IU Indianapolis ScholarWorks :: Browsing by Subject "Metformin"

Browsing by Subject "Metformin"

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Activation of AMPK sensitizes medulloblastoma to Vismodegib and overcomes Vismodegib‐resistance
(Federation of American Societies for Experimental Biology, 2021-03-17) Gampala, Silpa; Zhang, GuangJun; Chang, Chun Ju; Yang, Jer-Yen; Pediatrics, School of Medicine
Vismodegib, a Smoothened antagonist, is clinically approved for treatment of human basal cell carcinoma (BCC), in the clinical trials of medulloblastoma (MB) and other cancers. However, a significant proportion of these tumors fail to respond to Vismodegib after a period of treatment. Here, we find that AMPK agonists, A769662, and Metformin, can inhibit GLI1 activity and synergize with Vismodegib to suppress MB cell growth in vitro and in vivo. Furthermore, combination of AMPK agonists with Vismodegib is effective in overcoming Vismodegib‐resistant MB. This is the first report demonstrating that combining AMPK agonist (Metformin) and SHH pathway inhibitor (Vismodegib) confers synergy for MB treatment and provides an effective chemotherapeutic regimen that can be used to overcome resistance to Vismodegib in SHH‐driven cancers.
Baseline leptin predicts response to metformin in adolescents with type 1 diabetes and increased body mass index
(Wiley, 2023) Ismail, Heba M.; Barua, Souptik; Wang, Johnny; Sabharwal, Ashutosh; Libman, Ingrid; Bacha, Fida; Nadeau, Kristen J.; Tosur, Mustafa; Redondo, Maria J.; Pediatrics, School of Medicine
Breastfeeding patterns among parturients with diabetes: a secondary analysis of the MOMPOD randomized clinical trial
(Wiley, 2025) Sarker, Minhazur; Jacobs, Marni B.; Boggess, Kim; Battarbee, Ashley N.; Refuerzo, Jerrie; Zork, Noelia; Eichelberger, Kacey; Durnwald, Celeste; Landon, Mark; Aagaard, Kjersti; Wallace, Kedra; Scifres, Christina; Longo, Sherri; Stuebe, Alison; Ramos, Gladys A.; Obstetrics and Gynecology, School of Medicine
Introduction: Insulin resistance is associated with decreased milk supply in lactating people. Metformin is hypothesized to increase breast milk production by decreasing insulin resistance, suggesting use may increase breastfeeding success. We aimed to determine the association between metformin use during pregnancy and breastfeeding initiation and continuation. Methods: This was a secondary analysis of the MOMPOD randomized controlled trial of metformin versus placebo in addition to insulin therapy among pregnant people with type 2 diabetes and early diabetes. We included parturients who delivered a living neonate, received at least one dose of study drug or placebo, endorsed an intention to breastfeed, and completed a breastfeeding survey. Breastfeeding intentions and breastfeeding outcomes were collected utilizing a breastfeeding questionnaire at 24-30 weeks and 30-days postpartum respectively. The primary outcome was breastfeeding at 30-days postpartum defined by exclusive or partial breastfeeding. Secondary outcomes included immediate breastfeeding defined as any breastfeeding during the postpartum hospital admission until at least postpartum day 3, onset of lactogenesis (days), breast and bra size, and breastfeeding challenges. Baseline characteristics and outcomes were compared using chi-square, t-test, or Wilcoxon tests, as appropriate. Results: Among the 794 women randomized and receiving either placebo or metformin in the primary trial, 378 (47.6%) met inclusion criteria with 194 (51.3%) in metformin and 184 (48.7%) in placebo groups. There were no significant differences in baseline characteristics. Immediate breastfeeding was comparable between groups (91.1% vs 88.9%, p=0.53) and there was no difference in onset of lactogenesis. Thirty days postpartum, breastfeeding rates were lower among all parturients and there was no difference between metformin and placebo groups (76.0% vs 66.7%, p=0.11). Also, there were no differences in partial or exclusive breastfeeding, breast cup or bra size, or breastfeeding challenges. Conclusion: Our data suggest no association between metformin use and breastfeeding patterns in those with type 2 or early diabetes in pregnancy. Antepartum metformin should not be recommended solely to improve breastfeeding success.
Differential loss of β-cell function in youth vs. adults following treatment withdrawal in the Restoring Insulin Secretion (RISE) study
(Elsevier, 2021) Utzschneider, Kristina M.; Tripputi, Mark T.; Kozedub, Alexandra; Barengolts, Elena; Caprio, Sonia; Cree-Green, Melanie; Edelstein, Sharon L.; El Ghormli, Laure; Hannon, Tamara S.; Mather, Kieren J.; Palmer, Jerry; Nadeau, Kristen J.; RISE Consortium; Medicine, School of Medicine
Aims: To compare OGTT-derived estimates of β-cell function between youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes after treatment discontinuation in RISE. Methods: Youth (n = 89) and adults (n = 132) were randomized to 3 months glargine followed by 9 months metformin (G/M) or 12 months metformin (MET). Insulin sensitivity and β-cell responses were estimated from 3-hour OGTTs over 21 months. Linear mixed models tested for differences by time and age group within each treatment arm. Results: After treatment withdrawal, HbA1c increased in both youth and adults with a larger net increase in G/M youth vs. adults at 21 months. Among youth, β-cell function decreased starting at 12 months in G/M and 15 months in MET. Among adults, β-cell function remained relatively stable although insulin secretion rates decreased in G/M at 21 months. At 21 months vs. baseline β-cell function declined to a greater extent in youth vs. adults in both the G/M and MET treatment arms. Conclusions: After treatment withdrawal youth demonstrated progressive decline in β-cell function after stopping treatment with either G/M or MET. In contrast, β-cell function in adults remained stable despite an increase in HbA1c over time.
Emerging Concepts About Prenatal Genesis, Aberrant Metabolism and Treatment Paradigms in Polycystic Ovary Syndrome
(Springer, 2012) Witchel, Selma F.; Recabarren, Sergio E.; Gonzalez, Frank; Diamanti-Kandarakis, Evanthia; Cheang, Kai I.; Duleba, Antoni J.; Legro, Richard S.; Homburg, Roy; Pasquali, Renato; Lobo, Rogerio; Zouboulis, Christos C.; Kelestimur, Fahrettin; Fruzzetti, Franca; Futterweit, Walter; Norman, Robert J.; Abbott, David H.; Obstetrics and Gynecology, School of Medicine
The interactive nature of the 8th Annual Meeting of the Androgen Excess and PCOS Society Annual Meeting in Munich, Germany (AEPCOS 2010) and subsequent exchanges between speakers led to emerging concepts in PCOS regarding its genesis, metabolic dysfunction, and clinical treatment of inflammation, metabolic dysfunction, anovulation and hirsutism. Transition of care in congenital adrenal hyperplasia from pediatric to adult providers emerged as a potential model for care transition involving PCOS adolescents.
Hepatic Fat in Participants With and Without Incident Diabetes in the Diabetes Prevention Program Outcome Study
(The Endocrine Society, 2021) Goldberg, Ronald B.; Tripputi, Mark T.; Boyko, Edward J.; Budoff, Matthew; Chen, Zsu-Zsu; Clark, Jeanne M.; Dabelea, Dana M.; Edelstein, Sharon L.; Gerszten, Robert E.; Horton, Edward; Mather, Kieren J.; Perreault, Leigh; Temprosa, Marinella; Wallia, Amisha; Watson, Karol; Irfan, Zeb; Medicine, School of Medicine
Context: There is little information about fatty liver in prediabetes as it transitions to early diabetes. Objective: This study is aimed at evaluating the prevalence and determinants of fatty liver in the Diabetes Prevention Program (DPP). Methods: We measured liver fat as liver attenuation (LA) in Hounsfield units (HU) in 1876 participants at ~14 years following randomization into the DPP, which tested the effects of lifestyle or metformin interventions versus standard care to prevent diabetes. LA was compared among intervention groups and in those with versus without diabetes, and associations with baseline and follow-up measurements of anthropometric and metabolic covariates were assessed. Results: There were no differences in liver fat between treatment groups at 14 years of follow-up. Participants with diabetes had lower LA (mean ± SD: 46 ± 16 vs 51 ± 14 HU; P < 0.001) and a greater prevalence of fatty liver (LA < 40 HU) (34% vs 17%; P < 0.001). Severity of metabolic abnormalities at the time of LA evaluation was associated with lower LA categories in a graded manner and more strongly in those with diabetes. Averaged annual fasting insulin (an index of insulin resistance [OR, 95% CI 1.76, 1.41-2.20]) waist circumference (1.63, 1.17-2.26), and triglyceride (1.42, 1.13-1.78), but not glucose, were independently associated with LA < 40 HU prevalence. Conclusion: Fatty liver is common in the early phases of diabetes development. The association of LA with insulin resistance, waist circumference, and triglyceride levels emphasizes the importance of these markers for hepatic steatosis in this population and that assessment of hepatic fat in early diabetes development is warranted.
Lifestyle and Metformin Ameliorate Insulin Sensitivity Independently of the Genetic Burden of Established Insulin Resistance Variants in Diabetes Prevention Program Participants
(American Diabetes Association, 2016-02) Hivert, Marie-France; Christophi, Costas A.; Franks, Paul W.; Jablonski, Kathleen A.; Ehrmann, David A.; Kahn, Steven E.; Horton, Edward S.; Pollin, Toni I.; Mather, Kieren J.; Perreault, Leigh; Barrett-Connor, Elizabeth; Knowler, William C.; Florez, Jose C.; Department of Medicine, IU School of Medicine
Large genome-wide association studies of glycemic traits have identified genetics variants that are associated with insulin resistance (IR) in the general population. It is unknown whether people with genetic enrichment for these IR variants respond differently to interventions that aim to improve insulin sensitivity. We built a genetic risk score (GRS) based on 17 established IR variants and effect sizes (weighted IR-GRS) in 2,713 participants of the Diabetes Prevention Program (DPP) with genetic consent. We tested associations between the weighted IR-GRS and insulin sensitivity index (ISI) at baseline in all participants, and with change in ISI over 1 year of follow-up in the DPP intervention (metformin and lifestyle) and control (placebo) arms. All models were adjusted for age, sex, ethnicity, and waist circumference at baseline (plus baseline ISI for 1-year ISI change models). A higher IR-GRS was associated with lower baseline ISI (β = -0.754 [SE = 0.229] log-ISI per unit, P = 0.001 in fully adjusted models). There was no differential effect of treatment for the association between the IR-GRS on the change in ISI; higher IR-GRS was associated with an attenuation in ISI improvement over 1 year (β = -0.520 [SE = 0.233], P = 0.03 in fully adjusted models; all treatment arms). Lifestyle intervention and metformin treatment improved the ISI, regardless of the genetic burden of IR variants.
Lifestyle and metformin interventions have a durable effect to lower CRP and tPA levels in the diabetes prevention program except in those who develop diabetes
(American Diabetes Association, 2014-08) Goldberg, Ronald B.; Temprosa, Marinella G.; Mather, Kieren J.; Orchard, Trevor J.; Kitabchi, Abbas E.; Watson, Karol E.; Diabetes Prevention Program Research Group; Department of Medicine, IU School of Medicine
OBJECTIVE: We evaluate whether lifestyle and metformin interventions used to prevent diabetes have durable effects on markers of inflammation and coagulation and whether the effects are influenced by the development of diabetes. RESEARCH DESIGN AND METHODS: The Diabetes Prevention Program was a controlled clinical trial of 3,234 subjects at high risk for diabetes who were randomized to lifestyle, metformin, or placebo interventions for 3.4 years. Diabetes was diagnosed semiannually by fasting glucose and annually by oral glucose tolerance testing. In addition to baseline testing, anthropometry was performed every 6 months; fasting insulin yearly; and hs-CRP, tissue plasminogen activator (tPA), and fibrinogen at 1 year and end of study (EOS). RESULTS: CRP and tPA levels were unchanged in the placebo group but fell in the lifestyle and metformin groups at 1 year and remained lower at EOS. These reductions were not seen in those who developed diabetes over the course of the study despite intervention. Fibrinogen was lower at 1 year in the lifestyle group. Differences in weight and weight change explained most of the influence of diabetes on the CRP response in the lifestyle group, but only partly in the placebo and metformin groups. Weight, insulin sensitivity, and hyperglycemia differences each accounted for the influence of diabetes on the tPA response. CONCLUSIONS: Lifestyle and metformin interventions have durable effects to lower hs-CRP and tPA. Incident diabetes prevented these improvements, and this was accounted for by differences in weight, insulin resistance, and glucose levels.
Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study
(Wiley, 2013) Diabetes Prevention Program Outcomes Study Research Group; Orchard, T. J.; Temprosa, M.; Barrett-Connor, E.; Fowler, S.; Goldberg, R.; Mather, K.; Marcovina, S.; Montez, M.; Ratner, R.; Saudek, C.; Sherif, H.; Watson, K.; Medicine, School of Medicine
Aims: Whether long-term cardiovascular risk is reduced by the Diabetes Prevention Program interventions is unknown. The aim of this study was to determine the long-term differences in cardiovascular disease risk factors and the use of lipid and blood pressure medications by the original Diabetes Prevention Program intervention group. Methods: This long-term follow-up (median 10 years, interquartile range 9.0-10.5) of the three-arm Diabetes Prevention Program randomized controlled clinical trial (metformin, intensive lifestyle and placebo), performed on 2766 (88%) of the Diabetes Prevention Program participants (who originally had impaired glucose tolerance), comprised a mean of 3.2 years of randomized treatment, approximately 1-year transition (during which all participants were offered intensive lifestyle intervention) and 5 years follow-up (Diabetes Prevention Program Outcomes Study). During the study, participants were followed in their original groups with their clinical care being provided by practitioners outside the research setting. The study determined lipoprotein profiles and blood pressure and medication use annually. Results: After 10 years' follow-up from Diabetes Prevention Program baseline, major reductions were seen for systolic (-2 to -3) and diastolic (-6 to -6.5 mmHg) blood pressure, and for LDL cholesterol (-0.51 to -0.6 mmol/l) and triglycerides (-0.23 to -0.25 mmol/l) in all groups, with no between-group differences. HDL cholesterol also rose significantly (0.14 to 0.15 mmol/l) in all groups. Lipid (P = 0.01) and blood pressure (P = 0.09) medication use, however, were lower for the lifestyle group during the Diabetes Prevention Program Outcomes Study. Conclusion: Overall, intensive lifestyle intervention achieved, with less medication, a comparable long-term effect on cardiovascular disease risk factors, to that seen in the metformin and placebo groups.
Metabolic syndrome components and their response to lifestyle and metformin interventions are associated with differences in diabetes risk in persons with impaired glucose tolerance
(Wiley Blackwell (Blackwell Publishing), 2014-04) Florez, Hermes; Temprosa, Marinella G.; Orchard, Trevor J.; Mather, Kieren J.; Marcovina, Santica M.; Barrett-Connor, Elizabeth; Horton, Edward; Saudek, Christopher; Pi-Sunyer, Xavier F.; Ratner, Robert E.; Goldberg, Ronald B.; Department of Medicine, IU School of Medicine
AIMS: To determine the association of metabolic syndrome (MetS) and its components with diabetes risk in participants with impaired glucose tolerance (IGT), and whether intervention-related changes in MetS lead to differences in diabetes incidence. METHODS: We used the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) revised MetS definition at baseline and intervention-related changes of its components to predict incident diabetes using Cox models in 3234 Diabetes Prevention Program (DPP) participants with IGT over an average follow-up of 3.2 years. RESULTS: In an intention-to-treat analysis, the demographic-adjusted hazard ratios (95% confidence interval) for diabetes in those with MetS (vs. no MetS) at baseline were 1.7 (1.3-2.3), 1.7 (1.2-2.3) and 2.0 (1.3-3.0) for placebo, metformin and lifestyle groups, respectively. Higher levels of fasting plasma glucose and triglycerides at baseline were independently associated with increased risk of diabetes. Greater waist circumference (WC) was associated with higher risk in placebo and lifestyle groups, but not in the metformin group. In a multivariate model, favourable changes in WC (placebo and lifestyle) and high-density lipoprotein cholesterol (placebo and metformin) contributed to reduced diabetes risk. CONCLUSIONS: MetS and some of its components are associated with increased diabetes incidence in persons with IGT in a manner that differed according to DPP intervention. After hyperglycaemia, the most predictive factors for diabetes were baseline hypertriglyceridaemia and both baseline and lifestyle-associated changes in WC. Targeting these cardiometabolic risk factors may help to assess the benefits of interventions that reduce diabetes incidence.

Browsing by Subject "Metformin"

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