Glucose Homeostasis In Patients Research Articles

Clinical investigation of glucokinase activators for the restoration of glucose homeostasis in diabetes.

As a sensor, glucokinase (GK) controls glucose homeostasis, which progressively declines in patients with diabetes. GK maintains the equilibrium of glucose levels and regulates the homeostatic system set points. Endocrine and hepatic cells can both respond to glucose cooperatively when GK is activated. GK has been under study as a therapeutic target for decades due to the possibility that cellular GK expression and function can be recovered, hence restoring glucose homeostasis in patients with type 2 diabetes. Five therapeutic compounds targeting GK are being investigated globally at the moment. They all have distinctive molecular structures and have been clinically shown to have strong antihyperglycemia effects. The mechanics, classification, and clinical development of GK activators are illustrated in this review. With the recent approval and marketing of the first GK activator (GKA), dorzagliatin, GKA's critical role in treating glucose homeostasis disorder and its long-term benefits in diabetes will eventually become clear.

A Non-Toxic Binuclear Vanadium(IV) Complex as Insulin Adjuvant Improves the Glycemic Control in Streptozotocin-Induced Diabetic Rats.

Diabetes mellitus (DM) complications are a burden to health care systems due to the associated consequences of poor glycemic control and the side effects of insulin therapy. Recently. adjuvant therapies, such as vanadium compounds, have gained attention due to their potential to improve glucose homeostasis in patients with diabetes. In order to determine the anti-diabetic and antioxidant effects of the oxidovanadium(IV) complex (Et3NH)2[{VO(OH}2)(ox)2(µ-ox)] or Vox2), rats with streptozotocin (STZ)-induced diabetes were treated with 30 and 100 mg/kg of Vox2, orally administered for 12 days. Vox2 at 100 mg/kg in association with insulin caused a 3.4 times decrease in blood glucose in STZ rats (424 mg/dL), reaching concentrations similar to those in the normoglycemic animals (126 mg/dL). Compared to insulin alone, the association with Vox2 caused an additional decrease in blood glucose of 39% and 65% at 30 and 100 mg/kg, respectively, and an increased pancreatic GSH levels 2.5 times. Vox2 alone did not cause gastrointestinal discomfort, diarrhea, and hepatic or renal toxicity and was not associated with changes in blood glucose level, lipid profile, or kidney or liver function. Our results highlight the potential of Vox2 in association with insulin in treating diabetes.

Population Study Insights Linked to Genetic Variants (rs16890979 and rs206833) and Type 2 Diabetes Control in Northern Jordan

Abstract Background: The relationships between uric acid levels, specific single nucleotide polymorphisms (SNPs) in genes linked to uric acid metabolism [xanthine dehydrogenase (XDH) and Solute carrier family 2 member 9 (SLC2A9) genes], and control of HbA1c levels in type 2 diabetes mellitus (T2DM) within the Jordanian population were determined. Methods: A total of 184 T2DM patients who received care in the Endocrine Clinic at KAUH in Northern Jordan were enrolled in this study. These patients were classified into controlled and uncontrolled T2DM groups based on the HbA1c test results. Genotyping of two SNPs from the SLC2A9 gene and one SNP related to the XDH gene was performed using the tetra ARMS PCR method. Uric acid concentrations were measured using enzymatic colorimetric reagents. Results: The study revealed no significant correlation between uric acid levels and T2DM control. However, statistically significant correlations (P<0.05) were detected between the AA genotype at the rs206833 variant related to the XDH gene and reduced control over T2DM, as well as the CT genotype at the rs16890979 variant in the SLC2A9 gene. Notably, the rs206833 variant had an association between allele frequency level with T2DM regulation. Conclusion: Genetic variants (rs16890979 and rs206833) may influence T2DM control and could be associated with an elevated risk of impaired glucose homeostasis in patients with diabetes.

Impacts of the development of acute-on-chronic liver failure and bacterial infections on β-cell function and glucose homeostasis in patients with liver cirrhosis

BackgroundThe pathogenesis involved in glucose metabolism disorders (GMDs) in patients with liver cirrhosis remains unclear. AimsWe investigated the effects of acute-on-chronic liver failure (ACLF) development and bacterial infections (BIs) on pancreatic β-cell function and glucose homeostasis in individuals with liver cirrhosis. MethodsA retrospective analysis was conducted on 327 patients experiencing acute deterioration of liver cirrhosis. Oral glucose tolerance tests (OGTTs) and OGTT-based β-cell function indices were employed to assess β-cell function and glucose homeostasis. Univariate and multivariate logistic regression analyses were employed to identify GMD-associated risk factors. ResultsBoth the development of ACLF and BIs significantly increased the prevalence of GMDs. Both ACLF and BIs markedly elevated the homeostasis model of assessment 2-insulin resistance (HOMA2-IR). ACLF significantly impaired glucose-stimulated insulin secretion, as evidenced by reduced insulinogenic index (IGI). Patients with GMDs exhibited significantly lower IGI levels than those without GMDs. Independent risk factors associated with GMDs were prothrombin activity (odds ratio [OR]=0.981, 95% confidence interval [CI]: 0.960–0.995), HOMA2-IR (OR=1.749, 95% CI: 1.130–2.707), and IGI (OR=0.963, 95% CI: 0.947–0.978). ConclusionsIn liver cirrhosis, the onset of ACLF impairs glucose-stimulated insulin secretion from β-cells. Both liver impairment and BIs contribute to increased insulin resistance, ultimately disturbing glucose homeostasis.

Association between xanthinoxidase activity andparameters of glucose homeostasis in patients with type 2 diabetes mellitus

Background. The purpose of the study is to determine the associations between clinical and anthropometric parameters, glucose homeostasis and serum xanthinoxidase (XO) activity in patients with type 2 diabetes mellitus (T2DM) taking into account gender, glycemic control and serum XO activity. Materials and methods. One hundred and twenty-five T2DM patients aged 34 to 81 years were examined, with an average age of 58.9±9.4 years, disease duration from 1 month to 29 years (average of 8.9±6.6 years). The age of patients at the time of the disease manifestation in the general sample was from 29 to 71 years, on average 50.6±9.1 years. Results. The authors have found a nonlinear dependence of serum XO activity on fasting insulin concentration in patients with T2DM in the total sample, described by the multiplicative model (r=0.45; p=0.001). Serum XO activity in patients with T2DM in the general sample increases with adaptive increase in secretory activity of β-cells on an empty stomach according to the HOMA_β%. Serum ХO activity was highest in T2DM patients with low fasting insulin sensitivity (HOMA_S% < 50%). In addition, it has been determined that the serum ХО activity in the subjects is nonlinearly associated with the QUICKI (r=–0.35; p=0.016) and Caro indices (r=–0.40; p=0.007). We have found a nonlinear dependence of serum XO activity on fasting insulin (r=0.50; p=0.08), HOMA_β% (r=–0.53; p=0.06), HOMA_S% (r=–0.48; p=0.09), HOMA-IR (r=–0.48; p=0.09) in men with optimal glycemic control (HbA1c < 7.5%) at the trend level and Caro (r=–0.64; p=0.02). In women of this group, there was a nonlinear dependence of serum XO activity on fasting insulin (r=0.56; p=0.004), HOMA_β% (r=0.56; p=0.003), HOMA_S% (r=–0.54; p=0.005), HOMA-IR (r=0.54; p=0.005), QUICKI (r=–0.50; p=0.01) and Caro (r=–0.61; p=0.003). Conclusions. In patients with T2DM, the serum uric acid is linearly associated with the level of serum XO activity, which determines 34% of its variability. In patients with T2DM, regardless of the state of glycemic control, serum XO activity is nonlinearly associated with parameters characterizing the state of glucose homeostasis (fasting insulin, HOMA_S%, HOMA_β%, QUICKI and Caro indices). Predictors of high serum XO activity in patients with T2DM are the level of postprandial blood glucose (t=–3.53; p=0.004) and serum uric acid (t=4.73; p=0.0005).

Central GLP-1 Resistance Induced by Severe Traumatic Brain Injury Was Associated with Persistent Hyperglycemia in Humans

Introduction: Whether central glucagon-like peptide 1 (GLP-1)/GLP-1 receptor system mediated peripheral glucose homeostasis in patients with traumatic brain injury (TBI) is not clear. We aim to determine if plasma GLP-1 level could distinguish the non-survivors from the survivors during the first 14 days after TBI that could prognose 6 months mortality. Methods: Metabolic, inflammatory, and hematologic profiles were examined in 73 patients with TBI in neurological intensive care unit. Factors that discriminate non-survivors from survivors were determined by two-way ANOVA. Biomarkers associated with mortality were determined by binary logistic regression and Cox proportional hazard regression. Results: The non-survivors had higher infectious SOFA scores (p < 0.001), lower first 3 days’ body temperature (p = 0.017), greater chance of cerebral hernia (p = 0.048), and decompressive craniectomy (p = 0.001) than the survivors. Higher 14-day plasma GLP-1 (p < 0.0001), glucose (p = 0.002), and IL-6 (p = 0.005) levels, in contrast with lower insulin level at days 4–7 (p = 0.020) were found in non-survivors than in survivors. Except the survivors who had an increased 14-day platelet number (p < 0.001), the two groups did not differ in hematological profile and intestinal barrier function. Although GLP-1 correlated closely with IL-6 in both the groups, it correlated with neither insulin nor glucose in each group. GLP-1 on days 8–10 and IL-6 on days 1–3 were positively, while insulin on days 4–7 was negatively associated with mortality. Conclusion: Persistent higher GLP-1 level in non-survivors over the survivors may present more severe central resistance to endogenous GLP-1 in non-survivors, which may be associated with progressive hyperglycemia with increased mortality in TBI.

Activation of PDGF Signaling in the Adult Muscle Stem Cell Niche in Patients With Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2D) negatively affects muscle mass and function throughout life. Whether adult muscle stem cells contribute to the decrease in muscle health is not clear and insights into the stem cell niche are difficult to obtain. To establish the upstream signaling pathway of microRNA (miR)-501, a marker of activated myogenic progenitor cells, and interrogate this pathway in muscle biopsies from patients with T2D. Analysis of primary muscle cell cultures from mice and 4 normoglycemic humans and muscle biopsies from 7 patients with T2D and 7 normoglycemic controls using gene expression, information on histone methylation, peptide screening, and promoter assays. miR-501 shares the promoter of its host gene, isoform 2 of chloride voltage-gated channel 5 (CLCN5-2), and miR-501 expression increases during muscle cell differentiation. We identify platelet-derived growth factor (PDGF) as an upstream regulator of CLCN5-2 and miR-501 via Janus kinase/signal transducer and activator of transcription. Skeletal muscle biopsies from patients with T2D revealed upregulation of PDGF (1.62-fold, P = .002), CLCN5-2 (2.85-fold, P = .03), and miR-501 (1.73-fold, P = .02) compared with normoglycemic controls. In addition, we observed a positive correlation of PDGF and miR-501 in human skeletal muscle (r = 0.542, P = .045, n = 14). We conclude that paracrine signaling in the adult muscle stem cells niche is activated in T2D. Expression analysis of the PDGF-miR-501 signaling pathway could represent a powerful tool to classify patients in clinical trials that aim to improve muscle health and glucose homeostasis in patients with diabetes.

The Effect of Prebiotics and Oral Anti-Diabetic Agents on Gut Microbiome in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials.

Nutritional interventions such as the use of prebiotics can promote eubiosis of gut microbiome and maintain glucose homeostasis in patients with type 2 diabetes (T2D). However, it would appear that results of the effects of prebiotics on the community of microbes in the gut are not consistent. To examine the effect of prebiotics and oral antidiabetic agents on gut microbiome in patients with T2D. The PRISMA Extension Statement for Systematic Reviews and Network Meta-analyses was used to conduct this review. Searches were carried out in EMBASE, EBSCO-host databases, Google Scholar and the reference lists of articles for studies that are relevant to the research question, from database inception to 15 August 2022. The search strategy was based on PICOS framework. Network Meta-analysis which allows the estimation of relative treatment effects by combing both direct trial evidence (e.g., treatment A vs. treatment B) and indirect evidence was conducted. Furthermore, pairwise meta-analysis was also carried out to estimate effect sizes based on head-to-head comparisons of treatments and/or control conditions. Findings of the Network meta-analysis revealed that prebiotics significantly reduced HbA1c compared with control and the SMD was -0.43 [95% CI, -0.77, -0.08; p = 0.02], whereas there was no significant difference (p &gt; 0.05) between the other treatments and control. In addition, anti-diabetic agents including glipizide and metformin also reduced HbA1C, although these were not significantly different (p &gt; 0.05) from control. While prebiotics promoted Bifidobacterium and Akkermansia, the improvements were not significantly different (p &gt; 0.05) from control. On the other hand, metformin decreased the relative abundance of Bifidobacterium, but increased Lactobacillus and Akkermansia, although the differences were not significant (p &gt; 0.05) compared with control. With respect to fasting blood glucose and BMI, the effects of prebiotics and oral antidiabetic agents did not differ significantly (p &gt; 0.05) from controls. The findings of the systematic review and Network meta-analysis demonstrated prebiotics were significantly (p &lt; 0.05) more effective in reducing HbA1c than control in patients with T2D. However, the effects of prebiotics and oral antidiabetic agents did not differ significantly (p &gt; 0.05) from the controls in relation to fasting blood glucose, post-prandial blood glucose, body mass index and the genera of gut bacteria examined. More studies are required to fully investigate the effects of prebiotics and oral antidiabetic agents in patients with T2D.

Probiotics supplementation for management of type II diabetes risk factors in adults with polycystic ovarian syndrome: a meta-analysis of randomized clinical trial

This meta-analysis of randomized controlled trials aimed to evaluate the effects of probiotic supplementation on glucose homeostasis in patients with polycystic ovary syndrome (PCOS). The meta-analysis was performed in accordance with the Cochrane Handbook guidelines and relevant the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria. Of 825 identified reports, 11 randomized clinical trials were included in the meta-analysis. An analysis of pooled extracted data revealed that supplementation with probiotics significantly decreased fasting blood glucose (FBG, n = 7; standardized mean difference (SMD) = −0.40; 95 % confidence interval (CI): −2.02, −0.02; P = 0.04) and insulin levels (n = 6; SMD = −0.57; 95 % CI: −0.89, −0.25; P = 0.0004) and the homeostatic model assessment of insulin resistance (n = 7; SMD = −0.64; 95 % CI: −0.96, −0.31; P = 0.0001) while increasing the quantitative insulin sensitivity check index (QUICKI, n = 5; SMD = 0.58; 95 % CI: 0.08, 1.09; P = 0.02) in patients with PCOS. The FBG-reducing effect decreased as the baseline body mass index (BMI) and mean age of the participants increased. Indeed, a greater number of bacterial species and a higher bacterial dose were shown to reduce QUICKI effectively. The systematic review indicated that probiotic supplementation may help to control glucose homeostasis in adults with polycystic ovarian syndrome.

Pancreas Transplantation: Current Challenges, Considerations, and Controversies.

Pancreas transplantation (PTx) reestablishes an autoregulating source of endogenous insulin responsive to normal feedback controls. In addition to achieving complete β-cell replacement that frees the patient with diabetes from the need to monitor serum glucose and administer exogenous insulin, successful PTx provides counterregulatory hormone secretion and exocrine function. A functioning PTx mitigates glycemic variability, eliminates the daily stigma and burden of diabetes, restores normal glucose homeostasis in patients with complicated diabetes, and improves quality of life and life expectancy. The tradeoff is that it entails a major surgical procedure and requisite long-term immunosuppression. Despite the high likelihood of rendering patients euglycemic independent of exogenous insulin, PTx is considered a treatment rather than a cure. In spite of steadily improving outcomes in each successive era coupled with expansion of recipient selection criteria to include patients with a type 2 diabetes phenotype, a decline in PTx activity has occurred in the new millennium related to a number of factors including: (1) lack of a primary referral source and general acceptance by the diabetes care community; (2) absence of consensus criteria; and (3) access, education, and resource issues within the transplant community. In the author's experience, patients who present as potential candidates for PTx have felt as though they needed to circumvent the conventional diabetes care model to gain access to transplant options. PTx should be featured more prominently in the management algorithms for patients with insulin requiring diabetes who are failing exogenous insulin therapy or experiencing progressive diabetic complications regardless of diabetes type. Furthermore, all patients with diabetes and chronic kidney disease should undergo consideration for simultaneous pancreas-kidney transplantation independent of geography or location.

Metabolic properties of irisin in health and in diabetes mellitus

Irisin is a polypeptide hormone of muscle tissue (myokine), the synthesis and secretion of which increase against the background of physical exertion, which plays a significant role in the metabolism of fat, muscle and bone tissues. It is known that irisin promotes the transformation of white adipose tissue into brown adipose tissue. It has also been experimentally proven that the introduction of irisin contributed to an increase in bone mass and the prevention of osteoporosis and muscular atrophy. There are works indicating a positive effect of irisin in the functioning of bone, fat and muscle tissues in humans. Diabetes mellitus (DM) is an independent risk factor for osteoporotic fractures and the development of specific diabetic myopathy, at the cellular level similar to the aging of muscle tissue, and type 2 diabetes is also associated with the presence of obesity. Thus, it is of particular interest to study the effect of irisin on the state of bone, muscle and adipose tissues and glucose homeostasis in patients with diabetes. This literature review highlights the biological functions of irisin in healthy people and patients with DM.

Novel leukocyte and thrombocyte indexes in patients with prediabetes and type 2 diabetes mellitus.

To our knowledge, there are no studies that investigated the relationship between diabetes mellitus type 2 (T2D) and some novel indexes, such as monocyte/granulocyte to lymphocyte ratio (M/GLR), derived neutrophil to lymphocyte ratio (dNLR), and platelets to neutrophil ratio (PNR). The aim of this study was to examine the association between these novel indexes and glycated hemoglobin (HbA1c) in patients with prediabetes and T2D. A total of 827 participants were consecutively recruited. According to the American Diabetes Association (ADA) criteria, participants were divided into control, prediabetes, and T2D group. White blood cell count (WBC), neutrophil count, NLR, dNLR, and M/GLR were higher in T2D patients than in the other two groups, whereas PNR was the lowest in T2D group. Lymphocyte count was higher in prediabetes and T2D patients than in control group. Multivariable ordinal regression analysis showed that WBC, neutrophil count, lymphocyte count, NLR, dNLR, and M/GLR were positively associated [OR (95% CI) 1.287 (1.191-1.390), p<0.001; 1.427 (1.275-1.594), p<0.001; 1.347 (1.130- 1.606), p=0.001; 1.350 (1.090-1.670), p=0.006; 1.662 (1.189-2.326), p=0.003; 1.275 (1.057-1.540), p=0.012, respectively] with HbA1c. However, PNR was negatively associated with HbA1c [0.987 (0.981-0.993), p<0.001]. Novel, modified NLR indexes, such as dNLR and M/GLR were independently correlated with HbA1c. Also, PNR showed superiority over platelets (PLT) in relation to HbA1c. These novel indexes might give a significant contribution to the timely recognition of disturbances of glucose homeostasis in patients with prediabetes and overt diabetes.

Effect of Camel Milk on Glucose Homeostasis in Patients with Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The effects of camel milk (CM) intake on glycemic control in patients with diabetes are controversial. This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to summarize the effect of CM intake on glucose homeostasis parameters in patients with both types of diabetes mellitus; T1DM and T2DM. We searched Google Scholar, PubMed/MEDLINE, EBSCO host, CINAHL, ScienceDirect, Cochrane, ProQuest Medical, Web of Science, and Scopus databases from inception until the end of November 2021. Relevant RCTs were identified, and the effect size was reported as mean difference (MD) and standard deviation (SD). Parameters of glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), postprandial blood glucose (PBG), fasting serum insulin (FI), insulin resistance (expressed in terms of HOMA-IR), insulin dose (ID) received, serum insulin antibody (IA), and C-peptide (CP) were tested. Out of 4054 collected articles, 14 RCTs (total 663 subjects) were eligible for inclusion. The pooled results obtained using a random-effects model showed a statistically significant decrease in HbA1c levels (MD, −1.24, 95% confidence interval (CI): −2.00, −0.48, p < 0.001 heterogeneity (I2) = 94%) and ID received (MD, −16.72, 95% CI: −22.09, −11.35 p < 0.00001, I2 = 90%), with a clear tendency was shown, but non-significant, to decrease FBG (MD, −23.32, 95% CI: −47.33, 0.70, p = 0.06, I2 = 98%) in patients with diabetes who consumed CM in comparison to those on usual care. Conversely, the consumption of CM did not show significant reductions in the rest of the glucose homeostasis parameters. Subgroup analysis revealed that patients with T2DM were more beneficially affected by CM intake than those with T1DM in lowering FBG, while patients with T1DM were more beneficially affected by CM intake than those with T2DM in lowering HbA1c. Both fresh and treated (pasteurized/fermented) CM gave similar beneficial effects in lowering HbA1c. Lastly, a relatively superior effect for longer duration on shorter duration (>6 months, ≤6 months, respectively) of CM intake is found in lowering HbA1c. To conclude, long-term consumption of CM by patients with diabetes could be a useful adjuvant therapy alongside classical medications, especially in lowering the required insulin dose and HbA1c. Due to the high heterogeneity observed in the included studies, more controlled trials with a larger sample size are warranted to confirm our results and to control some confounders and interfering factors existing in the analyzed articles.

Abstract P4-02-01: Targeting insulin receptor in estrogen receptor positive breast cancer

Abstract Obesity and metabolic dysfunction are on the rise in the United States. Hyperinsulinemia, frequently seen in these conditions, correlates with an increased risk of development and mortality from estrogen receptor (ER) positive breast cancer. Expression of components of the insulin and insulin-like growth factor (IGF) family of proteins promote cancer cell growth in vitro, link to shorter progression-free survival, and is associates with an increased risk of metastatic disease and death in breast cancer patients. Previously our lab found that development of resistance to the commonly used ER-targeting drug tamoxifen (Tam) in vitro is associated with a loss of the type I IGF receptor expression with an increased dependence on the homologous insulin receptor (IR). These data argue for targeting IR in breast cancer, but concern has been raised due to the potential of disrupting glucose homeostasis in patients with or without existing metabolic disease. To address this concern, a novel insulin-Fc fusion protein (AKS-130) was developed to lower blood glucose levels without causing clinical hypoglycemia with a potential to target tumor IR. AKS-130 was found to downregulate IR expression in models of colorectal cancer (HCT-116) and malignant melanoma (WM266.4). Further, AKS-130 suppressed xenograft growth in fed and fasted states. We examined if AKS-130 had similar effects on ER positive breast cancer cells. To test the hypothesis that resistance to endocrine therapy increases the reliance of ER positive breast cancer cells on IR signaling, we utilized the ER positive breast cancer cell lines (MCF-7L, T47D) and their Tam resistant derivatives (MCF-7L TamR, T47D TamR). Similar to in HCT-116 and WM266.4 cells, we found that AKS-130 is a modest agonist of IR in ER+ breast cancer cells. Exposure to AKS-130 led to a marked reduction in IR expression in both parental and TamR cell lines, and was associated with partially suppressed downstream signaling to Akt. Interestingly, AKS130 induced IR downregulation was inhibited by pretreatment of BMS 536924, a dual IGF1R/IR kinase inhibitor. In vivo, AKS-130 treatment by itself scaled down MCF7L parental xenograft growth as compared to vehicle group, and AKS-130 in combination with Tam trended toward extending time to a tumor size of 500mm3. In MCF7L TamR xenografts, addition of AKS-130 to Tam treatment also trended toward delaying xenograft growth, though it was not statistically significant. Importantly, prolonged treatment with AKS-130 did not lead to significant changes in weight or blood glucose. Taken together these data show that novel agents, such as AKS-130, may serve as way to disrupt IR signaling in cancer cells without affecting host glucose metabolism. Addition of AKS-130 to Tam treatment trended toward delaying xenograft growth though further studies are needed, especially animal model systems of insulin resistance. These data indicate that IR signaling may represent a target to overcome or delay endocrine therapy resistance in breast cancer. Citation Format: Jingran Cao, Lynsey M. Fettig, Kelly LaPara, Xihong Zhang, Sylaja Murikipudi, Andrea R. Delpero, Thomas M. Lancaster, Todd C. Zion, Douglas Yee. Targeting insulin receptor in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-01.

The Impact of Pancreatic Head Resection on Blood Glucose Homeostasis in Patients with Chronic Pancreatitis.

Background: Chronic pancreatitis (CP) often leads to recurrent pain as well as exocrine and/or endocrine pancreatic insufficiency. This study aimed to investigate the effect of pancreatic head resections on glucose metabolism in patients with CP. Methods: Patients who underwent pylorus-preserving pancreaticoduodenectomy (PPPD), Whipple procedure (cPD), or duodenum-preserving pancreatic head resection (DPPHR) for CP between January 2011 and December 2020 were retrospectively analyzed with regard to markers of pancreatic endocrine function including steady-state beta cell function (%B), insulin resistance (IR), and insulin sensitivity (%S) according to the updated Homeostasis Model Assessment (HOMA2). Results: Out of 141 pancreatic resections for CP, 43 cases including 31 PPPD, 2 cPD and 10 DPPHR, met the inclusion criteria. Preoperatively, six patients (14%) were normoglycemic (NG), 10 patients (23.2%) had impaired glucose tolerance (IGT) and 27 patients (62.8%) had diabetes mellitus (DM). In each subgroup, no significant changes were observed for HOMA2-%B (NG: p = 0.57; IGT: p = 0.38; DM: p = 0.1), HOMA2-IR (NG: p = 0.41; IGT: p = 0.61; DM: p = 0.18) or HOMA2-%S (NG: p = 0.44; IGT: p = 0.52; DM: p = 0.51) 3 and 12 months after surgery, respectively. Conclusion: Pancreatic head resections for CP, including DPPHR and pancreatoduodenectomies, do not significantly affect glucose metabolism within a follow-up period of 12 months.

Increased Risk of Type 2 Diabetes in Patients With Thyroid Cancer After Thyroidectomy: A Nationwide Cohort Study.

Abnormal thyroid function after thyroidectomy and subsequent thyroid-stimulating hormone suppression can have detrimental effects on glucose homeostasis in patients with thyroid cancer. To investigate whether thyroidectomy increases the risk of type 2 diabetes in patients with thyroid cancer and to explore the association between levothyroxine dosage and type 2 diabetes risk. A retrospective population-based cohort study using the Korean National Health Insurance database. We included 36 377 thyroid cancer patients without known diabetes who underwent thyroidectomy between 2004 and 2013. Matched subjects with nonthyroid cancer were selected using 1:1 propensity score matching. The main outcome measure was newly developed type 2 diabetes mellitus. Patients with thyroid cancer who underwent thyroidectomy had a higher risk of developing type 2 diabetes mellitus than the matched controls (hazard ratio [HR] 1.43, 95% CI 1.39-1.47). Among patients with thyroid cancer, when the second quartile group (in terms of the mean levothyroxine dosage; 101-127 μg/day) was considered the reference group, the risk of type 2 diabetes mellitus increased in the first quartile (<101 μg/day; HR 1.45, 95% CI 1.36-1.54) and fourth quartile groups (≥150 μg/day; HR 1.37, 95% CI 1.29-1.45); meanwhile, the risk decreased in the third quartile group (128-149 μg/day; HR 0.91, 95% CI 0.85-0.97). Patients with thyroid cancer who underwent thyroidectomy were more likely to develop type 2 diabetes mellitus than the matched controls. There was a U-shaped dose-dependent relationship between the levothyroxine dosage and type 2 diabetes mellitus risk.

18: Effect of clinical initiation of elexacaftor/tezacaftor/ivacaftor on glucose homeostasis in patients with cystic fibrosis

18: Effect of clinical initiation of elexacaftor/tezacaftor/ivacaftor on glucose homeostasis in patients with cystic fibrosis

Effect of Collagen Hydrolysate and Fish Oil on High-Sensitivity C-Reactive Protein and Glucose Homeostasis in Patients with severe Burn; a Randomized Clinical Trial.

Introduction:Collagen and omega-3 fatty acids (FAs) are suggested to have anti-inflammatory, anti-oxidant, and insulin-sensitizing properties. The aim of this study was to investigate the effect of collagen hydrolysate and omega-3 FAs on inflammation and insulin resistance in patients with major burns.Methods:In this double-blind randomized clinical trial, 66 patients with 20-45% burns were assigned to either of the three groups of collagen (40 gr/d), collagen (40 gr/d) plus fish oil (10 ml/d), or control. High-sensitivity C-reactive protein (hs-CRP), fasting blood glucose (FBG) and insulin concentrations, and homeostatic model assessment for insulin resistance (HOMA-IR) were assessed at baseline, as well as end of weeks two and three.Results:Based on post-hoc analyses, hs-CRP levels were significantly lower in the collagen (p=0.026) and collagen+omega-3 (p=0.044) groups compared to the control group, at week three. However, pre- to post- (week three) changes of hs-CRP were significantly higher only in the collagen+omega-3 group compared to the control group (173.2 vs. 103.7 mg/l, p=0.024). After three weeks of the intervention, insulin (11.3 and 11.9 vs. 22.8 µIU/ml) and HOMA-IR (2.9 and 2.8 vs. 7.9) values seemed to be clinically, but not statistically, lower in both intervention groups compared to the control group. Pre- to post- (week three) values of FBG decreased significantly in the collagen (p=0.002) and collagen+omega-3 (p=0.036) groups. Insulin (p=0.008) and HOMA-IR (p=0.001) decreased significantly only in the collagen+omega-3 group at week three compared to the baseline. Conclusions:Supplementation with collagen hydrolysate and omega-3 FAs can improve hs-CRP concentration and probably insulin resistance in patients with severe burns. Omega-3 FAs had additional effects on modulating inflammation. Larger clinical trials are needed to confirm the current findings especially in terms of glucose homeostasis.

Obstructive sleep apnoea increases lipolysis and deteriorates glucose homeostasis in patients with type 2 diabetes mellitus

Obstructive sleep apnoea (OSA) is associated with type 2 diabetes mellitus (T2DM). However, mechanisms mediating association between these two conditions remain unclear. This study investigated, whether the OSA-associated changes in adipose tissue lipolysis might contribute to impaired glucose homeostasis in patient with T2DM. Thirty-five matched subjects were recruited into three groups: T2DM + severe OSA (T2DM + OSA, n = 11), T2DM with mild/no OSA (T2DM, n = 10) and healthy controls (n = 14). Subcutaneous abdominal adipose tissue microdialysis assessed spontaneous, epinephrine- and isoprenaline-stimulated lipolysis. Glucose metabolism was assessed by intravenous glucose tolerance test. Spontaneous lipolysis was higher in the T2DM + OSA compared with the T2DM (60.34 ± 23.40 vs. 42.53 ± 10.16 μmol/L, p = 0.013), as well as epinephrine-stimulated lipolysis (236.84 ± 103.90 vs. 167.39 ± 52.17 µmol/L, p < 0.001). Isoprenaline-stimulated lipolysis was unaffected by the presence of OSA (p = 0.750). The α2 anti-lipolytic effect was decreased in T2DM + OSA by 59% and 315% compared with T2DM and controls (p = 0.045 and p = 0.007, respectively). The severity of OSA (AHI) was positively associated with spontaneous (p = 0.037) and epinephrine-stimulated (p = 0.026) lipolysis. The α2-adrenergic anti-lipolytic effect (p = 0.043) decreased with increasing AHI. Spontaneous lipolysis was positively associated with Insulin resistance (r = 0.50, p = 0.002). Epinephrine-stimulated lipolysis was negatively associated with the Disposition index (r = − 0.34, p = 0.048). AHI was positively associated with Insulin resistance (p = 0.017) and negatively with the Disposition index (p = 0.038). Severe OSA in patients with T2DM increased adipose tissue lipolysis, probably due to inhibition of the α2-adrenergic anti-lipolytic effect. We suggest that dysregulated lipolysis might contribute to OSA-associated impairments in insulin secretion and sensitivity.

The Pancreatic changes affecting glucose homeostasis in transfusion dependent β- thalassemia (TDT): a short review.

Background: The natural history of the glycometabolic state in transfusion-dependent β-thalassemia (TDT) patients is characterized by a deterioration of glucose tolerance over time.Aims:This review depicts our current knowledges on the complex and multifacet pathophysiologic mechanisms implicated in the development of alteration of glucose homeostasis in patients with TDT.Search strategy:A systematic search was done on December 2020 including Web of Science (ISI), Scopus, PubMed, Embase, and Scholar for papers published in the last 20 years. Moreover, we checked the reference lists of the relevant articles and previously performed reviews for additional pertinent studies. The personal experience on the care of patients with thalassemias is also reported.Conclusion:A regular packed red blood cells (PRBCs) transfusion program, optimization of chelation therapy, and prevention and treatment of liver infections are critical to achieve adequate glucometabolic control in TDT patients. Many exciting opportunities remain for further research and therapeutic development. (www.actabiomedica.it)