Chronic Hyperinsulinemia Research Articles

Digoxin reduces senescence and restores dysfunctional endothelial-subcutaneous adipocyte cross-talk and dysregulated glucose homeostasis in patients with type 2 diabetes mellitus

Abstract Background Normal subcutaneous adipose tissue (SAT) function is dependent on SAT microvascular expansion. Heart failure with reduced ejection fraction (HF) and type 2 diabetes mellitus (DM) have a synergistic deleterious relationship and, of relevance to this, metabolic dysregulation may drive HF progression in DM. Chronic hyperinsulinemia is associated with adipocyte senescence, however any contributing role of SAT microvascular endothelial cell (SATMVEC) senescence on adverse microvascular expansion in type 2 diabetes mellitus (DM) remains unknown. Digoxin has been shown to have senolytic activity in murine cancer models. However, the potential therapeutic role of digoxin on SAT metabolic function is unexplored. Purpose We establish the presence of SATMVEC senescence and its effects on adipocyte function in people with HF and DM (HFDM). Moreover, we establish a therapeutic role for digoxin in targeting SATMVEC senescence, modulating SATMVEC-adipocyte crosstalk and restoring metabolic homeostasis. Methods We took pectoral SAT biopsies from 59 patients undergoing pacemaker implantation of whom 25 (42%) had HF and DM (HFDM). SATMVEC were isolated from SAT and were treated with 1ng/mL digoxin vs control for 24 hours before characterisation (cell function, expression of senescence-associated ß-galactosidase (ß-gal) and senescence associated secretory phenotype, SASP). Crosstalk between SATMVEC and subcutaneous white adipocytes were examined using co-culture techniques (Fig 1A). Paired digoxin vs control treated SATMVEC were seeded co-cultured with adipocytes for 24 hours, before adipocyte health was quantified, through 2-NBD-glucose uptake and expression of key adipogenic genes and proteins. Results Compared to HF alone, isolated SATMVEC from patients with HFDM had a senescent phenotype with increased SASP and ß-gal expression (p<0.05), reduced metabolic activity, ATP production, proliferative capacity, and impaired angiogenesis (p<0.05). In co-culture, SATMVEC from patients with HFDM had deleterious effects on adipocyte function: increasing expression of IL-6 (Fig 1C) and reducing 2-NBD-glucose uptake (p<0.05). Treatment of SATMVEC with digoxin reduced the SATMVEC senescent phenotype (Fig 1B) and increased 2-NBD-glucose adipocyte uptake (Figure 1D) (p<0.001). Conclusions SATMVEC from patients with HFDM have a senescent phenotype, and when in co-culture induce a proinflammatory adipocyte phenotype, resistant to glucose uptake. Digoxin reduces SATMVEC senescence, restores healthy adipocyte glucose homeostasis, and thus has the potential to repair dysfunctional SAT in patients with HFDM.

Overnutrition, Hyperinsulinemia and Ectopic Fat: It Is Time for A Paradigm Shift in the Management of Type 2 Diabetes

The worldwide incidence of prediabetes/type 2 has continued to rise the last 40 years. In the same period, the mean daily energy intake has increased, and the quality of food has significantly changed. The chronic exposure of pancreatic β-cells to calorie excess (excessive energy intake) and food additives may increase pancreatic insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing chronic hyperinsulinemia and peripheral insulin resistance. Chronic calorie excess and hyperinsulinemia may promote lipogenesis, inhibit lipolysis and increase lipid storage in adipocytes. In addition, calorie excess and hyperinsulinemia can induce insulin resistance and contribute to progressive and excessive ectopic fat accumulation in the liver and pancreas by the conversion of excess calories into fat. The personal fat threshold hypothesis proposes that in susceptible individuals, excessive ectopic fat accumulation may eventually lead to hepatic insulin receptor resistance, the loss of pancreatic insulin secretion, hyperglycemia and the development of frank type 2 diabetes. Thus, type 2 diabetes seems (partly) to be caused by hyperinsulinemia-induced excess ectopic fat accumulation in the liver and pancreas. Increasing evidence further shows that interventions (hypocaloric diet and/or bariatric surgery), which remove ectopic fat in the liver and pancreas by introducing a negative energy balance, can normalize insulin secretion and glucose tolerance and induce the sustained biochemical remission of type 2 diabetes. This pathophysiological insight may have major implications and may cause a paradigm shift in the management of type 2 diabetes: avoiding/reducing ectopic fat accumulation in the liver and pancreas may both be essential to prevent and cure type 2 diabetes.

Effects of hypertriglyceridemia with or without NEFA elevation on β-cell function and insulin clearance and sensitivity.

Hypertriglyceridemia is a risk factor for developing type 2 diabetes (T2D) and might contribute to its pathogenesis either directly or through elevation of non-esterified fatty acids (NEFAs). This study aimed at comparing the glucometabolic effects of acute hypertriglyceridemia alone or combined with NEFA elevation in non-diabetic subjects. Twenty-two healthy lean volunteers underwent two 5-h intravenous infusions of either saline or Intralipid, without (n=12) or with heparin (I+H; n=10) to activate the release of NEFAs. Oral glucose tolerance tests (OGTTs) were performed during the last 3h of infusion. Insulin sensitivity, insulin secretion rate (ISR), model-derived β-cell function, and insulin clearance were measured after 2h of lipid infusion and during the OGTTs. In fasting conditions, both lipid infusions increased plasma insulin and ISR and reduced insulin clearance, without affecting plasma glucose and insulin sensitivity. These effects on insulin and ISR were more pronounced for I+H than Intralipid alone. During the OGTT, the lipid infusions markedly impaired glucose tolerance, increased plasma insulin and ISR, and decreased insulin sensitivity and clearance, without significant group differences. Intralipid alone inhibited glucose-stimulated insulin secretion (i.e. β-cell glucose sensitivity) and increased β-cell potentiation, whereas I+H had neutral effects on these β-cell functions. In healthy non-obese subjects, mild acute hypertriglyceridemia directly reduces glucose tolerance, insulin sensitivity and clearance, and has selective and opposite effects on β-cell function that are neutralized by NEFAs. These findings provide new insight into plausible biological signals that generate and sustain insulin resistance and chronic hyperinsulinemia in the development of T2D.

The effects of metabolic syndrome on arterial stiffness: A concise review.

Madam, The term "metabolic syndrome" describes a collection of diseases that escalates a person’s risk of cardiovascular disease, stroke, adult-onset diabetes, and other severe health issues. It is also known as Insulin resistance syndrome. A major cause of metabolic syndrome is the development of resistance to insulin due to high levels of fats. (1) Multiple risk factors, including abdominal and central obesity, increased blood pressure, low amount of HDL, and higher amount of LDL and triacylglycerides characterize it. Metabolic syndrome and arterial stiffness are interconnected conditions that can significantly impact cardiovascular health. (2) Arterial stiffness is a condition that considers the rigidity of the arterial wall. It involves modification of the automated aspects of the walls of arteries. The macroscopic geometry as well as the intrinsic characteristics of the artery, play a role in its stiffness. (3) Several mechanisms lead to arterial stiffness in metabolic syndrome patients, the first being inflammation. Upon excess nutrition, adipocytes increase in size and number, which causes decreased perfusion, causing hypoxia. Cell necrosis with the invasion of macrophages and the synthesis of adipocytokines, which consist of the pro-inflammatory mediators, might result from this condition. (1) The increased vascular inflammation will promote vascular fibrosis, smooth muscle cell proliferation, and endothelial-mediated vasodilation, which will ultimately increase arterial stiffness. (4) Metabolic syndrome is also related to insulin resistance, lipidemia, and central obesity. Chronic hyperglycemia and hyperinsulinemia may enhance sympathetic nervous system activity, vascular inflammation, and renin-angiotensin system activity. Vascular tissue's angiotensin-aldosterone system results in fibrosis and wall enlargement. Middle-aged people transitioning from gaining body weight to established conditions like hypertension and type 2 diabetes experience arterial stiffness. This transition typically starts with a few minor changes, but Metabolic Syndrome develops when several risk factors are present. (5) In conclusion, there is evidence to suggest arterial stiffness and metabolic syndrome are closely related and have significant implications for the well-being of an individual. It is essential to address both conditions as they may lead to atherosclerosis, followed by more frequent cardiovascular events and higher mortality. There are various strategies to counter the rise of arterial stiffness, like adding exercises to routines and vitamin K-rich foods to the diet, which will in turn reduce the occurrence of metabolic syndrome disorders in individuals, thus leading to a healthier society.

Healthy dietary patterns and risk of prostate cancer in men at high genetic risk.

Prostate cancer has high heritability. Healthy lifestyle has been associated with lower lethal prostate cancer risk among men at increased genetic susceptibility, but the role of healthy dietary patterns remains unknown. We prospectively followed 10,269 genotyped men in the Health Professionals Follow-up Study (1993-2019). Genetic risk was quantified using an established polygenic risk score (PRS). Five dietary patterns were investigated: healthy eating index, Mediterranean, diabetes risk-reducing, hyperinsulinemic and inflammatory diet. Overall and lethal prostate cancer rates (metastatic disease/prostate cancer-specific death) were analyzed using multivariable Cox proportional hazards models. During 26 years of follow-up, 2133 overall and 253 lethal prostate cancer events were documented. In the highest PRS quartile, higher adherence to a diabetes risk-reducing diet was associated with lower rates of overall (top vs. bottom quintile HR [95% CI], 0.74 [0.58-0.94]) and lethal prostate cancer (0.43 [0.21-0.88]). A low insulinemic diet was associated with similar lower rates (overall, 0.76 [0.60-0.95]; lethal, 0.46 [0.23-0.94]). Other dietary patterns showed weaker, but similar associations. In the highest PRS quartile, men with healthy lifestyles based on body weight, physical activity, and low insulinemic diet had a substantially lower rate (0.26 [0.13-0.49]) of lethal prostate cancer compared with men with unhealthy lifestyles, translating to a lifetime risk of 3.4% (95% CI, 2.3%-5.0%) among those with healthy lifestyles and 9.5% (5.3%-16.7%) among those with unhealthy lifestyles. Our findings indicate that lifestyle modifications lowering insulin resistance and chronic hyperinsulinemia could be relevant in preventing aggressive prostate cancer among men genetically predisposed to prostate cancer.

Targeting the Metabolic Paradigms in Cancer and Diabetes.

Dysregulated metabolic dynamics are evident in both cancer and diabetes, with metabolic alterations representing a facet of the myriad changes observed in these conditions. This review delves into the commonalities in metabolism between cancer and type 2 diabetes (T2D), focusing specifically on the contrasting roles of oxidative phosphorylation (OXPHOS) and glycolysis as primary energy-generating pathways within cells. Building on earlier research, we explore how a shift towards one pathway over the other serves as a foundational aspect in the development of cancer and T2D. Unlike previous reviews, we posit that this shift may occur in seemingly opposing yet complementary directions, akin to the Yin and Yang concept. These metabolic fluctuations reveal an intricate network of underlying defective signaling pathways, orchestrating the pathogenesis and progression of each disease. The Warburg phenomenon, characterized by the prevalence of aerobic glycolysis over minimal to no OXPHOS, emerges as the predominant metabolic phenotype in cancer. Conversely, in T2D, the prevailing metabolic paradigm has traditionally been perceived in terms of discrete irregularities rather than an OXPHOS-to-glycolysis shift. Throughout T2D pathogenesis, OXPHOS remains consistently heightened due to chronic hyperglycemia or hyperinsulinemia. In advanced insulin resistance and T2D, the metabolic landscape becomes more complex, featuring differential tissue-specific alterations that affect OXPHOS. Recent findings suggest that addressing the metabolic imbalance in both cancer and diabetes could offer an effective treatment strategy. Numerous pharmaceutical and nutritional modalities exhibiting therapeutic effects in both conditions ultimately modulate the OXPHOS-glycolysis axis. Noteworthy nutritional adjuncts, such as alpha-lipoic acid, flavonoids, and glutamine, demonstrate the ability to reprogram metabolism, exerting anti-tumor and anti-diabetic effects. Similarly, pharmacological agents like metformin exhibit therapeutic efficacy in both T2D and cancer. This review discusses the molecular mechanisms underlying these metabolic shifts and explores promising therapeutic strategies aimed at reversing the metabolic imbalance in both disease scenarios.

Kinin B1 receptor controls maternal adiponectin levels and influences offspring weight gain

Given the importance of the kinin B1 receptor in insulin and leptin hormonal regulation, which in turn is crucial in maternal adaptations to ensure nutrient supply to the fetus, we investigated the role of this receptor in maternal metabolism and fetoplacental development. Wild-type and kinin B1 receptor-deficient (B1KO) female mice were mated with male mice of the opposite genotype. Consequently, the entire litter was heterozygous for kinin B1 receptor, ensuring that there would be no influence of offspring genotype on the maternal phenotype. Maternal kinin B1 receptor blockade reduces adiponectin secretion by adipose tissue exvivo, consistent with lower adiponectin levels in pregnant B1KO mice. Furthermore, fasting insulinemia also increased, which was associated with placental insulin resistance, reduced placental glycogen accumulation, and heavier offspring. Therefore, we propose the combination of chronic hyperinsulinemia and reduced adiponectin secretion in B1KO female mice create a maternal obesogenic environment that results in heavier pups.

The Negative Impact of Insulin Resistance/Hyperinsulinemia on Chronic Heart Failure and the Potential Benefits of Its Screening and Treatment.

This opinion article highlights the potential alterations caused by insulin resistance and hyperinsulinemia on the cardiovascular system and their negative impact on heart failure (HF), and describes the potential benefits of an early screening with consequent prompt treatment. HF is the final event of several different cardiovascular diseases. Its incidence has been increasing over the last decades because of increased survival from ischemic heart disease thanks to improvements in its treatment (including myocardial revascularization interventions) and the increase in life span. In particular, incidence of HF with preserved ejection fraction (HFpEF) is significantly increasing, and patients with HFpEF often are also affected by diabetes mellitus and insulin resistance (IR), with a prevalence > 45%. Concentric left ventricular (LV) remodeling and diastolic dysfunction are the main structural abnormalities that characterize HFpEF. It is well documented in the literature that IR with chronic hyperinsulinemia, besides causing type 2 diabetes mellitus, can cause numerous cardiovascular alterations, including endothelial dysfunction and increased wall thicknesses of the left ventricle with concentric remodeling and diastolic dysfunction. Therefore, it is conceivable that IR might play a major role in the pathophysiology and the progressive worsening of HF. To date, several substances have been shown to reduce IR/hyperinsulinemia and have beneficial clinical effects in patients with HF, including SGLT2 inhibitors, metformin, and berberine. For this reason, an early screening of IR could be advisable in subjects at risk and in patients with heart failure, to promptly intervene with appropriate therapy. Future studies aimed at comparing the efficacy of the substances used both alone and in association are needed.

Does Insulin Resistance Contribute to Neuroinflammation, Cognitive Decline and Brain Senescence in Obesity?

The burgeoning prevalence of obesity and overweight conditions from the age of adolescence and throughout the lifespan has reached epidemic proportions in industrialized nations throughout the globe. The development of insulin resistance is one of the most common observations in obesity and is associated with a systemic hypoxia in adipose tissue and a chronic inflammatory state. The insulin resistance affects multiple elements of substrate oxidation and oxidative free radical generation in both somatic and neural tissues and with cytokine-linked chronic inflammation likely originating in adipose tissue depots. In studies with aging congenic lean and obese rats chronic hyperinsulinemia and brain shrinkage has now been reported, albeit it in the absence of Type 2 diabetes (NIDDM), hypertension (HTN) or other comorbidities, thereby suggesting that aspects of disordered substrate metabolism including insulin resistance as commonly observed in obesity may be a key contributory factor in the development of a neuroinflammatory linked brain shrinkage with accompanying decreases in brain mass, protein and DNA content, and which were further compromised when fed an isocaloric high vs. a low glycemic insulinogenic diet containing sucrose vs. cornstarch respectively. These results suggest that chronic insulin resistance of obesity secondary at least in part to dietary factors represents a likely independent risk factor in the progression of neuroinflammation, DNA damage, brain shrinkage and neural senescence in this strain of obese rats.

Metal transporter SLC39A14/ZIP14 modulates regulation between the gut microbiome and host metabolism.

Metal transporter SLC39A14/ZIP14 is localized on the basolateral side of the intestine, functioning to transport metals from blood to intestine epithelial cells. Deletion of Slc39a14/Zip14 causes spontaneous intestinal permeability with low-grade chronic inflammation, mild hyperinsulinemia, and greater body fat with insulin resistance in adipose. Importantly, antibiotic treatment reverses the adipocyte phenotype of Slc39a14/Zip14 knockout (KO), suggesting a potential gut microbial role in the metabolic alterations in the Slc39a14/Zip14 KO mice. Here, we investigated the hypothesis that increased intestinal permeability and subsequent metabolic alterations in the absence of Zip14 could be in part due to alterations in gut microbial composition. Dietary metals have been shown to be involved in the regulation of gut microbial diversity and composition. However, studies linking the action of intestinal metal transporters to gut microbial regulation are lacking. We showed the influence of deletion of metal transporter Slc39a14/Zip14 on gut microbiome composition and how ZIP14-linked changes to gut microbiome community composition are correlated with changes in host metabolism. Deletion of Slc39a14/Zip14 generated Zn-deficient epithelial cells and luminal content in the entire intestinal tract, a shift in gut microbial composition that partially overlapped with changes previously associated with obesity and inflammatory bowel disease (IBD), increased the fungi/bacteria ratio in the gut microbiome, altered the host metabolome, and shifted host energy metabolism toward glucose utilization. Collectively, our data suggest a potential predisease microbial susceptibility state dependent on host gene Slc39a14/Zip14 that contributes to intestinal permeability, a common trait of IBD, and metabolic disorders such as obesity and type 2 diabetes.NEW & NOTEWORTHY Metal dyshomeostasis, intestinal permeability, and gut dysbiosis are emerging signatures of chronic disorders, including inflammatory bowel diseases, type-2 diabetes, and obesity. Studies in reciprocal regulations between host intestinal metal transporters genes and gut microbiome are scarce. Our research revealed a potential predisease microbial susceptibility state dependent on the host metal transporter gene, Slc39a14/Zip14, that contributes to intestinal permeability providing new insight into understanding host metal transporter gene-microbiome interactions in developing chronic disease.

Alterations in Adipose Tissue Distribution, Cell Morphology, and Function Mark Primary Insulin Hypersecretion in Youth With Obesity.

Excessive insulin secretion independent of insulin resistance, defined as primary hypersecretion, is associated with obesity and an unfavorable metabolic phenotype. We examined the characteristics of the adipose tissue in youths with primary insulin hypersecretion and the longitudinal metabolic alterations influenced by the complex adipo-insular interplay. In a multiethnic cohort of non-diabetic adolescents with obesity, primary insulin hypersecretors had enhanced model-derived β-cell glucose sensitivity and rate sensitivity, but worse glucose tolerance, despite similar demographics, adiposity, and insulin resistance measured by both OGTT and euglycemic-hyperinsulinemic clamp. Hypersecretors had greater intrahepatic and visceral fat depots at abdominal MRI, hypertrophic abdominal subcutaneous adipocytes, higher FFA and leptin serum levels per fat mass, and faster in vivo lipid turnover assessed by a long-term 2H2O labeling protocol. At 2-year follow up, hypersecretors had greater fat accrual and 3-fold higher risk for abnormal glucose tolerance, while individuals with hypertrophic adipocytes or higher leptin levels showed enhanced β-cell glucose sensitivity. Primary insulin hypersecretion is associated with marked alterations in adipose tissue distribution, cellularity, and lipid dynamics, independent of whole-body adiposity and insulin resistance. Pathogenetic insight into the metabolic crosstalk between β-cell and adipocyte may help identify individuals at risk for chronic hyperinsulinemia, body weight gain, and glucose intolerance.

Dual Tracer Test to Measure Tissue-Specific Insulin Action in Individual Mice Identifies InVivo Insulin Resistance Without Fasting Hyperinsulinemia.

The ability of metabolically active tissues to increase glucose uptake in response to insulin is critical to whole-body glucose homeostasis. This report describes the Dual Tracer Test, a robust method involving sequential retro-orbital injection of 14C-2-deoxyglucose (14C-2DG) alone, followed 40 min later by injection of 3H-2DG with a maximal dose of insulin to quantify both basal and insulin-stimulated 2DG uptake in the same mouse. The collection of both basal and insulin-stimulated measures from a single animal is imperative for generating high-quality data since differences in insulin action may be misinterpreted mechanistically if basal glucose uptake is not accounted for. The approach was validated in a classic diet-induced model of insulin resistance and a novel transgenic mouse with reduced GLUT4 expression that, despite ubiquitous peripheral insulin resistance, did not exhibit fasting hyperinsulinemia. This suggests that reduced insulin-stimulated glucose disposal is not a primary contributor to chronic hyperinsulinemia. The Dual Tracer Test offers a technically simple assay that enables the study of insulin action in many tissues simultaneously. By administering two tracers and accounting for both basal and insulin-stimulated glucose transport, this assay halves the required sample size for studies in inbred mice and demonstrates increased statistical power to detect insulin resistance, relative to other established approaches using a single tracer. The Dual Tracer Test is a valuable addition to the metabolic phenotyping toolbox.

Pancreatic beta-cell specific BAG3 knockout results in chronic hyperinsulinemia inducing insulin resistance

BackgroundInsulin, secreted from pancreatic islets of Langerhans, is of critical importance in regulating glucose homeostasis. Defective insulin secretion and/or the inability of tissues to respond to insulin results in insulin resistance and to several metabolic and organ alterations. We have previously demonstrated that BAG3 regulates insulin secretion. Herein we explored the consequences of beta-cells specific BAG3 deficiency in an animal model. MethodsWe generated a beta-cells specific BAG3 knockout mouse model. Glucose and insulin tolerance tests, proteomics, metabolomics, and immunohistochemical analysis were used to investigate the role of BAG3 in regulating insulin secretion and the effects of chronic exposure to excessive insulin release in vivo. ResultsBeta-cells specific BAG3 knockout results in primary hyperinsulinism due to excessive insulin exocytosis finally leading to insulin resistance. We demonstrate that resistance is mainly muscle-dependent while the liver remains insulin sensitive. The chronically altered metabolic condition leads in time to histopathological alterations in different organs. We observe elevated glycogen and lipid accumulation in the liver reminiscent of non-alcoholic fatty liver disease as well as mesangial matrix expansion and thickening of the glomerular basement membrane, resembling the histology of chronic kidney disease. ConclusionAltogether, this study shows that BAG3 plays a role in insulin secretion and provides a model for the study of hyperinsulinemia and insulin resistance.

Regulation and mechanism of action of miRNAs on insulin resistance in skeletal muscles.

The term "insulin resistance" is commonly understood as a decrease in the response of insulin-sensitive tissues to insulin at its sufficient concentration, leading to chronic compensatory hyperinsulinemia. Type 2 diabetes mellitus is based on mechanisms consisting in the development of resistance to insulin in target cells (hepatocytes, adipocytes, skeletal muscle cells), resulting in the termination of an adequate response of these tissues to interaction with insulin. Since in healthy people 75-80% of glucose is utilized by skeletal muscle, it is more likely that the main cause of insulin resistance is impaired insulin-stimulated glucose utilization by skeletal muscle. With insulin resistance, skeletal muscles do not respond to insulin at its normal concentration, thereby determining an increase in glucose levels and a compensatory increase in insulin production in response to this. Despite many years of studying diabetes mellitus (DM) and insulin resistance, the molecular genetic basis for the development of these pathological conditions is still the subject of numerous studies. Recent studies point to the involvement of microRNAs (miRNAs) as dynamic modifiers in the pathogenesis of various diseases. MiRNAs are a separate class of RNA molecules that play a key role in the post-transcriptional regulation of gene expression. Recent studies have shown that miRNAs dysregulation in DM is closely related to miRNAs regulatory abilities in skeletal muscle insulin resistance. This gave grounds to consider an increase or decrease in the expression of individual microRNAs in muscle tissue and consider them as new biomarkers for diagnosing and monitoring insulin resistance and promising directions for targeted therapy. This review presents the results of scientific studies examining the role of miRNAs in skeletal muscle insulin resistance.

Effect of Carbohydrate Type on Brain Composition and Senescence in Aging, Hyperinsulinemia-prone OBESE LA/Ntul//-cp Rats

To determine if phenotype and the carbohydrate type resulted in alterations in brain composition in the obese phenotype of the congenic LA/Ntul//-cp rat, groups (n= 8 rats/group) of male littermate lean and obese rats were fed standardized isocaloric diets containing 54% (w/w) cornstarch (ST diet) or 54% (w/w) sucrose (SUC diet) from 1 until 10.5 ± 0.5 months of age. The obese phenotype of his strain develops early onset chronic hyperinsulinemia without NIDDM associated with hypertrophic-hyperplastic obesity during early postweaning growth. Brain tissues were dissected, and representative aliquots subjected to total fat, protein, and DNA analysis. Body weights of obese >> lean and were greater when fed the SUC than the ST diet in both phenotypes. Brain mass of lean > obese, and diet was associated with modestly lower brain weights in rats fed the SUC than the ST diet. Brain total Protein and DNA content of lean rats were > obese rats and were modestly Lower in SUC than ST fed rats in both phenotypes, but the percent of lipid content was proportional to brain mass. Total body fat mass of obese was significantly greater than occurred in lean littermates and was only modestly greater in SUC than ST fed rats in both phenotypes. These results indicate that brain growth and cellular development is impaired in the aging, hyperinsulinemia-prone obese phenotype of this strain, were further impaired when fed SUC than ST diets, and the decreased brain parameters were likely associated with development of a chronic neuronal inflammatory syndrome common to excessive fat accretion and obesity, resulting in premature brain senescence.

Effect of the obese phenotype on brain composition in congenic lean and obese LA/Ntul//-cp rats

To determine if the obese phenotype impacted on brain development and composition, groups of congenic male lean and obese littermates of the LA/Ntul//-cp rat strain were fed on a standardized nutritionally adequate diet in littermate pairs from weaning until adulthood. The obese phenotype of his strain develops early onset chronic hyperinsulinemia associated with hypertrophic-hyperplastic obesity during early postweaning growth. At 10.5 months of age, animals were sacrificed by cervical dislocation, and brain tissues excised in its entirety, weighed to the nearest mg, and measures of protein, DNA and lipid determined. Body weights (BW) of obese were significantly greater than lean. Brain mass (BrM) of lean > obese, and BrM:BW of lean was greater obese. Brain protein content (BPC) and Brain DNA (BDNA) of lean was greater than obese. Brain lipid as a percent was similar in both phenotypes and net brain lipid content was proportional to brain mass. Total body fat mass of obese was significantly greater than occurred in lean littermates. Inflammatory cytokines residing in adipose tissue have been reported to contribute to DNA damage in neuronal and other tissues, impede cell replication, and accelerate cell senescence. These results indicate that brain growth and cellular development is impaired in the hyperinsulinemia-prone obese phenotype of this strain, and are likely associated with development of a chronic inflammatory syndrome and cytokine expression common to excessive fat accretion and obesity

Abstract 6456: Association of dietary inflammatory and insulinemic potential with risk of liver cancer and chronic liver disease mortality

Abstract Background: Increasing burdens of liver cancer and chronic liver disease (CLD) urge investigation of modifiable risk factors for primary prevention. Despite strong experimental evidence showing the role of chronic insulin resistance/hyperinsulinemia and inflammation in liver cancer and CLD, whether the insulinemic and inflammatory potential of diet are independently associated with higher risk of these outcomes requires further investigation. Methods: We conducted a prospective cohort study among 78,356 postmenopausal women in the Women’s Health Initiative Observational Study. Two validated dietary indices that predict circulating C-peptide or biomarkers of inflammation, namely, the empirical dietary index for hyperinsulinemia (EDIH) and the empirical dietary inflammation pattern (EDIP), were estimated from a food frequency questionnaire. Incident cases of liver cancer and CLD mortality were ascertained via review of medical records and linkage to national registries. Multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazard models, adjusted for age, diabetes, body mass index (BMI), and other covariates. Results: During a median 22.1 years of follow-up, we documented 176 primary liver cancer cases and 156 CLD mortality cases. The EDIH was positively associated with incident liver cancer risk (HRQuartile4 vs. Quartile1 = 1.70; 95% CI: 1.03, 2.81; p-trend = 0.03) and CLD mortality risk (HRQ4 vs. Q1 = 2.75; 95% CI: 1.54, 4.93; p-trend = 0.01) in the multivariable adjusted model, including diabetes and BMI as covariates. The EDIP was also positively associated with liver cancer (HRQ4 vs. Q1 = 1.93; 95% CI: 1.21, 3.09; p-trend <0.001) and CLD mortality risk (HRQ4 vs. Q1 = 2.09; 95% CI: 1.24, 3.52; p-trend <0.001) in the multivariable adjusted model. The estimates remained significant and robust in sensitivity analyses, after exclusion of cases in the first 2 years of follow-up or with liver disease history. There was no additive effect between the two dietary indices. Further analyses of individual food groups and liver outcomes indicated positive associations with refined grains, processed meat, butter, and eggs, and inverse associations with coffee, poultry, green leafy vegetables, and dark yellow vegetables. Conclusions: Dietary insulinemic and inflammatory potential were independently associated with higher risk of liver cancer and CLD mortality in US postmenopausal women. Monitoring dietary patterns to reduce chronic hyperinsulinemia and inflammation may contribute to the primary prevention of liver cancer and CLD mortality. Citation Format: Xinyuan Zhang, Longgang Zhao, Cami Christopher, Fred K. Tabung, Wei Bao, David O. Garcia, Marian L. Neuhouser, Aladdin H. Shadyab, Nazmus Saquib, Lesley Tinker, Xuehong Zhang. Association of dietary inflammatory and insulinemic potential with risk of liver cancer and chronic liver disease mortality. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6456.

Clinical Efficacy of Shatapushpa Taila Matra Basti in PCOS – A Case Study

The most prevalent reproductive health issues in adolescent girls face nowadays are irregular periods, acne, and obesity. Polycystic ovarian syndrome is the underlying condition that causes these issues in the most severe way. Initially, PCOS was only thought to be associated to infertility, but it is now well-established that for many people, it begins during puberty and lasts until menopause. In addition to contributing significantly to infertility, the associated endocrine and metabolic disorders with PCOS raise women's risk for type II diabetes mellitus, chronic heart disease, dyslipidemia, hypertension, hyper-insulinemia, and obesity. In order to avoid the problems listed above, it is crucial to treat this illness as soon as possible, not just from the perspective of infertility. One of the Panchakarma procedures is called Basti, in which medicine is given through the anal region, urinary region, or vaginal region in the form of Kwatha or Sneha. The most successful therapies for Artava Kshaya are Basti Chikitsa. A 24-year-old female patient arrived to the OPD and complained of hair loss, acne, weight gain and menstrual irregularities. A USG abdominal scan identified PCOS. The patient sought out Ayurvedic treatment because she had tried numerous allopathic treatments without success. She was therefore treated in accordance with the Artava Kshaya fundamental course of treatment in Ayurveda. With the Ayurvedic treatment, remarkable changes in the ovaries and in menstrual bleeding were seen.

Viscoelastic or Viscoplastic Glucose Theory (VGT #61): A Simplified Mathematical Model to Estimate Pancreatic Cancer (PC) Risk Probability Percentages and Its Moving Trend Over an ~7 Years Period from Y2015 to Y2022 Using Hyperglycemia, Insulin Resistance, Obesity, Chronic Inflammation and Metabolism Index as the PC Risk’s 5 Contribution Factors Based on GH-Method: Math-Physical Medicine (No. 649)

Recently, the author read a few published medical articles regarding pancreatic cancer (PC) and will outline some key information in the Introduction section. “Insulin resistance is an interrupted state in the biological response to insulin. It is reported that chronic hyperinsulinemia is associated with various types of cancer such as colorectal cancer, pancreatic cancer, endometrial cancer, and breast cancer.

Advances in "adiponcosis": Insights in the inner mechanisms at the base of adipose and tumour tissues interplay.

The epidemic spread of obesity is nowadays recognized as a global health and economic burden, arising great interest in the scientific community. The rate of adult obesity steadily increases concomitantly with the cancer incidence. As has been comprehensively reported, obesity is included among the multiple cancer risk factors and can progressively cause and/or exacerbate certain cancer types, as colorectal and breast cancers. The term adiponcosis was forged precisely to emphasize the interconnection between obesity and cancer onset and progression. The underlying mechanisms of adiponcosis have not been fully elucidated yet, may vary on cancer type, and depend on body fat distribution. It has been proposed that insulin resistance and related chronic hyperinsulinemia, increased insulin-like growth factors production, chronic inflammation or increased bioavailability of steroid hormones could be responsible of cancer hallmarks. Additionally, it has been suggested that adipose tissue-derived hormones, cytokines and adipokines, such as leptin, adiponectin and inflammatory markers, may reflect mechanisms linked to tumorigenesis. This review summarizes the current evidence on pathways, hormones, cytokines and low-chronic inflammation subtending adiponconsis, focusing on breast and colorectal cancers. In addition, we analyzed the lifestyle interventions that could attenuate the driving forces of obesity-related cancer incidence and progression. Moreover, current targets and drugs, their pros and cons, as well as new mechanisms and targets with promising therapeutic potential in cancer are discussed. Depicting this complex interconnection will provide insights for establishing new therapeutic approaches to halt the obesity impacts and thwart cancer onset and progression.