Robert Semple

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

Significance The characterization of rare monogenic human disorders can and has yielded unique biological insights. Our phenotypic description and functional characterization of human loss-of-function mutations in PCYT1A is both clinically important for patients and their families afflicted with this rare but serious metabolic disease and biologically helpful in advancing understanding of the physiological consequences of impaired PCYT1A activity in humans. Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action.

Successful Treatment of Type B Insulin Resistance With Rituximab

Context: Type B insulin resistance is a very rare disease caused by autoantibodies against the insulin receptor. The mortality of type B insulin resistance is high (>50%), and management of this disease is not yet standardized. We report the successful treatment of a patient with type B insulin resistance with rituximab, cyclophosphamide, and prednisone. Case Description: A 45-year-old woman presented with unintended weight loss of 20 kg, unusually widespread acanthosis nigricans, and glucose levels > 500 mg/dL, which could not be controlled with up to 600 IU/d of insulin. Because of the severity of the insulin resistance combined with features of insulin deficiency, type B insulin resistance was suspected. Detection of high levels of insulin receptor autoantibodies confirmed the diagnosis. Neither immunosuppressive therapy with Ig iv nor plasmapheresis had an effect on glucose levels or insulin dose. Because the patients condition was deteriorating, we started rituximab (750 mg/m2 in two doses 2 wk apart) together with cyclophosphamide (100 mg/d orally) and dexamethasone 40 mg/d for 4 days. Two months after initiation of rituximab therapy, fasting glucose levels ranged from 80 to 110 mg/dL and could be controlled with very low insulin doses. Glycated hemoglobin decreased from 11.8 to 6.5%. Two months later, insulin therapy was stopped, and the patient showed normal blood glucose readings. Conclusion: In this patient with type B insulin resistance, Ig treatment and plasmapheresis failed to improve the condition. Finally, treatment with rituximab, cyclophosphamide, and steroids was successful in inducing a complete remission.

Constitutive activation of AKT2 in humans leads to hypoglycemia without fatty liver or metabolic dyslipidemia

Context: The activating p.Glu17Lys mutation in AKT2, a kinase mediating many of insulin’s metabolic actions, causes hypoinsulinemic hypoglycemia and left-sided hemihypertrophy. The wider metabolic profile and longer-term natural history of the condition has not yet been reported. Objective: To characterize the metabolic and cellular consequences of the AKT2 p.Glu17Lys mutation in two previously reported males at the age of 17 years. Design and Intervention: Body composition analysis using dual-energy X-ray absorptiometry, overnight profiling of plasma glucose, insulin, and fatty acids, oral glucose tolerance testing, and magnetic resonance spectroscopy to determine hepatic triglyceride content was undertaken. Hepatic de novo lipogenesis was quantified using deuterium incorporation into palmitate. Signaling in dermal fibroblasts was studied ex vivo. Results: Both patients had 37% adiposity. One developed hypoglycemia after 2 hours of overnight fasting with concomitant suppression of plasma fatty acids and ketones, whereas the other maintained euglycemia with an increase in free fatty acids. Blood glucose excursions after oral glucose were normal in both patients, albeit with low plasma insulin concentrations. In both patients, plasma triglyceride concentration, hepatic triglyceride content, and fasting hepatic de novo lipogenesis were normal. Dermal fibroblasts of one proband showed low-level constitutive phosphorylation of AKT and some downstream substrates, but no increased cell proliferation rate. Conclusions: The p.Glu17Lys mutation of AKT2 confers low-level constitutive activity upon the kinase and produces hypoglycemia with suppressed fatty acid release from adipose tissue, but not fatty liver, hypertriglyceridemia, or elevated hepatic de novo lipogenesis. Hypoglycemia may spontaneously remit.

Roux-en-Y Gastric Bypass Surgery in the Management of Familial Partial Lipodystrophy Type 1

Context: Familial partial lipodystrophy type 1 (FPLD1) is an extreme form of central adiposity, with peripheral lipodystrophy associated with severe manifestations of the metabolic syndrome, often poorly responsive to standard therapeutic approaches. Body mass index in FPLD1 varies but, in many cases, is below the level at which metabolic surgery is usually considered as a therapeutic option. Design: We detailed the metabolic response to gastric bypass surgery of three patients with FPLD1, refractory to medical therapy. Results: Roux-en-Y gastric bypass (RYGB) was associated with weight loss and substantial improvements in glycemic control and insulin sensitivity. All three patients were able to stop using insulin. Glucose tolerance testing in one patient demonstrated an increase in L-cell–derived gut hormone responses postoperatively. Conclusion: RYGB surgery substantially improved glycemic control in three patients with FPLD1, two of whom had body mass indices below 30 kg/m2. RYGB should be considered in patients with partial lipodystrophy and refractory metabolic disease.

Insulin Resistance and Diabetes Associated with Lipodystrophies

Obesity is strongly associated with insulin resistance, diabetes mellitus, fatty liver disease, and dyslipidaemia. The opposite perturbation, namely absence or paucity of adipose tissue in lipodystrop

Non-alcoholic fatty liver disease in patients attending the National Severe Insulin Resistance Service

1 Metabolic Research Laboratories, University of Cambridge, Cambridge, UK, 2 Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK, 3 Wolfson Department of Diabetes and Endocrinology, Addenbrooke’s Hospital, Cambridge, UK 4 Department of Radiology, University of Cambridge, Cambridge, UK 5 Department of Radiology, Addenbrooke’s Hospital, Cambridge, UK 6 Department of Medicine, Addenbrooke’s Hospital, Cambridge, UK