlling food intake and regulating cognitive functions, particularly memory. Notably, defects in insulin signaling in the brain may contribute to neurodegenerative disorders. Insulin resistance may damage the cognitive system and lead to dementia states. Furthermore, inflammatory processes in the hypothalamus, where insulin receptors are expressed at high density, impair local signaling systems and cause glucose and energy metabolism disorders. Excessive caloric intake and high-fat diets initiate insulin and leptin resistance by inducing mitochondrial dysfunction and endoplasmic reticulum stress in the hypothalamus. This may lead to obesity and diabetes mellitus (DM). Exercise can enhance brain and hypothalamic insulin sensitivity, but it is the option least preferred and/or continuously practiced by the general population. Pharmacological treatments that increase brain and hypothalamic insulin sensitivity may provide new insights into the prevention of dementia disorders, obesity, and type 2 DM in the future.

Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial lipodystrophy

OBJECTIVE Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by partial lack of subcutaneous fat. METHODS This multicenter prospective observational study included data from 56 subjects with FPLD (18 independent Turkish families). Thirty healthy controls were enrolled for comparison. RESULTS Pathogenic variants of the LMNA gene were determined in nine families. Of those, typical exon 8 codon 482 pathogenic variants were identified in four families. Analysis of the LMNA gene also revealed exon 1 codon 47, exon 5 codon 306, exon 6 codon 349, exon 9 codon 528, and exon 11 codon 582 pathogenic variants. Analysis of the PPARG gene revealed exon 3 p.Y151C pathogenic variant in two families and exon 7 p.H477L pathogenic variant in one family. A non-pathogenic exon 5 p.R215Q variant of the LMNB2 gene was detected in another family. Five other families harbored no mutation in any of the genes sequenced. MRI studies showed slightly different fat distribution patterns among subjects with different point mutations, though it was strikingly different in subjects with LMNA p.R349W pathogenic variant. Subjects with pathogenic variants of the PPARG gene were associated with less prominent fat loss and relatively higher levels of leptin compared to those with pathogenic variants in the LMNA gene. Various metabolic abnormalities associated with insulin resistance were detected in all subjects. End-organ complications were observed. CONCLUSION We have identified various pathogenic variants scattered throughout the LMNA and PPARG genes in Turkish patients with FPLD. Phenotypic heterogeneity is remarkable in patients with LMNA pathogenic variants related to the site of missense mutations. FPLD, caused by pathogenic variants either in LMNA or PPARG is associated with metabolic abnormalities associated with insulin resistance that lead to increased morbidity.

Interference in ACTH immunoassay negatively impacts the management of subclinical hypercortisolism

PurposeLow plasma corticotropin is considered a useful parameter for the diagnosis of subclinical hypercortisolism in patients with an adrenal incidentaloma. However, immunoassays are vulnerable to interference from endogenous antibodies. In this study, subjects who underwent Hypothalamus-pituitary-adrenal axis evaluation for the assessment of subclinical hypercortisolism were evaluated. The objective of the study was to ascertain whether antibody interference in corticotropin immunoassay affected the diagnostic work-up and clinical decisions.MethodsThe 437 consecutive patients with incidentally discovered adrenal adenomas were included in this single centre study. Patients who had a combination of a nonsuppressed corticotropin concentration (>4.4 pmol/L) and a non-suppressed cortisol concentration after 1 mg overnight dexamethasone suppression test (>50 nmol/L) were selected. Eight eligible subjects without specific features of Cushings syndrome were identified and recruited for interference studies and follow-up. Nine controls including one patient with unilateral adrenalectomy and one patient with Cushings disease were recruited as well.MeasurementsEligible subjects and controls were subjected to hormonal tests and investigations for suspected interference. Interference studies included measurement of corticotropin on a different analytical platform, serial dilutions, polyethylene glycol precipitation and heterophilic antibody analysis. Patients were followed with clinical and laboratory parameters for a median duration of 30 (12–90) months.ResultsAntibody interference was identified in four patients. Rheumatoid factor was responsible for the interference in one patient. Clinical management of the patients was affected by the erroneous results. Interference tests were negative in control subjects.ConclusionsErroneous results associated with analytical interference negatively impacted on clinical decision making in this patient group. This should be considered particularly in conditions such as subclinical hypercortisolism which decisions depend on laboratory investigations mainly. Analytical interference could explain the high variability observed both in field measurements from patients who were expected to have lower corticotropin concentrations and in subclinical hypercortisolism prevalence reported by different studies. Many problems can be resolved by ensuring good communication between clinical and laboratory staff.

A case of an ectopic prolactinoma.

A 34-year-old female presented to our clinic with a 1.5 year history of secondary amenorrhea and galactorrhea. Prolactin (PRL) level was found to be 151.89 ng/ml. Pituitary imaging was reported to be normal. An examination of the patient revealed that PRL level was still high so the dose of cabergoline was further increased and subsequently, bromocriptine was added to the treatment. There was no reduction in PRL levels in controls. A scanning was performed to look for an ectopic focus. Abdominal computerized tomography revealed a heterogenous mass lesion originating from the uterus. Octreotide scintigraphy was performed and we observed an involvement consistent with the mass in the uterus. The patient underwent abdominal total hysterectomy. PRL dropped to 0.4 ng/ml the next day after the operation. The pathology result was a low-grade malignant mesenchymal tumor. Prolactin was found to be immunohistochemically negative. However, galactorrhea disappeared postoperative and PRL levels are still low. Elevated levels of PRL, resistant to bromocriptine and cabergoline, rapidly returned to normal after hysterectomy, which obviously indicates that hyperprolactinemia was associated with the myoma of the uterus.

Determining residual adipose tissue characteristics with MRI in patients with various subtypes of lipodystrophy

PURPOSE We aimed to investigate residual adipose tissue with whole-body magnetic resonance imaging to differentiate between subtypes of lipodystrophy. METHODS A total of 32 patients (12 with congenital generalized lipodystrophy [CGL], 1 with acquired generalized lipodystrophy [AGL], 12 with familial partial lipodystrophy [FPLD], and 7 with acquired partial lipodystrophy [APL]) were included. RESULTS Despite generalized loss of metabolically active adipose tissue, patients with CGL1 caused by AGPAT2 mutations had a significant amount of residual adipose tissue in the scalp, earlobes, retro-orbital region, and palms and soles. No residual adipose tissue was noted particularly in the head and neck, palms and soles in CGL2 caused by BSCL2 mutations. CGL4 caused by mutations in the PTRF gene was characterized with well-preserved retro-orbital and bone marrow fat in the absence of any visible residual adipose tissue in other areas. No residual adipose tissue was observed in AGL. Despite loss of subcutaneous fat, periarticular adipose tissue was preserved in the lower limbs of patients with FPLD. Retro-orbital adipose tissue was surprisingly preserved in APL, although they lacked head and neck fat. CONCLUSION Lipodystrophies are a heterogeneous group of disorders characterized by generalized or partial loss of adipose tissue, which can be congenital or acquired. Our results suggest that residual adipose tissue characteristics can help distinguish different subtypes of lipodystrophy.

Can an Oral Antidiabetic (Rosiglitazone) be of Benefit in Leukemia Treatment

PPARs are ligand-regulated transcription factors and regulate expression of several gene products. Therefore, PPARs are being studied for their possible contribution to the treatment of cancer, atherosclerosis, inflammation, infertility and demyelinating diseases. Primary AML patients were observed to have significantly elevated PPARγ mRNA expression compared to normal peripheral blood or bone marrow mononuclear cells. This study investigated the cytotoxic effects of rosiglitazone maleate, a pure PPARγ agonist, in vitro in HL-60 cell line. This study obtained results which can provide guidance for future studies. Whether the PPARy agonist rosiglitazone maleate may provide additive effects in refractory or relapsing cases of acute leukemia may be set as an objective for the future studies.

Glucagon like peptide-1 (GLP-1) likes Alzheimer’s disease

Glucagon-like peptide-1 (GLP-1) is a 30 amino acid long peptide hormone derived from the proglucagon gene and secreted in the distal small intestine when food enters the duodenum. GLP-1 is also produced in the central nervous system (CNS), predominantly in the brainstem, and subsequently transported to a large number of regions in the CNS. Neuronal cells in nucleus tractus solitarius (NTS) can synthesize GLP-1 and extends to hypothalamus, some thalamic and cortical areas. A G protein coupled receptor (GPCR) provides the majority of GLP-1 actions. GLP-1 receptor activation triggers some in vivo signaling pathways. GLP-1 receptor agonists (GLP-1 RA) are used in the treatment diabetes and obesity. GLP-1 stimulates insulin secretion, inhibits glucagon secretion, decreases food intake, reduces appetite, delays gastric emptying, provides weight reduction, and protects β cells from apoptosis. Alzheimers disease (AD) is the most prevalent form of dementia. It is characterized by cognitive insufficiencies and behavioral changes that impact memory and learning abilities, daily functioning and quality of life. Hyperinsulinemia and insulin resistance, which are known as pathophysiological features of the T2DM, have also been demonstrated to have significant impact on cognitive impairment. It is thought that GLP-1 affects neurological and cognitive functions, as well as its regulatory effect on glucose metabolism. The pathophysiological relationship between GLP-1 and AD is discussed in this review.

First metreleptin treatment for generalized lipodystrophy in Turkey.

To the Editor: We report the first patient with generalized lipodystrophy (GL) treated with metreleptin in Turkey. GL is a rare disorder characterized by near total lack of adipose tissue that is associated with ectopic lipid accumulation and hypoleptinaemia. Patients with GL develop metabolic abnormalities associated with insulin resistance in the early years of life. Metreleptin is a recombinant analogue of human leptin which has recently been authorized for the treatment of metabolic complications of leptin deficiency in patients with GL. In a recent paper published in Diabetes Obesity and Metabolism, Vatier et al. reported that metreleptin improves β-cell function in patients with diabetes and lipodystrophy. The authors showed that metreleptin treatment resulted in increased insulin sensitivity during euglycaemic–hyperinsulinaemic clamp, and also increased the disposition index (Acute Insulin Response (AIR) × M-value), which adjusts the acute β-cell function to insulin sensitivity after 1 year of metreleptin. A 22-year-old woman with congenital GL, caused by a homozygous c.144C > A (p.C48*) AGPAT2 mutation, was treated with 5 mg/d of metreleptin for 9 months. She had polycystic ovaries, acanthosis nigricans, hypertension, diabetes, proteinuria, diabetic neuropathy and recurrent acute pancreatitis. She was receiving metformin, pioglitazone, gemfibrozil, fish oil, ramipril, and 210 units/d of insulin. She had also previously received multiple courses of plasmapheresis for hypertriglyceridaemia. Her basal leptin level was 0.1 ng/mL. Metreleptin acted rapidly on glycaemic control which, we believe, was mostly affected by appetite control during the 1st month of treatment (Figure 1A). In the following months, we observed a gradual improvement in her glycaemic control, along with a decrease in the amount of insulin that she used (Figure 1B). The need for insulin disappeared on the 9th month of treatment. On her latest visit, we observed that glycated haemoglobin remained at target levels after insulin discontinuation for 2 months. Insulin resistance, represented by homeostatic model assessment of the insulin resistance index, decreased from 6.53 to 1.06. Insulin secretion measured by the ratio of the area under the insulin curve to the area under the glucose curve (AUCins/ glu) on mixed-meal tolerance test increased. Insulin sensitivity, measured using the Matsuda index, improved after metreleptin treatment, from 3.56 to 12.59. Her insulin secretion-sensitivity index-2 score, the product of insulin secretion represented by AUCins/glu and insulin sensitivity represented by Matsuda index, increased from a baseline level of 0.12 to 2.87 by the 9th month of treatment. Triglyceride levels dropped progressively, starting from the 1st weeks of treatment (Figure 1C). Hepatic steatosis improved significantly (Figure 1D). The regression in abdominal protrusion caused by hepatomegaly was remarkable even on physical examination (Figure 1E). We observed a dramatic decrease in proteinuria which was at extreme levels before treatment (Figure 1F). Excessive sweating secondary to hypermetabolic state, which was associated with leptin deficiency, disappeared by the 5th month of treatment. No treatment-related side effect was observed. We previously reported that the prevalence of congenital GL in Turkey is higher than the worldwide prevalence of this condition as a result of relatively high rates of consanguineous marriages. Our first experience shows that metreleptin treatment leads to a dramatic improvement in metabolic control, ectopic lipid accumulation, proteinuria and appetite control. Metreleptin has an orphan drug designation in the European Union, and it is available in selected European centres through compassionate programmes. Metreleptin was provided by such a local compassionate-use agreement in this particular case. As members of the Turkish Lipodystrophy Study Group, we are looking forward to the opportunity of using metreleptin in all Turkish patients with GL, either through standard reimbursement protocols approved by the national authorities or through a wider national compassionate-use agreement between the authorities and supplier.