Significant Hyperinsulinemia Research Articles

Comparison Between Maternal Blood Glucose and Fetal Cord Insulin Level Among Gestational Diabetes Mellitus Women

Introduction: Offspring of gestational diabetes mellitus (GDM) mothers are at high risk of developing insulin resistance, type 2 diabetes mellitus (T2 DM), and cardiovascular complications later in life. So, screening maternal blood glucose during pregnancy and identifying high-risk infants immediately after birth is necessary to prevent the potential long-term implications. Aim: To correlate the maternal fasting and post-prandial blood glucose withfetal insulin level. Materials and methods:A case-control study, was conducted at Chettinad Hospital and Research Institute, India, between May 2019 to May 2020. A 75-gram OGTT was performed among pregnant women between 24 to 28 weeks of pregnancy for diagnosing GDM according to American Diabetes Association (ADA) guidelines. 94 GDM mothers and Non-GDM mothers and theirnew-bornswere taken up for this study. 2.5ml of maternal venous blood was collected in a vacutainer containing sodium fluoride and EDTA as an anticoagulant for FBS and PPBS estimation. Some mothers on induction of labor were posted for emergency LSCS (for failed induction and non - progression of labor) and some had normal vaginal deliveries. Plasma FBS and PPBS estimation in the mother’s blood sample was assayed by the Hexokinase method in Siemen'sDimension RxLMachine immediately after centrifugation. 2.5ml of umbilical cord blood was collected in a vacutainer without an anticoagulant after the 2nd stage of labor. 0.5 ml of cord blood serum was separated and stored at -80°C in an eppendorf for later estimation of insulin by CLIA method in Beckman Coulter – Access 2 Immunoassay System. Independent students’ t-tests and Pearson’s correlation were used as statistical methods. p-value <0.05 is considered significant. Results: There is a positive correlation and significant difference between maternal FBS, PPBS, and fetal insulin levels in the GDM group (p-value 0.008, r-value 0.272 and p-value 0.005, r-value 0.286) compared to the Non-GDM group (p-value -0.087, r-value 0.243 and p-value 0.018, r-value 0.212). Conclusion: Significant hyperinsulinemia was noted in the offspring of the GDM group compared to the NON-GDM group.Those hyper-insulinemic babies are at very high risk of developing obesity, metabolic syndrome, and type 2 DM in the future and possess a threat to society.

189-OR: FGF21-Mediated Signaling Defects and Their Effects on Insulin Resistance in Insulin-Mediated Pseudoacromegaly

Insulin-mediated pseudoacromegaly (IMPA) is a rare, severe insulin resistance syndrome linked to digenic mutations in FGFR1 and KLB. These proteins form the receptor complex for FGF21, a hepatokine that plays a critical role in adipose tissue insulin sensitivity. Patients with IMPA have normal growth hormone and IGF-1. However, they have markedly increased insulin levels, tall stature, and obesity. To assess the pathogenicity of these mutations, we isolated iPSC from the proband with IMPA. We used CRISPR gene editing to correct the FGFR1 and KLB mutations and differentiated the iPSC lines into adipocytes. Western immunoblotting demonstrated that the uncorrected (mutant) cells demonstrated decreased levels of FGFR1 and pERK1/2 in response to insulin and/or FGF21 compared to corrected (wild-type) cells. Additionally, mutant adipocytes demonstrated significantly larger lipid droplets when stained with BODIPY. To complement the iPSC work, a humanized transgenic knock-in mouse line was created using CRISPR gene editing. When exposed to a high fat diet (HFD), female mice harboring variants in FGFR1 and KLB (DM - Double Mutant) developed significant weight gain compared to wild-type (WT) littermates. The difference in body weight was attributed to a difference in body fat. Similar to the human phenotype, the DM mice experience intermittent hyperglycemia and significant hyperinsulinemia. Explants of gonadal white adipose tissue demonstrated decreased lipolysis and pAKT and pERK. Mac-2 staining of white adipose tissue demonstrated abundant adipose tissue macrophages forming crown-like structures, suggesting adipose tissue inflammation. Additionally, we measured gene expression in brown adipose tissue, and noting that Ucp1 expression in DM mice was 37% when compared to WT. These results suggest pathogenic mechanisms in which FGFR1 and KLB mutations lead to IMPA via decreased FGF21-mediated signaling in the adipose tissue. Disclosure N.Phan: None. D.M.Ornitz: None. S.I.Stone: None. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD098872); National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK124574, P30DK020579, P30DK056341); National Center for Advancing Translational Sciences

Association of paraoxonase 1 activity and insulin resistance models in type 2 diabetes mellitus: Cross-sectional study.

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia due to defects in insulin secretion, insulin action, or both. Chronic hyperglycemia induces reactive oxygen species and increases oxidative stress. Human serum paraoxonase-1 (PON-1) is an enzyme synthesized in the liver, and it is an antioxidant enzyme with a beneficial role in fighting oxidative stress. The objective of the study was to compare PON-1 activity in type 2 diabetes mellitus (T2DM) and nondiabetics, as well as to find the association between PON-1 activity and different insulin resistance (IR) models in diabetics. The cross-sectional study recruited 100 diabetic and 100 age and gender-matched controls. Fasting blood glucose, insulin, and C-peptide, were assayed. PON-1 activity was measured by the spectrophotometric method. Various insulin resistance models based on insulin and C-peptide were constructed using appropriate formulae. Receiver operating characteristic was constructed to find if PON-1 can be a good marker for diabetes. PON-1 activity was found to be significantly higher (p < 0.0001) in diabetics compared to controls. Highly significant hyperinsulinemia (p < 0.0001) was noted in diabetics. C-peptide levels were significantly lower in cases (p = 0.0215) as compared to controls. Homeostasis model assessment (HOMA)-IR C was insignificantly higher in cases. HOMA B cell, HOMA 1% B cell, and C-peptide-based IR (CIR) were significantly lower in cases (p < 0.0001 and p = 0.002), respectively, as compared to controls. An odds ratio of 3.15 was obtained, which suggests that the risk of T2DM is 3 times higher in subjects with elevated PON-1 levels. Chi-square showed a significant association (p = 0.0001) between DM and PON-1 levels; the chi-square statistic value (with Yates correction) was 14.49. Correlation data showed that PON-1 activity had a significant negative correlation with quantitative insulin sensitivity check index (r = -0.265, p = 0.019). A significant negative correlation (r = -0.22, p = 0.016) was also seen between PON-1 and CIR (HOMA-IR C). There was no significant correlation seen between PON-1 and other IR models. It can be concluded from our study that PON-1 activity is elevated in T2DM patients, which can be a beneficial marker.

A Case of Autoimmune Hypoglycemia (Insulin Autoimmune Syndrome)

Introduction: Insulin Autoimmune Syndrome (IAS) is a condition caused by Insulin Autoantibody (IAA). IAS was initially reported in 1970 by Yukimasa Hirata from Japan. From 1970 to 2009, 380 cases were reported worldwide. We report a case of IAS in an African-American man who had recurrent episodes of syncope secondary to hypoglycemia. Case Report: A 50-year-old African American man with hypertension presented to emergency room after syncope. His initial blood glucose (BG) was 27 mg/dl. After Dextrose and glucagon injection, BG became 270 and he regained consciousness without any deficit. Vital signs and physical examination were unremarkable. He was not on any medication, and had no access to insulin or oral hypoglycemic agents. No family history of endocrine disorders, malignancy or autoimmune diseases were reported. He had been hospitalized two times for syncope secondary to hypoglycemia. During hospitalization, fasting insulin level was >1000 IU/ml with high C-peptide (3.5ng/ml). Hypoglycemic agents assay was negative. During outpatient follow-ups, fasting labs showed C-peptide 1.59 ng/ml, Insulin antibody 37.6 U/ml while venous BG was 65 mg/dl. Random BG at different occasions were 65, 68 and 55 mg/dl. HbA1C was normal. BMI was gradually increased from 32.4 to 34.8 in 6 months. During the third hospitalization, fasting venous BG were 45 and 57 on two different days, Insulin was 2111 IU/ml and C-Peptide was 1.78 ng/ml. Other labs including cortisol and TSH were normal. CT abdomen was unremarkable. Discussion: In IAS, Insulin secreted after meal is bound by IAA. It causes hyperglycemia unchecked which triggers further insulin secretion. When the bound insulin dissociates from antibodies, it causes significant hyperinsulinemia and subsequent hypoglycemia. IAS can occur regardless of previous insulin exposure, as a solitary autoimmune manifestation or in association with other autoimmune disorders. It can be induced by drugs that contain sulfhydryl group. Etiology of IAS is still not fully understood but there are theories that genetic predisposition such as class II Human Leukocyte Antigen (HLA) and environmental triggers such as medications, viruses, hematological diseases etc. might play a role. In our patient, failure to test IAA in past admissions and lack of continuity of care delayed the diagnosis. Conclusion: IAS should be considered especially in those who have no clear etiology of hypoglycemia in order to avoid unnecessary diagnostic and therapeutic procedures. Gold standard test for definitive diagnosis is IAA. As IAS is frequently self-remitting, supportive management is usually recommended. In severe cases, pharmacotherapies that reduce insulin secretion and immunosuppressants are occasionally necessary. But there is still no study that compares different treatment measures.

Markers of the course of obliterating atherosclerosis of lower limb arteries

The purpose of the study was to determine the level of substances damaging the vascular endothelium, as well as to assess their effect on the functional state of the endothelium and the course of obliterating atherosclerosis of lower limb arteries. The study included a total of 112 people, subdivided into three groups: those with an unfavourable course of obliterating atherosclerosis of lower limbs arteries (n=48) - group 1, patients with obliterating atherosclerosis of lower limbs arteries with a conventionally favourable course (n=48) - group 2, and apparently healthy volunteers (n=16). In all subjects, the following parameters were analysed: stable metabolites of nitric oxide II, endothelin-1, homocysteine and basal insulin. The level of stable nitric oxide metabolites (p<0.001 as compared with group 1; p<0.045 compared with group 2) was lower in the groups of patients with obliterating atherosclerosis of lower limb arteries (88.5±7.3 μmol/L in group 1; 161.5±8.6 μmol/L in group 2) as compared with healthy volunteers (226.0±28.6 μmol/L). In its turn, the level of nitric oxide was statistically significantly lower (p<0.001) in group 1 patients as compared with those of group 2. The level of endothelin-1 turned out to be higher (p<0.001) in group 1 (2.1±0.1 ng/ml) as compared with group 2 (1.6±0.1 ng/ml). Comparing group 1 patients with healthy volunteers (1.4±0.1 ng/ml), the level of endothelin-1 had also higher values (p<0.001). The level of endothelin-1 did not differ (p=0.270) as compared with group 2 and healthy volunteers. Comparing the homocysteine level in patients of the examined groups (20.7±0.8 μmol/L in group 1 patients and 18.1±0.6 μmol/L in group 2 patients) with healthy volunteers (13.0±0.4 μmol/L) demonstrated an increase in the parameters (p<0.001). The level of homocysteine turned out to be higher in group 1 patients than in those of group 2 (p<0.001). The level of basal insulin turned out to be significantly higher in the studied groups of patients with obliterating atherosclerosis of lower limb arteries (24.9±4.6 mIU/L in group 1; 8.0±0.7 mIU/L in group 2) than in healthy volunteers (5.1±0.5 mIU/L). Statistically significant (p<0.001) hyperinsulinemia was observed in group 1 as compared with group 2. Hyperhomocysteinemia and hyperinsulinemia are predictors of an unfavourable course of the disease. In a high level of these parameters, one may predict an unfavourable course of obliterating atherosclerosis of lower limb arteries.

Вплив ожиріння, гіперінсулінемії IGF-1 та гіперглікемії у розвитку колоректального раку у хворих на цукровий діабет 2-го типу

The latest studies prove an increased risk of colorectal cancer in patients with type 2 diabetes mellitus. The pathogenetic factors of type 2 diabetes have been recognized as mechanisms of association between these diseases. The objective: to investigate the effects of obesity, hyperinsulinemia, IGF-1 and hyperglycemia on the development of colorectal cancer in patients with type 2 diabetes. Materials and methods. 36 patients were divided into groups: I – healthy (control group), II – patients with type 2 diabetes mellitus, III – patients with colorectal cancer without diabetes, IV – patients with a combination of two diseases. Using the method of enzyme-linked immunosorbent assay were determined levels of insulin and insulin-like growth factor-1 (IGF-1). DM compensation was assessed by the level of glycosylated hemoglobin (HbA1c) that was determined by immuno-exchange chromatography. The data obtained were analyzed using Statistica 12.0 (StatSoft Inc.,USA). Differences between the values in the control and experimental groups were determined by the Student’s t-test. The differences were considered significant at р&lt;0.05. Results. According to the data obtained, colorectal cancer was diagnosed in patients with the age of over 60 years old with obesity. The body mass index (BMI) in patients of all study groups was higher than 30 kg/m2. Patients of group IV with a combination of type 2 diabetes and a circle of rectal cancer had significantly higher BMI compared to the control group (р&lt;0.05). Significant hyperinsulinemia and increased IGF-1 levels were detected in patients in all study groups (р&lt;0.05). Most patients with diabetes in both groups had HbA1c levels higher than 7.5%. Conclusions. Obesity, hyperinsulinemia, increased bioavailability of IGF-1, and hyperglycemia are pathogenetic factors in the risk of colorectal cancer in patients with type 2 diabetes. Patients over the age of 55 with diabetes, obesity, and hyperinsulinemia are advised to be screened for colorectal cancer.

Obesity, Hyperinsulinemia, IGF-1, and Hyperglycemia as Risk Factors for Colorectal Cancer in Patients with Type 2 Diabetes mellitus

The latest studies prove an increased risk of colorectal cancer in patients with type 2 diabetes mellitus. The pathogenetic factors of type 2 diabetes have been recognized as mechanisms of association between these diseases.The objective: to investigate the effects of obesity, hyperinsulinemia, IGF-1 and hyperglycemia on the development of colorectal cancer in patients with type 2 diabetes.Materials and methods. 36 patients were divided into groups: I – healthy (control group), II – patients with type 2 diabetes mellitus, III – patients with colorectal cancer without diabetes, IV – patients with a combination of two diseases. Using the method of enzyme-linked immunosorbent assay were determined levels of insulin and insulin-like growth factor-1 (IGF-1). DM compensation was assessed by the level of glycosylated hemoglobin (HbA1c) that was determined by immuno-exchange chromatography. The data obtained were analyzed using Statistica 12.0 (StatSoft Inc.,USA). Differences between the values in the control and experimental groups were determined by the Student’s t-test. The differences were considered significant at р&lt;0.05.Results. According to the data obtained, colorectal cancer was diagnosed in patients with the age of over 60 years old with obesity. The body mass index (BMI) in patients of all study groups was higher than 30 kg/m2. Patients of group IV with a combination of type 2 diabetes and a circle of rectal cancer had significantly higher BMI compared to the control group (р&lt;0.05). Significant hyperinsulinemia and increased IGF-1 levels were detected in patients in all study groups (р&lt;0.05). Most patients with diabetes in both groups had HbA1c levels higher than 7.5%.Conclusions. Obesity, hyperinsulinemia, increased bioavailability of IGF-1, and hyperglycemia are pathogenetic factors in the risk of colorectal cancer in patients with type 2 diabetes. Patients over the age of 55 with diabetes, obesity, and hyperinsulinemia are advised to be screened for colorectal cancer.

Effect of long-term overfeeding of a high-energy diet on glucose tolerance in Shetland pony mares.

BackgroundOverfeeding is associated with obesity and insulin dysregulation (ID), which are both risk factors for equine metabolic syndrome. How chronic overfeeding affects development of these factors is poorly understood.ObjectivesTo examine the influence of long‐term high‐energy diet provision on body condition and ID.AnimalsEleven Shetland pony mares.MethodsIn a 3‐phase study, the high‐energy group (n = 7) was fed 200% of net energy (NE) requirements (hay; concentrate: 36% sugar and starch, 13% fat) for 24 weeks, followed by 17 weeks hay‐only feeding before resuming the high‐energy diet (n = 4) for an additional 29 weeks. Mares were weighed weekly. Oral glucose tolerance tests were performed 3 to 4 times per dietary period. Results were compared with those of a control group (phase 1, n = 4; phases 2 and 3, n = 6) that received 100% NE requirements, using a general linear mixed model with post hoc Bonferroni testing.ResultsThe mean body weight of the high‐energy group increased by 27% per high‐energy feeding period. During both feeding periods, area under the curve (AUC) for plasma glucose concentration decreased (P < .01), whereas AUC for plasma insulin concentration increased. Mean basal plasma glucose concentration and peak plasma insulin concentrations were higher (P < .05) in the high‐energy group than in the control group.Conclusion and Clinical ImportanceFeeding a high‐energy diet to healthy nonobese Shetland pony mares led to more efficient glucose metabolism within 5 weeks, followed by significant hyperinsulinemia and obesity. Hyperinsulinemic status was reversed during 17 weeks of hay‐only feeding, regardless of body condition, but returned rapidly after restarting the high‐energy diet.

Female Offspring of Hyperandrogenemic Female (HAF) Rat Model Exhibit Insulin Resistance and Increased Blood Pressure With Aging

BackgroundPolycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia, oligo/an‐ovulation and polycystic ovaries. It is also associated with metabolic dysfunction and elevated blood pressure (BP). Whether daughters born to PCOS mothers exhibit a PCOS phenotype is controversial. In addition, whether daughters of PCOS women develop metabolic dysfunction and elevated BP with aging has not been reported.ObjectivesThe present study aimed to test the hypothesis that aging causes an increase in MAP and metabolic dysfunction in female offspring of HAF rats (model of PCOS).MethodsHyperandrogenemia was induced in Sprague Dawley (SD) females by implantation of 5α‐dihydrotestosterone pellets (DHT; 7.5 mg/90 days, subcutaneously) starting at 4 weeks of age. Rats were mated with SD males, and allowed to deliver and lactate. Female offspring (F1HAF) were weighed at birth, left untreated and studied at 4–6 (adult) or 16–18 (aging) months of age. Control dams were implanted with placebo pellets subcutaneously, allowed to mate, deliver and suckle their offspring (F1Placebo).ResultsDespite the similar litter size, body weight (BW) at birth was significantly lower in female F1HAF compared to F1Placebo (6.0 ± 0.1 vs 6.5 ± 0.1 g, n=13–15). As adults (4–6 months), BW, fat and lean masses, proteinuria and mean arterial pressure (MAP, radiotelemetry) of female F1HAF were not different compared to F1Placebo. With aging, female F1HAF rats showed increased MAP compared to F1Placebo (109 ± 1 versus 96 ± 1 mmHg, n=3–4). Fasting blood glucose was not different between groups (91 ± 3 vs 90 ± 2 mg/dl), but female F1HAF rats showed significant hyperinsulinemia (0.90 ± 0.05 vs 0.78 ± 0.03 ng/ml, p ≤ 0.05) and insulin resistance (­ HOMA‐IR index; 3.3 ± 0.2 vs 2.8 ± 0.1, p ≤ 0.05, (n = 5–6)). Despite the insulin resistance, lean mass (248.4 ± 8.5 vs 241.2 ± 3.9 g) and fat mass (41.2 ± 7.9 vs 39.7 ± 1.8 g) by Echo MRI, in addition to body weight (307.5 ± 16.2 vs 298.1 ± 6.4 g; (n = 2–4)) were also not different between groups.ConclusionAdult female offspring of hyperandrogenemic females do not show a PCOS phenotype (e.g. no hypertension, insulin resistance, metabolic phenotype), whereas with aging, they develop hypertension, hyperinsulinemia and insulin resistance with no changes in fasting glucose, lean/fat mass or body weight. These data suggest that women whose mothers had PCOS may be at increased risk for hypertension and metabolic dysfunction with aging, although the mechanisms for the hypertension are not clear.Support or Funding InformationR01HL135089, P01HL051971, P20GM121334, P20GM104357

Dysmetabolic and intracellular mechanisms of type 2 diabetes mellitus and colorectal cancer association

According to the results of modern research, patients with diabetes mellitus (DM) have an increased risk of oncological diseases, including colorectal cancer (CRC) that is one of the main reasons of mortality from malignant diseases among the population of Ukraine. Uncompensated diabetes is a reason of chronic metabolic stress, which causes defections of regulatory properties of intracellular signalling systems and activation of oncogenesis processes. Objective — to investigate the mechanisms of association between type 2 DM and colorectal cancer by determining the content of phospho-PRAS40, insulin and IGF-1. Materials and methods. 36 persons were examined. Patients were divided into groups: I — healthy (control group) (n = 10), II — patients with type 2DM (n = 10), III — patients with CRC without DM (n = 8), IV — patients with a combination CRC and type 2DM (n = 8). Using enzyme-linked immunosorbent assay the levels of insulin and IGF-1 in serum, and phospho-PRAS40 levels in peripheral blood mononuclear cells were determined. The level of glycosylated haemoglobin (HbA1c) was determined using ion exchange chromatography. Results and discussion. It was found that CRC occurs in people with obesity older than 60 years. Significant hyperinsulinemia and increased IGF-1 levels were found in the study groups compared to the control group (р < 0.05), with no gender differences (р > 0.05). Patients of group II with type 2 DM and group III with CRC had an increased level of phospho-PRAS40 compared to the control group (р < 0.05); in patients of group IV with combination of DM and CRC the level of phospho-PRAS40 was significantly lower than in the control group (р < 0.05). The level of HbA1c in patients with DM of the II and IV groups was more than 7.5 %, with no significant difference between these two groups (р > 0.05). Conclusions. Dysmetabolic disorders by type 2 DM,namely obesity, hyperinsulinemia, elevated IGF-1 levels, and hyperglycemia cause the development of molecular stress and syndrome of cancrophilia (a «cancer susceptibility») in patients with type 2 DM. The increased level of phosphorylated PRAS40 is a reflection of mTORC1 activation and a consequence of chronic metabolic stress caused by type 2 diabetes.

Abstract 018: Female Offspring of Polycystic Ovary Syndrome Rat Model Exhibit Insulin Resistance and Tendency Toward Increased Blood Pressure With Aging

Background: Polycystic ovary syndrome (PCOS) is associated with metabolic dysfunction and elevated blood pressure (BP). Whether daughters born to PCOS mothers exhibit a PCOS phenotype is controversial. In addition, whether daughters of PCOS women develop metabolic dysfunction and elevated BP with aging has not been reported. Objectives: The present study tested the hypothesis that aging causes an increase in MAP and metabolic dysfunction in female offspring of PCOS rats (F1 DHT ) along with changes in matrix metalloproteinase-9 (MMP-9) and transforming growth factor-β (TGF-β). Methods: PCOS was induced in SD females by implantation of 5α-dihydrotestosterone pellets (DHT; 7.5 mg/90 days, sc) starting at 4 wks of age. Rats were mated with SD males, and allowed to deliver and lactate. F1 DHT were left untreated and were studied at 14-16 wks or 16-18 mos of age. Control dams were implanted with placebo pellets sc, allowed to mate, deliver and suckle their offspring (F1 PL ). Results: MAP (radiotelemetry) in 14-16 wk F1 DHT females was not different from F1 PL, nor did they exhibit other PCOS characteristics. With aging, F1 DHT rats showed a strong tendency for increased MAP compared to F1 PL (107 ± 4 versus 93 ± 1 mmHg; p = 0.07 (n=2-4)). Plasma MMP-9 and TGF- β1, 2 and 3 were not different between groups. Fasting blood glucose was not different between groups (91 ± 2.6 vs 90 ± 1.6 mg/dl), but F1 DHT rats showed significant hyperinsulinemia (0.9 ± 0.05 vs 0.78 ± 0.03 ng/ml, p ≤ 0.05) and insulin resistance (increased HOMA-IR index; 3.3 ± 0.2 vs 2.8 ± 0.1, p ≤ 0.05, (n = 5-6)). Lean mass (248.3 ± 5.5 vs 241.2 ± 2.5 g), fat mass (38.7 ± 4.8 vs 39.7 ± 2.2 g) and total water (185.8 ± 4.8 vs 179.9 ± 3 g) by Echo MRI, in addition to body weight (310.7 ± 7.7 vs 298.1 ± 4.6 g ; (n = 6-8)) were also not different between groups. Conclusion: MAP in aging female offspring of PCOS rat model tends to be increased along with hyperinsulinemia and insulin resistance with no changes in fasting glucose, lean/fat mass, body weight, MMP9 or TGF-β. The data suggest that women whose mothers had PCOS may be at increased risk for hypertension and metabolic dysfunction with aging, although the mechanisms for the hypertension are not clear.

Influence of pathogenetic factors of type 2 diabetes on activation of PI3K/AkT/mTOR pathway and on the development of endometrial and breast cancer

Type 2 diabetes (T2D), which is an epidemic of the 20th century, increases mortality, caused not only by cardiovascular diseases but also cancer. Pathogenetic factors of T2D lead to dysfunction of intracellular regulatory systems, particularly of PI3K/Akt/mTOR signaling pathway, which is involved in development of breast and endometrial cancer. During the study, the activation of this pathway by cancer and T2D was examined by determining the content of phosphorylated PRAS40 and p70S6K1. We studied the link between these kinases and pathogenetic factors of T2D. 65 women were examined. Patients were divided into four groups: І – healthy, ІІ – women with T2D, ІІІ – women with cancer without diabetes, IV – women with cancer and T2D. Level of HbA1c was determined by the ion-exchange chromatography. Levels of insulin, IGF-1, phospho-PRAS40, phospho-p70S6K1 were determined in PBMCs by immune-enzymatic methods. According to research results, significant hyperinsulinemia was detected in both groups with T2D. The highest level of insulin was in group II. A significantly higher level of IGF-1 was found only in patients with cancer of group III. The content of phospho-PRAS40 and phospho-p70S6K1 was higher in women with T2D of group II and in women with cancer of group III. Patients in group IV with combination of cancer and T2D had a lower level of phospho-PRAS40 in comparison to other groups. Phospho-PRAS40 in group II correlates with insulin, IGF-1 and HbA1c; in groups III and IV only with BMI. Phospho-p70S6K1 correlates with IGF-1 and with HbA1c in group II. Pathogenetic factors of T2D activate the signal path PI3K/Akt/mTOR, which is involved in the regulation of oncogenesis and metabolism. Phosphorylation of PRAS40 and p70S6K1 reflects the activation of P13K/Akt/mTOR pathway in women with T2D. Increased levels the phospho-PRAS40 and phospho-p70S6K1 can be used as early markers of oncogenesis in women with T2D.

Impaired compensatory hyperinsulinemia among nonobese type 2 diabetes patients: a cross-sectional study.

Aims:Obesity associated prolonged hyperinsulinemia followed by β-cell failure is well established as the pathology behind type 2 diabetes mellitus (T2DM). However, studies on nonobese T2DM have reported it to be a distinct clinical entity with predominant insulin secretory defect. We, therefore, hypothesized that compensatory hyperinsulinemia in response to weight gain is impaired in nonobese subjects.Methods:This was a cross-sectional study from a community-based metabolic health screening program. Adiposity parameters including body mass index (BMI), waist circumference (WC), body fat percentage, plasma leptin concentration and metabolic parameters namely fasting insulin, glucose, total cholesterol, and triglycerides were measured in 650 individuals (73% healthy, 62% nonobese with a BMI <25).Results:In contrast to obese T2DM, nonobese T2DM patients did not exhibit significant hyperinsulinemia compared with the nonobese healthy group. Age, sex, and fasting glucose adjusted insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR) and HOMA-beta cell function (HOMA-B) were increased in obese T2DM compared with nonobese T2DM. Although adiposity parameters showed strong correlation with fasting insulin in obese healthy (r = 0.38, 0.38, and 0.42, respectively; all p values < 0.001) and T2DM (r = 0.54, 0.54, and 0.66, respectively; all p < 0.001), only BMI and leptin showed a weak correlation with insulin in the nonobese healthy group (0.13 and 0.13, respectively; all p < 0.05) which were completely lost in the nonobese T2DM.Conclusions:Compensatory hyperinsulinemia in response to weight gain is impaired in the nonobese population making insulin secretory defect rather than IR the major pathology behind nonobese T2DM.

Reduced GLP-1 Secretion at 30 Minutes After a 75-g Oral Glucose Load Is Observed in Gestational Diabetes Mellitus: A Prospective Cohort Study.

Glucagon-like peptide 1 (GLP-1) levels may be reduced in type 2 diabetes, but whether a similar impairment exists in gestational diabetes mellitus (GDM) has not been established. We studied this in a prospective cohort study of pregnant women (n = 144) during oral glucose tolerance test (OGTT). GLP-1, glucose, and insulin were sampled at 30-min intervals during a 2-h 75-g OGTT, and indices of insulin secretion and sensitivity were calculated. In a nested case-control study, women with GDM (n = 19) had 12% lower total GLP-1 secretion area under the curve (AUC) compared with control subjects matched for age, ethnicity, and gestational age (n = 19), selected from within the lowest quartile of glucose120 min values in our cohort. GDM had lower GLP-1 response in the first 30 min (19% lower GLP-130 min and 17% lower AUC0-30 min) after adjustment for possible confounders. Their glucose levels began to diverge at 30 min of the OGTT with increasing insulin levels, and by 120 min, their insulin levels were three times higher. In a secondary cohort of 57 women that included "high-normal" glucose120 min values, low GLP-1 AUC0-30 min was independently associated with lower indices of insulin secretion and sensitivity. In conclusion, we have observed that women with GDM have lower GLP-1 response at 30 min of an OGTT and hyperglycemia at 120 min despite significant hyperinsulinemia.

Homeostasis Model Assessment - Insulin Resistance and Sensitivity (HOMA-IR and IS) Index in Overweight Children Born Small for Gestational Age (SGA).

Abstract Introduction: Children born small for gestational age (SGA) have increased prevalence of metabolic syndrome, diabetes mellitus type 2 (DM2), hypertension and cardiovascular and cerebrovascular events in adulthood. Patients and Methods: In 100 children born SGA, and in second cohort having 32 obese children born in term with normal birth weight and height, anthropometric measurements and biochemical metabolic profiles were analysed. The Homeostasis Model Assessment - Insulin Resistance and Sensitivity (HOMA-IR and IS) were calculated. Results: Four overweight/obese children (M:F=3:1) with normal height were found among 100 SGA children. The body mass index (BMI) in all 4 children was above the 98th percentile and the mean BMI z-score was (2.04±0.30 SDS). The HOMA-IR index in all four children was increased: 1.26-2.65 (&gt;1). Two teenagers had significant hyperinsulinemia (198.00 uIU/ml and 275 uIU/ml) and were treated with metformin. Two girls needed only a diet and increased physical activity. The mean values of HOMA-IR (1.26-2.65; N&lt; 1) and IS (58 ±17.12) in fo-ur SGA overweight/obese children who caught-up growth had indistinguishable values with the group of 32 (M: F=21:11) obese children (HOMA-IR 1.83±1.2 SDS; IS 82.99±64.53 SDS) born in term with normal birth weight and height. Conclusions: SGA born children are usually thin; nevertheless we found overweight and obesity in 4% of the patients. Two of those children have metabolic syndrome. Excess weight, obesity and metabolic syndrome in SGA children result with increase of their inherent risk for DM2, cardiovascular and cerebrovascular diseases in adulthood.

Prevention of the adverse effects of olanzapine on lipid metabolism with the antiepileptic zonisamide

BackgroundAtypical antipsychotic drugs, particularly olanzapine, represent a mainstay in the treatment of psychoses; however, their use is commonly associated with weight gain and diabetes. The aim of this study was to determine whether combined administration of olanzapine and zonisamide can be used to prevent olanzapine-induced metabolic disturbances. Methods and resultsThese experiments involved female Sprague Dawley rats (n = 6–8/group) that were administered olanzapine, either acutely (6 mg/kg, s. c) or via continuous osmotic minipump infusion (6 mg/kg/day for 6 or 14 days), in combination with zonisamide (26 mg/kg/day,i.p.). Continuous infusion of olanzapine induced accumulation of adipose tissue and an associated reduction in stimulated lipolysis and reduced protein expression of CGI-58, a critical co-activator of ATGL. Olanzapine treatment caused a preferential shift toward carbohydrate oxidation (or reduced fat oxidation), elevated blood triglycerides and a reduction in locomotor activity. Olanzapine had a direct effect on glucose regulation, causing rapid hyperglycemia, and a reduction in glucose tolerance and insulin sensitivity. Continuous administration of olanzapine caused significant hyperinsulinemia and a significant reduction in insulin sensitivity. Zonisamide did not affect the impact of olanzapine on glucose homeostasis. On the other hand, co-administration of olanzapine with zonisamide completely ameliorated olanzapine-mediated shifts in lipid metabolism resulting in a normalization of olanzapine-induced weight gain. ConclusionThese data collectively show an impact of olanzapine on body weight and lipid metabolism, which is ameliorated by co-administration with zonisamide. These findings suggest that a combined olanzapine and zonisamide approach might reduce weight gain, but will not provide protection against olanzapine-induced glucose intolerance.

The effect of mare obesity and endocrine function on foal birthweight in Thoroughbreds.

Birthweight of Thoroughbred foals has increased in recent years. It is unknown whether this is associated with increased broodmare obesity or endocrine dysfunction. To determine insulin, leptin and triglyceride concentrations in Thoroughbred mares throughout gestation and investigate their association with obesity and foal birthweight. Cohort study. A total of 66 mares were included from 40 days post-breeding. Body condition score (BCS), weight and blood samples were obtained every 60 days throughout gestation. Serum/plasma insulin, leptin and triglyceride concentrations and foal birthweight were recorded. Associations between hormone/triglyceride concentration with BCS, stage of gestation and birthweight were analysed using a linear mixed effects model. Serum insulin concentrations were greater at 1-60 days (4.31 μiu/mL) compared with 241-300 days (3.13 μiu/mL) and 61-120 days (5.33 μiu/mL) compared with 181-240, 241-300 and 301-360 days (3.78, 3.13, 3.37 μiu/mL) gestation (P<0.05). There was no significant hyperinsulinaemia and no association of insulin concentration with BCS. Leptin concentration was greater at 181-240 days (2.28 μg/L, P<0.0001) compared with all other time points and correlated with BCS (P<0.0003). Triglyceride concentration was greater at 241-300 days (0.245 mmol, P<0.02) compared with earlier time points, but was not associated with BCS. Foal birthweight was weakly positively correlated with BCS (r = 0.13, P<0.001) and inversely correlated with leptin concentrations at 61-120 and 241-300 days gestation (r = -0.64, P<0.05). Reduction in sample size over the study and tight clustering of BCS. Mare BCS correlated with foal birthweight; obese mares had heavier foals. Significant hyperinsulinaemia was not identified in this population. Increased leptin concentration in early and late gestation was associated with decreased foal birthweight. Further work is required to establish whether leptin concentration in late gestation could predict foal birthweight.

SERUM NESFATIN-1 LEVELS IN EXPERIMENTALLY-INDUCED POLYCYSTIC OVARY IN LEAN AND OBESE ALBINO RATS

Background: Polycystic ovary syndrome (PCOS) is a very common problem in reproductive age; Obesity and insulin resistance (IR) play critical roles in its etiology. Limited studies have investigated the link between nesfatin-1 levels and PCOS. However, these studies are controversial. Objectives: This study aimed to evaluate possible changes of serum nesfatin-1 Levels in letrozole-induced PCOS in lean and obese rats, and its association with some hormonal and metabolic parameters. Material and methods: Forty two young virgin healthy female albino rats were used. Rats were divided into three equal groups: Group I (control), group II (lean PCOS) rats fed ordinary rodent diet for 9 weeks, and then received a daily single dose of letrozole orally (0.5 mg/kg/BW) for 21 days. Group III (obese PCOS) rats fed high fat diet for 9 weeks, and then received a daily single dose of letrozole (0.5 mg/kg/BW) orally for 21 consecutive days. At the end of experiment, serum levels of Nesfatin-1, free testosterone, LH, FSH, estradiol, progesterone, glucose and insulin were detected. BMI and HOMA-IR were calculated. Ovarian histopathology was done. Results: In obese polycystic ovary group, serum nesfatin-1 level was significantly lower and accompanied by significant hyperinsulinemia, hyperglycemia, insulin resistance, and high BMI when compared to both of lean polycystic and control groups. Moreover, serum nesfatin-1 level significantly negative correlated with serum insulin levels, serum glucose levels, HOMA-IR, and BMI, but correlated positively with LH levels. In lean polycystic group, serum nesfatin-1 level did not significantly change, when compared to control group, In addition, there was an absence of any significant change in serum insulin levels, serum glucose levels, HOMA-IR, or BMI. Conclusion: Serum nesfatin-1 level seemed to be related to several metabolic syndrome parameters rather than to polycystic ovary syndrome. Our findings raised a possibility that nesfatin-1 level played some role in PCOS. Therefore, larger scale and more detailed molecular studies in vivo and vitro on ovarian function are needed.

Obesity, diet and nutraceuticals.

Migraine is the most prevalent neurological disorder worldwide, affecting on average 12% of the general population. Recent data support migraine as part of the metabolic syndrome (MetSyn) spectrum. The evidence of an association between obesity, insulin resistance, and migraine, all having in common the ability to favor a general pro-inflammatory state, reinforces this view. Under a neuronal point of view, another possible link between migraine and MetSyn is, other than the inflammatory state, the cellular energetic deficit. Indeed, it is well known that a mitochondrial energetic dysfunction may play a role in migraine pathogenesis, that MetSyn could further impair mitochondrial metabolism increasing oxidative stress, and that nutraceuticals involved in mitochondrial oxidative phosphorylation (OXPHOS) metabolism (Riboflavin, CoQ10, and magnesium) can be used as migraine prophylactic treatments. Here we review the evidence of MetSyn and migraine association and possible therapeutic implications. There is a close relationship between migraine and MetSyn, especially insulin resistance and obesity. More in detail, obesity is regarded as an important factor of chronification for migraineur patients, while weight-loss seems to have a protective effect. The main player of this association seems to be the obesity-related inflammation and an adequate slimming diet can act to reduce this inflammatory mechanism. In fact, inflammatory cytokines are higher in obese subjects and normalized by weight reduction. Moreover, several foods could act as triggers for some patients by an inflammatory antibody mediated pathway, by a direct histamine or other vasoactive peptides effect, or by modifying the quality and quantity of fat intake. Also, altered insulin metabolism could be related to leptins and nitric oxide (NO) stress, both inducing inflammatory effects involved in migraine pathogenesis. Some prophylactic treatments induce increase of weight, insulin and leptins that can counteract the therapeutic effect; it is the “prophylactic paradox”: a long lasting migraine could be worsened by the drug-induced obesity. Therefore, there is the rationale for the adoption of specific dietetic patterns as complementary treatment in migraine management. In particular, the ketogenic diet is worthy of mention because of its multiple effects on the above-mentioned mechanisms, since it induces a significant weight-loss (when prescribed as very-low calorie diet), normalizes leptins and hyperinsulinemia, improves mitochondrial OXPHOS metabolism, and has a ketone bodies induced anti-inflammatory effect. In summary, more attention should be paid to metabolic implications of migraine and its treatment to further improve, or at least not worsen, patients’ conditions and reduce migraine-related comorbidities and complications.

Abstract 013: Early Life Stress Increases Susceptibility to Develop Obesity and Metabolic Syndrome in a Sex-specific Manner

Recent epidemiological studies demonstrate that women have a greater prevalence of metabolic syndrome with associated increases in fasting glucose not seen in men. Lifestyle factors including diet and physical activity contribute to the risk of developing metabolic disease; however, it has been reported that exposure to early life stress (ELS) has enduring emotional, immune, and metabolic disturbances resulting in increased risk for obesity and type II diabetes. To investigate the effects of ELS as an independent risk factor for metabolic disease, we expose C57Bl/6 mice to maternal separation (MSep), an established behavioral stress model during postnatal life. At weaning, mice were placed on a low-fat diet (LFD, n=6-10) or high-fat diet (HFD, 60% fat calories, n=10) for 16 weeks. Body weight (BW) gain was not different between MSep and control (C) mice when fed a LFD; however, only female MSep mice display higher fat mass compared to C (6.7 ± 0.5 vs. 5.2±0.5 g, p&lt;0.05). Magnetic resonance spectroscopy revealed elevated levels of visceral fat in female MSep mice compared to C, suggesting that MSep increases central adiposity. HFD increased BW in male MSep mice vs C (54.2± 0.7 vs 51.3 ± 0.5, p&lt;0.05); however, BW was dramatically exaggerated in female MSep mice vs. C (48.2± 1.3 vs 34.4 ±2.3 g, p&lt;0.05). Accordingly, fat mass was increased in female MSep mice vs. C (18.2 ± 1.4 vs. 7.6 ± 0 g, p&lt;0.05). Only female MSep exhibited significant impaired glucose tolerance (AUC: 18445±507 vs 22070± 696 AU, p&lt;0.05), hepatomegaly, hypercholesterolemia (156±20 vs. 82 ± 2 mg/dl, p&lt;0.05), hyperleptinemia and hyperinsulinemia (p&lt;0.05) compared to C. Because impaired metabolic function has been linked to inflammation, we characterized splenocytes in female HFD-fed mice. We found a lower population of T-cells but no difference in B-cells in MSep mice vs. C. Functional studies of T cell differentiation demonstrated a reduced capability of naïve T cells to differentiate into anti-inflammatory T regulatory cells in MSep mice vs. C (54± 4 vs. 66± 1 % FoxP3+/CD25+ cells, p&lt;0.05, n=3). The ability to polarize into the pro-inflammatory Th17 phenotype remained intact. These data suggest that the mechanisms by which MSep primes the metabolic responses are sex-specific. NIH R00 HL111354