Andreas F.H. Pfeiffer

Adiponectin and protection against type 2 diabetes mellitus

Adiponectin is an adipocyte-derived peptide, which has anti-inflammatory and insulin-sensitising properties. We designed a nested case-control study to assess whether baseline adiponectin concentrations in plasma are independently associated with risk of type 2 diabetes. We found that adiponectin concentrations in plasma were lower among individuals who later developed type 2 diabetes than among controls (mean 5.34 microg/mL [SD 3.49] vs 6.87 microg/mL [4.58], p<0.0001). High concentrations of adiponectin were associated with a substantially reduced relative risk of type 2 diabetes after adjustment for age, sex, waist-to-hip ratio, body-mass index, smoking, exercise, alcohol consumption, education, and glycosylated haemoglobin A(1c) (odds ratio 4th vs 1st quartile 0.3 [95% CI 0.2-0.7], p=0.0051). We conclude that adiponectin is independently associated with a reduced risk of type 2 diabetes in apparently healthy individuals.

The Diet, Obesity and Genes (Diogenes) Dietary Study in eight European countries – a comprehensive design for long-term intervention

Diogenes is a Pan‐European, randomized, controlled dietary intervention study investigating the effects of dietary protein and glycaemic index on weight (re)gain, metabolic and cardiovascular risk factors in obese and overweight families in eight European centres. The article is methodological in character, and the presentation of ‘results’ will be limited to baseline characteristics of the study populations included. A total of 891 families with at least one overweight/obese parent underwent screening. The parents started an initial 8‐week low‐calorie diet and families with minimum one parent attaining a weight loss of ≥8%, were randomized to one of five energy ad libitum, low‐fat (25–30 E%) diets for 6 or 12 months: low protein/low glycaemic index, low protein/high glycaemic index, high protein/low glycaemic index, high protein/high glycaemic index or control (national dietary guidelines). At two centres the families were provided dietary instruction plus free foods for 6 months followed by 6‐month dietary instruction only. At the remaining six centres the families received dietary instruction only for 6 months. The median weight loss during the low‐calorie diet was 10.3 kg (inter‐quartile range: 8.7–12.8 kg, n = 775). A total of 773 adults and 784 children were randomized to the 6‐month weight (re)gain prevention phase. Despite major cultural and dietary regional differences in Europe, interventions addressing effects of dietary factors are feasible with a reasonable attrition.

Psychotomimesis mediated by kappa opiate receptors

The kappa opioid agonists are analgesics that seem to be free of undesired morphine-like effects. Their dysphoric actions observed with the kappa agonist cyclazocine are thought to be mediated by an action at sigma-phencyclidine receptors. The benzomorphan kappa agonist MR 2033 is inactive at sigma-phencyclidine receptors. In male subjects, the opiate-active (-)-isomer, but not the (+)-isomer, elicited dose-dependent dysphoric and psychotomimetic effects that were antagonized by naloxone. Thus, kappa opiate receptors seem to mediate psychotomimetic effects. In view of the euphorigenic properties of mu agonists, our results imply the existence of opposed opioid systems affecting emotional and perceptual experiences.

Obesity Associated with a Mutation in a Genetic Regulator of Adipocyte Differentiation

BACKGROUND There is increasing evidence of genetic factors leading to obesity, but the exact genes involved have not been defined. Peroxisome-proliferator-activated receptor gamma2 (PPARgamma2) is a transcription factor that has a key role in adipocyte differentiation, and therefore mutations of the gene for this factor might predispose people to obesity. METHODS We studied 358 unrelated German subjects, including 121 obese subjects (defined as those with a body-mass index [the weight in kilograms divided by the square of the height in meters] of more than 29). We evaluated these subjects for mutations in the gene for PPARgamma2 at or near a site of serine phosphorylation at position 114 that negatively regulates the transcriptional activity of the protein, using a polymerase-chain-reaction-based assay coupled with specific endonuclease digestion. The activity of the mutation identified was analyzed by retroviral transfection and overexpression in murine fibroblasts. RESULTS Four of the 121 obese subjects had a missense mutation in the gene for PPARgamma2 that resulted in the conversion of proline to glutamine at position 115, as compared with none of the 237 subjects of normal weight (P=0.01). All the subjects with the mutant allele were markedly obese, with body-mass-index values ranging from 37.9 to 47.3, as compared with a mean of 33.6 in the other obese subjects. Overexpression of the mutant gene in murine fibroblasts led to the production of a protein in which the phosphorylation of serine at position 114 was defective, as well as to accelerated differentiation of the cells into adipocytes and greater cellular accumulation of triglyceride than with the wild-type PPARgamma2. These effects were similar to those of an in vitro mutation created directly at the Ser114 phosphorylation site. CONCLUSIONS A Pro115Gln mutation in PPARgamma2 accelerates the differentiation of adipocytes and may cause obesity.

Opiate receptor binding sites in human brain

Subclasses of opiate receptor binding sites in human brain membranes were investigated by means of competitive binding techniques. The experimental data were analyzed by use of a computerized non-linear regression curve fitting program. mu-, delta-and chi-types of opiate binding were found in 5 different regions of the brain. A more extensive analysis of the regional distribution of subclasses of opiate binding sites was performed using a simple sequential inhibition technique. This method was shown to yield results which are comparable to those obtained by computer analysis of multiple tracer displacement curves. Chi-and mu-sites represented the major component of binding in most brain areas whereas delta-sites were fewer in number. The 3 types of binding showed different distribution patterns, suggesting that they are independent from each other. The distribution pattern observed in human brain resembled the one observed in rat brain, although chi-sites appear to represent a more important, and delta-sites appear to represent a less important, fraction of binding in human as compared to rat brain.

Euglycemic hyperinsulinemia, but not lipid infusion, decreases circulating ghrelin levels in humans

The orexigenic and anabolic gastric hormone ghrelin is secreted in response to acute and chronic energy requirements. While pre-prandial increases and post-prandial decreases of plasma ghrelin levels in rodents and humans seem to indicate a role for the novel peptide hormone as an afferent meal initiator or “hunger hormone”, the precise mechanisms which are suppressing ghrelin secretion in response to caloric intake remain largely unknown. We show here that human ghrelin levels decrease by almost 50% under hyperinsulinemic euglycemic clamp conditions (no.=4, p=0.001), revealing physiologically relevant increases of insulin levels as an independent determinant of circulating ghrelin levels. In a second study, 3–4-fold increased plasma free fatty acid levels, as another metabolic candidate for the modulation of circulating ghrelin concentrations, were generated by constant lipid infusion, but failed to change plasma ghrelin. Simultaneous elevation of free fatty acids and insulin again markedly decreased ghrelin concentration (no.=4, p=0.01). Insulin induced suppression of circulating ghrelin levels (or the lack thereof) could be a mechanism with relevance for the understanding of the (patho-) physiology of meal initiation and termination, the pathogenesis of the metabolic syndrome and for the development of respective therapeutic perspectives.

Vitreous levels of the insulin-like growth factors I and II, and the insulin-like growth factor binding proteins 2 and 3, increase in neovascular eye disease. Studies in nondiabetic and diabetic subjects.

Retinal capillary nonperfusion results in neovascularization of the eye, which is restricted to the retina in less severe cases and progresses to the anterior chamber and the iris angle in the most advanced case, called rubeosis. This angioneogenesis may be induced by the release of retinal growth factors into the vitreous. This study compared levels of the IGF-I and IGF-II, and of the IGF binding protein-2 (IGFBP-2) and IGFBP-3 in vitreous from three groups with different degrees of retinal ischemia, as judged by the extent of neovascularization: a control group without new vessel formation, retinal neovascularization in patients with proliferative diabetic retinopathy, and massive ischemia of various causes resulting in rubeosis. IGF-I and IGFBP-3 were increased 10- and 13-fold in rubeosis (P << 0.01) compared with no ischemia (n = 10), while IGF-II and IGFBP-2 were elevated 2.7- and 4.3-fold (P < 0.01). Within the rubeosis group similar changes were observed independently of the cause of ischemia, which was central vein occlusion, ischemic ophthalmopathy, or intraocular tumor in seven cases and diabetic retinopathy in three samples from two patients. Vitreous from patients with proliferative diabetic retinopathy but without rubeosis (n = 16) contained 2.5- and 2.2-fold elevated levels of IGF-I and of IGFBP-2 (P < 0.05), while IGF-II and IGFBP-3 were increased 1.4- and 1.6-fold, which was not significant. We conclude that: (a) ischemia appears to be a strong stimulus for the local production of IGF-I and -II and of IGFBP-2 and -3 in the eye. (b) Changes in IGF-I and IGFBP-2 in proliferative diabetic retinopathy may be secondary to local ischemia rather than being specific for diabetic retinopathy. (c) IGF-I and IGFBP-3 may play a role in mediating angioneogenesis in the eye.

Take Action to Prevent Diabetes – The IMAGE Toolkit for the Prevention of Type 2 Diabetes in Europe

When we ask people what they value most, health is usually top of the list. While effective care is available for many chronic diseases, the fact remains that for the patient, the tax payer and the whole of society: prevention is better than cure. Diabetes and its complications are a serious threat to the survival and well-being of an increasing number of people. It is predicted that one in ten Europeans aged 20-79 will have developed diabetes by 2030. Once a disease of old age, diabetes is now common among adults of all ages and is beginning to affect adolescents and even children. Diabetes accounts for up to 18 % of total healthcare expenditure in Europe. The good news is that diabetes is preventable. Compelling evidence shows that the onset of diabetes can be prevented or delayed greatly in individuals at high risk (people with impaired glucose regulation). Clinical research has shown a reduction in risk of developing diabetes of over 50 % following relatively modest changes in lifestyle that include adopting a healthy diet, increasing physical activity, and maintaining a healthy body weight. These results have since been reproduced in real-world prevention programmes. Even a delay of a few years in the progression to diabetes is expected to reduce diabetes-related complications, such as heart, kidney and eye disease and, consequently, to reduce the cost to society. A comprehensive approach to diabetes prevention should combine population based primary prevention with programmes targeted at those who are at high risk. This approach should take account of the local circumstances and diversity within modern society (e.g. social inequalities). The challenge goes beyond the healthcare system. We need to encourage collaboration across many different sectors: education providers, non-governmental organisations, the food industry, the media, urban planners and politicians all have a very important role to play. Small changes in lifestyle will bring big changes in health. Through joint efforts, more people will be reached. The time to act is now.

Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity

Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

A dietary pattern protective against type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)--Potsdam Study cohort.

Aims/hypothesisThe aim of this study was to identify a dietary pattern associated with diabetes-related biomarkers and to investigate whether this pattern is associated with the incidence of type 2 diabetes.MethodsA nested case–control study of 192 cases of incident type 2 diabetes and 382 control subjects matched for sex and age was conducted. All subjects were participants in the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)—Potsdam Study. Dietary pattern score was derived using intake data on 48 food groups as exposure variables and the biomarkers HbA1c, HDL cholesterol, C-reactive protein and adiponectin as response variables in reduced rank regression. The association of the score with diabetes risk was estimated by conditional logistic regression analysis.ResultsA high score for the identified dietary pattern was characterised by a high intake of fresh fruit and a low intake of high-caloric soft drinks, beer, red meat, poultry, processed meat, legumes and bread (excluding wholegrain bread). Subjects with high scores had high plasma concentrations of HDL cholesterol and adiponectin and low plasma concentrations of HbA1c and C-reactive protein. After multivariate adjustment, the odds ratios for type 2 diabetes across increasing quintiles of the dietary pattern score were 1.0, 0.59, 0.51, 0.26 and 0.27, respectively (p=0.0006 for trend).Conclusions/interpretationA high score for the identified dietary pattern is associated with a more favourable biomarker profile and a substantially reduced incidence of type 2 diabetes.