Fundamentals about onset and progressive disease character of type 2 diabetes mellitus

ResearchGate is a world wide web for scientists and researchers to share papers, ask and answer questions, and find collaborators. As one of the more than 15 million members, the author uploads research output and reads and responds to some of the questions raised, which are related to type 2 diabetes. In that way, he noticed a serious gap of knowledge of this disease among medical professionals over recent decades. The main aim of the current study is to remedy this situation through providing a comprehensive review on recent developments in biochemistry and molecular biology, which can be helpful for the scientific understanding of the molecular nature of type 2 diabetes. To fill up the shortcomings in the curricula of medical education, and to familiarize the medical community with a new concept of the onset of type 2 diabetes, items are discussed like: Insulin resistance, glucose effectiveness, insulin sensitivity, cell membranes, membrane flexibility, unsaturation index (UI; number of carbon-carbon double bonds per 100 acyl chains of membrane phospholipids), slow-down principle, effects of temperature acclimation on phospholipid membrane composition, free fatty acids, energy transport, onset of type 2 diabetes, metformin, and exercise. Based on the reviewed data, a new model is presented with proposed steps in the development of type 2 diabetes, a disease arising as a result of a hypothetical hereditary anomaly, which causes hyperthermia in and around the mitochondria. Hyperthermia is counterbalanced by the slow-down principle, which lowers the amount of carbon-carbon double bonds of membrane phospholipid acyl chains. The accompanying reduction in the UI lowers membrane flexibility, promotes a redistribution of the lateral pressure in cell membranes, and thereby reduces the glucose transporter protein pore diameter of the transmembrane glucose transport channel of all Class I GLUT proteins. These events will set up a reduction in transmembrane glucose transport. So, a new blood glucose regulation system, effective in type 2 diabetes and its prediabetic phase, is based on variations in the acyl composition of phospholipids and operates independent of changes in insulin and glucose concentration. UI assessment is currently arising as a promising analytical technology for a membrane flexibility analysis. An increase in mitochondrial heat production plays a pivotal role in the existence of this regulation system.     

Autonomy, solidarity, and self-realization: policy views of Dutch service providers

The popularity of autonomy and self-determination in thinking and talking about quality of life of individuals with mental retardation suggests a dominance of these concepts in the field today. Here we offer an analysis and evaluation of this view and compare it with two alternative and complementary views--solidarity and self-realization. Recent policy documents of central government and parents' organizations and recent policy documents of 22 agencies for people with mental retardation in the Netherlands are the basis of this analysis. Results suggest that proponents of these alternative views offer valuable criticisms of the dominant view. We appeal for an open discussion of various concepts and their respective strengths and weaknesses in relation to different clients and institutional contexts.     

Heart function and molecular biological parameters are comparable in young adult and aged rats after chronic myocardial infarction

OBJECTIVE: To test the hypothesis that IL-1beta and IL-6 play a pivotal role after myocardial infarction (MI) particularly in aged rats. METHODS: Chronic MI was induced in young adult (3.5 months) and aged (18 months) female Sprague-Dawley rats by ligation of the left coronary artery. Sham-operated animals of corresponding age served as controls. Heart function was measured by catheterization 4 weeks after MI. The expression of IL-1beta, IL-6, TGF-beta-isoforms, ANF, and components of the extracellular matrix (pro-collagen I and III, colligin, MMP-2 and TIMP2) was measured by ribonuclease protection assay. RESULTS: Aged control rats differed from young adult rats in that LV-developed pressure (LVDP) was higher (161 vs. 147 mmHg, p<0.05) in response to the elevated total peripheral resistance (0.71 vs. 0.47 mmHg ml min/kg, p<0.05). Contractility was reduced in aged controls as indicated by decreased LV dP/dt (8.106 vs. 10.606 mmHg/s, p<0.05). LV function was severely depressed in both MI groups (reduction in LVDP by about 35% and LV dP/dt by about 30%, increase in LVEDP to 24 mmHg) while RVP and RV dP/dt markedly increased by about 100%. This was not different between both MI groups. ANF expression as a marker of hypertrophy was induced in both MI groups, but less pronounced in the LV of aged rats. Also, the mRNA expression pattern was qualitatively comparable, but showed gradual differences. CONCLUSION: These results indicate that aged rats compensate well for hemodynamic overload induced by MI. Also, the mechanisms of myocardial post-MI remodeling are comparable in young adult and aged rats.     

Significance of the 5-Phosphoribosyl-1-Pyrophosphate Pool for Cardiac Purine and Pyrimidine Nucleotide Synthesis: Studies with Ribose,Adenine, Inosine,and Orotic Acid in Rats

Several experimental approaches have been applied to examine the significance of the available pool of 5-phosphoribosyl-1-pyrophosphate (PRPP) for purine and pyrimidine nucleotide metabolism in the rat heart. In a series of studies including some pentoses and pentitols, in particular ribose, it was shown that these sugars were all capable of elevating the cardiac PRPP pool and stimulating the rate of adenine nucleotide biosynthesis. In several pathophysiological situations that were characterized by a decrease in ATP content, the increase in adenine nucleotide biosynthesis elicited by ribose was of such magnitude that the ATP level was replenished partially or completely in a considerably shorter period of time than that without any intervention. In two experimental models, in cardiac hypertrophy induced by aortic constriction with additional isoproterenol administration and in the noninfarcted rat heart after permanent coronary artery ligation, there was also an improvement in global heart function under the influence of ribose. The myocardial cell damage induced by isoproterenol was prevented by ribose. Combination of ribose with adenine or inosine led to an even quicker ATP normalization in the isoproterenol-stimulated rat heart than with either intervention alone. Ribose had no functional effects on the cardiovascular system, whereas adenine, inosine, and orotic acid were demonstrated to have different hemodynamic influences. Adenine and inosine had negative chronotropic and inotropic effects in the intact rat, whereas orotic acid had a positive influence both on the left and right rat heart. On the basis of these experimental studies, a new therapeutic strategy is suggested in which elevation of the available PRPP plays a key role. Once this has been elevated by ribose, additional substrates, such as adenine, inosine, and orotic acids, should be included. This would exploit the full potential of a therapeutic approach that corrects a natural metabolic deficiency of the heart that is the low capacity of the oxidative pentose phosphate pathway in which PRPP is generated.     

Afterload- and preload-dependent interactions in the isolated biventricular working rat heart

OBJECTIVES:

The afterload- (AL) and preload- (PL) dependent interactions between the left and right ventricle (LV, RV, respectively) of an isolated biventricular ejecting rat heart were measured in terms of left (L) and right (R) intraventricular peak pressure (LP_max and RP_max, respectively) and aortic and pulmonary flow (AF, PF, respectively).

METHODS:

Starting with standardized loading conditions, LVPL was varied in six steps for each of five distinct LVALs (n=28) and then RVPL was varied in seven steps for each of five distinct RVALs (n=37). Thus, the entire range of loading conditions was covered.

RESULTS:

Identification of AL-dependent systolic interactions revealed an important ΔLP_max–ΔRP_max gain of 0.25 (r²=0.78) and a still more dominant ΔRP_max–ΔPF gain of 0.45 (r²=0.84). At least 26% of maximal PF were attributable to LV systolic function. In contrast, R-L systolic interaction impeded PF; there was no global crosstalk pressure gain and no ipsilateral pressure-flow gain. Reduction of RV activity augmented AF by at least 15%. PL-dependent L-R interactions were absent except for minimal LVAL. In contrast, the reverse interaction reflected an inverse correlation between RVPL and AF, which is coincidential with other studies (−11% AF for a doubling of the standard RVPL). For the minimal RVAL, there was a biphasic response of AF to RVPL. Unloading the maximally loaded RV revealed an overall inhibition of AF by 37% for the standardized LV. Unloading the standardized RV revealed a basal inhibition of AF by 6% for the standardized LV and a 4.5% augmentation for the highly loaded LV. Consequently, basal contribution of RV to LV performance depended on the conditions of LV loading.

CONCLUSIONS:

The authors suggest a unidirectional transseptal R-L mechanism for diastolic interactions, and transseptal L-R and paraseptal R-L mechanisms for systolic interactions.     

Effect of tube angulation on the measurement of intermetatarsal angles

We systematically investigated the effect of tube angulation on angular distortion of the anteroposterior radiograph of the foot. Three-dimensional data from the metatarsals originating from computed tomographic scans of ten healthy volunteers were projected onto the supporting surface at various tube angulations to simulate radiography. The distortion of the intermetatarsal angles decreased from 1.2 degrees to 3.5 degrees at 20 degrees tube angulation to 0.4 degrees to 2.7 degrees at 0 degrees tube angulation. The relatively small improvement in angular measurement using 0 degrees instead of 15 degrees tube angulation would not outweigh the adverse effects of changing the standard radiographic technique. Physician awareness of this source of error when planning surgical therapy seems more important.