Untangling the interplay of genetic and metabolic influences on beta-cell function: Examples of potential therapeutic implications involving TCF7L2 and FFAR1.

Deteriorating beta-cell function is a common feature of type 2 diabetes. In this review, we briefly address the regulation of beta-cell function, and discuss some of the main determinants of beta-cell failure. We will focus on the role of interactions between the genetic background and metabolic environment (insulin resistance, fuel supply and flux as well as metabolic signaling).

Lower plasma creatinine and urine albumin in individuals at increased risk of type 2 diabetes with factor v leiden mutation.

The factor V Leiden (FVL) mutation is the most frequent genetic cause of venous thrombosis in Caucasians. However, protective effects have been suggested to balance the disadvantages. We have recently observed protective effects of FVL mutation on experimental diabetic nephropathy in mice as well as an association with reduced albuminuria in two human cohorts of diabetic patients.

Metabolic signatures of cultured human adipocytes from metabolically healthy versus unhealthy obese individuals.

Background And Aims: Among obese subjects, metabolically healthy and unhealthy obesity (MHO/MUHO) can be differentiated: the latter is characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Aim of this study was, to identify adipocyte-specific metabolic signatures and functional biomarkers for MHO versus MUHO.

Methods: 10 insulin-resistant (IR) vs.

Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity.

Aims/hypothesis: Fetal programming plays an important role in the pathogenesis of type 2 diabetes. The aim of the present study was to investigate whether maternal metabolic changes during OGTT influence fetal brain activity.

Methods: Thirteen healthy pregnant women underwent an OGTT (75 g).

Impact of the adipokine adiponectin and the hepatokine fetuin-A on the development of type 2 diabetes: prospective cohort- and cross-sectional phenotyping studies.

Background: Among adipokines and hepatokines, adiponectin and fetuin-A were consistently found to predict the incidence of type 2 diabetes, both by regulating insulin sensitivity.

Objective: To determine to what extent circulating adiponectin and fetuin-A are independently associated with incident type 2 diabetes in humans, and the major mechanisms involved.

Methods: Relationships with incident diabetes were tested in two cohort studies: within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study (628 cases) and the Nurses' Health Study (NHS; 470 cases).

Variation in the obesity risk gene FTO determines the postprandial cerebral processing of food stimuli in the prefrontal cortex.

Variation in FTO is the strongest genetic determinant of body weight and has recently been linked with impaired neural processing of food stimuli. However, whether this brain-expressed gene affects neuronal processing of food-related stimuli after ingestion is still poorly understood. In this study, twenty-four participants were examined before, 30 and 120 min after ingesting 75 g of glucose solution or water on two separate days.

Association between erythrocyte membrane fatty acids and biomarkers of dyslipidemia in the EPIC-Potsdam study.

Background/objective: Blood proportions of fatty acids (FAs) and FA-ratios reflecting desaturase activity are associated with the risk of chronic diseases like type 2 diabetes mellitus or cardiovascular diseases. Biomarkers of dyslipidemia are considered as potential mediators of this association. We evaluated associations of erythrocyte membrane proportions of individual disease-related polyunsaturated fatty acids (PUFAs), trans-FAs, dairy-derived saturated FAs (SFAs) (15:0, 17:0) and FA-ratios with biomarkers of dyslipidemia (high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, non-HDL-cholesterol, triglycerides).

Evaluation of osseointegration of titanium alloyed implants modified by plasma polymerization.

By means of plasma polymerization, positively charged, nanometre-thin coatings can be applied to implant surfaces. The aim of the present study was to quantify the adhesion of human bone cells in vitro and to evaluate the bone ongrowth in vivo, on titanium surfaces modified by plasma polymer coatings. Different implant surface configurations were examined: titanium alloy (Ti6Al4V) coated with plasma-polymerized allylamine (PPAAm) and plasma-polymerized ethylenediamine (PPEDA) versus uncoated.

Intranasal insulin suppresses systemic but not subcutaneous lipolysis in healthy humans.

Context: Insulin infused into the central nervous system of rats suppresses lipolysis in white adipose tissue, indicating a role of brain insulin in regulating systemic lipid metabolism.

Objective: We investigated whether central nervous insulin delivery suppresses lipolysis in healthy humans.

Design: Placebo-controlled, balanced within-subject comparisons were performed in both a main and an independent corroborative experiment.

Relationships of body composition and liver fat content with insulin resistance in obesity-matched adolescents and adults.

Objective: While in adults not total body- or visceral fat mass, but liver fat content was found to independently determine insulin resistance, it is unclear whether these relationships are already present in obese adolescents.

Methods: Thirty-nine overweight/obese adolescents were matched for sex and BMI with 39 adults. To compare the age- and sex-specific BMI values of adolescents and adults, the percentile value of each adolescent was projected to the age of 18.

Evidence for altered transport of insulin across the blood-brain barrier in insulin-resistant humans.

Eating behavior, body weight regulation, peripheral glucose metabolism, and cognitive function depend on adequate insulin action in the brain, and recent studies in humans suggested that impaired insulin action in the brain emerges upon fat intake, obesity, and genetic variants. As insulin enters into the brain in a receptor-mediated fashion, we hypothesized that whole-body insulin sensitivity might affect the transport of insulin into the brain and contribute to the aversive effect of insulin resistance in the central nervous system. In this study, we aimed to determine the ratio of insulin in the cerebrospinal fluid and serum to whole-body insulin sensitivity.

Plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, e-selectin and C-reactive protein levels in response to 4-week very-high-fructose or -glucose diets.

Background/objectives: High intake of added sweeteners is considered to have a causal role in the pathogenesis of cardiometabolic disorders. Especially, high-fructose intake is regarded as potentially harmful to cardiometabolic health. It may cause not only weight gain but also low-grade inflammation, which represents an independent risk factor for developing type 2 diabetes and cardiovascular disease.

Adiponectin and risk of stroke: prospective study and meta-analysis.

Background And Purpose: The favorable cardiovascular effects attributed to adiponectin may lower risk of stroke. We investigated this in a prospective study and meta-analysis.

Methods: A case-cohort study nested within the Potsdam cohort of the European Prospective Investigation into Cancer was performed, with 170 incident cases of ischemic stroke and a randomly selected subcohort of 2155 participants without major cardiovascular disease at baseline.

Nor-1, a novel incretin-responsive regulator of insulin genes and insulin secretion.

B-cell failure at the onset of type 2 diabetes is caused by a decline in β-cell function in the postprandial state and loss of pancreatic β-cell mass. Recently, we showed an association between increased insulin secretion and a single nucleotide polymorphism (SNP), SNP rs12686676, in the NR4A3 gene locus encoding the nuclear receptor Nor-1. Nor-1 is expressed in β-cells, however, not much is known about its function with regard to insulin gene expression and insulin secretion.

Olive oil aroma extract modulates cerebral blood flow in gustatory brain areas in humans.

Background: Low- and high-fat meals affect homeostatic and gustatory brain areas differentially. In a previous study, we showed that a high-fat meal decreased cerebral blood flow (CBF) in homeostatic brain areas (hypothalamus), whereas a low-fat meal increased CBF in gustatory regions (anterior insula).

Objective: The aim of this study was to investigate the long-lasting effect of fat-free flavor-active compounds of olive oil on the brain and whether those aroma components can trigger fat-associated brain responses in homeostatic and gustatory regions.

Family history of diabetes is associated with higher risk for prediabetes: a multicentre analysis from the German Center for Diabetes Research.

Aims/hypothesis: Prediabetes is a collective term for different subphenotypes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]) with different pathophysiologies. A positive family history for type 2 diabetes (FHD) is associated with increased risk for type 2 diabetes. We assumed that it would also associate with prediabetes, but wondered whether all subphenotypes are related to a positive family history.

Polymorphism rs3123554 in CNR2 reveals gender-specific effects on body weight and affects loss of body weight and cerebral insulin action.

Objective: The cannabinoid-receptor system is involved in the regulation of food intake. Here, we test whether single nucleotide polymorphisms (SNPs) in CNR2, encoding the cannabinoid-receptor 2, are associated with weight in a cross-sectional cohort. Furthermore, we wanted to investigate if the identified hits influence weight loss during lifestyle intervention; and study a potential involvement of cerebral insulin action.

Age-dependent association of serum prolactin with glycaemia and insulin sensitivity in humans.

The dopamine agonist bromocriptine has been approved for the treatment of type 2 diabetes in the United States. Bromocriptine inhibits prolactin secretion, and patients with hyperprolactinaemia display impaired insulin sensitivity. We therefore hypothesized that low prolactin levels are associated with lower glycaemia and higher insulin sensitivity in healthy subjects.

[Rare cause of recurrent hypoglycaemia in type 1 diabetes mellitus--case 6/2013].

History And Admission Findings: We report on a 44-year-old patient with type 1 diabetes who suffered from vomiting and diarrhoea for 10 days as well as episodes of recurrent hypoglycaemia with reduced insulin requirements. Medical history was remarkable for nasopharyngeal carcinoma that had been treated by radiation and chemotherapy five years earlier.

Investigations: Laboratory results showed hyponatraemia, reduced free thyroxine with normal thyroid- stimulating hormone and diminished morning serum cortisol levels.

Long-term stabilization effects of leptin on brain functions in a leptin-deficient patient.

Context: Congenital leptin deficiency, caused by a very rare mutation in the gene encoding leptin, leads to severe obesity, hyperphagia and impaired satiety. The only systemic treatment is the substitution with metreleptin leading to weight reduction based on hormonal changes. Several studies have also shown alterations in brain function after metreleptin therapy.

Altered brain activity in severely obese women may recover after Roux-en Y gastric bypass surgery.

Objective: Neuroimaging studies have demonstrated alterations in brain activity in obese (OB) subjects that might be causally linked to their disorder. Roux-en Y gastric bypass (RYGB) surgery induces a marked and sustained weight loss and may affect brain activity. The aim of this study was to compare brain activity pattern between severely OB women (n=11), normal-weight women (NW, n=11) and previously severely OB women who had undergone RYGB surgery (RYGB, n=9) on average 3.

The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway.

The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances β-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤ 8.