Maturity Onset Diabetes of the Young (MODY)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147788/1/dme199613s690.pd

Hormonal/metabolic regulation of the human GLUT4/muscle-fat facilitative glucose transporter gene in transgenic mice

To examine the hormonal/metabolic as well as tissue-specific expression of the GLUT4/muscle-fat facilitative glucose transporter gene, we have generated several transgenic mouse lines expressing a human GLUT4 mini-gene which extends 5.3 kilobases (kb) upstream of transcription start and terminates within exon 10. This construct (hGLUT4-11.5) was expressed in a tissue- specific pattern identical to the endogenous mouse GLUT4 gene. The transcription initiation sites of the transgenic construct were similar to the GLUT4 gene expressed in human tissues. To investigate the hormonal/metabolic-dependent regulation of GLUT4, the transgenic animals were made insulin-deficient by streptozotocin (STZ) treatment. In these animals, STZ-induced diabetes resulted in a parallel decrease in endogenous mouse GLUT4 mRNA and the transgenic human GLUT4 mRNA in white adipose tissue, brown adipose tissue, and cardiac muscle. Similarly, insulin treatment of the STZ- diabetic animals restored both the endogenous mouse and transgenic human GLUT4 mRNA levels. To further define cis-regulatory regions responsible for this hormonal/metabolic regulation, the same analysis was performed on transgenic animals which carry 2.4 kb of the human GLUT4 5'-flanking region fused to a CAT reporter gene (hGLUT4[2.4]-CAT). This reporter construct responded similarly to the human GLUT4 mini-gene demonstrating that the element(s) controlling hormonal/metabolic regulation and tissue specificity all reside exclusively within 2.4 kb of the transcriptional initiation site

Expression and regulation of the human GLUT4/muscle-fat facilitative glucose transporter gene in transgenic mice

To study the molecular basis of tissue-specific expression of the GLUT4/muscle-fat facilitative glucose transporter gene, we generated lines of transgenic mice carrying 2.4 kilobases of the 5'-flanking region of the human GLUT4 gene fused to a chloramphenicol acetyltransferase (CAT) reporter gene (hGLUT4[2.4]-CAT). This reporter gene construct was specifically expressed in tissues that normally express GLUT4 mRNA, which include both brown and white adipose tissues as well as cardiac, skeletal, and smooth muscle. In contrast, CAT reporter activity was not detected in brain or liver, two tissues that do not express the GLUT4 gene. In addition, the relative levels of CAT mRNA driven by the human GLUT4 promoter in various tissues of these transgenic animals mirrored those of the endogenous mouse GLUT4 mRNA. Since previous studies have observed alterations in GLUT4 mRNA levels induced by fasting and refeeding (Sivitz, W. I., DeSautel, S. L., Kayano, T., Bell, G. I., and Pessin, J. E. (1989) Nature 340, 72-74), the regulated expression the hGLUT4[2.4]-CAT transgene was also assessed in these animals. Fasting was observed to decrease CAT activity in white adipose tissue which was super- induced upon refeeding. These alterations in CAT expression occurred in parallel to the changes in endogenous mouse GLUT4 mRNA levels. Although CAT expression in skeletal muscle and brown adipose tissue was unaffected, the endogenous mouse GLUT4 mRNA was also refractory to the effects of fasting/refeeding in these tissues. These data demonstrate that 2.4 kilobases of the 5'-flanking region of the human GLUT4 gene contain all the necessary sequence elements to confer tissue-specific expression and at least some of the sequence elements controlling the hormonal/metabolic regulation of this gene

Model for the hydration of non-polar compounds and polymers

We introduce an exactly solvable statistical-mechanical model of the hydration of non-polar compounds, based on grouping water molecules in clusters where hydrogen bonds and isotropic interactions occur; interactions between clusters are neglected. Analytical results show that an effective strengthening of hydrogen bonds in the presence of the solute, together with a geometric reorganization of water molecules, are enough to yield hydrophobic behavior. We extend our model to describe a non-polar homopolymer in aqueous solution, obtaining a clear evidence of both ``cold'' and ``warm'' swelling transitions. This suggests that our model could be relevant to describe some features of protein folding.Comment: REVTeX, 6 pages, 3 figure

Generalized thermodynamics and Fokker-Planck equations. Applications to stellar dynamics, two-dimensional turbulence and Jupiter's great red spot

We introduce a new set of generalized Fokker-Planck equations that conserve energy and mass and increase a generalized entropy until a maximum entropy state is reached. The concept of generalized entropies is rigorously justified for continuous Hamiltonian systems undergoing violent relaxation. Tsallis entropies are just a special case of this generalized thermodynamics. Application of these results to stellar dynamics, vortex dynamics and Jupiter's great red spot are proposed. Our prime result is a novel relaxation equation that should offer an easily implementable parametrization of geophysical turbulence. This relaxation equation depends on a single key parameter related to the skewness of the fine-grained vorticity distribution. Usual parametrizations (including a single turbulent viscosity) correspond to the infinite temperature limit of our model. They forget a fundamental systematic drift that acts against diffusion as in Brownian theory. Our generalized Fokker-Planck equations may have applications in other fields of physics such as chemotaxis for bacterial populations. We propose the idea of a classification of generalized entropies in classes of equivalence and provide an aesthetic connexion between topics (vortices, stars, bacteries,...) which were previously disconnected.Comment: Submitted to Phys. Rev.

Continued lessons from the INS gene: An intronic mutation causing diabetes through a novel mechanism

Background Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus. Methods Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry (http://monogenicdiabetes. uchicago.edu). Results The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional ß cells. Whole-exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site. Conclusions Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without ß cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life

Zinc Single Crystal Deformation Experiments using a "6 Degrees of Freedom" Apparatus

A new experimental technique to study crystallographic slip system activity in metallic single crystals deformed under a condition of uniaxial stress is applied to study the behavior of Zn single crystals. The experimental apparatus allows essentially unconstrained shape change of inherently anisotropic materials under a condition of uniaxial stress by allowing 3 translational and 3 rotational degrees of freedom during compression; hence we have named the experiment 6 degrees of freedom (6DOF). The experiments also utilize a 3-D digital image correlation system to measure full-field displacement fields, which are used to calculate strain and make direct observations of slip system activity. We show that the experimental results associated with a pristine zinc single crystal are precisely consistent with the theoretical predicted shape change (sample distortion) assuming that the most favored slip system on the basal plane is the only one that is active. Another experiment was performed on a processed and annealed Zn single crystal to investigate slip that is inconsistent with the critical resolved shear stress (CRSS) theory. These experiments on zinc illustrate the ability of the 6DOF experiment, together with image correlation (IC) data, to measure slip system activity with a high degree of fidelity

The Similarity Hypothesis in General Relativity

Self-similar models are important in general relativity and other fundamental theories. In this paper we shall discuss the ``similarity hypothesis'', which asserts that under a variety of physical circumstances solutions of these theories will naturally evolve to a self-similar form. We will find there is good evidence for this in the context of both spatially homogenous and inhomogeneous cosmological models, although in some cases the self-similar model is only an intermediate attractor. There are also a wide variety of situations, including critical pheneomena, in which spherically symmetric models tend towards self-similarity. However, this does not happen in all cases and it is it is important to understand the prerequisites for the conjecture.Comment: to be submitted to Gen. Rel. Gra