From bending DNA to diabetes: the curious case of HMGA1

Although mice lacking the architectural DNA binding factor HMGA1 are diabetic and express very low levels of the insulin receptor, they have increased insulin sensitivity. A study in BMC Biology now suggests that changes in circulating retinol binding protein partly account for this paradox

Achievements, Prospects and Challenges in Precision Care for Monogenic Insulin Deficient and Insulin Resistant Diabetes

Integration of genomic and other data has begun to stratify type 2 diabetes in prognostically meaningful ways, but this has yet to impact on mainstream diabetes practice. The subgroup of diabetes caused by single gene defects thus provides the best example to date of the vision of ‘precision diabetes’. Monogenic diabetes may be divided into primary pancreatic beta cell failure, and primary insulin resistance. In both groups, clear examples of genotype-selective responses to therapy have been advanced. The benign trajectory of diabetes due to pathogenic GCK mutations, and the sulfonylurea-hyperresponsiveness conferred by activating KCNJ11 or ABCC8 mutations, or loss-of-function HNF1A or HNF4A mutations, often decisively guide clinical management. In monogenic insulin-resistant diabetes, subcutaneous leptin therapy is beneficial in some severe lipodystrophy. Increasing evidence also supports use of ‘obesity therapies’ in lipodystrophic people even without obesity. In beta cell diabetes the main challenge is now implementation of the precision diabetes vision at scale. In monogenic insulin-resistant diabetes genotype-specific benefits are proven in far fewer patients to date, although further genotype-targeted therapies are being evaluated. The conceptual paradigm established by the insulin-resistant subgroup with ‘adipose failure’ may have a wider influence on precision therapy for common type 2 diabetes, however. For all forms of monogenic diabetes, population-wide genome sequencing is currently forcing reappraisal of the importance assigned to pathogenic mutations when gene sequencing is uncoupled from prior suspicion of monogenic diabetes. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s00125-022-05720-7) contains a slideset of the figures for download, which is available to authorised users

Representing Partitions on Trees

In evolutionary biology, biologists often face the problem of constructing a phylogenetic tree on a set X of species from a multiset Π of partitions corresponding to various attributes of these species. One approach that is used to solve this problem is to try instead to associate a tree (or even a network) to the multiset ΣΠ consisting of all those bipartitions {A,X − A} with A a part of some partition in Π. The rational behind this approach is that a phylogenetic tree with leaf set X can be uniquely represented by the set of bipartitions of X induced by its edges. Motivated by these considerations, given a multiset Σ of bipartitions corresponding to a phylogenetic tree on X, in this paper we introduce and study the set P(Σ) consisting of those multisets of partitions Π of X with ΣΠ = Σ. More specifically, we characterize when P(Σ) is non-empty, and also identify some partitions in P(Σ) that are of maximum and minimum size. We also show that it is NP-complete to decide when P(Σ) is non-empty in case Σ is an arbitrary multiset of bipartitions of X. Ultimately, we hope that by gaining a better understanding of the mapping that takes an arbitrary partition system Π to the multiset ΣΠ, we will obtain new insights into the use of median networks and, more generally, split-networks to visualize sets of partitions

2nd International Consensus Report on Gaps & Opportunities for the Clinical Translation of Precision Diabetes Medicine

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for the heterogeneous etiology, clinical presentation, and pathogenesis of common forms of diabetes and risk of complications. This 2nd International Consensus Report on Precision Diabetes Medicine summarize the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; further, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability, and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine

Microsatellite analysis of female mating behaviour in lek-breeding sage grouse

We used microsatellite DNA markers to genotype chicks in 10 broods of lek-breeding sage grouse, Centrocercus urophasianus, whose mothers’ behaviour was studied by radio tracking and observing leks. Previous behavioural studies suggested that almost all matings are performed by territorial males on leks and that multiple mating is rare. Two broods (20%) were sired by more than one male. Genetic analyses of the broods of eight females that visited an intensively studied lek were consistent with behavioural observations. Four females observed mating produced singly sired broods and males other than the individual observed copulating were excluded as sires for most or all of their chicks. Territorial males at the study lek were excluded as sires of broods of four other females that visited the lek but were not observed mating there. Radio-tracking suggested that two of these females mated at other leks. Our results confirm the reliability of mating observations at leks, but do not rule out a possible unseen component of the mating system