Forms Of Insulin Resistance Research Articles

Hepatokines: unveiling the molecular and cellular mechanisms connecting hepatic tissue to insulin resistance and inflammation.

Insulin resistance arising from Non-Alcoholic Fatty Liver Disease (NAFLD) stands as a prevalent global ailment, a manifestation within societies stemming from individuals' suboptimal dietary habits and lifestyles. This form of insulin resistance emerges as a pivotal factor in the development of type 2 diabetes mellitus (T2DM). Emerging evidence underscores the significant role of hepatokines, as hepatic-secreted hormone-like entities, in the genesis of insulin resistance and eventual onset of type 2 diabetes. Hepatokines exert influence over extrahepatic metabolism regulation. Their principal functions encompass impacting adipocytes, pancreatic cells, muscles, and the brain, thereby playing a crucial role in shaping body metabolism through signaling to target tissues. This review explores the most important hepatokines, each with distinct influences. Our review shows that Fetuin-A promotes lipid-induced insulin resistance by acting as an endogenous ligand for Toll-like receptor 4 (TLR-4). FGF21 reduces inflammation in diabetes by blocking the nuclear translocation of nuclear factor-κB (NF-κB) in adipocytes and adipose tissue, while also improving glucose metabolism. ANGPTL6 enhances AMPK and insulin signaling in muscle, and suppresses gluconeogenesis. Follistatin can influence insulin resistance and inflammation by interacting with members of the TGF-β family. Adropin show a positive correlation with phosphoenolpyruvate carboxykinase 1 (PCK1), a key regulator of gluconeogenesis. This article delves into hepatokines' impact on NAFLD, inflammation, and T2DM, with a specific focus on insulin resistance. The aim is to comprehend the influence of these recently identified hormones on disease development and their underlying physiological and pathological mechanisms.

1471-P: Metabolomic Profiling of Type 2 Diabetes Pathway-Partitioned Polygenic Risk Scores Offers Insights into Disease Etiology

Previous studies have identified type 2 diabetes (T2D) subtypes using clinical phenotypes and/or genetic information. This study aimed to identify molecular signatures associated with genetically based T2D subtypes. We analyzed data from ~100,000 unrelated European UK Biobank participants without T2D and not taking lipid-lowering medications. T2D subtypes were characterized using five polygenic scores denoting three forms of insulin resistance (lipodystrophy, obesity, and impaired lipid/hepatic metabolism) and two subtypes of insulin secretion (beta-cell dysfunction and impaired proinsulin synthesis). Nuclear magnetic resonance profiles of 249 plasma metabolites on the Nightingale platform were tested for association with T2D subtypes using linear regression adjusted for age, sex, batch, and ancestry-derived principal components; P<0.0002 was considered significant. Independent validation was conducted in two independent cohorts, including 720 from the ANTORCHA cohort. In general, the T2D subtypes driven by insulin resistance were characterized by alterations in lipid and lipoproteins, while the impaired insulin secretion subtypes showed aberrant plasma amino acid levels. The lipodystrophy cluster showed the most distinct molecular signature, with higher concentrations of extremely large, very large, and large VLDL particles which were enriched by triglycerides and phospholipids, and lower concentrations of HDL. The beta-cell dysfunction cluster was characterized by higher concentrations of amino acids (alanine, valine, leucine, and tyrosine). These associations were broadly consistent after adjusting for BMI, and the pattern of alterations in lipid metabolites was partially replicated in the ANTORCHA cohort. We identified specific metabolic signatures related to T2D genetic clusters before T2D onset, offering further characterization of the putative underlying pathways. Disclosure M.Sevilla: None. I.Lamiquiz-moneo: None. K.Smith: None. M.Canyelles: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. A.Manning: None. F.Civeira: None. J.Merino: None. M.Udler: None. Funding American Diabetes Association (9-22-PDFPM-04 to M.S.)

Does increasing insulin resistance in adolescence actively decrease cerebral perfusion to oral glucose tolerance test?

Background: Approximately 20% of American adolescents are obese, and nearly half demonstrate some form of insulin resistance (IR). Insulin acts as a metabolic hormone, a neurotrophic growth factor, and a vasodilator. Notably, adults with neurologic disease often exhibit IR and reduced cerebral blood flow (CBF). Adolescent brains are actively growing such that IR may negatively impact brain health in part due to lower brain perfusion. Specifically, given the role of insulin as a potential vasodilator, we hypothesized CBF would increase in response to a physiologic glucose-insulin surge, but this effect would lessen as IR level increased. Methods: Adolescents (n=11, 3 females, age=14.8±2 yr, BMI=24.7±7) taking no medications were studied. IR was estimated by calculating HOMA-IR using fasting glucose and insulin, spanning a spectrum of IR (excluding diabetes). Subjects completed a magnetic resonance imaging (MRI) study visit to assess cerebral perfusion using arterial spin labeling (ASL). Heart rate (HR), mean arterial pressure (MAP) and end tidal CO 2 (ETCO 2 ) were assessed at baseline and during oral glucose tolerance test (OGTT); ingesting 75g glucose in 296mL water (Trutol). Venous blood was sampled at baseline and 5, 10, 20, 30, 45, and 60 minutes post OGTT. Perfusion at peak plasma insulin was compared to baseline. Significance was determined using linear regression of change in perfusion (peak- baseline) versus HOMA-IR and set at p≤0.05. Results: Results are mean±SD. HR (p=0.9), MAP (p=0.22) and ETCO 2 (p=0.75) were similar across HOMA-IR. MAP (p=0.44) and ETCO 2 (p=0.15) did not change during OGTT at insulin peak. Peak insulin occurred at 44±13 min post OGTT (baseline: 8±4 vs. peak: 65±38 μU/mL, p=0.001). Glucose changed from 79±6 to 142±30 mg/dL at peak insulin (p=0.0005). There were no significant associations between HOMA-IR and changes in perfusion in gray matter (R 2 =0.06, p=0.43) and white matter (R 2 =0.07, p=0.13). There were no significant associations for the following regions: hippocampus, amygdala, thalamus, anterior and posterior insula, and precuneus (R 2 all <0.2, p all >0.14). There was a trend toward negative regression in anterior cingulate gyrus (R 2 =0.25, p=0.11). Conclusions: These data suggest an OGTT does not acutely change brain perfusion at a global or regional level in adolescents, except possibly the anterior cingulate gyrus that is negatively impacted by increasing IR. The majority of present findings do not support our hypothesis that OGTT-mediated changes in cerebral perfusion are associated with IR in adolescents. NIH R21HD097510 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of increasing insulin resistance on cerebral perfusion in adolescents

Background: Adolescence is a key growth period that heavily influences future brain health. Approximately 1 in 5 adolescents are obese in the US, and up to half of them exhibit some form of insulin resistance (IR). Notably, insulin acts as a metabolic hormone, a neurotrophic growth factor, and a vasodilator. Reduced vasodilation may lead to reduced cerebral perfusion, and lower perfusion in older adults is associated with reduced cognition and increased risk of stroke and neurologic disease. Given this background, IR may negatively impact adolescent brain health in part due to lower brain perfusion. Therefore, we hypothesized cerebral perfusion would decrease as the level of insulin resistance increased. Method s: Adolescents (n=15, 4 females, age 15±2 yr) were studied. IR was estimated by calculating HOMA-IR (using fasting glucose and insulin), which spanned a spectrum of IR up to but excluding diabetes. Subjects underwent a magnetic resonance imaging (MRI) study visit to assess cerebral perfusion using arterial spin labeling (ASL). The CAT12 toolbox extension for SPM12 was used to process MRI data. Heart rate (HR), mean arterial pressure (MAP), and end tidal CO 2 (ETCO 2 ) were assessed. Significance was determined using linear regression and set at p≤0.05. Results: Results are mean±SD. HR (72±10 bpm, p=0.98), MAP (73±6 mmHg, p=0.67), and ETCO 2 (37±2 mmHg, p=0.91) were similar across HOMA-IR (0.5 to 3.8). Perfusion (ml/100g/min) at the amygdala (r 2 =0.33, p=0.02) and parahippocampal gyrus (r 2 =0.28, p=0.04) decreased as HOMA-IR increased. Borderline significant decreases were found for total gray matter (r 2 =0.26, p=0.051), anterior cingulate cortex (r 2 =0.26, p=0.052), and hippocampus (r 2 =0.23, p=0.07) perfusion as HOMA-IR increased. No associations were found between HOMA-IR and the following: total white matter (r 2 =0.18, p=0.11), precuneus (r 2 =0.20, p=0.10), thalamus proper (r 2 =0.14, p=0.17), and entorhinal cortex (r 2 =0.16, p=0.14) perfusion. Total gray matter (p=0.49) and white matter (p=0.73) volume had no significant relationship with HOMA-IR. HOMA-IR was not associated with any differences in regional volumes. Conclusions: Our results suggest with increasing HOMA-IR there is a significant reduction in gray matter perfusion in key brain regions associated with memory in adolescents. In contrast, structural changes were not detected, indicating functional decrements occur prior to structural deficits. These findings support our hypothesis that cerebral perfusion is associated with insulin resistance in adolescents, which may negatively impact long-term brain health. NIH R21 HD097510 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Neonatal diabetes mellitus and polycystic ovaries in a child with severe insulin resistance caused by a variant in the INSR gene. Description of the clinical case

Rare severe insulin resistance syndromes such as Donohue syndrome, RabsonMendenhall syndrome, and type A insulin resistance are caused by mutations in the insulin receptor (INSR) gene. Donohue and RabsonMendenhall syndromes are caused by biallelic mutations in the - and / or -subunits of INSR, are characterized by a severe course with severe clinical symptoms and an unfavorable prognosis. The difficulty of managing and treating these patients is associated with a low incidence, lack of practice in managing such patients, as well as a lack of experience in surgical interventions in these patients.
 All insulin resistance syndromes are characterized by a significant increase in the level of insulin in the blood plasma in the absence of obesity, progressive diabetes mellitus and an excess of androgens. Polycystic ovary syndrome or stromal hyperthecosis develops in adult patients with syndromic forms of insulin resistance.
 We present a rare clinical case of a complicated course of Donohue syndrome, diagnosed in a 2-month-old patient. A feature of this clinical case was the giant growing multifollicular ovaries, which became an absolute indication for organ resection surgery.
 The experience of treatment and observation of this patient reflects the importance of early verification of the diagnosis, timely appointment of adequate therapy, allows you to objectively assess the effectiveness of the treatment, helps in choosing medical tactics and predicting the course and outcome of the disease.

Динаміка показників кардіогемодинаміки у хворих на гострий інфаркт міокарда з супутнім цукровим діабетом 2 типу протягом 6 місяців спостереження

The purpose of the study was to monitor the dynamics of cardiohemodynamics in patients with acute myocardial infarction in combination with type 2 diabetes mellitus during 6 months of follow-up. Materials and methods. The study involved 120 patients: group 1 – patients with acute myocardial infarction with type 2 diabetes mellitus (n = 70), group 2 – patients with acute myocardial infarction (n = 50). The control group included 20 healthy individuals. All patients underwent general instrumental and clinical examinations. In the course of echocardiographic (echocardiography) study, the parameters of the left ventricle were determined and calculated: end diastolic volume, end systolic volume, end diastolic size, end systolic size, posterior thickness, the thickness of the interventricular septum, the ejection fraction of the left ventricle, the size of the left atrium, the size of the aorta, stroke volume. Results and discussion. The average indicators of cardiohemodynamics on the first day of hospitalization were as follows: end diastolic volume in patients of the 1st group was 165.85±36.22 ml; of the 2nd – 133.44±27.19 ml; control – 54.54±21.48 ml; end systolic volume – 104.57±28.86 ml; 77.93±21.56 ml; 21.69±7.49 ml, respectively; end diastolic size – 5.74±0.6 ml; 5.22±0.49 ml; 3.55±0.58 ml, respectively; end systolic size – 4.66±0.62 ml; 4.11±0.52 ml; 2.41±0.32 ml, respectively; the ejection fraction of the left ventricle – 37.51±6.27%; 42.9±7.45%; 56.75±7.22%, respectively; posterior thickness – 1.37±0.13 cm; 1.32±0.13 cm; 1.07±0.08 cm, respectively; the thickness of the interventricular septum – 1.26±0.11 cm; 1.27±0.11 cm; 1.13±0.08 cm, respectively; the size of the left atrium – 4.07±0.31 cm; 3.75±0.46 cm; 3.19±0.15 cm, respectively; the size of the aorta – 3.39±0.27 cm; 3.3±0.22 cm; 2.97±0.16 cm, respectively; stroke volume – 60.27±13.3 cm3; 2nd – 57.01±10.72 cm3; 28.39±12.38 cm3, respectively. Six months after acute myocardial infarction, a positive trend in cardiohemodynamic parameters was observed, maintaining a tendency for worse indicators in the presence of acute myocardial infarction. Conclusion. Thus, impaired carbohydrate metabolism in the form of insulin resistance, hyperinsulinemia and stress hyperglycemia on the background of coronary events in type 2 diabetes mellitus leads to negative changes in geometry, mass, systolic and diastolic function of the left ventricle, which must be paid special attention to hemodynamic predictors of cardiovascular complications and heart failure

A PDK-1 allosteric agonist neutralizes insulin signaling derangements and beta-amyloid toxicity in neuronal cells and in vitro.

The Alzheimer’s brain is affected by multiple pathophysiological processes, which include a unique, organ-specific form of insulin resistance that begins early in its course. An additional complexity arises from the four-fold risk of Alzheimer’s Disease (AD) in type 2 diabetics, however there is no definitive proof of causation. Several strategies to improve brain insulin signaling have been proposed and some have been clinically tested. We report findings on a small allosteric molecule that reverses several indices of insulin insensitivity in both cell culture and in vitro models of AD that emphasize the intracellular accumulation of β-amyloid (Aβi). PS48, a chlorophenyl pentenoic acid, is an allosteric activator of PDK-1, which is an Akt-kinase in the insulin/PI3K pathway. PS48 was active at 10 nM to 1 μM in restoring normal insulin-dependent Akt activation and in mitigating Aβi peptide toxicity. Synaptic plasticity (LTP) in prefrontal cortical slices from normal rat exposed to Aβ oligomers also benefited from PS48. During these experiments, neither overstimulation of PI3K/Akt signaling nor toxic effects on cells was observed. Another neurotoxicity model producing insulin insensitivity, utilizing palmitic acid, also responded to PS48 treatment, thus validating the target and indicating that its therapeutic potential may extend outside of β-amyloid reliance. The described in vitro and cell based-in vitro coupled enzymatic assay systems proved suitable platforms to screen a preliminary library of new analogs.

Hyperinsulinemia and age-related diseases: interrelations and approaches to treatment

Hyperinsulinemia is closely related with insulin resistance, that is the key mechanism for the progression of age-related diseases. A lot of aspects of hyperinsulinemia and interrelations between the mentioned conditions are very scarcely covered in Russian publications. The present review is designed to fill the gaps in understanding the causal relationships between hyperinsulinemia, insulin resistance, age-related diseases and lifestyle factors. Material and methods. Based on sources from PubMed and Google Scholar, using the keywords "hyperinsulinemia" + "chronic disease" OR "age-related disease" the authors analyzed the causes of hyperinsulinemia, the mechanisms of its influence on various aspects of insulin resistance, and the role of hyperinsulinemia in pathogenesis of a wide range of clinical syndromes and age-related diseases. Consideration of the effects that lifestyle factors produce on hyperinsulinemia opens up opportunities for its correction. Results. The major causes of hyperinslinemia are improper diet and nutrition regime (frequent meals and excess of highly glycemic food, too short fasting window), along with other factors causing hyperreactivity of pancreatic beta-cells (fructose, systemic inflammation, oxidative stress, low vitamin D level, etc.). Hyperinsulinemia affects cellular energy balance (primarily, in liver, muscle, brain and adipose tissue); a major factor is suppression of 5'AMP-activated protein kinase (AMPK) along with stimulation of mitogen-activated protein kinase. Insulin resistance is a consequence of AMPK inhibition, an adaptive response designed to preserve cellular homeostasis. Conclusion. Obesity, metabolic syndrome, chronic systemic inflammation, age-related syndromes and diseases (including arterial hypertension, atherosclerosis, neurodegenerative diseases, tumors, osteoarthritis, sarcopenia, etc.) can be considered as clinical manifestations of the body's systemic adaptation to hyperinsulinemia in the form of insulin resistance. Available approach to reduce insulin resistance is correction of lifestyle factors to mitigate hyperinsulinemia and restore AMPK activity. The revealed causal relationships can provide background for personalized strategy of prevention and treatment for age-related diseases through reduction of insulin resistance and correction of energy homeostasis.

Management of altered metabolic activity in Drosophila model of Huntington's disease by curcumin.

Huntington's disease (HD) is a devastating polyglutamine disorder characterized by extensive neurodegeneration and metabolic abnormalities at systemic, cellular and intracellular levels. Metabolic alterations in HD manifest as abnormal body weight, dysregulated biomolecule levels, impaired adipocyte functions, and defective energy state which exacerbate disease progression and pose acute threat to the health of challenged individuals in form of insulin resistance, cardiovascular disease, and energy crisis. To colossally mitigate disease symptoms, we tested the efficacy of curcumin in Drosophila model of HD. Curcumin is the bioactive component of turmeric (Curcuma longa Linn), well-known for its ability to modulate metabolic activities. We found that curcumin effectively managed abnormal body weight, dysregulated lipid content, and carbohydrate level in HD flies. In addition, curcumin administration lowered elevated reactive-oxygen-species levels in adult adipose tissue of diseased flies, and improved survival and locomotor function in HD flies at advanced disease stage. Altogether, these findings clearly suggest that curcumin efficiently attenuates metabolic derangements in HD flies and can prove beneficial in alleviating the complexities associated with HD.

Energy expenditure due to gluconeogenesis in pathological conditions of insulin resistance.

Gluconeogenesis (GNG), the formation of glucose from noncarbohydrate precursors, requires adenosine triphosphate (ATP). Previous studies have estimated the energetic cost of GNG in humans based on theoretical calculations of rates of GNG, moles of oxygen consumption by GNG, and average oxygen consumption. Few human studies have measured the energy expenditure (EE) due to GNG. We estimated EE attributable to GNG in patients with three insulin resistance conditions and high GNG rates (insulin receptor pathogenic variants, lipodystrophy, and type 2 diabetes) and obesity without diabetes. Fractional GNG was measured by incorporation of deuterium from body water into newly formed glucose, endogenous glucose production (EGP) as glucose appearance following administration of [6,6-2H2]glucose, and total GNG as fractional GNG × EGP. EE was measured by indirect calorimetry and compared with predicted EE from the Mifflin St. Jeor equation. EE attributable to GNG was estimated using linear regression after accounting for age and fat-free mass (FFM). EE in patients with insulin resistance was significantly higher than predicted by the Mifflin St. Jeor equation. GNG correlated with resting EE (REE). EE attributable to GNG in patients with insulin resistance was almost one-third of REE, substantially higher than theorized in healthy subjects. Our findings demonstrate that GNG is a significant contributor to EE in insulin-resistant states. Prediction equations may underestimate caloric needs in patients with insulin resistance. Therefore, targeting caloric needs to account for higher EE due to increased GNG should be considered in energy balance studies in patients with insulin resistance.NEW & NOTEWORTHY Gluconeogenesis is an energy-requiring process that is upregulated in diabetes, contributing to hyperglycemia. Previous studies have estimated that gluconeogenesis accounts for less than 10% of resting energy expenditure. This study estimates the energy expenditure attributable to gluconeogenesis in uncommon and severe forms of insulin resistance and common, milder forms of insulin resistance. In these populations, gluconeogenesis accounts for almost one-third of resting energy expenditure, substantially higher than previously theorized in the literature.

Probing the Relationship Between Declining Renal Glomerular Filtration Over the Life Span and General Biological Aging: Does the Former Provide Means to Estimate the Latter?

Background: While a consistent, gradual decline in the renal glomerular filtration rate (GFR) is a characteristic occurrence over the human life span, the exact pathophysiology behind this event remains unresolved. Evidence to date suggests that the endogenous glucose-insulin system could be involved at some level. Diabetic-induced nephropathy, one of the most prevalent chronic renal diseases, is closely linked to a severe form of insulin resistance (IR). Nevertheless, it is less certain that the ubiquitous milder forms of IR in nondiabetics ascribed customarily to routine, poor choices in diet and exercise management can over time diminish GFR and adversely influence other renal functions to any perceptible extent. Methodology: Baseline data for cross-sectional analyses were obtained from a cohort of healthy, nondiabetic volunteers (fasting blood glucose [FBG] ≤ 125 mg/dL) involved in prior clinical studies. Slope-based rather than threshold analyses were mainly employed. These measurements were applied for the most part to correlate age, FBG levels used as an estimate of IR activity, and systolic blood pressure (SBP) to a variety of metabolic parameters during aging with a primary focus on GFR. Results: Considering cause and effect, FBG and SBP correlate positively with the diminishing GFR over a major part of the life span. The decline in GFR begins somewhere around the mid-20s and coincides with key temporal increases in FBG and SBP levels. Conclusions: A close time-based setting suggests that IR plays a prominent role in the declining GFR that occurs over the life span. This is perhaps due in part through deleterious effects of rising levels of insulin, glucose, and SBP individually or combined that are also popular proposed causative factors for human aging in general. On the philosophical side, the latter fact suggests that the declining GFR might provide a practical way to estimate the rate of overall human biological aging.

Unique Metabolic Features of Adults Discordant for Indices of Insulin Resistance.

Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and Adipose Insulin Resistance index (ADIPO-IR) values are often concordant. In this study we evaluated whether there are groups discordant for HOMA-IR and ADIPOpalmitate-IR and, if so, what are their defining characteristics. The body composition, basal metabolic rate (BMR), fasting plasma lipids, insulin, glucose, and free fatty acid (FFA) palmitate concentrations data of 466 volunteers from previous research studies were abstracted and analyzed. The middle 2 population quartiles for HOMA-IR and Adipose Insulin Resistance index palmitate concentration (ADIPOpalmitate-IR) defined medium HOMA-IR and ADIPOpalmitate-IR (MH and MA), the top and bottom quartiles were defined as high/low HOMA (HH/LH), and high/low ADIPOpalmitate as HA/LA. Because ADIPOpalmitate-IR was significantly greater in women than in men, we established sex-specific quartiles for each index. We identified groups discordant for HOMA-IR and ADIPO-IR (HHMA, LHMA, MHHA, and MHLA). Body fat and fasting triglycerides (TGs) were significantly greater with higher indices in the concordant groups (HHHA > MHMA > LHLA). MHHA differed from MHLA by visceral fat (P < .01) and fasting TGs (P < .05), whereas HHMA differed (P < .01) from LHMA by BMR. By multivariate regression, the group factor contributed to BMR (P < .01) and visceral fat (P < .05). Adults discordant for HOMA-IR and ADIPO-IR have unique features including differences in visceral fat, TGs, and BMR. This suggests different forms of insulin resistance are present, which should be considered when studying insulin resistance in the future.

Metabolic syndrome in children.

Despite plenty of currently available information on metabolic syndrome (MetS) in children and adolescents, there are still uncertainties regarding definition, prevention, management and treatment of MetS in children. The first approach to MetS in children consists of lifestyle interventions (nutritional education, physical activity). These recommendations are often difficult to achieve, especially for adolescents, therefore, there is usually a lack of successful outcomes. A pharmacological intervention in obese children may be needed in some cases, with the aim to improve the effects of these primary prevention interventions. Metformin seems to be safe and presents evident positive effects on insulin sensitivity, but long-term and consistent data are still missing to establish its role in the pediatric population and the possible effectiveness of other emergent treatments such as glucagon-like peptide-1 analogues, dipeptidylpeptidase-4 inhibitors, dual inhibitors of SGLT1 and SGLT2 and weight loss drugs. Bariatric surgery might be helpful in selected cases. The aim of this review is to present the most recent available treatments for the main components of metabolic syndrome, with a focus on insulin resistance. A short mention of management of congenital forms of insulin resistance will be included too.

Vascular Dysfunction and Insulin Resistance in Aging.

Insulin was discovered in 1922 by Banting and Best. Since that time, extensive research on the mechanisms of insulin activity and action has continued. Currently, it is known that the role of insulin is much greater than simply regulating carbohydrate metabolism. Insulin in physiological concentration is also necessary to maintain normal vascular function. Insulin resistance is defined as a pathological condition characterized by reduced sensitivity of skeletal muscles, liver, and adipose tissue, to insulin and its downstream metabolic effects under normal serum glucose concentrations. There are also selective forms of insulin resistance with unique features, including vascular insulin resistance. Insulin resistance, both classical and vascular, contributes to vascular impairment resulting in increased risk of cardiovascular disease. Furthermore, in the elderly population, additional factors including redistribution of fat concentrations, low-grade inflammation, and decreased self-repair capacity [or cell senescence] amplify the vascular abnormalities related to insulin resistance.

Late Cognitive Consequences of Gestational Diabetes to the Offspring, in a New Mouse Model.

Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during gestation, which affects approximately 10% of pregnant women. Although previously considered a transient condition with few long-term consequences, growing evidence suggest that GD may be linked to permanent metabolic and neurologic changes in the offspring. Currently available GD models fail to recapitulate the full spectrum of this disease, thus providing limited information about the true burden of this condition. Here, we describe a new mouse model of GD, based on the administration of an insulin receptor antagonist (S961, 30nmol/kgs.c. daily) during pregnancy. Pregnant mice developed increased fasting glycemia and glucose intolerance in the absence of maternal obesity, with a return to normoglycemia shortly after parturition. Moreover, we showed that the adult offspring of GD dams presented pronounced metabolic and cognitive dysfunction when exposed to short-term high-fat diet (HFD). Our data demonstrate that S961 administration to pregnant mice comprises a valuable approach to study the complex pathophysiology of GD, as well as strategies focused on prevention and treatment of both the mother and the offspring. Our findings suggest that the offspring of GD mothers are more susceptible to metabolic and cognitive impairments when exposed to high-fat diet later in life, thus indicating that approaches to prevent and treat these late effects should be pursued.

Insulin Resistance and Polycystic ovary Syndrome: A Review

Polycystic Ovary Syndrome (PCOS) is the most common, yet complex, endocrine disorder affecting women in their reproductive years and is a leading cause of infertility. This disease appears to be multifactorial and polygenic in nature involving multisystem dysfunction, namely reproduction, endocrine and metabolic. Hyperandrogenism and insulin resistance appear to be central cause to the pathophysiology of the disease. The glucose and insulin metabolism pathways have been studied and debated to understand whether Insulin Resistance is due to a defect in insulin action or a primary defect in β-cell function or decreased hepatic clearance of insulin, or a combination of all these factors. Numerous studies have demonstrated that obese, normal weight and thin women with PCOS have a form of insulin resistance that is unique and intrinsic to the disorder. Moreover obese women with PCOS possess an additional burden of insulin resistance resulting from their excess adiposity. Hyperinsulinemia leads to increase in androgen production directly by acting as a co-gonadotropin, augmenting Luteinizing Hormone activity within the ovary, and indirectly by increasing serum LH pulse amplitude. Whereas Androgens may in turn contribute at least partially to the insulin resistance state linked with PCOS. In this review, we will briefly study the role of insulin resistance in polycystic ovary syndrome.&#x0D; Keywords: Polycystic ovary syndrome, insulin resistance, Hyperandrogenism.

Androgens and Severe Insulin Resistance States: Basic and Clinical Aspects.

Hyperandrogenism with or without polycystic ovary syndrome can be sustained by an extreme form of insulin resistance (IR), and is thus a secondary form of hyperandrogenism, which may be due to a defect in insulin signal transduction or in the adipose tissue. Severe IR due to adipose tissue dysfunction is the most frequent form, which may be the result of a deficiency in the adipose tissue, that is, the lipodystrophies, or to the unrestrained accumulation of adipose tissue. These forms are in some cases produced by a single-gene defect. The diagnosis remains predominantly clinical by examining patients in their underwear and looking out for clinical hallmarks, supported by biochemical biomarkers. Gene screening is necessary to corroborate the diagnosis of some forms. Clinicians who deal with hyperandrogenic disorders should be alerted to the forms that are secondary to severe IR, as they are not as uncommon as often imagined and frequently respond to tailored therapies.

Consequences of gestational diabetes to the brain and behavior of the offspring.

Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during the second/third trimesters of pregnancy in previously normoglycemic women. It is currently estimated that 10% of all pregnancies in the United States show this condition. For many years, the transient nature of GD has led researchers and physicians to assume that long-term consequences were absent. However, GD diagnosis leads to a six-fold increase in the risk of developing type 2 diabetes (T2D) in women and incidence of obesity and T2D is also higher among their infants. Recent and concerning evidences point to detrimental effects of GD on the behavior and cognition of the offspring, which often persist until adolescence or adulthood. Considering that the perinatal period is critical for determination of adult behavior, it is expected that the intra-uterine exposure to hyperglycemia, hyperinsulinemia and pro-inflammatory mediators, hallmark features of GD, might affect brain development. Here, we review early clinical and experimental evidence linking GD to consequences on the behavior of the offspring, focusing on memory and mood disorders. We also discuss initial evidence suggesting that downregulation of insulin signaling cascades are seen in the brains of GD offspring and could contribute to the consequences on their behavior.

Glucose Metabolism in Children With Growth Hormone Deficiency.

The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis has a fundamental impact on glucose metabolism. Therefore, both untreated GH deficiency (GHD) and GH treatment (GHT) may be associated with some metabolic alterations, although the abnormalities of glucose metabolism have been investigated by relatively few studies as main outcomes. The present review summarizes the available data on glucose metabolism in children with GHD, providing an overview of the current state of the art in order to better clarify the real metabolic impact of GHD and GHT. Among all the existing studies, we evaluated all original studies that fulfilled our criteria for analysis reporting parameters of glucose metabolism as the primary or secondary objective. The reported impact of GHD per se on glucose metabolism is quite homogeneous, with the majority of studies reporting no significant difference in metabolic parameters between GHD children and controls. Conversely, GHT proves to be more frequently associated with a subtle form of insulin resistance, while both fasting glucose and HbA1c levels remain almost always within the normal range. The different methods to study glucose metabolism, the heterogeneity of the populations evaluated, the different doses of GH used together with the variable duration of follow-up may be responsible for discrepancy in the results. Long-term longitudinal studies having glucose homeostasis as their primary outcome are still needed in order better to clarify the real metabolic impact of GHD and GHT in children.

Insulin resistance in cavefish as an adaptation to a nutrient-limited environment.

Periodic food shortages are a major challenge faced by organisms in natural habitats. Cave-dwelling animals must withstand long periods of nutrient deprivation, as-in the absence of photosynthesis-caves depend on external energy sources such as seasonal floods. Here we show that cave-adapted populations of the Mexican tetra, Astyanax mexicanus, have dysregulated blood glucose homeostasis and are insulin-resistant compared to river-adapted populations. We found that multiple cave populations carry a mutation in the insulin receptor that leads to decreased insulin binding in vitro and contributes to hyperglycaemia. Hybrid fish from surface-cave crosses carrying this mutation weigh more than non-carriers, and zebrafish genetically engineered to carry the mutation have increased body weight and insulin resistance. Higher body weight may be advantageous in caves as a strategy to cope with an infrequent food supply. In humans, the identical mutation in the insulin receptor leads to a severe form of insulin resistance and reduced lifespan. However, cavefish have a similar lifespan to surface fish and do not accumulate the advanced glycation end-products in the blood that are typically associated with the progression of diabetes-associated pathologies. Our findings suggest that diminished insulin signalling is beneficial in a nutrient-limited environment and that cavefish may have acquired compensatory mechanisms that enable them to circumvent the typical negative effects associated with failure to regulate blood glucose levels.