Insulin-resistant Type 2 Diabetes Research Articles

MiR-10a/b-5p-NCOR2 Regulates Insulin-Resistant Diabetes in Female Mice.

Gender and biological sex have distinct impacts on the pathogenesis of type 2 diabetes (T2D). Estrogen deficiency is known to predispose female mice to T2D. In our previous study, we found that a high-fat, high-sucrose diet (HFHSD) induces T2D in male mice through the miR-10b-5p/KLF11/KIT pathway, but not in females, highlighting hormonal disparities in T2D susceptibility. However, the underlying molecular mechanisms of this hormonal protection in females remain elusive. To address this knowledge gap, we utilized ovariectomized, estrogen-deficient female mice, fed them a HFHSD to induce T2D, and investigated the molecular mechanisms involved in estrogen-deficient diabetic female mice, relevant cell lines, and female T2D patients. Initially, female mice fed a HFHSD exhibited a delayed onset of T2D, but ovariectomy-induced estrogen deficiency promptly precipitated T2D without delay. Intriguingly, insulin (INS) was upregulated, while insulin receptor (INSR) and protein kinase B (AKT) were downregulated in these estrogen-deficient diabetic female mice, indicating insulin-resistant T2D. These dysregulations of INS, INSR, and AKT were mediated by a miR-10a/b-5p-NCOR2 axis. Treatment with miR-10a/b-5p effectively alleviated hyperglycemia in estrogen-deficient T2D female mice, while β-estradiol temporarily reduced hyperglycemia. Consistent with the murine findings, plasma samples from female T2D patients exhibited significant reductions in miR-10a/b-5p, estrogen, and INSR, but increased insulin levels. Our findings suggest that estrogen protects against insulin-resistant T2D in females through miR-10a/b-5p/NCOR2 pathway, indicating the potential therapeutic benefits of miR-10a/b-5p restoration in female T2D management.

A Long Non-coding RNA, LOC157273, Is an Effector Transcript at the Chromosome 8p23.1-PPP1R3B Metabolic Traits and Type 2 Diabetes Risk Locus.

AimsCausal transcripts at genomic loci associated with type 2 diabetes (T2D) are mostly unknown. The chr8p23.1 variant rs4841132, associated with an insulin-resistant diabetes risk phenotype, lies in the second exon of a long non-coding RNA (lncRNA) gene, LOC157273, located 175 kilobases from PPP1R3B, which encodes a key protein regulating insulin-mediated hepatic glycogen storage in humans. We hypothesized that LOC157273 regulates expression of PPP1R3B in human hepatocytes.MethodsWe tested our hypothesis using Stellaris fluorescent in situ hybridization to assess subcellular localization of LOC157273; small interfering RNA (siRNA) knockdown of LOC157273, followed by RT-PCR to quantify LOC157273 and PPP1R3B expression; RNA-seq to quantify the whole-transcriptome gene expression response to LOC157273 knockdown; and an insulin-stimulated assay to measure hepatocyte glycogen deposition before and after knockdown.ResultsWe found that siRNA knockdown decreased LOC157273 transcript levels by approximately 80%, increased PPP1R3B mRNA levels by 1.7-fold, and increased glycogen deposition by >50% in primary human hepatocytes. An A/G heterozygous carrier (vs. three G/G carriers) had reduced LOC157273 abundance due to reduced transcription of the A allele and increased PPP1R3B expression and glycogen deposition.ConclusionWe show that the lncRNA LOC157273 is a negative regulator of PPP1R3B expression and glycogen deposition in human hepatocytes and a causal transcript at an insulin-resistant T2D risk locus.

The Padova Type 2 Diabetes Simulator from Triple-Tracer Single-Meal Studies: In Silico Trials Also Possible in Rare but Not-So-Rare Individuals.

Background:In silico trials in type 2 diabetes (T2D) would be useful for testing diabetes treatments and accelerating the development of new antidiabetic drugs. In this study, we present a T2D simulator able to reproduce the variability observed in a T2D population. The simulator also allows to safely experiment on virtual subjects with severe (and possibly rare) pathological conditions. Methods: A meal simulation model of glucose, insulin, and C-peptide systems, made of 15 differential equations and 39 parameters, has been identified using a system decomposition and forcing function Bayesian strategy on data of 51 T2D subjects undergoing a single triple-tracer mixed meal. One hundred T2D in silico subjects have been generated from the joint distribution of estimated model parameters. A case study is presented to illustrate the simulator use for testing a virtual drug (improving insulin action and secretion) in a subpopulation of rare, extremely impaired, T2D subjects. Results: The model well fitted T2D data and parameters were estimated with precision. Simulated plasma glucose, insulin, and C-peptide well matched the data (e.g., median [25th-75th percentile] glucose area under the curves of 6.9 [6.1-8.5] 104 mg/dL·min in silico vs. 7.0 [5.6-8.2] 104 mg/dL·min in vivo). The potential use of the simulator was shown in a case study, in which the (virtual) antidiabetic drug dose was optimized for very insulin-resistant T2D subjects. Conclusions: We have developed a T2D simulator that captures the behavior of T2D population during a meal, both in terms of average and intersubject variability. The simulator represents a cost-effective way to test new antidiabetic drugs, before moving to human trials.

Glycemic and Metabolic Effects of Liraglutide as Additive Treatment to Different Therapeutic Regimens in Type 2 Diabetes Patients Followed in Primary Care Clinics

Background: Liraglutide improved metabolic derangement in type 2 diabetes (T2D). The study aimed to measure changes in glycemic and metabolic parameters after addition of liraglutide in obese insulin-resistant T2D patients Methods: liraglutide was added to 45 Adult T2D patients, who were on 4 regimens as follows:18 on Sulphonylurea(SU), 9 on SU and Basal insulin, 3 on basal insulin and 15 on multiple daily insulin injections(MDIs). Five patients had history of cardiovascular diseases (CVD).The cohort was followed for 6 months and Liraglutide dose 0.6 escalated to 1.2 mg based on patient tolerance. Glycemic, metabolic and anthropometric parameters were measured every 3 months Results: Mean age and T2D duration were 51.5±12.9 and 11.6±1.6 years, respectively. Body weight significantly reduced from 98.7kg to 96.0kg, p< 0.001, with a mean difference of 3.39kg ± 5.6kg. Systolic blood pressure reduced from 131.7mmHg to 126.6mmHg (Diff. 6.1mmHg), p = 0.015 while Diastolic blood pressure reduced from 73.3mmHg to 68.6mmHg (Diff. 4.7mmHg), p = 0.026. Most HbA1c reduction observed in the liraglutide 1.2 mg dose group with changes from 9.8% to 8.2% (Diff. 1.6%); and also the most weight reduction observed in the 1.2 mg liraglutide dose group with changes from 103.3kg to 99.7kg (Diff. 3.6kg) compared to 0.6 and 1.8 mg dose groups. HbA1c reduction was largest in MDIs group from 10.2 to 8.6% (Diff. 1.6%). Meanwhile, the most weight reduction noticed in the treatment group on SU and Basal insulin from 97.2kg to 92.8kg (Diff. 4.4kg). Interestingly, patients with CVD had improved HbA1c with changes from 10.62% to 9.77% (Diff. 0.85%) and weight from 86.96kg to 85.72kg (Diff. 1.24kg) without evident hypoglycemia. Conclusions: Addition of liraglutide to different T2D therapeutic regimen in obese Insulin- resistant patients showed significant improvement in HbA1c, weight, and Blood pressure. These results support the use in primary care clinics. Disclosure T. Alharbi: None. A. Tourkmani: None. S. Altwaijri: None. M. Kofi: None.

Complex Assessment of Metabolic Effectiveness of Insulin Pump Therapy in Patients with Type 2 Diabetes Beyond HbA1c Reduction.

Background: This prospective single-center study recruited insulin-resistant continuous subcutaneous insulin infusion (CSII) therapy-naive patients with type 2 diabetes (T2D) using insulin analog-based multiple daily injections (MDI) therapy and metformin.Methods: A total of 23 individuals with T2D (70% male), aged a mean ± standard deviation 57.2 ± 8.03 years, with body mass index of 36.2 ± 7.02 kg/m2, diabetes duration of 13.3 ± 4.64 years, and HbA1c of 10.0% ± 1.05% were randomly assigned to a CSII arm or an MDI continuation arm to explore glucose control, weight loss, total daily insulin dose (TDD), and insulin resistance. Insulin dosing was optimized over a 2-month run-in period.Results: At 6 months, patients assigned to the CSII arm achieved a significant mean HbA1c reduction of −0.9% (95% confidence interval [CI] = −1.6, −0.1), while reducing their TDD by −29.8 ± 28.41 U/day (33% of baseline [92.1 ± 20.35 U/day]) and achieving body mass (BM) reduction of −0.8 ± 5.61 kg (0.98% of baseline [104.8 ± 16.15 kg]). MDI patients demonstrated a nonsignificant HbA1c reduction of −0.3% (95% CI = −0.8, 0.1) with a TDD reduction of 5% from baseline (99.0 ± 25.25 U/day to 94.3 ± 21.25 U/day), and a BM reduction of −1.0 ± 2.03 kg (0.99% of baseline [108.9 ± 20.55 kg]). After 6 months, the MDI arm crossed over to CSII therapy. At 12 months, patients continuing CSII demonstrated an additional mean 0.7% HbA1c reduction with 54.6% achieving HbA1c<8%. The final TDD reduction was −9.7 U/day in comparison to baseline; BM increased by 1.1 ± 6.5 kg from baseline. The MDI patients that crossed to CSII showed an HbA1c reduction of −0.5% ± 1.04%, HbA1c response rate of 27.3%, a TDD reduction of −17.4 ± 21.06 U/day, and a BM reduction of −0.3 ± 3.39 kg. Diabetic ketoacidosis or severe hypoglycemia did not occur in either arm.Conclusion: CSII therapy safely and significantly improved metabolic control with less insulin usage, with no sustainable reduction of BM, blood pressure, and lipid profile, in insulin-resistant T2D patients. Treatment adherence and satisfaction in these patients were excellent.

Waist Circumference Independently Associates with the Risk of Insulin Resistance and Type 2 Diabetes in Mexican American Families

ObjectiveIn spite of the growing recognition of the specific association of waist circumference (WC) with type 2 diabetes (T2D) and insulin resistance (IR), current guidelines still use body mass index (BMI) as a tool of choice. Our objective was to determine whether WC is a better T2D predictor than BMI in family-based settings.Research Design and MethodsUsing prospectively collected data on 808 individuals from 42 extended Mexican American families representing 7617.92 person-years follow-up, we examined the performance of WC and BMI as predictors of cumulative and incident risk of T2D. We used robust statistical methods that accounted for the kinships and included polygenic models, discrete trait modeling, Akaike information criterion, odds ratio (OR), relative risk (RR) and Kullback-Leibler R2. SOLAR software was used to conduct all the data analyses.ResultsWe found that in multivariate polygenic models, WC was an independent predictor of cumulative (OR = 2.76, p = 0.0002) and future risk of T2D (RR = 2.15, p = 3.56×10−9) and outperformed BMI when compared in a head-to-head fashion. High WC (≥94.65 cm after adjusting for age and sex) was also associated with high fasting glucose, insulin and triglyceride levels and low high-density lipoprotein levels indicating a potential association with IR. Moreover, WC was specifically and significantly associated with insulin resistant T2D (OR = 4.83, p = 1.01×10−13).ConclusionsOur results demonstrate the value of using WC as a screening tool of choice for future risk of T2D in Mexican American families. Also, WC is specifically associated with insulin resistant T2D.

Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes

In type 2 diabetes (T2D), postprandial and fasting hyperglycemia are important predictors of cardiovascular diseases; however, few drugs are currently available to simultaneously suppress these conditions. Here, we report an enduring antidiabetic effect of the heme oxygenase (HO) inducer hemin on Goto-Kakizaki rats (GK), a nonobese insulin-resistant T2D model. HO breaks down the heme-moiety-generating antioxidants (biliverdin/bilirubin and ferritin) and carbon monoxide, which stimulate insulin secretion. Hemin induces HO-1 to potentiate HO activity and the HO-derived products. Chronically applied hemin (30 mg/kg ip) for a month reduced and maintained fasting glucose at physiological levels for 3 mo. Before therapy, glucose levels were 9.3 +/- 0.3 mmol/l (n = 14). At 1, 2, and 3 mo posttherapy, we recorded 6.7 +/- 0.13, 5.9 +/- 0.2, and 7.2 +/- 0.2 mmol/l, respectively. Hemin was also effective against postprandial hyperglycemia (14.6 +/- 1.1 vs. 7.5 +/- 0.4 mmol/l; n = 14; P < 0.01), and the effect remained sustained for 3 mo after therapy. The reduction of hyperglycemia was accompanied by enhanced HO-1, HO activity, and cGMP of the soleus muscle, alongside increased plasma bilirubin, ferritin, SOD, total antioxidant capacity, and insulin levels, whereas markers/mediators of oxidative stress like urinary-8-isoprostane and soleus muscle nitrotyrosine, NF-kappaB, and activator protein-1 and -2 were abated. Furthermore, inhibitors of insulin signaling including soleus muscle glycogen synthase kinase-3 and JNK were reduced, while the insulin-sensitizing adipokine, adiponectin, alongside AMPK were increased. Correspondingly, hemin improved glucose tolerance, suppressed insulin intolerance, reduced insulin resistance, and overturned the inability of insulin to enhance glucose transporter 4, a protein required for glucose uptake. Hemin also upregulated HO-1/HO activity and cGMP and lowered glucose in euglycemic Sprague-Dawley control rats albeit less intensely, suggesting greater selectivity of the HO system in diabetic conditions. In conclusion, reduced oxidative stress alongside the concomitant and paradoxical enhancement of insulin secretion and insulin-sensitizing pathways may account for the 3-mo-enduring antidiabetic effect. The synergistic interaction among HO, adiponectin, and GLUT4 may be explored against insulin-resistant diabetes.

The Heme Oxygenase System Abates Hyperglycemia in Zucker Diabetic Fatty Rats by Potentiating Insulin-Sensitizing Pathways

Emerging evidence indicates that aldosterone causes oxidative stress by stimulating proinflammatory/oxidative mediators, including nuclear factor-kappaB, activating protein (AP-1), and c-Jun N-terminal kinase. Thus, in insulin-resistant type 2 diabetes (T2D), oxidative stress generated by hyperglycemia and aldosterone would potentiate the oxidative destruction of tissue and important regulators of glucose metabolism like adiponectin and insulin. Although heme oxygenase (HO)-1 is cytoprotective, its effects on T2D have not been fully characterized. Here we report an enduring antidiabetic effect of the HO inducer, hemin, on Zucker diabetic-fatty rat (ZDF), a model of insulin-resistant T2D. Chronically applied hemin to ZDF reduced and maintained significantly low fasting and postprandial hyperglycemia for 4 months after therapy. The antidiabetic effect was accompanied by enhanced HO activity, catalase, cyclic GMP, bilirubin, ferritin, total antioxidant capacity, and insulin. In contrast, reduced aldosterone alongside markers/mediators of oxidative stress, including 8-isoprostane, c-Jun N-terminal kinase, nuclear factor-kappaB, AP-1, and AP-2 were observed. Interestingly, in hemin-treated ZDF, inhibitory proteins of insulin-signaling, such as glycogen synthase kinase-3 and protein-tyrosine phosphatase-1B were reduced, whereas agents that promote insulin signaling including adiponectin, cAMP, AMP-activated protein kinase, aldolase-B, and glucose transporter-4 (GLUT4), were robustly increased. Correspondingly, hemin improved ip glucose tolerance, reduced insulin intolerance, and lowered insulin resistance (homeostasis model assessment of insulin resistance), and the inability of insulin to enhance GLUT4 was overturned. These results suggest that the suppression of hyperglycemia and aldosterone-induced oxidative stress alongside the potentiation of insulin-sensitizing pathways may account for the 4-month enduring antidiabetic effect. The synergistic interaction between the HO system, aldolase-B, adiponectin, AMP-activated protein kinase, and GLUT4 may be explored for novel strategies against postprandial/fasting hyperglycemia and insulin-resistant T2D.