High-dose Insulin Research Articles

BETA BLOCKER AND CALCIUM CHANNEL BLOCKER OVERDOSE COMPLICATED BY COVID-19 PNEUMONIA AND RENAL FAILURE IN A PATIENT WITH SEVERE OBESITY

BETA BLOCKER AND CALCIUM CHANNEL BLOCKER OVERDOSE COMPLICATED BY COVID-19 PNEUMONIA AND RENAL FAILURE IN A PATIENT WITH SEVERE OBESITY

SUDDEN CARDIOVASCULAR COLLAPSE DUE TO CALCIUM CHANNEL BLOCKER OVERDOSE: SUCCESSFUL MANAGEMENT WITH HIGH-DOSE INSULIN EUGLYCEMIC THERAPY

SUDDEN CARDIOVASCULAR COLLAPSE DUE TO CALCIUM CHANNEL BLOCKER OVERDOSE: SUCCESSFUL MANAGEMENT WITH HIGH-DOSE INSULIN EUGLYCEMIC THERAPY

Factors associated with high glucose variability in patients with type 1 diabetes

BACKGROUND: High glucose variability (GV) is recognized as a risk factor for vascular diabetic complications and hypoglycemia. Factors affecting GV in patients with diabetes needed to be clarified.AIM: To determine the factors associated with high GV in adult patients with type 1 diabetes.MATERIALS AND METHODS: We conducted a single center cross-sectional observational study. In-patients with type 1 diabetes aged 18 to 65 years on basal bolus insulin therapy were included. Day-time and nocturnal Coefficient of Variation (CV), Mean Amplitude of Glycemic Excursions (MAGE), Mean Absolute Glucose (MAG) were calculated from continuous glucose monitoring data. The values of CV, MAGE, MAG within the upper quartile were considered high.RESULTS: The study included 400 individuals, including 111 on continuous subcutaneous insulin infusion (CSII). Patients with high GV had lower fasting and postprandial C-peptide levels and higher insulin doses. According to ROC analysis, daily insulin dose >0.69 U/kg and estimated glomerular filtration rate (eGFR) ≥90.5 ml/min×1.73 m2 were associated with high nocturnal CV values. Dose of basal insulin >0.292 U/kg and bolus insulin >0.325 U/day were associated with nocturnal MAGE. Body mass index (BMI) ≤23.2 kg/m2, waist circumference ≤80.5 cm, daily insulin dose ≥0.69 U/kg, HbA1c ≥8.3%, eGFR ≥89.5 ml/ min×1.73m2 increased risk of high MAG at night. High day-time CV values were associated with daily insulin dose ≥0.675 U/kg and daily dose of BI ≥0.286 U/kg. The risk of high MAGE was increased with HbA1c ≥8.24% and basal insulin dose ≥0.286 U/kg. BMI ≤23.2 kg/m2, waist circumference ≤80.5 cm, daily insulin dose ≥0.69 U/kg, daily dose of bolus and basal insulin ≥0.325 and ≥0.29 U/kg respectively, and HbA1c ≥8.33% were the risk factors for high day-time MAG. Patients on CSII had lower MAGE (p<0.001) and MAG (p=0.008) compared to those on multiple daily injections.CONCLUSION: In type 1 diabetes, high GV is associated with undetectable residual insulin secretion, normal or reduced body weight, preserved kidney function, supraphysiological doses of insulin, and non-target HbA1c. Patients on CSII have a lower GV than those on multiple daily injections.

Insulin antibody as a biomarker to monitor the development of type 2 diabetes in county hospitals in China

BackgroundThe significance of insulin antibody (IA) detection in type 2 diabetes mellitus (T2DM) has received scant attention from county hospitals in China. We aimed to introduce exogenous IA positive rate and its relative factors in T2DM treated with insulin in Xiangshan County of Ningbo City, analyzing the immunogenicity of different kinds of insulin.MethodsPatients who were residents from the Danxi community and six towns (Dongchen, Xizhou, Maoyang, Sizhoutou, Juexi, and Qiangtou) in Xiangshan County and diagnosed with T2DM and treated with insulins at Xiangshan Hospital of TCM Medical and Health Group between August 2019 and June 2020 were identified. Those who met the eligibility criteria were included and assigned to the IA-positive or IA-negative group. The immunogenicity of different insulins was compared between the two groups.ResultsAmong 992 patients, 781 were eligible for IA detection, and 40.2% of them were IA positive. Blood IA was closely associated with fasting and 2-h glucose, insulin, and C peptide levels and higher insulin dosage. Patients receiving basal insulin treatment showed significantly lower blood IA than those treated with mixed human insulin, premixed human insulins, rapid-acting analogs, or a combination of basal and rapid-acting analogs.

The Effects of Adding Semaglutide to High Daily Dose Insulin Regimens in Patients With Type 2 Diabetes.

Escalating doses of insulin required with progression of type 2 diabetes may lead to weight gain. Weight loss associated with semaglutide may be beneficial. However, data on the use of semaglutide in patients requiring high daily doses of insulin are currently lacking. The purpose of this project was to evaluate the impact of semaglutide on total daily dose (TDD) of insulin when initiated in patients with type 2 diabetes mellitus (T2DM) on high daily doses of insulin. Secondary objectives assessed included changes in weight, body mass index (BMI), blood pressure, heart rate, and diabetes and blood pressure medications. This IRB exempt retrospective medical record review included patients with T2DM prescribed semaglutide and at least 100 units TDD of insulin between January 1, 2019, and December 31, 2019. Of the 72 patients included, the TDD of insulin decreased from baseline to 6 months (183 ± 98 units and 143 ± 99 units, P < 0.001). Average A1c and body weight also decreased from baseline to 6 months (8.9% ± 1.3% and 7.6% ± 1.5%, P < 0.001 and 123.9 ± 23.5 kg and 118.9 ± 22.9 kg, P < 0.001, respectively). Limitations included a homogenous patient population and inability to control confounding factors. Improvement in glycemic control occurred despite reductions in TDD of insulin. Improvements in A1c and body weight were clinically significant. This analysis adds to existing literature supporting the use of GLP-1 RAs in patients on high daily doses of insulin.

Tolerability and Effectiveness of Switching to Dulaglutide in Patients With Type 2 Diabetes Inadequately Controlled With Insulin Therapy.

AimsGlucagon‐like peptide 1 (GLP-1) receptor agonists have demonstrated strong glycemic control. However, few studies have investigated the effects of switching from insulin to GLP-1 receptor agonists. We aimed to investigate, using real-world data, whether switching to dulaglutide improves glycemic control in patients with type 2 diabetes mellitus (T2D) inadequately controlled with conventional insulin treatment.Materials and methodsWe retrospectively evaluated 138 patients with T2D who were switched from insulin to dulaglutide therapy. We excluded 20 patients who dropped out during the follow-up period. The participants were divided into two groups according to whether they resumed insulin treatment at 6 months after switching to a GLP-1 receptor agonist (group I) or not (group II). A multiple logistic regression analysis was performed to evaluate the parameters associated with the risk of resuming insulin after replacement with dulaglutide.ResultsOf 118 patients initiated on the GLP-1 receptor agonist, 62 (53%) resumed insulin treatment (group I), and 53 (47%) continued with GLP-1 receptor agonists or switched to oral anti-hypoglycemic agents (group II). Older age, a higher insulin dose, and lower postprandial glucose levels while switching to the GLP-1 receptor agonist were associated with failure to switch to the GLP-1 receptor agonist from insulin.ConclusionsA considerable proportion of patients with T2D inadequately controlled with insulin treatment successfully switched to the GLP-1 receptor agonist. Younger age, a lower dose of insulin, and a higher baseline postprandial glucose level may be significant predictors of successful switching from insulin to GLP-1 receptor agonist therapy.

PI3K/Akt pathway mediates the positive inotropic effects of insulin in Langendorff-perfused rat hearts

Insulin exerts positive inotropic effects on cardiac muscle; however, the relationship between cardiac contractility and phosphoinositol-3-kinase/Akt (PI3K/Akt) activation remains unclear. We hypothesized that the positive inotropic effects of insulin are dose-dependent and mediated via the PI3K/Akt pathway in isolated normal rat hearts. The Institutional Animal Investigation Committee approved the use of hearts excised from rats under pentobarbital anesthesia. The hearts were perfused at a constant pressure using the Langendorff technique. After stabilization (baseline), the hearts were randomly divided into the following four insulin (Ins) groups: 1) Ins0 (0 IU/L), 2) Ins0.5 (0.5 IU/L), 3) Ins5 (5 IU/L), and 4) Ins50 (50 IU/L) (n = 8 in each group). To clarify the role of the PI3K/Akt pathway in insulin-dependent inotropic effects, we also treated the insulin groups with the PI3K inhibitor wortmannin (InsW): 5) InsW0 (0 IU/L), 6) InsW0.5 (0.5 IU/L), 7) InsW5 (5 IU/L), and 8) InsW50 (50 IU/L). Hearts were perfused with Krebs–Henseleit buffer solution with or without wortmannin for 10 min, followed by 20 min perfusion with the solution containing each concentration of insulin. The data were recorded as the maximum left ventricular derivative of pressure development (LV dP/dt max). Myocardial p-Akt levels were measured at 3 min, 5 min, and at the end of the perfusion. In the Ins groups, LV dP/dt max in Ins5 and Ins50 increased by 14% and 48%, respectively, 3 min after insulin perfusion compared with the baseline. Tachyphylaxis was observed after 10 min in the Ins5 and Ins50 treatment groups. Wortmannin partially inhibited the positive inotropic effect of insulin; although insulin enhanced p-Akt levels at all time points compared with the control group, this increase was suppressed in the presence of wortmannin. The positive inotropic effect of insulin is dose-dependent and consistent with Akt activation. This effect mediated by high doses of insulin on cardiac tissue was temporary and caused tachyphylaxis, potentially triggered by Akt overactivation, which leads beta 1 deactivation.

Combination Use of U-500 Regular Insulin via Insulin Pump and Rapid-Acting U-100 Prandial Injections for Treatment of Pre-Existing Type 2 Diabetes in Pregnancy.

The high-dose large-volume insulin injections that may become necessary during pregnancy due to marked pregnancy-induced insulin resistance may result in suboptimal therapeutic effectiveness. Use of U-500 insulin, a concentrated insulin formulation, has been suggested during pregnancy. However, the pharmacokinetic properties of U-500 insulin monotherapy can impede achievement of strict pregnancy glycemic targets. We propose a novel regimen for treatment of severe pregnancy-induced insulin resistance that enables precise delivery of U-500 basal insulin therapy through continuous subcutaneous insulin infusion (CSII) while maintaining the desired kinetics of prandial rapid-acting U-100 insulin therapy. This combination approach, guided by continuous glucose monitoring data, enabled achievement of pregnancy glycemic targets while reducing basal insulin requirements by approximately one-third. We report our method for (1) conversion to U-500 insulin delivery through CSII during pregnancy and (2) conversion from U-500 basal insulin delivery through CSII to U-100 intravenous insulin infusion therapy at delivery, to offer clinicians who encounter similar challenging scenarios a novel approach to diabetes management during pregnancy in the setting of marked insulin resistance.

195-OR: A Novel 13C5 Glutamine Tracer Method (Q Flux) Reveals a Key Role of Succinyl CoA Anaplerosis in Promoting Increased Rates of Hepatic Gluconeogenesis during Hyperglucagonemia

Hyperglucagonemia is a hallmark of type 2 diabetes mellitus (T2DM) and contributes to increased rates of endogenous glucose production (EGP) , mostly through increased rates of hepatic gluconeogenesis (GNG) , but the anaplerotic pathways and respective substrates that support this process are unclear. To address this question, we developed a novel and extensively validated 13C5 glutamine-based in vivo metabolic flux analysis method (Q Flux) , which allows for quantitation of both the relative and absolute rates of hepatic gluconeogenesis from pyruvate (via pyruvate carboxylase [PC]) , succinyl CoA (via methylmalonyl CoA mutase [MUT]) , glutamine (via glutaminase [GLS2]) , and glycerol. Male Sprague-Dawley rats (∼300 g) were infused for 90 minutes with either low-dose (LD) glucagon (1.25 ng/[kg-min]) or high-dose (HD) glucagon (ng/[kg-min]) , plus insulin (0.5 mU/[kg-min]) , somatostatin (4 μg/[kg-min]) , and 13C5 glutamine (3 μmol/[kg-min]) after a 16-hour fast to deplete hepatic glycogen. HD animals displayed significantly increased plasma glucose concentrations and EGP relative to LD controls. Analyses of liver tissues collected at sacrifice revealed that in LD animals, 70% of mitochondrial GNG was from pyruvate, 15% from succinyl CoA, and 15% from glutamine. In HD animals, 59% of mitochondrial GNG was derived from pyruvate (p=0.vs. LD) , 26% from succinyl CoA (p=0.0vs. LD) , and 15% from glutamine (p=0.99 vs. LD) . Conclusion: We find an unexpected role for succinyl CoA anaplerosis and methylmalonyl CoA mutase flux in supporting increased rates of mitochondrial GNG during hyperglucagonemia. Furthermore, relative contributions of glutamine to hepatic gluconeogenesis were unchanged, contrary to previous reports. Taken together, these results identify novel targets to reduce hyperglucagonemia-induced increases in rates of gluconeogenesis and hyperglycemia in T2DM. Disclosure B.T.Hubbard: None. G.I.Shulman: Advisory Panel; 89bio, Inc., AstraZeneca, Equator Therapeutics, Inc., Janssen Research &amp; Development, LLC, Merck &amp; Co., Inc., Consultant; DiCerna Pharmaceuticals, Inc. , Novo Nordisk, Other Relationship; Generian Pharmaceuticals, iMetabolic Biopharma Corporation, Maze Therapeutics, The Liver Company, Stock/Shareholder; Levels Health, Inc. .

Treatment of critical aluminum phosphide (rice tablet) poisoning with high-dose insulin: a case report

BackgroundAluminum phosphide (rice tablet) is a highly efficient agent for preserving grains against rodents and insects. It accounts for a large number of poisoning cases. Aluminum phosphide poisoning has a high mortality rate of about 90%, and to date, no antidote is available. It releases phosphine gas after exposure to moisture, and this reaction is catalyzed by the acidity of the stomach. Phosphine is then absorbed throughout the respiratory or gastrointestinal tracts and causes toxicity through inhibition of cytochrome c oxidase and formation of highly reactive free radicals. Treatment of patients with aluminum phosphide poisoning is supportive, including mechanical ventilation and vasopressors. The usage of infusion of glucose-insulin-potassium in rice tablet poisoning has been suggested, after its positive beneficial cardiac inotropic effects in patients with beta-blocker and calcium channel blocker poisoning.Case presentationWe report the case of a 30-year-old Iranian woman with critical aluminum phosphide poisoning, presented with hypotension and other signs of shock and severe metabolic acidosis, successfully treated with high-dose regular insulin and hypertonic dextrose and discharged from hospital in good condition. In contrast to our previous experiences, in which nearly all patients with critical aluminum phosphide poisoning died, this patient was saved with glucose-insulin-potassium.ConclusionAluminum phosphide poisoning has a high mortality rate, and to date, no antidote is available. Administration of high-dose intravenous regular insulin and dextrose is suggested as a potential life-saving treatment for patients with critical aluminum phosphide poisoning.

Rescue effects of insulin on the cytotoxic effects of bitter melon extract in the human breast cancer cells

Bitter melon extract (BME) is known to inhibit breast cancer cells proliferation. Due to the high metabolic rate of cancer cells, we hypothesized that low glucose levels are detrimental to cell survivability and that BME exerts a cytotoxic effect by altering the ability of a cell to utilize glucose. Through this study, we seek to investigate if insulin is capable of mitigating the cytotoxic effects of BME and provide a “rescue effect”.Fresh bitter melons were purchased from an Asian grocery store and the extract (BME) was prepared, centrifuged, and filter sterilized. The MCF‐7 cells were cultured in the DMEM medium (normal or low glucose) with either 1% or 2 % BME (v/v) and in the presence or absence of insulin at various doses [50ng/mL, 100ng/mL, 200ng/mL]. After culturing cells for 24 hours in standard DMEM complete medium, BME and insulin were added to corresponding wells and pictures of cultures were taken every 24 hours for 2 days. After the 2 days, cell viability was then assessed using an MTT colorimetric assay at 620 nm.BME dose‐dependently inhibited MCF‐7 cell viability. Insulin demonstrated a rescue effect and increased the cell viability despite the addition of BME. Insulin also dose‐dependently enhanced MCF‐7 cell viability to an extent when added alone. Following were the % absorbance values with increasing doses of insulin. All values are relative to control (without any addition of BME or Insulin) considered as 100% and corrected for absorbance of DMEM alone; [DMEM only – 38.33%, 1% BME – 34.33%, 0% BME + 200ng Insulin – 49.87%, 1% BME + 50ng Insulin – 39.53%, 1% BME + 100ng Insulin – 39.97%, 1% BME + 200ng Insulin – 41.70%]. The 1% BME (bitter melon extract) is the positive control in our studies as our lab have found BME to be toxic to MCF‐7 cells. The same trial was repeated with 2% BME in order to better visualize the cytotoxic effects of BME and further demonstrate the subsequent rebound in cell viability following addition of insulin. All values are relative to control (without any addition of BME or Insulin) considered as 100% and corrected for absorbance of DMEM alone; [DMEM only – 58.87%, 2% BME – 17.07%, 0% BME + 200ng Insulin – 63.97%, 2% BME + 50ng Insulin – 55.70%, 2% BME + 100ng Insulin – 55.43%, 2% BME + 200ng Insulin – 59.30%].When we treated cells with increasing doses of insulin, an enhanced rescue effect was seen as reflected by the increasing absorbance values. We further tested the effects of BME and insulin by culturing the cells in low glucose DMEM. The raw data is included in the abstract due to space limitation.Our data indicates the addition of insulin is capable of rescuing cells from the cytotoxic effects of BME. Insulin seems to be capable of mitigating the cytotoxic effects of BME and, in some cases, even enhancing the viability of cells despite the prior treatment with BME. The relatively diminished rescue effect with 200ng of insulin and 2% BME may be due to the inherent strain the cells were already experiencing with BME. The high dose of insulin, coupled with the strain of attempting to replicate in sub‐optimal conditions, may have led to cells that were incapable of meeting the metabolic demand placed by the large dose of insulin and subsequent influx of glucose. Further study may be warranted to discover the threshold of benefit that insulin can provide and amount of glucose necessary for, or detrimental to, cell survival.

Determination of insulin-related lipohypertrophy frequency and risk factors in patients with diabetes

IntroductionInsulin, which is used in the treatment of diabetes mellitus (DM), may lead to the development of lipohypertrophy (LH) which can negatively affect the management of diabetes mellitus. Two common methods to detect LH are palpation and superficial subcutaneous ultrasonography (SSU). We investigated the frequency of non-palpable LH using SSU, as well as examining risk factors. MethodWe included in our study patients who had been receiving insulin injections at least twice a day for over one year without palpable LH. The epidermis and the subcutaneous tissue thickness of each region were examined using SSU. The presence of LH and associated risk factors for LH were evaluated. ResultsWe included 136 patients in our study. The mean age of all patients was 52.87±14.93 years, 59.6% were female and 73.5% had type 2 DM. The duration of DM and insulin usage were 15.76±9.20 and 11.42±8.26 years, respectively. The mean body mass index (BMI) of all patients was 30.59±7.40kg/m2. Non-palpable LH was detected in 87.5% (n=116) of the patients using SSU. In the multivariate logistic regression analyses, total cholesterol level, short-acting insulin dose and coronary artery disease (CAD) were associated with LH presence. ConclusionNon-palpable LH can be seen at high rates in patients who have multiple insulin injections. Palpation is likely not enough to detect LH and we believe it would be appropriate to evaluate the presence of LH using SSU, especially for those who need high-dose insulin to control hyperglycaemia.

Profile of Patients with Diabetes Treated with Insulin Lispro 200 U/ml: A Real-World Study from Spain.

IntroductionInsulin lispro 200 U/ml (IL200) is a rapid-acting concentrated insulin used for the treatment of adults with diabetes requiring daily doses of > 20 units of rapid-acting insulin. The aim of this study was to describe the clinical/demographic and treatment characteristics of patients who initiated insulin IL200 therapy in Spain in a real-world setting (PROFILE-IL200).MethodsThis retrospective observational study based on the IQVIA database included adult (≥ 18 years) patients with type 1 (T1D) or type 2 (T2D) diabetes who initiated IL200 between June 2015 and December 2019. Demographic and clinical characteristics were analyzed descriptively.ResultsMain characteristics for the T1D/T2D groups (N = 65/167) were as follows: male, 63.1/55.7%; mean (standard deviation [SD]) age, 46.5 (15.5)/62.6 (12.8) years; time since first diabetes record, 6.6 (4.2)/7.9 (2.9) years; body mass index (BMI), 30.9 (5.8)/33.1 (5.5) kg/m2; glycated hemoglobin, 8.3 (2.1)/8.8 (1.8)%; and diabetes-associated comorbidity, 55.4/92.8%. Among patients with T1D/T2D and a prior diagnosis (N = 54/164), 96.3/90.2% had received previous insulin (rapid insulin in 81.5/62.2%), and 13.0/97.6% had received previous noninsulin antihyperglycemic therapy. The mean (SD) total insulin dose before IL200 initiation for T1D/T2D was 98.0 (73.9)/95.2 (59.8) U/day; IL200 was initiated at a dose of 56.3 (43.8)/51.5 (34.3) U/day, with basal insulin in 86.2/83.2% of the patients. IL200 was first prescribed by an endocrinologist or a primary care physician in 48.7% and 46.6% of patients, respectively.ConclusionsPROFILE-IL200 described the profile of patients treated with IL200 in clinical practice in Spain. Patients were middle-aged, with poor glycemic control, high BMI and associated comorbidities, and received high doses of insulin at IL200 initiation.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-022-01264-6.

The association between hypomagnesemia and poor glycaemic control in type 1 diabetes is limited to insulin resistant individuals

In a cohort of adults with type 1 diabetes, we examined the prevalence of hypomagnesemia and the correlation of serum magnesium levels with metabolic determinants, such as glycaemic control (as HbA1c), inflammatory markers and circulating cytokines. Furthermore, we assessed if a surrogate for insulin resistance is essential for the possible association of serum magnesium with metabolic determinants. Individuals with type 1 diabetes, aged above 18 years, were included and clinical characteristics were obtained from questionnaires and clinical records. In venous blood samples we measured cytokines and adipose-tissue specific secretion proteins. Serum magnesium concentrations were measured and correlated with clinical data and laboratory measurements using univariate and multivariate regression models. Hierarchical multiple regression of serum magnesium with insulin resistance was adjusted for diabetes and potential magnesium confounders. The prevalence of hypomagnesemia (serum magnesium levels < 0.7 mmol/L) was 2.9% in a cohort consisting of 241 individuals with type 1 diabetes. The magnesium concentration in the cohort was not associated with HbA1c (r = − 0.12, P-value = 0.068) nor with any inflammatory marker or adipokine. However, insulin dose (IU/kg), a surrogate measure of resistance in type 1 diabetes, moderated the association of serum magnesium (mmol/L) with HbA1c (mmol/mol) with a B coefficient of − 71.91 (95% CI: − 119.11; -24.71), P-value = 0.003) and Log10 high-sensitivity C-reactive protein (Log10 mg/L) − 2.09 (95% CI: − 3.70; − 0.48), P-value = 0.011). The association of low serum magnesium levels with glycaemic control (HbA1c) and high-sensitivity C-reactive protein in individuals with type 1 diabetes is limited to subjects using a high insulin dose and suggests that insulin resistance, a type 2 diabetes feature, is a prerequisite for hypomagnesemia.

Factors Associated With Improved A1C Values Among People With Uncontrolled Type 2 Diabetes.

Uncontrolled diabetes negatively affects millions of people in the United States and contributes to significant health burden. This retrospective case-control study evaluated which therapeutic interventions and patient factors were associated with improvement in A1C values from ≥9.0 to <9.0% in people with uncontrolled type 2 diabetes at a county health clinic serving primarily low-income, Hispanic patients. Medication adherence, high-dose insulin use, and clinical pharmacy specialist visits were found to be the most influential factors with regard to improving A1C.

Associations between continuous glucose monitoring-derived metrics and HbA1c in patients with type 2 diabetes mellitus

AimsThe aim of this study was to define the relationship between time in range (TIR) and hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM). MethodsThe glycemic profile of 999 Japanese patients was analyzed with FreeStyle Libre Pro Continuous Glucose Monitoring (FLP-CGM) while they continued their prescribed glucose-lowering medications. FLP-CGM data recorded over 8 consecutive days were analyzed. ResultsThe regression model for HbA1c on TIR was HbA1c = 9.4966–0.0309 × TIR. The predicted HbA1c level for TIR of 70% was 7.33% and is higher than reports subjecting mostly T1DM. The TIR corresponding to HbA1c 7.0% was 80.64%. The patients with low TIR tended to have long duration of diabetes, used high dose of daily insulin, high body mass index, high HbA1c, liver dysfunction and high triglyceride. Relatively higher percentages of patients of this group used sulfonylureas, glucagon like peptide-1 receptor agonists and insulin. ConclusionsOur data showed predicted HbA1c corresponding to TIR is largely depends on study population, thus is not uniform. Our results provide new insights on the management of T2DM. However, caution should be exercised in extending the HbA1C-TIR relationship using FLP-CGM to any other sensors since there could be a risk of hypoglycemia in doing so.

Efficacy and Safety of Enteral Recombinant Human Insulin in Preterm Infants

Feeding intolerance is a common condition among preterm infants owing to immaturity of the gastrointestinal tract. Enteral insulin appears to promote intestinal maturation. The insulin concentration in human milk declines rapidly post partum and insulin is absent in formula; therefore, recombinant human (rh) insulin for enteral administration as a supplement to human milk and formula may reduce feeding intolerance in preterm infants. To assess the efficacy and safety of 2 different dosages of rh insulin as a supplement to both human milk and preterm formula. The FIT-04 multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 46 neonatal intensive care units throughout Europe, Israel, and the US. Preterm infants with a gestational age (GA) of 26 to 32 weeks and a birth weight of 500 g or more were enrolled between October 9, 2016, and April 25, 2018. Data were analyzed in January 2020. Preterm infants were randomly assigned to receive low-dose rh insulin (400-μIU/mL milk), high-dose rh insulin (2000-μIU/mL milk), or placebo for 28 days. The primary outcome was time to achieve full enteral feeding (FEF) defined as an enteral intake of 150 mL/kg per day or more for 3 consecutive days. The final intention-to-treat analysis included 303 preterm infants (low-dose group: median [IQR] GA, 29.1 [28.1-30.4] weeks; 65 boys [59%]; median [IQR] birth weight, 1200 [976-1425] g; high-dose group: median [IQR] GA, 29.0 [27.7-30.5] weeks; 52 boys [55%]; median [IQR] birth weight, 1250 [1020-1445] g; placebo group: median [IQR] GA, 28.8 [27.6-30.4] weeks; 54 boys [55%]; median [IQR] birth weight, 1208 [1021-1430] g). The data safety monitoring board advised to discontinue the study early based on interim futility analysis (including the first 225 randomized infants), as the conditional power did not reach the prespecified threshold of 35% for both rh-insulin dosages. The study continued while the data safety monitoring board analyzed and discussed the data. In the final intention-to-treat analysis, the median (IQR) time to achieve FEF was significantly reduced in 94 infants receiving low-dose rh insulin (10.0 [7.0-21.8] days; P = .03) and in 82 infants receiving high-dose rh insulin (10.0 [6.0-15.0] days; P = .001) compared with 85 infants receiving placebo (14.0 [8.0-28.0] days). Compared with placebo, the difference in median (95% CI) time to FEF was 4.0 (1.0-8.0) days for the low-dose group and 4.0 (1.0-7.0) days for the high-dose group. Weight gain rates did not differ significantly between groups. Necrotizing enterocolitis (Bell stage 2 or 3) occurred in 7 of 108 infants (6%) in the low-dose group, 4 of 88 infants (5%) in the high-dose group, and 10 of 97 infants (10%) in the placebo group. None of the infants developed serum insulin antibodies. Results of this randomized clinical trial revealed that enteral administration of 2 different rh-insulin dosages was safe and compared with placebo, significantly reduced time to FEF in preterm infants with a GA of 26 to 32 weeks. These findings support the use of rh insulin as a supplement to human milk and preterm formula. ClinicalTrials.gov Identifier: NCT02510560.

Aortic intima media thickness in children and adolescents with type 1 diabetes: A systematic review.

AimsGreater aortic intima media thickness (aIMT), a marker of subclinical atherosclerosis, can identify individuals at risk of CVD. This systematic review with meta‐analysis compared aIMT in youth with type 1 diabetes and healthy controls.MethodsA systematic search of published literature (to July 2021) was undertaken using electronic databases MEDLINE, EMBASE, Scopus, CINAHL and AMED. Eligible studies reported aIMT in participants aged <20 years with type 1 diabetes and healthy controls. Meta‐analysis was used to combine outcome data, presented as forest plots. Moderator analysis and metaregression were conducted to identify study and participant characteristics associated with aIMT. Publication bias was assessed by funnel plot inspection.ResultsMeta‐analysis of nine studies (n = 1030 with type 1 diabetes and n = 498 healthy control participants) indicated, with high heterogeneity (I2 98%), that youth with type 1 diabetes have higher aIMT compared with healthy controls (mean difference [95% CIs]: 0.11 [0.04, 0.18] mm, P = 0.003). Factors associated with greater aIMT in type 1 diabetes compared to controls included: use of a phased array probe versus linear array probe; longer diabetes duration; higher insulin dose; higher BMI z score and waist circumference; higher LDL cholesterol; higher triglycerides; and higher diastolic blood pressure.ConclusionsType 1 diabetes in youth is associated with higher aIMT compared with healthy control individuals. Longer duration of diabetes and major CVD risk factors were also associated with higher aIMT. Together, these findings provide a strong rationale for targeting modifiable risk factors in CVD prevention. Registered in PROSPERO on 8 August 2019 (CRD42019137559).

Acute glycogenic hepatopathy in pregnancy: a case report and literature review

Abstract Objectives Acute glycogenic hepatopathy (AGH) is a rare complication of poorly controlled diabetes mellitus. This is the first report in the English literature describing accurate diagnosis and management of AGH during pregnancy. Case presentation A 46 year-old gravida 4 para 2 presented at 30 weeks gestation with uncontrolled diabetes, ketoacidosis, and severe hypertension. Euglycemia and normotension were achieved within 24 h of admission but serum transaminase levels which had been normal on admission increased to a very high level over several days, and then resolved spontaneously. Conclusions AGH may occur during pregnancy and should be considered in the context of chronic poorly controlled overt diabetes, rapid normalization of maternal blood glucose levels following high dose insulin therapy, and unexplained new-onset serum transaminase levels elevation. Accurate diagnosis is important because the correct treatment is conservative management, not delivery.

Weight gain trajectories and obesity rates in intensive and conventional treatments of type 1 diabetes from the DCCT compared with a control population without diabetes.

Obesity is a significant health issue for participants with type 1 diabetes undergoing intensive diabetes management. The temporal pattern and factors associated with weight gain after treatment initiation remain poorly understood including how weight gain in participants with and without type I diabetes compare. Our aim was to compare weight gain in those receiving intensive (INT) and conventional (CONV) type 1 diabetes treatment to a population without diabetes. Participants included men and women of 18years and older in the Diabetes Control and Complications Trial (DCCT) randomized to INT (n=562) or CONV (n=568) and a prospective, observational cohort without diabetes from the Coronary Artery Development in Young Adults (CARDIA, controls) study (n=2446). Body mass index (BMI) trajectories and obesity prevalence were compared between groups and candidate metabolic and therapeutic moderators investigated. Annual weight gain with INT peaked 1.3years after initiation and was greater than both CONV and controls before and after this peak. Obesity prevalence with INT was lower than controls at baseline, was similar to controls at 2years and surpassed controls by 5years. Obesity rates with CONV remained below controls at all time points. Greater annual weight gain in the DCCT was associated with lower haemoglobin A1c , higher insulin dose and family history of type 2 diabetes. Greater weight gain accompanying INT therapy occurs in two stages, leads to similar or greater obesity rates than controls after 2years and is primarily modified by glucose control and family history, supportive of a therapeutic-genetic influence on weight trajectories.