Lower Insulin Levels Research Articles

The Effects of Curcumin Supplementation on Glycaemic Index in Women with Polycystic Ovarian Syndrome: An Evidence Based Case Report

Background: PCOS is the most common cause of infertility around the world. PCOS is associated with impaired glucose tolerance and higher tendency to develop type 2 diabetes. Curcumin, which is known for its anti-inflammatory, antioxidant, and antidiabetic properties, may show promising effect in regulating blood glucose.
 Objective: This study aims to evaluate the effect of curcumin supplementation on improving glycaemic profile in women with PCOS.
 Methods: Literature searching was conducted by advanced searching in Pubmed, Cochrane Library, Scopus, and ProQuest database using MeSH Terms combined with Title/Abstract. After removing duplicates, the literatures were screened based on the eligibility criteria. Critical appraisal and level of evidence of the selected literatures were determined based on Oxford Centre for Evidence-Based Medicine.
 Results: Two selected literatures were relevant to answer our clinical question. The first literature is a systematic review/meta-analysis study by Chien et al (2021) and the latter is a randomized controlled trial by Asan et al (2020). Both literatures show that curcumin supplementation is beneficial in improving glycaemic profile in PCOS patients. These effects were marked by lower fasting blood glucose, insulin level, and HOMA-IR in curcumin group compared to the control group.
 Conclusion: Curcumin supplementation for at least 6 weeks significantly improve glycaemic profile in women with PCOS. Curcumin supplementation is also considered safe and well tolerable. However, more studies are needed to investigate further regarding the long-term effects of curcumin supplementation.
 Keywords: curcumin, turmeric, polycystic ovarian syndrome, glycaemic profile

Serum miR-4488 as a potential biomarker of lean nonalcoholic fatty liver disease.

In lean individuals, nonalcoholic fatty liver disease (NAFLD) is not a benign disease, and these patients have long-term morbidity and mortality similar to those of their nonlean counterparts. Finding biomarkers for noninvasive and early detection is urgent and microRNAs (miRNAs) show potential. The aims of this study were to investigate the potential role of serum miRNAs in the detection of lean NAFLD and to explore the possible pathogenesis of lean NAFLD. A total of 498 patients with NAFLD and 98 healthy controls were included to compare the clinical characteristics of lean NAFLD patients [LNs: body mass index (BMI) <23 kg/m2], nonlean NAFLD patients (NLNs: BMI ≥23 kg/m2) and normal healthy individuals (HIs). A total of 14 serum samples were collected from 4 LNs, 6 NLNs and 4 HIs for high-throughput profiling to identify altered miRNA expression patterns in lean NAFLD. The candidate miRNA, miR-4488, was identified by filtering based on studies in a second independent cohort (31 LNs, 62 NLNs, 72 HIs) that included quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction network analyses were performed to investigate the potential molecular mechanism of miR-4488 in lean NAFLD. LNs were older and had a smaller waist circumference, lower levels of alanine aminotransferase, glutamyl transpeptidase, fasting insulin, and uric acid, lower HOMA-IR score, and higher levels of total cholesterol, high-density lipoprotein cholesterol, and hemoglobin (P<0.05). The serum level of miR-4488 was increased in LNs compared with HIs (P<0.0001) and NLNs (P=0.025). miR-4488 had acceptable performance in predicting [area under the curve (AUC) =0.794, 0.698] lean NAFLD. Moreover, GO and KEGG enrichment analyses revealed that the differentially expressed target genes were mainly involved in choline metabolism in cancer, the tumor-necrosis factor (TNF) signaling pathway and the p53 signaling pathway. PPI analysis identified ARHGAP1, SLC10A1 and SIX5 as the hub genes. Taken together, our findings indicate that serum miR-4488 is a potential biomarker for diagnosing and predicting the pathogenetic mechanisms of lean NAFLD.

Retrospective Analysis of Hospitalized Patients with Type 2 Diabetes Mellitus Treated with Glucagon-Like Peptide 1 Receptor Agonist Therapy.

The use and overall benefit of glucagon-like peptide-1 (GLP-1) receptor agonist therapy for hospitalized patients with type 2 diabetes mellitus (DM) with chronic kidney disease (CKD) has limited data regarding impact and safety. We studied the impact and safety of GLP-1 receptor agonist therapy in hospitalized DM patients with CKD. Retrospective study of 51 patients using either dulaglutide (n = 3) or liraglutide (n = 48). Glomerular filtration rate (GFR) groups of stages 3 to 5 and 1 and 2 were compared. The primary outcome was total amount of insulin within the last 24 hours in the hospital. The secondary outcomes were glucose management and safety. Mean insulin total amount within the last 24 hours in the hospital significantly differed (P = 0.01) between the GFR groups, with the GFR stages 3 to 5 group (mean 0.5, standard deviation 0.36) having a lower mean insulin level than the GFR stages 1 and 2 group (mean 0.8, standard deviation 0.45). Point-of-care glucose reached the target of 140 to 180 mg/dL within the last 24 hours in hospital, with increased odds for the GFR stages 3 to 5 group as compared with the GFR stages 1 and 2 group (odds ratio 4.08, 95% confidence interval 1.05-15.83, P = 0.04). For both GFR groups, there were minimal adverse events. Almost all of them continued GLP-1 receptor agonist therapy at discharge (94.1%). The use of GLP-1 receptor agonist therapy had better outcomes in patients with GFR stages 3 to 5 as compared with GFR stages 1 and 2. There were minimal adverse events reported for both GFR groups. This study suggests that the off-label use of GLP-1 receptor agonists for hospitalized DM patients with CKD may be useful.

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.

Observing the Use of Insulin Sensitizers for Ovulation Induction among PCOS Women

Introduction: In women of reproductive age, PCOS is a prevalent endocrine illness characterized by irregular menstrual cycles, many tiny ovarian cysts, and high levels of androgens. Insulin resistance is one of the leading causes of PCOS. Insulin sensitizers can help increase cells' sensitivity to insulin, allowing them to respond more effectively to insulin and transport glucose into the cells. Aim of the Study: The study's objective was to evaluate how PCOS women used insulin sensitizer as an ovulation inducer. Methods: This was a prospective, observational, cross-sectional research at the Manikganj 250 Bedded Sadar hospital, Dhaka, Bangladesh. The study duration was 1 year, from January 2022 to December 2022. During this period, 100 patients with PCOS were selected following the inclusion and exclusion criteria for their participation in this study. Result: The study population consisted of young individuals with a mean age of 24.91 years, a moderate-to-high body mass index of 26.79 kg/m2, a moderate waist-to-hip ratio of 0.82, high fasting insulin level of 21.00 µIU/mL, high insulin area under the curve (AUC) of 308.32, moderate luteinizing hormone (LH) level of 10.90 mIU/mL, moderate follicle-stimulating hormone (FSH) level of 5.43 mIU/mL, a high LH:FSH ratio of 2.02, and moderate free testosterone level of 2.72 pg/mL. After 4 months of treatment with metformin, 80% of the participants had ovulation induction, with 33% having at least one ovulation, 25% having 2 ovulations, and 6% having 4 ovulations. After continuous treatment with metformin for 16 weeks, the study population had a mean body mass index of 26.22 kg/m2, a moderate waist-to-hip ratio of 0.81, low fasting insulin level of 10.55 µIU/mL, low insulin area under the curve (AUC) of 183.00, low to moderate luteinizing hormone (LH) level of 5.32 mIU/mL, moderate follicle- stimulating hormone (FSH) level of 4.80 mIU/mL, a low LH:FSH ratio of 1.10, and low free testosterone level of 1.33 pg/mL. .....

Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease.

Several population studies have observed lower serum bilirubin levels in patients with non-alcoholic fatty liver disease (NAFLD). Yet, treatments to target this metabolic phenotype have not been explored. Therefore, we designed an N-Acetylgalactosamine (GalNAc) labeled RNAi to target the enzyme that clears bilirubin from the blood, the UGT1A1 glucuronyl enzyme (GNUR). In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks to induce NAFLD and were treated subcutaneously with GNUR or sham (CTRL) once weekly for six weeks while continuing the HFD. The results show that GNUR treatments significantly raised plasma bilirubin levels and reduced plasma levels of the bilirubin catabolized product, urobilin. We show that GNUR decreased liver fat content and ceramide production via lipidomics and lowered fasting blood glucose and insulin levels. We performed extensive kinase activity analyses using our PamGene PamStation kinome technology and found a reorganization of the kinase pathways and a significant decrease in inflammatory mediators with GNUR versus CTRL treatments. These results demonstrate that GNUR increases plasma bilirubin and reduces plasma urobilin, reducing NAFLD and inflammation and improving overall liver health. These data indicate that UGT1A1 antagonism might serve as a treatment for NAFLD and may improve obesity-associated comorbidities.

Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice

BackgroundDeoxyguanosine kinase (DGUOK) deficiency is one of the genetic causes of mitochondrial DNA depletion syndrome (MDDS) in humans, leading to the hepatocerebral or the isolated hepatic form of MDDS. Mouse models are helpful tools for the improvement of understanding of the pathophysiology of diseases and offer the opportunity to examine new therapeutic options.MethodsHerein, we describe the generation and metabolic characterization of a mouse line carrying a homozygous DguokF180S/F180S mutation derived from an N-ethyl-N-nitrosourea-mutagenesis screen. Energy expenditure (EE), oxygen consumption (VO2) and carbon dioxide production (VCO2) were assessed in metabolic cages. LC-MS/MS was used to quantify plasma adrenal steroids. Plasma insulin and leptin levels were quantified with commercially available assay kits.ResultsMutant animals displayed significantly lower body weights and reduced inguinal fat pad mass, in comparison to unaffected littermates. Biochemically, they were characterized by significantly lower blood glucose levels, accompanied by significantly lower insulin, total cholesterol, high density lipoprotein and triglyceride levels. They also displayed an almost 2-fold increase in transaminases. Moreover, absolute EE was comparable in mutant and control mice, but EE in mutants was uncoupled from their body weights. Histological examination of inguinal white adipose tissue (WAT) revealed adipocytes with multilocular fat droplets reminiscent of WAT browning. In addition, mRNA and protein expression of Ucp1 was increased. Mutant mice also presented differing mitochondrial DNA content in various tissues and altered metabolic activity in mitochondria, but no further phenotypical or behavioral abnormalities. Preliminary data imply normal survival of DguokF180S/F180S mutant animals.ConclusionTaken together, DGUOK mutation F180S leads to a lean phenotype, with lower glucose, insulin, and lipid levels rendering this mouse model not only useful for the study of MDDS forms but also for deciphering mechanisms resulting in a lean phenotype.

Whipple's triad with high and low insulin levels

A69-year-old female patient and a70-year-old male patient were admitted to hospital with recurrent, severe hypoglycemic episodes and atypical manifestation of Whipple's triad. In the female, elevated levels of insulin, C‑peptide and pro-insulin together with pathological findings during afasting test proved the presence of an insulinoma, which could be detected by Ga-68-DOTATOC-PET-CT in the pancreas. There was avery rare co-existence of aneuroendocrine Merkel cell carcinoma. In the male, levels of insulin and C‑peptide were suppressed and adiagnosis of paraneoplastic hypoglycemia by IGF‑2 secretion was made with increased glucose disposal in skeletal muscle proven by 18F‑FDG-PET-CT.

Development of a Zebrafish Larvae Model for Diabetic Heart Failure With Reduced Ejection Fraction

Diabetes mellitus (DM)-associated heart failure (HF) causes high morbidity and mortality. In this study, we established a zebrafish larvae model for in vivo research on diabetic HF. DM-like phenotypes were induced by treating zebrafish larvae with a combination of D-glucose (GLU) and streptozotocin (STZ). HF was induced by treatment with terfenadine (TER), a potassium channel blocker. Additionally, myocardial contractility, motility, and viability were evaluated. The zebrafish larvae treated with a combination of GLU and STZ showed significantly higher whole-body glucose concentrations, lower insulin levels, and higher phosphoenolpyruvate carboxykinase levels, which are markers of abnormal glucose homeostasis, than the group treated with only GLU, with no effect on viability. When treated with TER, DM zebrafish showed significantly less myocardial fractional shortening and more irregular contractions than the non-DM zebrafish. Furthermore, in DM-HF with reduced ejection fraction (rEF) zebrafish, a significant increase in the levels of natriuretic peptide B, a HF biomarker, markedly reduced motility, and reduced survival rates were observed. We established a DM-HFrEF zebrafish model by sequentially treating zebrafish larvae with GLU, STZ, and TER. Our findings indicate the potential utility of the developed zebrafish larvae model not only in screening studies of new drug candidates for DM-HFrEF but also in mechanistic studies to understand the pathophysiology of DM-HFrEF.

Reduced Left Ventricular Function on Cardiac MRI in SLE Patients Correlates with Measures of SLE Disease Activity and Inflammation.

Women with SLE have an elevated risk of CVD morbidity and mortality and frequently report chest pain in the absence of obstructive CAD. Echocardiographic studies often demonstrate reduced LV function, correlating with higher disease activity. We used cardiac MRI (cMRI) to investigate the relationship between SLE, related inflammatory biomarkers and cardiac function in female SLE patients. Women with SLE reporting chest pain with no obstructive CAD (n=13) and reference controls (n=22) were evaluated using stress-rest cMRI to measure LV structure, function, tissue characteristics, and myocardial perfusion reserve index (MPRI). Coronary microvascular dysfunction (CMD) was defined as MPRI <1.84. Serum samples were analyzed for inflammatory markers. Relationships between clinical and cMRI values of SLE subjects were assessed, and groups were compared. 40% of SLE subjects had MPRI < 1.84 on cMRI. Compared to controls, SLE subjects had higher LV volumes and mass and lower LV systolic function. SLICC DI was related to worse cardiac function and higher T1. CRP was related to higher cardiac output and a trend to better systolic function, while ESR and fasting insulin were related to lower LV mass. Lower fasting insulin levels correlated with increased ECV. Among our female SLE cohort, 40% had CMD, and SLICC DI correlated with worse cardiac function and diffuse fibrosis. Higher inflammatory markers and low insulin levels may associate with LV dysfunction. Our findings underline the potential of non-invasive cMRI as a tool for monitoring cardiovascular function in SLE patients.

PS-R03-5: HYPOTENSIVE AND HYPERGLYCEMIC EFFECTS OF DIAZOXIDE IN A CASE OF INSULINOMA

Case report: We report the case of sporadic insulinoma in a 70-year-old female with breast cancer and hypertension treated by irbesartan 100 mg and benidipine 8 mg, who presented with a 1-month history of episodic tremulousness, diaphoresis, increased hunger, confusion and fainting. Initial laboratory investigations showed low blood glucose (21 mg/dL) and high blood insulin (107 μU/mL) levels. The hypoglycemic symptoms were relieved greatly by glucose administration and Whipple's triad for insulinoma was met. An abdominal contrast-enhanced computed tomography scan showed a 12 mm, small, well demarcated, heterogeneously enhancing lesion within the tail of pancreas without dilatation of pancreatic duct. The site also showed a well-defined accumulation of boundaries on PET-CT. Patient was diagnosed with insulinoma. Since Patient did not initially wish to undergo surgery, blood glucose control was performed by taking diazoxide 225 mg, gradually reduced to 50 mg. Before and after taking diazoxide, blood glucose increased from 75 ± 40 mg/dL to 124 ± 35 mg/dL significantly (p &lt; 0.05). On the other hand, blood pressure was significantly reduced from 141 ± 3/78 ± 3 mmHg to 126 ± 3/75 ± 3 mmHg. Benidipine was withdrawn to about 130/80 mmHg. Then, Patient changed her mind and underwent laparoscopic caudal pancreatic resection. Histopathological examination of the pancreatic mass confirmed neuroendocrine tumor (insulinoma). Patient had an uneventful recovery. Blood pressure re-increased above 140/90 mmHg and benidipine was resumed. Although diazoxide suppresses insulin secretion in the pancreas due to its KATP channel opening action and improves hypoglycemic attacks with insulinoma, it also acts on the KATP channel of vascular smooth muscle and show a hypotensive effect. It is important to pay close attention not only to blood glucose but also to blood pressure fluctuations when using diazoxide.

Diabetes Ketoacidosis Is a Cause of Concern in Sodium-Glucose Co-Transporter-2 Inhibitors Medication

Abstract: Diabetic ketoacidosis (DKA) is a dangerous complication that can afflict persons with Type 1 and Type 2 diabetes and is caused by a lack of glucose utilization and insulin generation. DKA is diagnosed by observing the anion gap values, blood glucose level, pH, serum bicarbonate level, and so on. DKA is associated with an elevated blood glucose of &gt; 250 mg/dl (16.7 mmol/l) and is diagnosed by observing the values of anion gap, blood glucose level, pH, serum bicarbonate level, and so on. It occurs more frequently in type 1 diabetics with low insulin levels. Sodium-glucose Co-transporter-2 (SGLT-2) inhibitors are a novel family of anti-diabetic medications that lower blood glucose levels and produce glucosuria. The US Food and Drug Administration (USFDA) has issued a drug safety warning about the increased risk of DKA when using SGLT-2 inhibitors. Following the USFDA's warning, the European Medicine Agency reported 101 more cases of ketoacidosis caused by SGLT-2 inhibitors in people with Type 2 Diabetes Mellitus (EMA). According to the American Association of Clinical Endocrinologists, all SGLT-2 inhibitors should be stopped 3-4 days before major surgery and 24 hours before elective surgery. This review article focuses on the metabolism of ketone bodies and many pathophysiologic mechanisms of SGLT-2 inhibitors, which lower insulin/glucagon ratios, promote glucagon secretion from alpha cells, and increase ketones levels by stimulating lipolysis and resulting in ketogenesis. The primary goal of this study is to improve our understanding of a significant consequence of DKA caused by sodium-glucose cotransporter-2 inhibitors in patients with Type 1 and Type 2 diabetes. Psychosocial factors linked to diabetic ketoacidosis in adults with type 1 diabetes, as well as the prevalence of DKA in COVID-19 patients, have been linked to higher severity of mortality and duration of stay in these patients, according to recent research.

Dietary Sinapic Acid Alleviates Adiposity and Inflammation in Diet-Induced Obese Mice.

Sinapic acid (SA), a hydroxycinnamic acid, is known to confer protection against oxidative stress, inflammation, diabetes, and liver disease. However, the effectiveness of SA in improving obesity remains obscure. Therefore, this study evaluated anti-obesity efficacy of SA and to elucidate its mechanism of action. Male mice were maintained for 16 weeks on high-fat diet (HFD) alone or with SA (0.004%, w/w) and bodyweight, fat mass, adipocyte size, food intake, and biochemical and molecular markers were evaluated. SA-supplemented mice demonstrated markedly decreased fat mass and adipocyte size compared to unsupplemented group, without any changes in bodyweight and food intake between the two groups. Plasma adipocytokines levels including leptin, resistin, monocyte chemoattractant protein (MCP)-1 and interleukin-6 were also markedly reduced by SA supplementation. SA tended to lower plasma insulin level and improved homeostatic index of insulin resistance and intraperitoneal glucose tolerance test in HFD-induced obese mice. The anti-adiposity effect of SA was maybe owing to down-regulation of the mRNA expression of lipogenic genes, including acetyl coenzyme A (CoA) carboxylase, fatty acid synthesis, stearoyl-CoA desaturase 1, and phosphatidate phosphatase, and peroxisome proliferator-activated receptor γ, a transcription factor responsible for governing lipid metabolism, in adipose tissues. SA significantly down-regulated pro-inflammatory nuclear factor kappa B, MCP-1, tumor necrosis factor-α, and Toll-like receptor 4 mRNA expression in adipose tissue. Thus, SA could be beneficial for the development of functional foods or herbal medications to combat obesity.

Curcumin improves metabolic response and increases expression of thermogenesis-associated markers in adipose tissue of male offspring from obese dams

Maternal obesity and dietary style in the pregnancy-lactation period may result in long-term effects on the metabolic health of the offspring, thus increasing the risk of diseases, such as obesity, diabetes, and cardiovascular diseases. Curcumin is a natural polyphenolic compound that has beneficial properties on metabolism. Accordingly, this study is intended to evaluate the effects of curcumin supplementation in pregnant and lactating female mice on the anthropometric, metabolic and molecular parameters of the offspring fed a hyperglycemic diet. The study was conducted with 24 male mice randomized into three groups: i) control group (SD) originating from dams fed a standard diet; ii) hyperglycemic group (HGD) originating from dams fed a hyperglycemic diet; iii) curcumin group (CUR) originating from dams fed a hyperglycemic diet and supplemented with curcumin in the pregnancy-lactation period. All offspring groups were fed a hyperglycemic diet for 12 weeks. Anthropometricand biochemical parameters were measured, as well as the expression of thermogenesis-associated markers in the interscapular brown and inguinal white adipose tissues. The results showed less weight gain in the CUR group, with a concomitant reduction in food consumption compared to the HGD group. Biochemical parameters indicated lower levels of total cholesterol, glucose, and insulin for the CUR group, in addition to improved glucose tolerance and insulin sensitivity. The molecular evaluation indicated increased mRNA expression levels of UCP1 and PRDM16 in the brown and white adipose tissues. It is concluded that curcumin supplementation in the pregnancy-lactation period in dams with diet-induced obesity may lead to improvements in the offspring's metabolic phenotype, even if they are submitted to an obesogenic environment, possibly via thermogenesis activation.

A Novel Somatic Mutation Implicates ATP6V0D1 in Proinsulin Processing.

Prohormone convertase 1/3 (PC1/3), encoded by protein convertase subtilisin kexin type 1 (PCSK1), converts inactive prohormones into biologically active peptides. Somatic mutations of insulinomas are associated with genetic defects interfering with control of insulin secretion from pancreatic beta cells. However, somatic mutations in proinsulinomas have not been described. We report a case of a proinsulinoma, with suppressed insulin and C-peptide levels. A 70-year-old woman presented with a 20-year history of "blackouts." During a 72-hour fast, blood glucose level dropped to 1.9 mmol/L with suppressed plasma insulin and C-peptide levels, but proinsulin levels were raised at 37 pmol/L (<10 pmol/L). Imaging revealed 3 distinct DOTATATE-avid pancreatic lesions. Laparoscopic spleen-preserving distal pancreatomy was performed. In view of discordant insulin, C-peptide, and proinsulin levels, whole exome sequencing analysis was performed on the tumor. In the somatic exome of the tumor, we found mutations in PCSK expression regulators, as well as a novel truncating somatic mutation in ATP6V0D1, a subunit of the ion pump that acidifies the β-cell compartments where the PCSKs act. Appropriately suppressed insulin levels in the context of hypoglycemia do not always indicate the absence of a neuroendocrine islet cell tumor and proinsulin levels may be indicated to solidify the diagnosis. In the context of elevated proinsulin levels, low insulin and C-peptide levels might be explained by somatic mutations that likely implicate proinsulin processing within the tumor. Furthermore, we propose several mechanistic candidates, including ATP6V0D1. Experimental validation using cellular approaches may in future confirm pathomechanisms involved in this rare condition.

Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection.

An effective treatment and possible cure for type 1 diabetes is transplantation of pancreatic islets. Unfortunately, transplanted islets are rejected by the immune system with humoral-mediated responses being an important part of rejection. Sertoli cells (SC), an immune regulatory cell shown to survive as allografts long-term without immunosuppressants, have the potential to be used as a cell-based gene therapy vehicle to deliver endogenous insulin-a possible alternative to islets. Previously, we transduced a mouse SC line to produce human insulin. After transplantation into diabetic mice, these cells consistently produced low levels of insulin with graft survival of 75% at 50 days post-transplantation. The object of this study was to assess humoral immune regulation by these engineered SC. Both nontransduced and transduced SC survived exposure to human serum with complement in vitro. Analysis of allografts in vivo at 20 and 50 days post-transplantation revealed that despite IgG antibody detection, complement factor deposition was low and grafts survived through 50 days post-transplantation. Furthermore, the transduced SC secreted elevated levels of the complement inhibitor C1q binding protein. Overall, this suggests SC genetically engineered to express insulin maintain their ability to prevent complement-mediated killing. Since inhibiting complement-mediated rejection is important for graft survival, further studies of how SC modifies the immune response could be utilized to advance the use of genetically engineered SC or to prolong islet allograft survival to improve the treatment of diabetes.

Lower insulin level is associated with sarcopenia in community-dwelling frail and non-frail older adults.

Sarcopenia is common among older individuals with and without type 2 diabetes mellitus (T2DM). There are conflicting evidence in support of the role of insulin in the development of age-related and T2DM-related sarcopenia. We investigated the relationships between the levels of fasting insulin and other blood biomarkers related to insulin or lipid metabolism with the presence of sarcopenia in two independent studies. In 246 pre-frail frail older individuals with (n = 41) and without T2DM (n = 205) in the Singapore Frailty Interventional Trial, sarcopenia was defined by low appendicular lean mass (ALM) relative to total body mass (skeletal muscle index, SMI = ALM/height2) and low lower limb strength or gait speed according to the Asian Working Group for Sarcopenia (AWGS) criteria released in 2019, and related to levels of fasting insulin and glucose, C-peptide, IGF-1, leptin, and active ghrelin. This investigation was validated in another independent study sample of 189 robust and pre-frail frail elderly in the Singapore Longitudinal Aging Study Wave 2 (SLAS-2). Compared to non-sarcopenic individuals, those with sarcopenia and possible sarcopenia showed significantly lower fasting insulin (p < 0.05) in pre-frail/frail and non-frail older individuals. Consistent trends of relationships were observed for serum levels of C-peptide, IGF-1, leptin, and active ghrelin. In multivariable logistic regression models, sarcopenia was independently associated with low insulin (p < 0.05). Levels of fasting insulin, C-peptide, and leptin were also significantly associated with BMI, SMI, knee extension strength, gait speed, and physical activity score. Dysregulated insulin secretion in diabetic and non-diabetic older individuals may play an important role in age-related and diabetes-related sarcopenia.

Insulin Secretion and β-Cell Function Are Preserved in Patients with Treated Hematological Malignancies

INTRODUCTION Cancer survivors are at elevated risk for developing type 2 diabetes mellitus, which decreases quality of life and increases mortality during cancer survivorship. Type 2 diabetes results from a combination of insulin resistance and decreased insulin secretion. Assessing pancreatic β-cell function by measuring insulin secretion dynamics in response to hyperglycemia can provide insight into the pathogenesis of type 2 diabetes. We investigated insulin secretion in patients with treated hematological malignancies and compared them to non-diabetic controls without cancer. We hypothesized that patients with hematological malignancies will have decreased insulin secretion compared to controls without cancer due to β-cell toxicity from previous treatment and chemotherapy. METHODS We evaluated insulin secretion in 16 non-diabetic adult patients with treated hematological malignancies using a hyperglycemic clamp, which assesses pancreatic β-cell function by measuring insulin secretion in response to hyperglycemia (200 mg/dL) maintained by a dextrose infusion. Clamp outcomes included first phase (T0-10 minutes), second phase (T90-120 minutes), and maximal (L-arginine stimulated) insulin response. The insulin sensitivity index (ISI) and disposition index (DI, a measure of the β-cell function to compensate for insulin resistance) were calculated. Controls (n=32) matched for age, sex, race, and body mass index (BMI) were selected 2:1 from a database of 154 hyperglycemic clamps in participants without diabetes or cancer. Demographic characteristics and clamp outcomes were compared using χ2, Wilcoxon rank-sum test, or linear regression. RESULTS Hyperglycemic clamps were performed in 48 individuals without diabetes (16 patients with treated hematological malignancies and 32 matched controls without cancer). Cancer survivors and controls without malignancy were well-matched for age, sex, race (Table 1). Myeloid malignancies were the most common diagnosis (n=11; 69%) with a median time from diagnosis to metabolic testing of 6 months. Treatment included cytotoxic chemotherapy (n=15; 94%), glucocorticoids (n=7; 44%), and radiation (n=1; 6%) with 7 (44%) patients achieving a remission prior to testing. Compared to controls, patients with malignancy had lower fasting glucose levels (93.0 mg/dL [IQR 86.3-96.6] vs 101.5 [IQR 94.9-107.6], p<0.001) and lower fasting insulin levels (11.5 uU/mL [IQR 9.3-15.0] vs 16.3 [IQR 12.3-21.5], p=0.023), suggesting greater insulin sensitivity within the cancer cohort. In univariable analysis, there were no significant differences between first and second phase insulin response between patients with or without treated hematological malignancies (Table 1). Cancer survivors had a higher maximal (L-arginine stimulated) insulin secretion (3606 uU/mL [IQR 3255-4594] vs 2278 [IQR 1900-3555], p=0.026) and a higher disposition index (2521 mg/kg/min [IQR 1986-3360] vs 1300 [IQR 939-1923], p=0.01) than in controls. Cancer survivors demonstrated a trend toward greater insulin sensitivity compared to controls (6.82 mg/kg/min per uU/mL [IQR 5.53-10.83] vs 4.98 [IQR 3.65-7.28], p=0.092). After adjustment for BMI and fasting glucose in linear regression models, both second phase (β=242.5, p=0.005) and maximal insulin secretion (β=1225.6, p=0.019) were greater in cancer survivors then in controls without cancer (Table 2). CONCLUSION Cancer survivors had higher maximal phase insulin secretion and disposition index (a measure of β-cell function adjusted for insulin resistance) compared to non-diabetic controls without cancer. Our data suggests that cancer survivors have preserved β-cell function following treatment of their hematological malignancies, contrary to our hypothesis. Longitudinal follow-up is needed to determine factors that promote diabetes susceptibility in cancer survivors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Relationship between Serum Adipokines, miR-222-3p, miR-103a-3p and Glucose Regulation in Pregnancy and Two to Three Years Post-Delivery in Women with Gestational Diabetes Mellitus Adhering to Mediterranean Diet Recommendations.

The San Carlos Gestational Diabetes Mellitus (GDM) prevention study, a nutritional intervention RCT based on a Mediterranean Diet (MedDiet), has been shown to reduce the incidence of GDM. The objective of this study is to investigate the relationship of leptin, adiponectin, interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), insulin and HOMA-IRand circulating miRNAs (miR-29a-3p, miR-103a-3p, miR-132-3p, miR-222-3p) with the appearance of GDM and with MedDiet-based nutritional intervention, at 24-28 gestational weeks (GW), and in glucose regulation 2-3 years post-delivery (PD). A total of 313 pregnant women, 77 with GDM vs. 236 with normal glucose tolerance (NGT), 141 from the control group (CG, MedDiet restricting the consumption of dietary fat including EVOO and nuts during pregnancy) vs. 172 from the intervention group (IG, MedDiet supplemented with extra virgin olive oil (EVOO) and pistachios during pregnancy) were compared at Visit 1 (8-12 GW), Visit 2 (24-28 GW) and Visit 3 (2-3 years PD). Expression of miRNAs was determined by the Exiqon miRCURY LNA RT-PCR system. Leptin, adiponectin, IL-6 and TNF-α, were measured by Milliplex® immunoassays on Luminex 200 and insulin by RIA. Women with GDM vs. NTG had significantly higher leptin median (Q1-Q3) levels (14.6 (9.2-19.4) vs. 9.6 (6.0-15.1) ng/mL; p &lt; 0.05) and insulin levels (11.4 (8.6-16.5) vs. 9.4 (7.0-12.8) µUI/mL; p &lt; 0.001) and lower adiponectin (12.9 (9.8-17.2) vs. 17.0 (13.3-22.4) µg/mL; p &lt; 0.001) at Visit 2. These findings persisted in Visit 3, with overexpression of miR-222-3p (1.45 (0.76-2.21) vs. 0.99 (0.21-1.70); p &lt; 0.05)) and higher levels of Il-6 and TNF-α. When the IG is compared with the CG lower levels of insulin, HOMA-IR-IR, IL-6 levels at Visit 2 and 3 and leptin levels only at Visit 2 were observed. An overexpression of miR-222-3p and miR-103a-3p were also observed in IG at Visit 2 and 3. The miR-222-3p and miR103a-3p expression correlated with insulin levels, HOMA-IR, IL-6 and TNF-α at Visit 2 (all p &lt; 0.05). These data support the association of leptin, adiponectin and insulin/HOMA-IR with GDM, as well as the association of insulin/HOMA-IR and IL-6 and miR-222-3p and miR-103a-3p expression with a MedDiet-based nutritional intervention.

PSUN278 Factitious hypoglycemia, diagnostic delay due to insulin assay failure to detect insulin analogues.

Abstract Factitious hypoglycemia may be difficult to diagnose clinically. Hypoglycemia due to insulin self-administration is established by the presence of a low c-peptide and elevated plasma insulin levels. Commercial insulin assays often fail to detect insulin analogs and can create confusion among providers investigating causes of hypoglycemia. A 20 year old female with no significant past medical history presented to an Emergency Room (ER) with hypoglycemia. She was treated with a single dose of octreotide 150 mcg, dexamethasone 10 mg PO and started on a D10W drip at 100ml/hr prior to transfer. Laboratory studies on transfer reported plasma glucose 52ng/dL (RR: 70-100), low C-peptide 0.02 (RR: 0.78-5.19), low insulin level &amp;lt;0.087 uIU/mL, normal IGF-I level 122 ng/mL (RR: 85-370). Normal IGF-II level 401 ng/mL (RR: 333-967), and low Pro-insulin level 1.8 pmol/L (RR: 3.6-22 pmol/L). Sulfonylurea Screen was negative. The patient and her mother both denied exogenous insulin use. The patient and her mother both work in healthcare. The patient's boyfriend has type 1 diabetes mellitus and the patient stated she keeps insulin in her purse for him. The patient was admitted for a 72 hour fast and remained normoglycemic. An aliquot of the admission ER insulin blood sample was sent to second laboratory utilizing an assay able to detect analog insulins. The patient's sample previously reporting an undetectable insulin level (&amp;lt;0.087 uIU/mL) now reported an insulin level 8 uIU/mL. Factitious hypoglycemia is a challenging clinical diagnosis. The term factitious implies an attempt to deceive and creates mistrust between the physician and patient. However, hypoglycemia may be the result of medication errors or administered by a second party with the intent to harm. Analog insulins (glargine, aspart, lispro, glulisine, etc) are genetically modified insulins developed to mimic the physiologic pattern of pancreatic beta cell insulin secretion. The amino acid modifications in analog insulins result in structural variations which alters the ability of highly specific commercial automated immunoassays to accurately quantitate these analog insulins. The variation in lab assay detection may cause confusion when interpreting the results. The DiaSorin Liaison XL platform in our hospital utilizes a chemiluminescence immunoassay which does not detect insulin analogs, but detects regular and NPH insulin as they are structurally identical to endogenous human insulin. The second laboratory uses the Siemens Advia Centaur platform, an immunoassay which reacts with insulin analogs "on a nearly equimolar basis with the analogs insulin aspart, insulin glargine, and insulin lispro. Insulin detemir exhibits approximately 50 percent cross-reactivity. Test reactivity with insulin glulisine is negligible (&amp;lt; 3 percent)". Many commercial insulin assays do not detect analog insulins and none qualitatively distinguish between different insulins. Failure to recognize this detection flaw may result in misdiagnosis, patient safety issues and costly unneeded additional studies Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.