Jean-François Gautier

Effect of a diabetic environment in utero on predisposition to type 2 diabetes

BACKGROUND Type 2 diabetes is affected by genetics and environmental factors. We aimed to assess the effect of an in-utero diabetic environment independently of the genetic background for type 2 diabetes. METHODS We measured insulin sensitivity and insulin secretion in response to oral and intravenous glucose in 15 non-diabetic adult offspring of mothers with type 1 diabetes (exposed participants) and 16 offspring of type 1 diabetic fathers (controls). No participants had type 1 diabetes-associated autoantibodies. We also measured pancreatic polypeptide, a marker of parasympathetic drive to the pancreas. FINDINGS There was no difference between the groups with respect to percent body fat and insulin sensitivity. Five of the 15 exposed participants, but none of the controls had impaired glucose tolerance (p=0.02). Early insulin secretion after an oral glucose tolerance test was lower in exposed participants than in controls: 8.6 IU/mmol (SD 5.4) in exposed participants with impaired glucose tolerance, 14.2 IU/mmol (6.5) in those with normal glucose tolerance and 17.7 IU/mmol (10.9) in controls (p=0.04). Mean insulin secretion rate during glucose infusion study was 4.7 pmol/kg per min (3.6) in people with impaired glucose tolerance, 5.5 pmol/kg per min (4.5) in exposed participants with normal glucose tolerance and 7.5 pmol/kg per min (6.1) in controls (p<0.0001). The area under the curve of pancreatic polypeptide 120 min after oral glucose ingestion was 1007 (429) in people with impaired glucose tolerance, 2829 (1701) in those with normal glucose tolerance, and 3224 (1352) in controls (p=0.04). INTERPRETATION Exposure to a diabetic environment in utero is associated with increased occurrence of impaired glucose tolerance and a defective insulin secretory response in adult offspring, independent of genetic predisposition to type 2 diabetes. This insulin secretory defect could be related to low parasympathetic tone. Epidemiological studies are needed to confirm our observations before therapeutic strategies can be devised.

Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes

Incretin hormones are defined as intestinal hormones released in response to nutrient ingestion, which potentiate the glucose-induced insulin response. In humans, the incretin effect is mainly caused by two peptide hormones, glucose-dependent insulin releasing polypeptide GIP, and glucagon-like peptide-1 GLP-1. GIP is secreted by K cells from the upper small intestine while GLP-1 is mainly produced in the enteroendocrine L cells located in the distal intestine. Their effect is mediated through their binding with specific receptors, though part of their biological action may also involve neural modulation. GIP and GLP-1 are both rapidly degraded into inactive metabolites by the enzyme dipeptidyl-peptidase-IV (DPP-IV). In addition to its effects on insulin secretion, GLP-1 exerts other significant actions, including stimulation of insulin biosynthesis, inhibition of glucagon secretion, inhibition of gastric emptying and acid secretion, reduction of food intake, and trophic effects on the pancreas. As the insulinotropic action of GLP-1 is preserved in type 2 diabetic patients, this peptide was a candidate as a therapeutic agent for this disease. A number of pharmacological strategies have been developed to provide continuous delivery of GLP-1 and to prevent degradation of GLP-1, including continuous administration of GLP-1, DPP-IV inhibitors and DPP-IV resistant GLP-1 analogues. Recent results of the most clinically advanced incretin mimetics confirmed their efficacy to improve glycemic control in type 2 diabetic patients. Further results are expected to confirm the efficacy/safety profile of these compounds, and to find their place in the therapeutic strategy of type 2 diabetes.

Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes

Incretin hormones are defined as intestinal hormones released in response to nutrient ingestion, which potentiate the glucose-induced insulin response. In humans, the incretin effect is mainly caused by two peptide hormones, glucose-dependent insulin releasing polypeptide (GIP), and glucagon-like peptide-1 (GLP-1). GIP is secreted by K cells from the upper small intestine while GLP-1 is mainly produced in the enteroendocrine L cells located in the distal intestine. Their effect is mediated through their binding with specific receptors, though part of their biological action may also involve neural modulation. GIP and GLP-1 are both rapidly degraded into inactive metabolites by the enzyme dipeptidyl-peptidase-IV (DPP-IV). In addition to its effects on insulin secretion, GLP-1 exerts other significant actions, including stimulation of insulin biosynthesis, inhibition of glucagon secretion, inhibition of gastric emptying and acid secretion, reduction of food intake, and trophic effects on the pancreas. As the insulinotropic action of GLP-1 is preserved in type 2 diabetic patients, this peptide was likely to be developed as a therapeutic agent for this disease.

How to measure hepatic insulin resistance

The liver plays a pivotal role in energy metabolism. Under the control of hormones, especially insulin, the liver stores or releases glucose as needed by the bodys systems. It is also responsible for an important part of non-esterified fatty-acid and aminoacid metabolism. Assessing hepatic insulin resistance is almost always synonymous with measuring hepatic glucose production (HGP) and calculating indices of hepatic insulin resistance. The most frequently used method to this end is the isotope dilution technique using a tracer. Among tracers, stable isotope-labelled glucose molecules are particularly advantageous over radioactive isotope-labelled glucose and are, therefore, the tracers of choice. The tracer is infused either on its own after an overnight fast to evaluate fasting HGP, or with some among the usual insulin-sensitivity tests to assess HGP suppression by insulin and/or glucose. In a fasting state, HGP is easily calculated whereas, during insulin or glucose infusion, some formula are needed to correct for the non-steady-state condition. The hepatic insulin-resistance index is the product of HGP and the corresponding plasma insulin concentration. Although subject to error, the isotope dilution method nevertheless remains an irreplaceable tool for assessing hepatic insulin resistance in clinical research. From a practical point of view, some easily obtainable indices and clinical or biochemical parameters can serve as surrogates or markers of hepatic insulin resistance in clinical practice. Finally, drugs such as metformin or glitazones can improve hepatic insulin resistance, hence their use in hepatic insulin-resistant states such as type 2 diabetes and non-alcoholic fatty liver disease.

Pronounced Reduction Of Postprandial Glucagon By Lixisenatide: A Meta-Analysis Of Randomized Clinical Trials.

Glucagon‐like peptide‐1 (GLP‐1) receptor agonists improve islet function and delay gastric emptying in patients with type 2 diabetes mellitus (T2DM). This meta‐analysis aimed to investigate the effects of the once‐daily prandial GLP‐1 receptor agonist lixisenatide on postprandial plasma glucose (PPG), glucagon and insulin levels.

Therapeutic use of recombinant methionyl human leptin.

Recombinant methionyl human leptin (r-metHuLeptin) was first used as a replacement therapy in patients bearing inactivating mutations in the leptin gene. In this indication, it was shown since 1999 to be very efficient in inducing a dramatic weight loss in rare children and adults with severe obesity due to the lack of leptin. These first clinical trials clearly showed that r-metHuLeptin acted centrally to reduce food intake, inducing loss of fat mass, and to correct metabolic alterations, immune and neuroendocrine defects. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due to primary defects in fat storage, which induce leptin deficiency. The beneficial effects, which could be mediated by central and/or peripheral mechanisms, are thought to mainly involve the lowering effects of leptin on ectopic lipid storage, in particular in liver and muscles, reducing insulin resistance. Interestingly, r-metHuLeptin therapy also reversed the hypothalamic-pituitary-gonadal axis dysfunctions associated with hypothalamic amenorrhea. However, if r-metHuLeptin treatment has been shown to be dramatically efficient in leptin-deficient states, its very limited effect in inducing weight loss in common obese patients revealed that, in patients with adequate leptin secretion, mechanisms of leptin resistance and leptin tolerance prevent r-metHuLeptin from inducing any additional effects. This review will present the current data about the effects of r-metHuLeptin therapy in humans, and discuss the recent perspectives of this therapy in new indications.

Lymphoma in acquired generalized lipodystrophy.

Acquired generalized lipodystrophy (AGL) is a rare disease thought to result from autoimmune destruction of adipose tissue. Peripheral T-cell lymphoma (PTCL) has been reported in two AGL patients. We report five additional cases of lymphoma in AGL, and analyze the role of underlying autoimmunity and recombinant human leptin (metreleptin) replacement in lymphoma development. Three patients developed lymphoma during metreleptin treatment (two PTCL and one ALK-positive anaplastic large cell lymphoma), and two developed lymphomas (mycosis fungoides and Burkitt lymphoma) without metreleptin. AGL is associated with high risk for lymphoma, especially PTCL. Autoimmunity likely contributes to this risk. Lymphoma developed with or without metreleptin, suggesting metreleptin does not directly cause lymphoma development; a theoretical role of metreleptin in lymphoma progression remains possible. For most patients with AGL and severe metabolic complications, the proven benefits of metreleptin on metabolic disease will likely outweigh theoretical risks of metreleptin in lymphoma development or progression.

Falsely elevated capillary glucose and ketone levels and use of skin lightening creams

Hand washing before glucose and ketone fingerprick testing prevents false results in users of skin lightening cosmetics

Non-severe hypoglycaemia is associated with weight gain in patients with type 1 diabetes: Results from the Diabetes Control and Complication Trial

It is unclear whether the frequent non‐severe episodes of hypoglycaemia observed during intensive glucose control in individuals with type 1 diabetes (T1D) are associated with subsequent weight gain. We analysed the association between non‐severe hypoglycaemia and weight gain in 1441 Diabetes Control and Complication Trial (DCCT) participants. Non‐severe hypoglycaemia was assessed by hypo‐score (ie, number of blood glucose values <70 mg/dL divided by the total number of measurements during the DCCT quarterly visits). Significant associations were observed between the hypo‐score and annual and total weight gain. The annual weight gain by hypo‐score tertiles was 0.8 ± 1.2 (T1), 1.3 ± 1.5 (T2) and 1.4 ± 1.3 kg/y (T3), P < .001 for T2 and T3 vs T1, and for T3 vs T2. The odds ratio for a weight gain of 1.8 kg/y was 2.14 (95% CI, 1.56‐2.93) for T2, and 2.53 (95%CI, 1.85‐3.45) for T3 vs T1. These differences in weight gain and in risk of weight gain remained significant after adjustment for sex, age, duration of diabetes, HbA1c at baseline and treatment arms. In conclusion, our analysis shows a significant association between non‐severe hypoglycaemia and weight gain in individuals with T1D from the DCCT.

Infections virales et diabète en Afrique

Resume La majorite des diabetes resultent d’une interaction gene-environnement. Il est reconnu que les infections virales en tant que facteurs environnementaux peuvent jouer un role dans l’apparition, le maintien, ou l’exacerbation, des desordres metaboliques observes au cours des diabetes. A cote des formes classiques de diabete, type 1 (DT1) et type 2 (DT2), le diabete atypique (Ketosis-prone diabetes, KPD), forme clinique intermediaire aux deux precedents, est tres frequent chez les Africains. Certains virus ont ete identifies comme associes, ou decrits comme etiologies probables, dans ces trois formes de diabete, a savoir les enterovirus dans le DT1, le virus de l’hepatite C et le virus de l’immunodeficience humaine (VIH) dans le DT2, et le virus herpes humain de type 8 (HHV-8) pour le KPD.