A family with severe insulin resistance and diabetes due to a mutation in AKT2

Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBbeta in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end points and inhibited the function of coexpressed, wild-type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans.     

Human diabetes associated with a mutation in the tyrosine kinase domain of the insulin receptor

Insulin receptor complementary DNA has been cloned from an insulin-resistant individual whose receptors have impaired tyrosine protein kinase activity. One of this individual's alleles has a mutation in which valine is substituted for Gly996, the third glycine in the conserved Gly-X-Gly-X-X-Gly motif in the putative binding site fo adenosine triphosphate. Expression of the mutant receptor by transfection into Chinese hamster ovary cells confirmed that the mutation impairs tyrosine kinase activity.     

Triggering of allostery in an enzyme by a point mutation: ornithine transcarbamoylase

The origin of allostery is an unanswered question in the evolution of complex regulatory proteins. Anabolic ornithine transcarbamoylase, a trimer of identical subunits, is not an allosteric enzyme per se. However, when the active-site residue arginine-106 of the Escherichia coli enzyme is replaced with a glycine through site-directed mutagenesis, the resultant mutant enzyme manifests substrate cooperativity that is absent in the wild-type enzyme. Both homotropic and heterotropic interactions occur in the mutant enzyme. The initial velocity saturation curves of the substrates, carbamoyl phosphate and L-ornithine, conform to the Hill equation. The observed cooperativity depends on substrate but not enzyme concentration. The finding underscores the possibility that a single mutation of the enzyme in the cell could turn transcarbamoylation into a regulatory junction in the biosynthesis of L-arginine and urea.     

A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse

In a pedigree derived from a mouse treated with the mutagen ethylnitrosourea, a mutation has been identified that predisposes to spontaneous intestinal cancer. The mutant gene was found to be dominantly expressed and fully penetrant. Affected mice developed multiple adenomas throughout the entire intestinal tract at an early age.     

2型糖尿病患者微血管病变与血液流变学变化、胰岛素抵抗的相关性

目的 :研究血液流变学变化和胰岛素抵抗与 2型糖尿病微血管病变的关系。方法 :检测 10 6例 2型糖尿病患者 ,其中有微血管并发症 5 3例 ,无微血管并发症 5 3例 ,以及 5 3例正常对照组的血液流变学、空腹血糖、空腹胰岛素 ,计算胰岛素敏感性指数 (ISI) ,并进行比较。结果 :糖尿病两组全血粘度和血浆粘度均显著高于正常对照组 ;ISI则显著低于正常对照组 (P<0 .0 1)。糖尿病有微血管病变组全血粘度和血浆粘度显著高于无微血管病变组 ;ISI显著低于无微血管病变组 (P<0 .0 1)。多元逐步回归分析显示 ,2型糖尿病微血管病变与糖尿病病程、血糖、全血粘度和血浆粘度呈显著正相关 (r=0 .62 4,0 .42 8,0 .3 46,0 .3 82 ,P值分别 <0 .0 0 1,0 .0 1,0 .0 5 ,0 .0 1) ,与 ISI呈显著负相关 (r=-0 .3 5 2 ,P<0 .0 5 )。结论 :2型糖尿病微血管病变患者存在持续性的高血糖、高血液粘度 ,糖尿病病程的延长 ,严重的胰岛素抵抗为 2型糖尿病微血管病变的主要危险因素。     

A point mutation in the c-myc locus of a Burkitt lymphoma abolishes binding of a nuclear protein

A 20-base pair region in the first intron of the human c-myc gene was identified as the binding site of a nuclear protein. This binding site is mutated in five out of seven Burkitt lymphomas sequenced to date. To investigate the protein-recognition region in greater detail, the abnormal c-myc allele from a Burkitt lymphoma line (PA682) that carries a t(8;22) chromosomal translocation was used. A point mutation in the binding region of the PA682 c-myc DNA abolished binding of this nuclear protein. This protein may be an important factor for control of c-myc expression, and mutations in its recognition sequence may be associated with c-myc activation in many cases of Burkitt lymphoma.     

Induction of T helper type 2 immunity by a point mutation in the LAT adaptor

The transmembrane protein LAT (linker for activation of T cells) couples the T cell receptor (TCR) to downstream signaling effectors. Mice homozygous for a mutation of a single LAT tyrosine residue showed impeded T cell development. However, later they accumulated polyclonal helper T (TH) cells that chronically produced type 2 cytokines in large amounts. This exaggerated TH2 differentiation caused tissue eosinophilia and massive maturation of plasma cells secreting to immunoglobulins of the E and G1 isotypes. This paradoxical phenotype establishes an unanticipated inhibitory function for LAT that is critical for the differentiation and homeostasis of TH cells.     

Evidence that the reactivity of the martian soil is due to superoxide ions

The Viking Landers were unable to detect evidence of life on Mars but, instead, found a chemically reactive soil capable of decomposing organic molecules. This reactivity was attributed to the presence of one or more as-yet-unidentified inorganic superoxides or peroxides in the martian soil. Using electron paramagnetic resonance spectroscopy, we show that superoxide radical ions (O2-) form directly on Mars-analog mineral surfaces exposed to ultraviolet radiation under a simulated martian atmosphere. These oxygen radicals can explain the reactive nature of the soil and the apparent absence of organic material at the martian surface.     

Visfatin: a protein secreted by visceral fat that mimics the effects of insulin

Fat tissue produces a variety of secreted proteins (adipocytokines) with important roles in metabolism. We isolated a newly identified adipocytokine, visfatin, that is highly enriched in the visceral fat of both humans and mice and whose expression level in plasma increases during the development of obesity. Visfatin corresponds to a protein identified previously as pre-B cell colony-enhancing factor (PBEF), a 52-kilodalton cytokine expressed in lymphocytes. Visfatin exerted insulin-mimetic effects in cultured cells and lowered plasma glucose levels in mice. Mice heterozygous for a targeted mutation in the visfatin gene had modestly higher levels of plasma glucose relative to wild-type littermates. Surprisingly, visfatin binds to and activates the insulin receptor. Further study of visfatin's physiological role may lead to new insights into glucose homeostasis and/or new therapies for metabolic disorders such as diabetes.     

Human diabetes associated with a deletion of the tyrosine kinase domain of the insulin receptor

The insulin receptor has an intrinsic tyrosine kinase activity that is essential for signal transduction. A mutant insulin receptor gene lacking almost the entire kinase domain has been identified in an individual with type A insulin resistance and acanthosis nigricans. Insulin binding to the erythrocytes or cultured fibroblasts from this individual was normal. However receptor autophosphorylation and tyrosine kinase activity toward an exogenous substrate were reduced in partially purified insulin receptors from the proband's lymphocytes that had been transformed by Epstein-Barr virus. The insulin resistance associated with this mutated gene was inherited by the proband from her mother as an apparently autosomal dominant trait. Thus a deletion in one allele of the insulin receptor gene may be at least partly responsible for some instances of insulin-resistant diabetes.     

TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver

Insulin resistance is a major hallmark in the development of type II diabetes, which is characterized by the failure of insulin to promote glucose uptake in muscle and to suppress glucose production in liver. The serine-threonine kinase Akt (PKB) is a principal target of insulin signaling that inhibits hepatic glucose output when glucose is available from food. Here we show that TRB3, a mammalian homolog of Drosophila tribbles, functions as a negative modulator of Akt. TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase. Amounts of TRB3 RNA and protein were increased in livers of db/db diabetic mice compared with those in wild-type mice. Hepatic overexpression of TRB3 in amounts comparable to those in db/db mice promoted hyperglycemia and glucose intolerance. Our results suggest that, by interfering with Akt activation, TRB3 contributes to insulin resistance in individuals with susceptibility to type II diabetes.     

Martian ionosphere: a component due to solar protons

The small magnetic field strength observed near Mars by Mariner IV suggests that protons from the solar wind may enter the Martian atmosphere and produce ionization in addition to that produced by ultraviolet light and x-rays. It is found that solar protons produce a thin ionized layer at a rate of the order of 3 x 10(3) per cubic centimeter per second at a depth corresponding to the F(1) region in the terrestrial atmosphere. Unless the effective recombinative coefficient is very large (greater than 10(-5) centimeter cubed per second) or unless unusual diffusion effects are present, this layer should have been detected by Mariner IV, and therefore must be present in one of the observed ionized regions. Because of its very compact shape, the subsidiary maximum near 95 kilometers discovered in the Mariner-IV occultation experiment may be the proton ionization peak. If so, the major 120-kilometer maximum is an F(2) layer. Distinction between photon and proton ionization regions can be made by microwave occultation experiments aboard planetary orbiters.     

Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis

Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.     

Selective pancreatic enzyme secretion due to a new peptide called chymodenin

Chymodenin, a peptide newly isolated from porcine duodenum, elicited a rapid threefold increase in secretion of chymotrypsinogen while increasing secrelion of total protein by only, about 40 percent; lipase secretion was unaffected. The pancreas appears able, under chymodenin stimulation, to rapidly alter the transport of an individual enzyme as opposed to producing en masse secretion of enzyme.