Identification of pathogenic variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment.

Background: Functionally disruptive variants in the glucokinase gene () cause a form of mild non-progressive hyperglycemia, which does not require pharmacological treatment. A substantial proportion of patients with type 2 diabetes (T2D) carry variants. We aimed to investigate whether carriers of rare variants diagnosed with T2D have a glycemic phenotype and treatment response consistent with -diabetes.

Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism.

Objectives: Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation.

Human and preclinical studies of the host-gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health.

Objective: Gut microbial products are involved in regulation of host metabolism. In human and experimental studies, we explored the potential role of hippurate, a hepatic phase 2 conjugation product of microbial benzoate, as a marker and mediator of metabolic health.

Design: In 271 middle-aged non-diabetic Danish individuals, who were stratified on habitual dietary intake, we applied H-nuclear magnetic resonance (NMR) spectroscopy of urine samples and shotgun-sequencing-based metagenomics of the gut microbiome to explore links between the urine level of hippurate, measures of the gut microbiome, dietary fat and markers of metabolic health.

Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents.

Objective: Patients with renal failure suffer from symptoms caused by uraemic toxins, possibly of gut microbial origin, as deduced from studies in animals. The aim of the study is to characterise relationships between the intestinal microbiome composition, uraemic toxins and renal failure symptoms in human end-stage renal disease (ESRD).

Design: Characterisation of gut microbiome, serum and faecal metabolome and human phenotypes in a cohort of 223 patients with ESRD and 69 healthy controls.

Glucose metabolism in children and adolescents: Population-based reference values and comparisons to children and adolescents enrolled in obesity treatment.

Background: Alterations in glucose metabolism that lead to the development of metabolic and cardiovascular disease may begin already in childhood.

Objective: This study aims to generate pediatric age and sex-specific reference values for fasting concentrations of glucose, hemoglobin A1c (HbA1c), insulin, C-peptide, and homeostasis model assessment: insulin resistance (HOMA-IR) in Danish/North-European white children and adolescents from a population-based cohort and to compare values from children and adolescents with overweight/obesity with this reference.

Methods: The population- and obesity clinic-based cohorts consisted of 2451 and 1935 children and adolescents between 6 and 18 years of age.

Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: a randomised cross-over trial.

Objective: To investigate whether a whole grain diet alters the gut microbiome and insulin sensitivity, as well as biomarkers of metabolic health and gut functionality.

Design: 60 Danish adults at risk of developing metabolic syndrome were included in a randomised cross-over trial with two 8-week dietary intervention periods comprising whole grain diet and refined grain diet, separated by a washout period of ≥6 weeks. The response to the interventions on the gut microbiome composition and insulin sensitivity as well on measures of glucose and lipid metabolism, gut functionality, inflammatory markers, anthropometry and urine metabolomics were assessed.

Plasma Alkylresorcinols Reflect Gluten Intake and Distinguish between Gluten-Rich and Gluten-Poor Diets in a Population at Risk of Metabolic Syndrome.

Background: Many patients with celiac disease experience difficulties in adherence to a gluten-free diet. Methods for testing compliance to a gluten-free diet are costly and cumbersome. Thus, a simple biomarker of gluten intake is needed in a clinical setting and will be useful for epidemiologic studies investigating wider effects of gluten intake.

[The genome and diabetes].

In terms of their genetic architecture monogenic diabetes and type 2 diabetes represent two extremes. Whereas each subtype of monogenic diabetes is caused by one penetrant, rare mutation in a single gene, the genetic susceptibility to type 2 diabetes can be attributed to many low-penetrant variants across the genome. At present, only 10% of the genetic susceptibility to type 2 diabetes can be explained by the hitherto identified 90 genomic loci.

[Gut microbiota may influence childhood and adolescent onset obesity].

Childhood and adolescent onset obesity has reached epidemical proportions worldwide. Recent evidence suggests that obesity is associated with phylogenetic changes in the gut microbiota, which could potentially reveal new avenues for obesity prevention and treatment. A vast number of variables are influencing the gut microbial ecology and though many are proposed, the exact physiological processes behind the relationship are yet to be revealed.

Lessons from whole-exome sequencing in MODYX families.

We report the first results from whole-exome sequencing performed in families with Maturity-Onset Diabetes of the Young without a known genetic cause of diabetes (MODYX). This next generation sequencing technique pointed out that routine testing of MODY needs constant awareness and regular re-evaluation of both clinical criteria and primer sequences.

[Gut microbiota may have influence on glucose and lipid metabolism].

New gene sequencing-based techniques and the large worldwide sequencing capacity have introduced a new era within the field of gut microbiota. Animal and human studies have shown that obesity and type 2 diabetes are associated with changes in the composition of the gut microbiota and that prebiotics, antibiotics or faecal transplantation can alter glucose and lipid metabolism. This paper summarizes the latest research regarding the association between gut microbiota, diabetes and obesity and some of the mechanisms by which gut bacteria may influence host metabolism.

Mutations in HNF1A result in marked alterations of plasma glycan profile.

A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups.

Intrafamilial Variability of Early-Onset Diabetes due to an INS Mutation.

Aim. The objective of this study was to describe the clinical characteristics of two siblings and their father carrying a C95Y mutation in the insulin (INS) gene. Methods/Results.

[Diabetes in infants may be treated with sulfonylurea as a replacement for insulin].

A two-month-old Danish girl was admitted to the hospital in diabetic ketoacidosis and diagnosed with permanent neonatal diabetes mellitus (PNDM). She received continuous insulin treatment until she was genetically tested at the Steno Diabetes Centre. She carried a KCNJ11 Arg201His mutation, an activating mutation in the KCNJ11-gene which encodes the ATP-sensitive potassium subunit Kir6.

Variation in CHI3LI in relation to type 2 diabetes and related quantitative traits.

Background: CHI3LI encoding the inflammatory glycoprotein YKL-40 is located on chromosome 1q32.1. YKL-40 is involved in inflammatory processes and patients with Type 2 Diabetes (T2D) have elevated circulating YKL-40 levels which correlate with their level of insulin resistance.

[Molecular pathogenesis in monogenic and polygenic obesity].

During the last few years, studies of the molecular pathogenesis of obesity both in mouse models and in the rare cases of monogenic obesity in humans have added significantly to our understanding of the key role of the hypothalamus in mediating hunger and satiety. These insights have brought us closer to the development of rational therapies of obesity, the epidemic of which is continuing in the post-industrial society, which is characterised by sedentary behaviour patterns.

[The genetics of obesity].

Although environmental factors clearly play a role, studies of twins and adoptees show that obesity is a familial trait which to a large degree can be ascribed to genetic factors. According to evolutionary models, obesity-causing variants may originally have had an evolutionary benefit, whereas in a modern environment they pose a risk. Despite a clear genetic cause, the molecular genetic variations underlying common forms of obesity are not clear.

A statistical approach based on substitution of macronutrients provides additional information to models analyzing single dietary factors in relation to type 2 diabetes in danish adults: the Inter99 study.

Most studies analyzing diet-disease relations focus on single dietary factors rather than combining different nutrients into the same statistical model. The objective of this study was to identify dietary factors associated with the probability of having diabetes identified by screening (SDM) in Danish men and women aged 30-60 y. A specific objective was to examine whether an alternative statistical approach could provide additional information to already existing statistical approaches used in nutritional epidemiology.

[Maturity-onset diabetes of the young--MODY. Molecular-genetic, pathophysiological and clinical characteristics].

Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of type 2 diabetes characterised by an early onset, an autosomal dominant inheritance, and a primary defect in insulin secretion. MODY comprises 2-5% of cases of type 2 diabetes. So far, six MODY genes have been identified (MODY1-6): hepatocyte nuclear factor (HNF-4 alpha), glucokinase, HNF-1 alpha, HNF-1 beta, insulin promoter factor 1(IPF-1), and neurogenic differentiation factor 1 (NEUROD1).