Pierre Lefebvre

Liver abnormalities in severely obese subjects: Effect of drastic weight loss after gastroplasty

OBJECTIVE: To examine the factors associated with liver steatosis in severely obese subjects and to test the potential reversibility of fatty liver after weight loss.DESIGN: Retrospective clinical study.SUBJECT: 528 obese patients before bariatric surgery and 69 obese subjects of the initial cohort evaluated before and 27±15 months after gastroplasty.MEASUREMENTS: Fatty deposition (scored as mild, moderate or severe) and inflammatory changes were evaluated in liver biopsies; clinical (body mass index (BMI), age, gender, duration of obesity) and biological (glucose, triglycerides, liver enzymes) parameters were related to histological findings.RESULTS: 74% of the 528 biopsies showed fatty change, estimated as mild in 41% of cases, moderate in 32% and severe in 27%. The prevalence of steatosis was significantly higher in men than in women (91% vs 70%, P=0.001) and in patients with impaired glucose tolerance or type 2 diabetes compared with nondiabetics (89% vs 69% P=0.001). The severity of the steatosis was associated with BMI (P=0.002) but not with the duration of obesity or the age of the patient. When compared with patients without fatty change, those with liver steatosis had significantly higher fasting plasma glucose (5.5 mmol/l vs 5.1 mmol/l, P=0.007) and triglycerides (1.8 mmol/l vs 1.3 mmol/l, P=0.002). Mean serum liver enzyme activities (alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl-transpeptidase (γGT) were significantly (P<0.001) increased in patients with fatty change but remained within laboratory reference values. In the 69 patients who have been evaluated after a marked weight reduction (−32±19 kg), 45% of the biopsies were considered as normal (vs 13% before, P<0.001) while pure fatty change was still observed in 38% of the patients (vs 83% before, P=0.001). However, the severity of the steatosis was significantly (P<0.001) reduced (mild: 62% vs 21%; moderate: 23% vs 37%; severe: 15% vs 42%). In addition, a significant increase of hepatitis was observed in 26% of the biopsies (vs 14% before, P<0.05).CONCLUSIONS: Liver steatosis in obese subjects is associated with men, diabetic status, BMI, higher fasting glucose and hypertriglyceridaemia. Postgastroplasty weight loss reduces liver steatosis, but seems to increase the incidence of inflammatory lobular hepatitis.

MAGNESIUM AND GLUCOSE HOMEOSTASIS

SummaryMagnesium is an important ion in all living cells being a cofactor of many enzymes, especially those utilising high energy phosphate bounds. The relationship between insulin and magnesium has been recently studied. In particular it has been shown that magnesium plays the role of a second messenger for insulin action; on the other hand, insulin itself has been demonstrated to be an important regulatory factor of intracellular magnesium accumulation. Conditions associated with insulin resistance, such as hypertension or aging, are also associated with low intracellular magnesium contents. In diabetes mellitus, it is suggested that low intracellular magnesium levels result from both increased urinary losses and insulin resistance. The extent to which such a low intracellular magnesium content contributes to the development of macro- and microangiopathy remains to be established. A reduced intracellular magnesium content might contribute to the impaired insulin response and action which occurs in Type 2 (non-insulin-dependent) diabetes mellitus. Chronic magnesium supplementation can contribute to an improvement in both islet Beta-cell response and insulin action in non-insulin-dependent diabetic subjects.

Vitamin E reduction of protein glycosylation in diabetes. New prospect for prevention of diabetic complications

Objective This study evaluated the possibility of inhibiting protein glycosylation in vivo with vitamin E. Research Design and Methods Two groups of 10 insulin-requiring diabetic patients, matched for duration of disease and metabolic control, received daily vitamin E supplementation of 1200 and 600 mg, respectively, for 2 mo. A third group of 10 diabetic patients, matched for duration of disease and metabolic control, served as the control group and received placebo. Fasting plasma glucose, mean daily plasma glucose, fasting labile HbA1, and glycosylated proteins were measured in the basal state and after 1 and 2 mo of treatment. In addition, hyperglycemic clamp studies were performed in basal state and after 1 mo of vitamin E administration in all patients. Results Glycemic indices did not show any significant changes during the study, whereas fasting labile HbA, and glycosylated proteins decreased significantly after 1 and 2 mo in patients on vitamin E administration. Stable HbA1 decreased after 2 mo. Mean glycemic incremental area in the hyperglycemic clamp procedure was similar before and after treatment, whereas a significant reduction in mean labile HbA1 incremental area was found after vitamin E supplementation. A significant difference was also found in both fasting and incremental labile HbA1 levels, stable HbA1, and glycosylated proteins between the two groups of diabetic patients on the two doses of vitamin E; the diabetic patients who received the higher dose of vitamin E showed the greater reduction. No significant changes in these parameters were observed in diabetic patients on placebo administration. Conclusions These results demonstrate that vitamin E administration may reduce protein glycosylation in diabetic subjects independently of changes in plasma glucose, an effect that may be due to the inhibition of labile glycosylation, the first step of the Maillard reaction. Long-term studies will help establish the usefulness of vitamin E administration for the prevention of diabetic complications.

New susceptibility loci associated with kidney disease in Type 1 diabetes

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Oral antidiabetic agents. A guide to selection.

SummaryType 2 diabetes mellitus (formerly named non-insulin-dependent diabetes mellitus or NIDDM) is a heterogeneous disease resulting from a dynamic interaction between defects in insulin secretion and insulin action. Various pharmacological approaches can be used to improve glucose homeostasis via different modes of action: sulphonylureas essentially stimulate insulin secretion, biguanides (metformin) act by promoting glucose utilisation and reducing hepatic glucose production, α-glucosidase inhibitors (acarbose) slow down carbohydrate absorption from the gut and thiazolidinediones (troglitazone) enhance cellular insulin action on glucose and lipid metabolism.These pharmacological treatments may be used individually for certain types of patients, or may be combined in a stepwise fashion to provide more ideal glycaemic control for most patients. Selection of oral antihyperglycaemic agents as first-line drug or combined therapy should be based on both the pharmacological properties of the compounds (efficacy and safety profile) and the clinical characteristics of the patient (stage of disease, bodyweight, etc.).Mildly hyperglycaemic patients should preferably be treated with metformin, acarbose or thiazolidinediones (which are not associated with any hypoglycaemic risk), while more severely hyperglycaemic individuals should receive a sulphonylurea. In moderately hyperglycaemic patients, sulphonylureas should be preferred in nonobese patients while metformin, and probably also thiazolidinediones, should have priority in obese insulin-resistant type 2 diabetic patients. Acarbose is mainly indicated to reduce post-prandial glucose fluctuations and improve glycaemic stability. Each antihyperglycaemic agent may also be combined with insulin therapy to improve glycaemic control and/or reduce the insulin requirement of diabetic patients after secondary failure to oral treatment. Finally, safety should be taken into account in elderly patients and/or those with renal impairment, especially as far as the use of sulphonylureas (higher risk of hypoglycaemia) and metformin (higher risk of lactic acidosis) is concerned.

Control by Insulin of Sodium Potassium and Water Excretion by the Isolated Dog Kidney

SummaryInsulin has been shown to decrease sodium, potassium and water excretion by direct action on the kidney. Reduction of sodium excretion is due to enhanced tubular reabsorption as a probable consequence of stimulated active sodium transport. The renal effect of insulin is demonstrated with plasma hormone concentration observable in pathophysiological conditions; it offers therefore a possible explanation for some clinical findings such as the changes in sodium, potassium and water excretion occurring in man after fasting and subsequent glucose feeding.

The postprandial state and risk of cardiovascular disease

Metabolism in man is regulated by complex hormonal signals and substrate interactions, and for many years the clinical focus has centred on the metabolic and hormonal picture after an overnight fast. More recently, the postprandial state, i.e. ‘the period that comprises and follows a meal’, has received more attention. The oral glucose tolerance test (OGTT), although highly non‐physiological, has been used largely as a model of the postprandial state. Epidemiological studies have shown that, when ‘impaired’, oral glucose tolerance is associated with an increased risk of cardiovascular disease. Postprandial hyperlipidaemia has been investigated more recently in epidemiological, mechanistical and intervention studies, most of which indicate that high postprandial triglyceride levels, and particularly postprandial rich triglyceride remnants, constitute an increased risk for cardiovascular disease. Recent studies have shown that excessive postprandial glucose excursions are accompanied by oxidative stress and, less well known, activation of blood coagulation (increase in circulating D‐dimers and prothrombin fragments). The mechanisms through which increased postprandial glucose levels and lipid concentrations may damage endothelial cells on blood vessel walls appear to be complex. These mechanisms include the activation of protein kinase C, increased expression of adhesion molecules, increased adhesion and uptake of leucocytes, increased production of proliferative substances such as endothelin, increased proliferation of endothelial cells, increased synthesis of collagen IV and fibronectin, and decreased production of nitric oxide (NO). In conclusion, the ‘postprandial state’ cumulatively covers almost half of the nycthemeral period, and its physiology involves numerous finely regulated motor, secretory, hormonal and metabolic events. Epidemiological and mechanistical studies have suggested that perturbations of the postprandial state are involved in cardiovascular disease. Correcting the abnormalities of the postprandial state must form part of the strategy for the prevention and management of cardiovascular diseases, particularly those that are associated with diabetes mellitus. Copyright

Metabolic Control May Influence the Increased Superoxide Generation in Diabetic Serum

Superoxide anion (O2‐) generation in serum from 10 Type 1 diabetic patients and 10 normal subjects was measured ex vivo. The amount of O2‐ production was significantly increased in diabetic serum 0.41 ± 0.04 (±SD) vs 0.14 ± 0.04 μmol l−1 min−1, p < 0.001) and correlated with fasting plasma glucose and glycosylated protein levels in both diabetic (r = 0.72, p < 0.01, and r = 0.62, p < 0.05) and normal (r = 0.75, p < 0.01 and r = 0.64, p < 0.05) subjects. Improved metabolic control in the diabetic patients was associated with a reduction of serum O2‐ production (0.28 ± 0.06 μmol l−1 min−1, p < 0.01), but the correlation between O2‐ levels and fasting plasma glucose and glycosylated protein concentrations was retained (r = 0.86 and r = 0.72, respectively, both p < 0.01).

Glucagon and its Family Revisited

Considered for decades as a contaminant of insulin preparations, gluca-gon was among the very first hormones to be isolated, purified, sequenced, and synthesized during the late 1950s. The field of glucagon research exploded after R.H. Unger and his colleagues in Dallas, TX, described a method permitting its measurement in the plasma by radioimmunoassay. Such assay made it possible to firmly establish the basic principles of glucagon physiology and to discover its pathophysiology. More recently, important progress has been made in exploring the molecular biology of this hormone: the glucagon gene and the glu-cagon-receptor gene have been identified and their expression investigated. Furthermore, the processing of the glucagon gene product has been elucidated and the function of the members of the glucagon family has been clarified. Finally, current investigations are in progress to develop glucagon agonists and antagonists and to identify new modes of administration of the hormone. These various topics will be considered in this review.

Influence of the bicarbonate pool and on the occurrence of 13CO2 in exhaled air

SummaryIn 13C02 breath tests, based on 13C:12C ratio measurements, the appearance of 13C in exhaled C02 was monitored after the administration of a 13C-la-belled compound. Independently of the substrate used, the existence of a bicarbonate pool into which the C02 produced enters before being exhaled, imposes a delay on the appearance of changes in the 13C:12C ratio. To estimate the nature and magnitude of this delay, we applied a two-compartment model to describe the kinetics of the body bicarbonate pool and we evaluated the 13C:12C ratio of C02 entering that pool from the measured 13C:12C ratio in the exhaled C02 after an oral intake of “naturally labelled” 13C-glucose. Our results demonstrated that discrepancies between total and exogenous glucose oxidation in relation to the peak occurrence time, as well as the absolute quantities, could be adequately explained by the interference of the bicarbonate stores.