Dunnigan lipodystrophy syndrome: French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins).

Dunnigan syndrome, or Familial Partial Lipodystrophy type 2 (FPLD2; ORPHA 2348), is a rare autosomal dominant disorder due to pathogenic variants of the LMNA gene. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins), is to provide health professionals with a guide to optimal management and care of patients with FPLD2, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French). Dunnigan syndrome is characterized by a partial atrophy of the subcutaneous adipose tissue and by an insulin resistance syndrome, associated with a risk of metabolic, cardiovascular and muscular complications. Its prevalence, assessed at 1/100.000 in Europe, is probably considerably underestimated. Thorough clinical examination is key to diagnosis. Biochemical testing frequently shows hyperinsulinemia, abnormal glucose tolerance and hypertriglyceridemia. Elevated hepatic transaminases (hepatic steatosis) and creatine phosphokinase, and hyperandrogenism in women, are common. Molecular analysis of the LMNA gene confirms diagnosis and allows for family investigations. Regular screening and multidisciplinary monitoring of the associated complications are necessary. Diabetes frequently develops from puberty onwards. Hypertriglyceridemia may lead to acute pancreatitis. Early atherosclerosis and cardiomyopathy should be monitored. In women, polycystic ovary syndrome is common. Overall, the management of patients with Dunnigan syndrome requires the collaboration of several health care providers. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are described to provide such a support.

Fenofibrate decreases plasma ceramide in type 2 diabetes patients: A novel marker of CVD?

AIM: The benefit of the lipid-lowering drug fenofibrate on cardiovascular outcomes is controversial. Our aim was to find new circulating markers to identify those patients most likely to benefit from fenofibrate prescription. METHODS: Analyses were conducted of plasma samples collected from 102 patients with type 2 diabetes, enrolled in the FIELD trial, before and after fenofibrate treatment (200mg/day). Non-targeted and targeted lipid analyses and apolipoprotein measurements were made using mass spectrometry methods. RESULTS: Lipidomics revealed a global decrease in ceramide after fenofibrate treatment confirmed by quantitative analysis (-18.2%, P<0.001). These changes were strongly associated with those found for plasma sphingomyelin (r=0.80, P<0.001) and, to a lesser extent, for sphingosine-1-phosphate (r=0.34, P<0.001). Ceramide levels decreased in 73.5% of patients. In addition to the expected lipid changes (decreases in triglycerides, total cholesterol and LDL cholesterol, and increase in HDL cholesterol), fenofibrate also lowered plasma apoC-II (-11.1%, P<0.01), apoC-III (-24.6%; P<0.001), apoB100 (-27.0%, P<0.01) and sphingomyelinase (-7.6%, P<0.001), and increased plasma apoA-II (22.4%, P<0.001) as well as adiponectin (11.4%, P<0.001). No significant association was found between ceramide decrease and these modulations except for total cholesterol (r=0.20, P=0.047) and HDL protein components. At baseline, only elevated sphingolipid levels were significantly associated with ceramide reduction after fenofibrate treatment. CONCLUSION: Fenofibrate lowers plasma ceramide independently of the usual lipid parameters. As ceramide is a strong marker of atherosclerosis, our study underpins the need to further evaluate its contribution to cardiovascular events in fenofibrate-treated patients.

Treatment of diabetic ketoacidosis with subcutaneous insulin lispro: a review of the current evidence from clinical studies.

AIM: Low-dose intravenous infusions of regular insulin, usually initiated in the emergency department and continued in the intensive care unit (ICU), are the standard care for patients with diabetic ketoacidosis (DKA) to ensure rapid resolution of hyperglycaemia and ketoacidosis. Several studies have evaluated whether subcutaneous injections of the rapid-acting analogue insulin lispro may be an alternative to intravenous insulin infusion for avoiding ICU admissions of uncomplicated DKA cases. METHODS: This review summarizes the current clinical evidence for the effectiveness and safety of subcutaneous insulin lispro injections in non-severe DKA patients. Relevant studies were identified by a systematic literature search through the PubMed database. RESULTS: To date, four small randomized studies (156 patients overall; three studies in adults and one in paediatric patients with diabetes) have directly compared subcutaneous insulin lispro injections every 1-2h vs continuous intravenous infusions of regular insulin. Patients with severe complications were excluded. In all studies, the mean time to resolution of DKA was similar in both treatment groups [range (three studies): lispro 10-14.8h; regular insulin 11-13.2h]. The mean time to resolution of hyperglycaemia, total insulin doses required, number of hospitalization days and number of hypoglycaemic episodes were similar in both treatment groups; no severe complications or DKA recurrences were reported, and one study showed a 39% cost reduction for the insulin lispro group. CONCLUSION: In patients with mild-to-moderate DKA, subcutaneous injections of insulin lispro every 1-2h offer a feasible alternative to continuous intravenous infusions of regular insulin, and should now be evaluated in larger, more appropriately powered studies.

Pancreatic exocrine function in patients with diabetes.

BACKGROUND: Decreased function of the exocrine pancreas is frequent in patients with diabetes. Our aim was to investigate clinical correlates of pancreatic exocrine failure in patients with diabetes. PATIENTS AND METHODS: We investigated exocrine function by assaying both elastase-1 concentration and chymotrypsin activity in 667 patients. We conducted separate analysis on patients with Type 1 diabetes and patients with Type 2 diabetes. Patients were separated into three groups according to whether both elastase-1 concentration and chymotrypsin activity were normal, or one or both were altered. RESULTS: A total of 667 consecutive patients were analysed, including 195 with Type 1 and 472 with Type 2 diabetes. Elastase-1 concentration was <200 µg/g in 23% of the patients. Chymotrypsin activity was <6 U/g in 26% of the patients. In 66% of the patients elastase-1 concentration was >200 ug/g and chymotrypsin activity >6 U/g. One test was below threshold in 19%, both in 15%. In patients with Type 1 diabetes, the three groups defined by results of elastase-1 concentration and chymotrypsin activity differed with regard to duration of diabetes and prevalence of glutamic acid decarboxylase antibodies, but not BMI or HbA(1c) , or prevalence of retinopathy, neuropathy, nephropathy or vascular disease. In patients with Type 2 diabetes, the three groups differed with regard to BMI, use of insulin and vascular disease, but not known duration. CONCLUSION: Factors associated with pancreatic exocrine failure differ in patients with Type 1 diabetes compared with patients with type 2 diabetes. In patients with Type 2 diabetes, association of decreased pancreatic exocrine function with BMI and vascular disease suggests a role of pancreatic arteriopathy.

Effects of cross-link breakers, glycation inhibitors and insulin sensitisers on HDL function and the non-enzymatic glycation of apolipoprotein A-I.

AIMS/HYPOTHESIS: Hyperglycaemia, a key feature of diabetes, is associated with non-enzymatic glycation of plasma proteins. We have shown previously that the reactive alpha-oxoaldehyde, methylglyoxal, non-enzymatically glycates apolipoprotein (Apo)A-I, the main apolipoprotein of HDL, and prevents it from activating lecithin:cholesterol acyltransferase (LCAT), the enzyme that generates almost all of the cholesteryl esters in plasma. This study investigates whether the glycation inhibitors aminoguanidine and pyridoxamine, the insulin sensitiser metformin and the cross-link breaker alagebrium can inhibit and/or reverse the methylglyoxal-mediated glycation of ApoA-I and whether these changes can preserve or restore the ability of ApoA-I to activate LCAT. METHODS: Inhibition of ApoA-I glycation was assessed by incubating aminoguanidine, pyridoxamine, metformin and alagebrium with mixtures of methylglyoxal and discoidal reconstituted HDL (rHDL) containing phosphatidylcholine and ApoA-I, ([A-I]rHDL). Glycation was assessed as the modification of ApoA-I arginine, lysine and tryptophan residues, and by the extent of ApoA-I cross-linking. The reversal of ApoA-I glycation was investigated by pre-incubating discoidal (A-I)rHDL with methylglyoxal, then incubating the modified rHDL with aminoguanidine, pyridoxamine or alagebrium. RESULTS: Aminoguanidine, pyridoxamine, metformin and alagebrium all decreased the methylglyoxal-mediated glycation of the ApoA-I in discoidal rHDL and conserved the ability of the particles to act as substrates for LCAT. However, neither aminoguanidine, pyridoxamine nor alagebrium could reverse the glycation of ApoA-I or restore its ability to activate LCAT. CONCLUSIONS/INTERPRETATION: Glycation inhibitors, insulin sensitisers and cross-link breakers are important for preserving normal HDL function in diabetes.

The impact of glycation on apolipoprotein A-I structure and its ability to activate lecithin:cholesterol acyltransferase.

AIMS/HYPOTHESIS: Hyperglycaemia, one of the main features of diabetes, results in non-enzymatic glycation of plasma proteins, including apolipoprotein A-I (apoA-I), the most abundant apolipoprotein in HDL. The aim of this study was to determine how glycation affects the structure of apoA-I and its ability to activate lecithin:cholesterol acyltransferase (LCAT), a key enzyme in reverse cholesterol transport. MATERIALS AND METHODS: Discoidal reconstituted HDL (rHDL) containing phosphatidylcholine and apoA-I ([A-I]rHDL) were prepared by the cholate dialysis method and glycated by incubation with methylglyoxal. Glycation of apoA-I was quantified as the reduction in detectable arginine, lysine and tryptophan residues. Methylglyoxal-AGE adduct formation in apoA-I was assessed by immunoblotting. (A-I)rHDL size and surface charge were determined by non-denaturing gradient gel electrophoresis and agarose gel electrophoresis, respectively. The kinetics of the LCAT reaction was investigated by incubating varying concentrations of discoidal (A-I)rHDL with a constant amount of purified enzyme. The conformation of apoA-I was assessed by surface plasmon resonance. RESULTS: Methylglyoxal-mediated modifications of the arginine, lysine and tryptophan residues in lipid-free and lipid-associated apoA-I were time- and concentration-dependent. These modifications altered the conformation of apoA-I in regions critical for LCAT activation and lipid binding. They also decreased (A-I)rHDL size and surface charge. The rate of LCAT-mediated cholesterol esterification in (A-I)rHDL varied according to the level of apoA-I glycation and progressively decreased as the extent of apoA-I glycation increased. CONCLUSIONS/INTERPRETATION: It is concluded that glycation of apoA-I may adversely affect reverse cholesterol transport in subjects with diabetes.

Defective antioxidative activity of small dense HDL3 particles in type 2 diabetes: relationship to elevated oxidative stress and hyperglycaemia.

AIMS/HYPOTHESIS: Elevated oxidative stress, hyperglycaemia, and dyslipidaemia involving low levels of HDL particles are key proatherogenic factors in type 2 diabetes mellitus. We examined the relationship of oxidative stress, and the degree of glycaemia and triglyceridaemia, to antioxidative function of HDL particle subspecies in type 2 diabetes. SUBJECTS AND METHODS: Five HDL subfractions (2b, 2a, 3a, 3b, 3c) were isolated by density gradient ultracentrifugation from well-controlled type 2 diabetic subjects (n=20) and normolipidaemic, non-diabetic controls (n=10). Specific antioxidative activity (capacity to protect LDL from oxidation on a unit particle mass or on a particle number basis), chemical composition and enzymatic activities were measured in each subfraction. Systemic oxidative stress was assessed as plasma levels of 8-isoprostanes. RESULTS: Specific antioxidative activity of small dense HDL3b and 3c particles in diabetic patients was significantly diminished (up to -47%, on a particle mass or particle number basis) as compared with controls. Plasma 8-isoprostanes were markedly elevated (2.9-fold) in diabetic patients, were negatively correlated with both specific antioxidative activity of HDL3 subfractions and plasma HDL cholesterol (HDL-C) levels, and were positively correlated with glycaemia and triglyceridaemia. Paraoxonase 1 activity was consistently lower in diabetic HDL subfractions and was positively correlated with HDL3 antioxidative activity. The altered chemical composition of diabetic HDL3 subfractions (core cholesteryl ester depletion, triglyceride enrichment) was equally correlated with diminished antioxidative activity. CONCLUSIONS/INTERPRETATION: Antioxidative activity of small dense HDL is deficient in type 2 diabetes, is intimately linked to oxidative stress, glycaemia and hypertriglyceridaemia and primarily reflects abnormal intrinsic physicochemical properties of HDL particles.