Introduction: Bariatric surgery is considered the most effective treatment for severe obesity. However, it is not clear if patients with diabetes mellitus or insulin resistance have the same response than patients without those conditions. Our objective was to evaluate association between pre-surgical HOMA-IR index and percentage of excess weight loss (EWL%) one year after bariatric surgery using sleeve gastrectomy. Methods: Retrospective cohort including patients ≥ 18 years old with BMI ≥ 35 kg/m2, who underwent primary sleeve gastrectomy between 2014-2017 at the Avendaño Medical Center, Peru. Only patients with Type 2 Diabetes, Hypertension, or Dyslipidemia were included. EWL% ≥ 60% one year after surgery was considered satisfactory. Crude and adjusted Lineal and Poisson regression with robustness was used to assess statistical associations with EWL%. Results: Ninety-one patients were included with a median of 34 years, and 57.1% were women. 85.7% had insulin resistance as per HOMA-IR. One year after surgery, 76.9% had a satisfactory EWL%. The lineal model showed. 29% less EWL% per each extra year of life (P = .019), and. 93% more EWL% per each extra HOMA-IR point (P = .004). The adjusted Poisson model showed 2% lower risk of having a satisfactory EWL% per each additional year of life (P = .050), and 2% more chance of success per each additional HOMA-IR point (P = .038). Conclusions: There was association between a higher pre-surgical HOMA-IR index and increased EWL% one year after surgery. It is possible that insulin resistance does not affect negatively sleeve gastrectomy outcomes. / Revisión por pares

Background: Hypoglycemia is a commonly encountered metabolic state in the patient population. It can be medically defined as a blood sugar <70mg/dL in a diabetic patient or <50mg/dL in a non-diabetic patient. It is less frequently seen in non-diabetics due to the body’s ability to autoregulate insulin administration. Common symptoms are sweating, tremors, palpitations, dizziness, drowsiness, and confusion. If left untreated, these symptoms can progress to seizures, arrythmias, or other complications that ultimately lead to death. Objective: To highlight the possible causes of hypoglycemia and the appropriate work-up for normally euglycemic patients. Case Description: We herein report a case of hypoglycemia in a 36-year-old female with Lupus related end-stage renal disease on hemodialysis via Ash-catheter who presented with peritonitis due to a defunct peritoneal dialysis catheter. The patient was found to be bacteremic; therefore both catheters were removed and antibiotics were started. Repeat blood cultures showed no growth for 48 hours, so the patient was held fasting at midnight for placement of a new catheter. On the day of surgery, she registered multiple blood sugar readings as low as 15mg/dL. Her symptoms were limited to drowsiness and shortness of breath. She was given four D50 boluses, glucagon IV, and a D5 drip that was adjusted to a D15 drip to stabilize her blood sugar. It was discovered that at an admission two months ago, the patient had a few readings in the 30s. She denied any recollection of this and claimed to have been asymptomatic. She also denied a history of low blood sugars and a diagnosis of diabetes. In surgery that day, the patient went into cardiac arrest on the operating table after being sedated. She was resuscitated after one round of chest compressions, and her catheter was placed. During the episodes of low blood sugar, specific labs were drawn for the work-up of hypoglycemia (glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, insulin antibodies, and sulfonylurea/meglitinide screen), but results yielded inconclusive values that prevented a diagnosis. The patient’s blood sugars became steady once her diet was restarted, and she was discharged in stable condition to a rehab facility after cautionary counseling was given. Discussion: This case highlights an optimal way to work-up a patient with new onset hypoglycemia, focusing on patient history and drawing the appropriate labs during hypoglycemic episodes. The specific labs listed above can be used to differentiate between various causes of hypoglycemia (exogenous insulin administration, an insulin secreting tumor [insulinoma], insulin antibodies, insufficient cortisol or glucagon levels, or improper sulfonylurea/meglitinide use) by comparing them to standards. If labs are unable to be obtained, a 72-Hour Fast can be conducted to create a controlled environment, and a Glucagon Tolerance Test can further explore if the cause of hypoglycemia is insulin related. The goal of all of this testing is to be able to identify and treat the underlying cause of the hypoglycemia and prevent future episodes and the complications that accompany it.

Resveratrol, a naturally-occurring phytoestrogenic stilbene derivative, has been shown to elicit shifts in physiology of obese animals consuming a high calorie or ad libitum diet toward that of lean counterparts. This study was designed to evaluate effects of oral resveratrol supplementation on parameters of metabolic health and reproductive cyclicity in obese mares on pasture. Seventeen healthy, mares were matched by age and assigned to obese control (OBC; n=5, mean BCS=7.4±0.3), obese supplemented with 5g/d resveratrol (OBR; n=6, mean BCS=7.4±0.2) or non-obese control (NOC; n=6, mean BCS=5.4±0.1) treatments. Control horses received the resveratrol carrier paste. Across three consecutive estrous cycles, morphometric measurements were collected biweekly and follicular dynamics were evaluated via transrectal ultrasonography every other day. Frequently-sampled intravenous glucose tolerance tests were conducted pre- and post- treatment. Insulin and glucose kinetics were analyzed via minimal model. Resveratrol supplementation had no discernible effect on reproductive parameters (P>0.05), however obese mares had more (6 vs. 0) hemorrhagic anovulatory follicles. Neither resveratrol treatment nor time on study influenced morphometric measurements or minimal model parameters (raw data or data adjusted for animal size). As a whole, horses became more insulin resistant over time (Si value < 0.78 (1/[mU/L"min]). NOC horses had lower (P=0.01) acute insulin response to glucose relative to OBC or OBR. Although resveratrol supplementation did not elicit detectable responses in this study, promising results in other species warrant further investigation of the compound in horses, including exploration of bioavailability and possible effects at the tissue or cellular levels. / Master of Science

Insulin is a necessary, life-changing medication for patients living with Type 1 or Type 2 Diabetes Mellitus. Yet, a recent study at an endocrinology clinic in New England indicated that one quarter of patients experienced cost-related suboptimal insulin use. A new study based out of a primary care clinic in the Appalachian region looked at the prevalence of cost-related suboptimal insulin use within this region. The hypothesis is cost-related insulin suboptimal use is higher in the Appalachian region than as reported in the New England area. Surveys were administered to patients who were 18 years of age or older, diagnosed with Type 1 or Type 2 Diabetes Mellitus, and who had been prescribed insulin in the last 12 months. The survey instrument used was adopted and modified from the previous New England study. The survey instrument included 28 items and was administered in person prior to the start of the COVID-19 pandemic from July 2019 to April 2020. Following the start of the COVID-19 pandemic, in person recruitment was suspended. Beginning November 2020, a revised telephonic recruitment began and continued through December 2021. Interested participants were mailed the survey and consent form along with a postage paid return envelope. After the COVID-19 outbreak, the original survey instrument was revised to include 12 additional items designed to measure the impact of COVID-19 on the participant’s diabetes management and on insulin utilization. The primary outcome was cost-related underuse of insulin within the past year. This was measured by a positive response in the questionnaire to at least 1 of 6 questions: did you… (1) use less insulin than prescribed, (2) try to stretch out your insulin, (3) take smaller doses of insulin than prescribed, (4) stop using insulin, (5) not fill an insulin prescription, or (6) not start insulin… because of cost? Descriptive analysis was conducted using SPSS software. The East Tennessee State University Institutional Review Board approved the study protocol. Ninety respondents completed the survey. The average age of respondents was 68 years. The majority were diagnosed with type 2 diabetes (83%), Caucasian race (99%), male (59%), retired or disabled (76%), and had Medicare Part D prescription benefits (63%). The average monthly out-of-pocket cost for insulin was $84.10 (range $0-$566). For the primary outcome, results indicate 44.4% of participants in the Appalachian Mountain community experience cost-related suboptimal therapy. Forty participants completed the revised survey measuring the impact of COVID-19 on their diabetes self-management. From this group, 85% of participants reported their income and job did not change during the pandemic. However, increased dosing of insulin (30%) and increased insulin cost (27.5%) was reported. Respondents also reported increased stress (57.5%), worsened diet (25%) and worsened exercise (40%) as a result of the pandemic. Overall, a higher proportion of people with diabetes in the Appalachian region reported cost-related suboptimal insulin use compared to a previous study. The COVID-19 pandemic also has reportedly contributed to increased insulin requirements in one-third of the surveyed participants.

The present study was designed to explore the mind-body connection within a psychosocial-cultural context. More specifically, the current investigator hoped to examine how various dimensions of the mind and body interact with psychosocial-environmental factors, which are significantly influenced by cultural processes and reference group membership A cross-sectional study was designed to examine the relationship between health beliefs and health behaviors in sample of 419 adults with Type II diabetes with a focus on the moderating effects of social support, emotional reactions, and experiences of unfair treatment. A self-report questionnaire comprised of 90-items obtained from previously established measures of health beliefs, psychosocial-cultural factors, and health behaviors was administered online via Qualtrics.com. Results of testing a series of measurement and structural models using confirmatory factor analysis (CFA) showed poor fit across all models specified. While these results indicated that the expanded Health Belief Model (eHBM) specified for this study did not adequately describe the diabetes-related thoughts, attitudes, and behaviors for the current sample of participants, findings may have provided preliminary evidence of a three-factor structure reflecting participants’ worries and concerns about their health & perceptions involving challenges or obstacles to successful behavior change, which could interfere with daily life. Although it is unclear whether these results were related to limitations in the measurement instruments and study design, or to differences in the nature of the constructs and the ways in which participants interpreted and responded to the scales, the overall findings of this study suggest a need for research that examines the equivalence of health belief and health behavior measures and greater empirical evidence to ensure that the theories and models used in health research are generalizable across groups of people with varying world-views, identities and lived experiences. Implications for the Health Belief Model (HBM) and ideas for future research are discussed.

No description available.

Background. Bisphenol A (BPA) and BPS are environmental pollutants that are associated with the development of insulin resistance and type 2 diabetes (T2D). Although skeletal muscle and adipose tissue dysfunction are involved the development of insulin resistance, there are few studies that have investigated the effects of bisphenols on their metabolism. In this study, we investigated the effects of BPA and BPS exposure on skeletal muscle and adipose tissue metabolism to determine how they contribute to the development of T2D. Methods. L6 muscle cells were treated with BPA during the last 24 hours of differentiation, and mitochondrial function and glucose metabolism was measured. Human subcutaneous adipose tissue was incubated for 24 or 72 hours with BPA or BPS, and adipokine gene expression and glucose metabolism was measured in adipose tissue. Results. L6 muscle cells treated with high concentrations of BPA (10⁵ nM) had mitochondrial dysfunction and a compensatory increase in glucose metabolism; however, there were no effects at environmentally-relevant concentrations. Adipose tissue treated with BPA for 24 hours had reduced expression of proinflammatory cytokines and adipokines, and reduced insulin-stimulated glucose uptake. Conclusions. BPA exposure for 24 hours did not alter L6 muscle cell mitochondrial function and glucose metabolism at environmentally-relevant concentrations; however, adipose tissue had altered proinflammatory expression and glucose metabolism at low concentrations. This has important implications in regulatory guidelines in the use of BPA in the manufacturing of consumer products.

Through endocrine and exocrine functioning, physiological needs are communicated to body systems. Physiological need is met through the actions of intracellular signaling cascades and calibrated through an extensive network of regulatory cross talk within the cells of a given tissue. The insulin receptor belongs to a family of perhaps one of the most well studied family of dual receptor and tyrosine kinases (RTK). The signaling cascade downstream of the insulin RTK can be initiated through Insulin or growth factor ligand binding and bears growing relevance to the projected epidemic of obesity related illness and associated cancers. The primary function of the post-prandial insulin response is to support nutrient uptake and storage. Insulin (IS), Insulin-Like Growth Factor (IGF), and Epidermal Growth Factors (EGF) contribute to glucose metabolism, energetic homeostasis, and anabolic applications through effector kinases downstream of activated (phosphorylated) insulin receptor substrates (IRS). Protein Kinase B (AKT) kinase is one such cytosolic effector known to be of critical importance to anabolic metabolism and general cell survival. Under normal circumstances, AKT activity is dependent upon dual phosphorylation events known to occur at the plasma membrane. In an attempt to better understand the mechanism of AKT recruitment to the plasma membrane, earlier experiments reported that IRS stimulation by Insulin-Like Growth Factors (IGF) and Epidermal Growth Factors (EGF) resulted in downstream poly-ubiquitination and subsequent activation of the AKT kinase. This sequence of post-translational modification events suggested that non-proteolytic AKT ubiquitination, accomplished by the E2 Ubiquitin Conjugating enzyme (UBC13), was an important mediator of AKT activation. Through subsequent experimentation, it was determined that non-proteolytic ubiquitination was a necessary step for AKT activation following IRS activation by Insulin. Furthermore, the same two sites previously described in the context of IGF/EGF signaling were exploited through targeted mutagenesis and shown to synergistically regulate AKT translocation to the plasma membrane. Mutant AKT variants with a single mutation to either ubiquitination site resulted in partial knock down of phosphorylated AKT (pAKT), while variants with double mutations resulted in a complete loss of pAKT detection. Under physiologic conditions UBC13 activity can be antagonized by a small multifunctional protein called G-Protein Pathway Suppressor 2 (GPS2). Bearing the kinetics of an endogenous inhibitor, GPS2-mediated regulation directly inhibits the ubiquitin conjugating activity of the enzyme; thereby restricting AKT non-proteolytic poly-ubiquitination and antagonizing the insulin signaling network through a conserved mechanism. In accordance with this role, we have previously shown that GPS2 presence in adipocytes modulates systemic metabolism by restricting the activation of insulin signaling during the fasted state, whereas in absence of GPS2, the adipose tissue is more efficient at lipid storage, and obesity becomes uncoupled from inflammation and insulin resistance. As we are just beginning to unravel the regulatory network governing the cellular response to nutrient excess and pro-growth signaling, it remains unclear whether UBC13 activity is universally engaged in AKT translocation and activation. Here we have focused on the mitochondrial pool of AKT and investigated its regulation. Our findings add to the growing body of knowledge by demonstrating that in pre-adipocytes mitochondrial AKT is activated, in a UBC13-dependent fashion, following insulin stimulation. We also show that GPS2-mediated inhibition of UBC13 equally antagonizes AKT activation in different subcellular compartments, and that mitochondrial AKT activation is partially Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) dependent.

Indiana University-Purdue University Indianapolis (IUPUI) / Insulin resistance, a hallmark of type 2 diabetes (T2D), is associated with accompanying derangements such as hyperinsulinemia that promote the progression of insulin resistance, yet a mechanism(s) is imperfectly understood. Data have demonstrated that hyperinsulinemia promotes insulin resistance as evidenced by diminished ability of insulin to mobilize glucose transporter GLUT4 to the plasma membrane (PM). We found that loss of PM phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated filamentous actin (F-actin) structure contributes to hyperinsulinemia-induced insulin resistance. We tested if increased glucose flux through hexosamine biosynthesis pathway (HBP) causes dysregulation of PM components necessary for GLUT4 translocation. Increased HBP activity was detected in 3T3-L1 adipocytes cultured in hyperinsulinemia (5 nM Ins; 12 h) and also 2 mM glucosamine (GlcN), a distal HBP activator, inducing losses of PM PIP2 and F-actin. In accordance with HBP flux directly weakening PIP2/F-actin structure, inhibition of the rate-limiting HBP enzyme (glutamine:fructose-6-phosphate amidotransferase) restored F-actin and insulin responsiveness. Furthermore, less invasive challenges with glucose led to PIP2/F-actin dysregulation. New findings support a negative correlation between PM cholesterol accrual, PIP2/F-actin structure and GLUT4 regulation. These data stemmed from parallel study aimed at understanding the antidiabetic mechanism of the nutrient chromium (Cr3+). We found that chromium picolinate (CrPic) enhanced insulin-stimulated GLUT4 trafficking via reduction in PM cholesterol. In line with glucose/cholesterol toxicity findings, we demonstrated that therapeutic effects of CrPic occurred solely in adipocytes with increased HBP activity and a concomitant elevation in PM cholesterol. Mechanistically, data are consistent with a role of AMP-activated protein kinase (AMPK) in CrPic action. These data show that CrPic increases AMPK activity and perhaps suppresses cholesterol synthesis via distal phosphorylation and inactivation of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR), a rate-limiting enzyme in cholesterol synthesis. Continued study of the consequence of increased HBP activity revealed alterations in cholesterogenic transcription factors – Sp1, SREBP-1, and NFY – with Sp1 showing a significant increase in O-linked glycosylation. Consistent with Sp1 modification eliciting maximal transcriptional activation of SREBP-1, Hmgr mRNA was significantly enhanced. In conclusion, these data are consistent with a central role of PM cholesterol in glucose transport and suggest perturbations in this lipid have a contributory role in developing insulin resistance.

Indiana University-Purdue University Indianapolis (IUPUI) / Diabetes mellitus is a complex metabolic disease that currently affects an estimated 422 million people worldwide, with incidence rates rising annually. Type 1 diabetes (T1D) accounts for 5-10% of these cases. Its complications remain a major cause of global deaths. T1D is characterized by autoimmune destruction of β-cell mass. Efforts to preserve and protect β-cell mass in the preclinical stages of T1D are limited by few blood-borne biomarkers of β-cell destruction. In healthy β-cells, insulin secretion requires soluble n-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE) complexes and associated accessory regulatory proteins to promote the docking and fusion of insulin vesicles at the plasma membrane. Two target membrane (t)-SNARE proteins, Syntaxin 1/4 and SNAP25/23, and one vesicle-associated (v)-SNARE protein, VAMP2, constitute the SNARE core complex. SNARE complex assembly is also facilitated by the regulatory protein, Double C2-domain protein β (DOC2B). I hypothesized that DOC2B deficiency may underlie β-cell susceptibility to T1D damage; conversely , overexpression of DOC2B may protect β-cell mass. Indeed, with regard to DOC2B abundance, my studies show reduced levels of DOC2B in platelets and islets of prediabetic rodents and new-onset T1D humans. Remarkably, clinical islet transplantation in T1D humans restores platelet DOC2B levels, indicating a correlation With regard to protection/functional effects, DOC2B deficiency enhances susceptibility to T1D in mice, while overexpression of DOC2B selectively in β-cells protects mice from chemically induced T1D; this correlates with preservation of functional β-cell mass. Mechanistically, overexpression of DOC2B and the DOC2B peptide, C2AB, protects clonal β-cell against cytokine or thapsigargin-induced apoptosis and reduces ER stress; this is dependent on C2AB’s calcium binding capacity. C2AB is sufficient to enhance glucose stimulated insulin secretion (GSIS) and SNARE activation in clonal β-cells to the same extent as full-length DOC2B. In summary, these studies identify DOC2B as a potential biomarker and novel therapeutic target for prevention/management of T1D.