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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Prescription pattern of antimicrobial agents prescribed in outpatient department of dermatology in a tertiary care hospital in India

Background: Skin diseases contribute largely to global disease burden. Antimicrobial agents are used for treatment of various skin diseases of microbial aetiology caused by fungi, bacteria, viruses and ectoparasites. The primary objective of this study was to study the prescription pattern of antimicrobial agents in dermatology, to provide insights into the disease patterns, profile of the drugs used and their rationality. Methods: Cross-sectional observational study was conducted in dermatology outpatient department of T. N. M. C. and B. Y. L. Nair Charitable Hospital, Mumbai for period of 6 months. 372 prescriptions containing an antimicrobial agent (AMA) were analysed. Demographic data, disease pattern, associated comorbidities and prescription details were recorded after taking written informed consent. Results: Fungal infections were the most common (48%) followed by bacterial infections (31%). The most encountered condition was dermatophytosis. Average number of AMA per prescription was 2.33±0.73. Percentage of AMA prescribed by generic name was 48%. Percentage of AMA prescribed from National list of essential medicines 2015 (NLEM) was 32.60%. 87.9% of AMA were prescribed as combination therapy and 12.10% were prescribed as monotherapy. The commonest prescribed drugs were antifungals followed by antibiotics. Topical creams were the commonest prescribed dosage form. Conclusions: The most common class of antimicrobial agents prescribed was antifungal agents. Prescribing combination of oral antimicrobials with topical antimicrobials was found to be high. This study provides a framework for continuous prescription audit of antimicrobials in an outpatient setting and thus can help in rational use of antimicrobials in dermatological prescribing

Evaluation of the Antiasthmatic Activity of Methanolic Extract of Trigonella Foenum Graecum on Experimental Models of Bronchial Asthma

The present study deals with the phytochemical screening and evaluation of antiasthmatic activity of methanolic extract of Trigonella foenumgraecum on experimental models of bronchial asthma and anaphylaxis. The antiasthmatic activity was studied on histamine-induced bronchospasm in guinea pig (Dunkey-Hartley) for respiratory parameters such as maximum airflow, minimum airflow, tidal volume, respiratory rate, minute volume, specific airway resistance determination on double chambered whole body plethysmography on un-anesthetized guinea pigs, for mast cell degranulation by compound 48/80 (in vitro) was done using rat (Albino Wistar) peritoneal fluid. Trigonella foenum graecum treated result indicated significant protection against histamine-induced bronchospasm in guinea pigs at highest dose i.e. 400mg/kg. The bronchodilatory effect of Trigonella foenum graecum was found comparable to the protection offered by the standard drug Salbutamol on respiratory parameters in double chambered whole body plethysmography, Treatment with Trigonella foenum graecum at a dose of 400mg/kg showed a significant decrease in degranulation rate of actively and passively sensitized mast cells of sensitized rats when challenged with antigen. Trigonella foenum graecum. Possess significant anti-asthmatic activity due to its potential anti inflammatory, antioxidant and the antihistaminic activity, which reflects as anti-degranulating effect on mast cells and on respiratory parameters. Keywords: Trigonella foenum graecum; asthma; mast cell; compound 48/80; histamin

A novel fluorescent "turn-on" chemosensor for nanomolar detection of Fe(III) from aqueous solution and its application in living cells imaging

An electronically active and spectral sensitive fluorescent “turn-on” chemosensor (BTP-1) based on the benzo-thiazolo-pyrimidine unit was designed and synthesized for the highly selective and sensitive detection of Fe³⁺ from aqueous medium. With Fe³⁺, the sensor BTP-1 showed a remarkable fluorescence enhancement at 554 nm (λex=314 nm) due to the inhibition of photo-induced electron transfer. The sensor formed a host-guest complex in 1:1 stoichiometry with the detection limit down to 0.74 nM. Further, the sensor was successfully utilized for the qualitative and quantitative intracellular detection of Fe³⁺ in two liver cell lines i.e., HepG2 cells (human hepatocellular liver carcinoma cell line) and HL-7701 cells (human normal liver cell line) by a confocal imaging technique

Patterns and causes of maternal mortality in tertiary care hospital in Maharashtra, India: a 10-year retrospective study

Background: Maternal death is a catastrophe, as death of a mother can the entire family. The aim of present study is to find out major patterns, reasons and complications leading to maternal deaths. Methods: A retrospective study was conducted for last 10 years from January 2013 to December 2022 by studying the records of a tertiary care hospital to study the maternal mortalities and complications leading to death. Maternal deaths were analyzed by considering different facets, such as age at death, gravida, locality of residence, admission death interval and direct and indirect cause/s of death, etc. Results: During the study period, total of 107753 live births and 202 maternal deaths have been recorded. The average maternal mortality rate of last ten years was 187.46/100000 live births. Age wise maternal mortality during the study period was high in the age 19 to 25. Major direct cause of maternal mortality was postpartum hemorrhage, (23%) and major indirect cause observed was anemia (43%). Admission to death interval time indicates that delay in provision of treatment and referral to tertiary care hospital might be the reason responsible for high maternal deaths. Conclusions: Maternal deaths can be prevented by improving the health care facilities, ensuring skilled attendants and required basic medication. This is high time to mobilize universal, national, regional, and community-based commitment to decrease maternal mortalities.

Fracture union in extra articular distal tibia fracture after definitive delta frame external fixation in COVID 19 pandemic: a case report

Distal tibia fractures account for 10% of lower limb fractures. Mode of trauma also determines the fate of soft tissue recovery. In low energy fractures soft tissue show better healing whereas fractures due to high energy trauma show high chances of soft tissue complications like poor soft tissue coverage, wound infection and necrosis. We presented a 50 years old male case of extra articular left distal tibia fibula open fracture managed by delta frame external fixator with fibular K wiring used as a definitive management with good fracture healing and range of motion 5 months postoperative. Ankle spanning external fixation is a good modality of surgical management of extra articular compound distal tibia fractures as both temporary and definitive surgical fixation

An efficient naphthalimide based receptor for selective detection of Hg2+and Pb2+ions

Naphthalimide based receptor 1 with N-substituted benzothiazole and pyrrolidine subunit is designed, synthesized, and characterized using FT-IR,1H and 13C NMR spectroscopy and mass spectrometry techniques. The receptor 1 exhibits prominent optical response for Hg2+and Pb2+ions allowing the detection of these ions in acetonitrile (ACN). The formation of the receptor 1:cation complexes have been investigated using UV-Vis and fluorescence emission titration. Further, the selectivity of the receptor 1towards Hg2+and Pb2+ ions on the presence of various interfering cations such as Mg2+, Ba2+, Ni2+, Co2+, Cu2+, Ag2+, Fe2+, Fe3+and Cr3+ has been confirmed by UV-Vis and fluorescence spectroscopy. The binding constant between receptor 1 and Hg2+ and Pb2+ was estimated by Benesi-Hildebrand plot and equations. The binding constants have been found to be Ka= 3.43286 ´ 10−6 and Ka= 2.84079 ´ 10−6 M for Hg2+ and Pb2+, respectively. The limit of detection (LOD) for Hg2+and Pb2+by receptor 1are down to 7.44 ´ 10−10 M and 1.26 ´ 10−9 M, respectively. In addition, Job’s plot analysis reveals 1:2 binding stoichiometry between the receptor 1 and Pb2+ and Hg2+ cations.

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation