Hyperinsulinemia and insulin resistance : What comes first ?

Background

1)	Classical explanation :
Classical explanation of diabetic pathophysiology states that obesity induced insulin resistance develops first and is followed by compensatory hyperinsulinnemia. Further insulin resistance leads to prolonged, increased secretary demand on beta cells leading to subsequent secondary beta cell failure, giving rise to hyperglycaemia and diabetes^2^.

2)	 Neurobehavioral origin hypothesis :
The Neurobehavioral origin hypothesis suggests that insulin resistance mediates a shift from muscle dependent (soldier) to brain dependent (diplomat) strategies of making a livelihood. If nutrient limitation affects intrauterine development, brain development is the least affected among all the organs^4,5^. As a result, in IUGR babies muscle weight is poor but the brain is relatively well developed. Such a person is more likely to be a successful diplomat rather than a soldier and insulin resistance is adaptive for such an individual^3^. Since insulin is involved in brain development and cognitive functions, higher levels of insulin are needed. As insulin is having strong anti-lipolytic effect, hyperinsulinnemia is followed by subsequent excess fat accumulation. Also compensatory insulin resistance is needed to avoid hypoglycemia. This hypothesis predicts a reverse order of pathophysiology i.e. primary hyperinsulinnemia followed by compensatory insulin resistance^3^

Objective-
To determine in diabetes whether hyperinsulinnemia develops first or insulin resistance develops first.

Methods :
We searched literature for studies that investigated directly or indirectly the sequence of development of hyperinsulinnemia and insulin resistance in humans and animal models from an early stage. Meta-analysis was conducted on published data.

Results-
1)	In low birth weight neonates in humans as well as in rat models, hyperinsulinnemia is found at very early stage.^6^
2)	Development of insulin resistance is preceded by hyperinsulinnemia in mice, rats as well as in humans.^7, 8^
3)	In normoglycaemic hyperinsulinemia state if insulin production is suppressed insulin sensitivity increases rapidly maintaining the normoglycaemic state.^9,10^
4)	Beta cell expansion beginning in intrauterine life is independent of glucose, Insulin and Insulin receptors.^6^


Conclusion-
All the four lines of evidence indicate that hyperinsulinnemia precedes insulin resistance supporting the predictions of neurobehavioral origin hypothesis over the orthodox view.



References :
1)	DeFronzo RA, Ferrannini E (1991). Diabetes Care 14:173-194
2)	Kruszynska YT, Olefsky JM (1996). J Investig Med 44: 413-428.
3)	Watve MG, Yajnik CY (2007). BMC Evolutionary Biology.7: 61-74.
 4) Winick M, Rosso P, Waterlow JC (1970). Exp Neurol, 26:393-400.
 5) Winick M. (1969) J Pediatr,74:667-679.
 6) Chakravarthy MV et.al. (2008) Diabetes, 57:2698-2707.
 7) Ramin A et. al. (1998) J Clin Endo and Met, 83 :1911-1915.
 8) Hansen BC (1990) Am J Physiol Regul Integr Comp Physiol 259: 612-617.
 9) Stanley L (1981) Life Sciences, 28: 1829-1840.
 10) Ratzmann KP et. al. (1983) Int J Obes, 7 : 453-458

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Sociobiological Control of Plasmid copy number

Background:
All known mechanisms and genes responsible for the regulation of plasmid replication lie with the plasmid rather than the chromosome. It is possible therefore that there can be copy-up mutants. Copy-up mutants will have within host selective advantage. This would eventually result into instability of bacteria-plasmid association. In spite of this possibility low copy number plasmids appear to exist stably in host populations. We examined this paradox using a computer simulation model.

Model:
Our multilevel selection model assumes a wild type with tightly regulated replication to ensure low copy number. A mutant with slightly relaxed replication regulation can act as a “cheater” or “selfish” plasmid and can enjoy a greater within-host-fitness. However the host of a cheater plasmid has to pay a greater cost. As a result, in host level competition, host cell with low copy number plasmid has a greater fitness. Furthermore, another mutant that has lost the genes required for conjugation was introduced in the model. The non-conjugal mutant was assumed to undergo conjugal transfer in the presence of another conjugal plasmid in the host cell.

Results:
The simulatons showed that if the cost of carrying a plasmid was low, the copy-up mutant could drive the wild type to extinction or very low frequencies. Consequently, another mutant with a higher copy number could invade the first invader. This process could result into an increasing copy number. However above a certain copy number within-host selection was overcompensated by host level selection leading to a rock-paper-scissor (RPS) like situation. The RPS situation allowed the coexistence of high and low copy number plasmids. The non-conjugal “hypercheaters” could further arrest the copy numbers to a substantially lower level.

Conclusions:
These sociobiological interactions might explain the stability of copy numbers better than molecular mechanisms of replication regulation alone

Gaze following in an asocial reptile (Eublepharis macularius)

Gaze following is the ability to utilise information from another's gaze. It is most often seen in a social context or as a reflexive response to interesting external stimuli. Social species can potentially reveal utilisable knowledge about another's future intentions by attending to the target of their gaze. However, in even more fundamental situations, being sensitive to another's gaze can also be useful such as when it can facilitate greater foraging efficiency or lead to earlier predator detection. While gaze sensitivity has been shown to be prevalent in a number of social species, little is currently known about the potential for gaze following in asocial species. The current study investigated whether an asocial reptile, the leopard gecko (Eublepharis macularius), could reliably use the visual indicators of attention to follow the gaze of a conspecific around a barrier. We operated three trial conditions and found subjects (N = 6) responded significantly more to the conspecific demonstrator looking up at a laser stimulus projected onto an occluder during the experimental condition compared to either of two control conditions. The study's findings point toward growing evidence for gaze-following ability in reptiles, who are typically categorised as asocial. Furthermore, our findings support developing comparative social cognition research showing the origins of gaze following and other cognitive behaviours that may be more widely distributed across taxonomic groups than hitherto thought

Drug discovery prospect from untapped species: Indications from approved natural product drugs

10.1371/journal.pone.0039782PLoS ONE77

Patterns in abundance and diversity of faecally dispersed parasites of tiger in Tadoba National Park, central India

BACKGROUND: Importance of parasites in ecological and evolutionary interactions is being increasingly recognized. However, ecological data on parasites of important host species is still scanty. We analyze the patterns seen in the faecal parasites of tigers in the Tadoba National Park, India, and speculate on the factors and processes shaping the parasite community and the possible implications for tiger ecology. RESULTS: The prevalence and intensities were high and the parasite community was dominated by indirect life cycle parasites. Across all genera of parasites variance scaled with the square of the mean and there was a significant positive correlation between prevalence and abundance. There was no significant association between different types of parasites. CONCLUSIONS: The 70 samples analyzed formed 14 distinct clusters. If we assume each of the clusters to represent individual tigers that were sampled repeatedly and that resident tigers are more likely to be sampled repeatedly, the presumed transient tigers had significantly greater parasite loads than the presumed resident ones

Phenotypic Plasticity and Effects of Selection on Cell Division Symmetry in Escherichia coli

Aging has been demonstrated in unicellular organisms and is presumably due to asymmetric distribution of damaged proteins and other components during cell division. Whether the asymmetry-induced aging is inevitable or an adaptive and adaptable response is debated. Although asymmetric division leads to aging and death of some cells, it increases the effective growth rate of the population as shown by theoretical and empirical studies. Mathematical models predict on the other hand, that if the cells divide symmetrically, cellular aging may be delayed or absent, growth rate will be reduced but growth yield will increase at optimum repair rates. Therefore in nutritionally dilute (oligotrophic) environments, where growth yield may be more critical for survival, symmetric division may get selected. These predictions have not been empirically tested so far. We report here that Escherichia coli grown in oligotrophic environments had greater morphological and functional symmetry in cell division. Both phenotypic plasticity and genetic selection appeared to shape cell division time asymmetry but plasticity was lost on prolonged selection. Lineages selected on high nutrient concentration showed greater frequency of presumably old or dead cells. Further, there was a negative correlation between cell division time asymmetry and growth yield but there was no significant correlation between asymmetry and growth rate. The results suggest that cellular aging driven by asymmetric division may not be hardwired but shows substantial plasticity as well as evolvability in response to the nutritional environment

Synthetic biology to access and expand nature's chemical diversity

Bacterial genomes encode the biosynthetic potential to produce hundreds of thousands of complex molecules with diverse applications, from medicine to agriculture and materials. Accessing these natural products promises to reinvigorate drug discovery pipelines and provide novel routes to synthesize complex chemicals. The pathways leading to the production of these molecules often comprise dozens of genes spanning large areas of the genome and are controlled by complex regulatory networks with some of the most interesting molecules being produced by non-model organisms. In this Review, we discuss how advances in synthetic biology — including novel DNA construction technologies, the use of genetic parts for the precise control of expression and for synthetic regulatory circuits — and multiplexed genome engineering can be used to optimize the design and synthesis of pathways that produce natural products

The 'K' selected oligophilic bacteria: a key to uncultured diversity?

Molecular techniques have made it increasingly clear that a large proportion of bacterial diversity in natural habitats is uncultured and therefore unexplored. We suggest and give evidence in support of a hypothesis that a large proportion, if not all, of the uncultured diversity from a variety of aquatic and terrestrial habitats are oligophilic (oligotrophic) bacteria. Oligophilic bacteria grow only on dilute nutrient media and form small or microscopic colonies. A technique to cultivate and isolate the moderately oligophilic bacteria was developed and 90 cultures isolated, The twelve bacterial cultures characterized showed high growth yield coefficients and carbon conversion efficiencies at low substrate concentrations and progressively decreased with increasing substrate concentrations. Most of the growth yields were substantially higher than those reported in the literature and lie near the theoretical maximum. Slow growth rates and high yields indicate that they are 'K' selected species. 16S rDNA partial sequence analysis of the isolates indicates that it is a novel as well as diverse group

Myxobacterial diversity of Indian soils - How many species do we have?

Myxobacteria of tropical soils is an under-explored bacterial group. We report below the results of sampling in Pune district of Western Ghats. A number of novel morphotypes were found in forest as well as urban/semi-urban soils. There was a high level of floral dissimilarity between habitats. The morphotypes detected in Pune district also differed from the northern Indian species recorded earlier. Using a species individual curve on the Pune, Lucknow and pooled data, we try to estimate the number of species that are likely to be present in India. A plausible estimate is several fold higher than the species recorded worldwide so far

A Model for Damage Load and Its Implications for the Evolution of Bacterial Aging

Deleterious mutations appearing in a population increase in frequency until stopped by natural selection. The ensuing equilibrium creates a stable frequency of deleterious mutations or the mutational load. Here I develop the comparable concept of a damage load, which is caused by harmful non-heritable changes to the phenotype. A damage load also ensues when the increase of damage is opposed by selection. The presence of a damage load favors the evolution of asymmetrical transmission of damage by a mother to her daughters. The asymmetry is beneficial because it increases fitness variance, but it also leads to aging or senescence. A mathematical model based on microbes reveals that a cell lineage dividing symmetrically is immortal if lifetime damage rates do not exceed a threshold. The evolution of asymmetry allows the lineage to persist above the threshold, but the lineage becomes mortal. In microbes with low genomic mutation rates, it is likely that the damage load is much greater than the mutational load. In metazoans with higher genomic mutation rates, the damage and the mutational load could be of the same magnitude. A fit of the model to experimental data shows that Escherichia coli cells experience a damage rate that is below the threshold and are immortal under the conditions examined. The model estimates the asymmetry level of E. coli to be low but sufficient for persisting at higher damage rates. The model also predicts that increasing asymmetry results in diminishing fitness returns, which may explain why the bacterium has not evolved higher asymmetry