Impact of tight glucose control on circulating 3-hydroxybutyrate in critically ill patients.

BACKGROUND: Recent evidence suggests a potentially protective effect of increasing ketone body availability via accepting low macronutrient intake early after onset of critical illness. The impact of blood glucose control with insulin on circulating ketones is unclear. Whereas lowering blood glucose may activate ketogenesis, high insulin concentrations may have the opposite effect. We hypothesized that the previously reported protective effects of tight glucose control in critically ill patients receiving early parenteral nutrition may have been mediated in part by activation of ketogenesis. METHODS: This is a secondary analysis of 3 randomized controlled trials on tight versus liberal blood glucose control in the intensive care unit, including 700 critically ill children and 2748 critically ill adults. All patients received early parenteral nutrition as part of the contemporary standard of care. Before studying a potential mediator role of circulating ketones in improving outcome, we performed a time course analysis to investigate whether tight glucose control significantly affected ketogenesis and to identify a day of maximal effect, if any. We quantified plasma/serum 3-hydroxybutyrate concentrations from intensive care unit admission until day 3 in 2 matched subsets of 100 critically ill children and 100 critically ill adults. Univariable differences between groups were investigated by Kruskal-Wallis test. Differences in 3-hydroxybutyrate concentrations between study days were investigated by Wilcoxon signed-rank test. RESULTS: In critically ill children and adults receiving early parenteral nutrition, tight glucose control, as compared with liberal glucose control, lowered mean morning blood glucose on days 1-3 (P < 0.0001) via infusing insulin at a higher dose (P < 0.0001). Throughout the study period, caloric intake was not different between groups. In both children and adults, tight glucose control did not affect 3-hydroxybutyrate concentrations, which were suppressed on ICU days 1-3 and significantly lower than the ICU admission values for both groups (P < 0.0001). CONCLUSION: Tight versus liberal glucose control in the context of early parenteral nutrition did not affect 3-hydroxybutyrate concentrations in critically ill patients. Hence, the protective effects of tight glucose control in this context cannot be attributed to increased ketone body availability.

Type 1 diabetes glycemic management: Insulin therapy, glucose monitoring, and automation.

Despite innovations in insulin therapy since its discovery, most patients living with type 1 diabetes do not achieve sufficient glycemic control to prevent complications, and they experience hypoglycemia, weight gain, and major self-care burden. Promising pharmacological advances in insulin therapy include the refinement of extremely rapid insulin analogs, alternate insulin-delivery routes, liver-selective insulins, add-on drugs that enhance insulin effect, and glucose-responsive insulin molecules. The greatest future impact will come from combining these pharmacological solutions with existing automated insulin delivery methods that integrate insulin pumps and glucose sensors. These systems will use algorithms enhanced by machine learning, supplemented by technologies that include activity monitors and sensors for other key metabolites such as ketones. The future challenges facing clinicians and researchers will be those of access and broad clinical implementation.

iGlarLixi reduces residual hyperglycemia in Japanese patients with type 2 diabetes uncontrolled on basal insulin: A post-hoc analysis of the LixiLan JP-L trial.

INTRODUCTION: Treatments for type 2 diabetes targeting baseline glucose levels but not postprandial glucose can result in normalized fasting blood glucose but suboptimal overall glycemic control (high glycated hemoglobin): residual hyperglycemia. In Japanese patients with type 2 diabetes the predominant pathophysiology is a lower insulin secretory capacity, and residual hyperglycemia is common with basal insulin treatment. Single-injection, fixed-ratio combinations of glucagon-like peptide-1 receptor agonists and basal insulin have been developed. iGlarLixi (insulin glargine 100 units/mL [iGlar]: lixisenatide ratio of 1 unit:1 µg) is for specific use in Japan. Post-hoc analysis of the LixiLan JP-L trial (NCT02752412) compared the effect of iGlarLixi with iGlar on this specific subpopulation with residual hyperglycemia. MATERIALS AND METHODS: Outcomes at week 26 (based on the last observation carried forward) were assessed in patients in the modified intent-to-treat population with baseline residual hyperglycemia. RESULTS: Overall, 83 (32.5%) patients in the iGlarLixi group and 79 (30.7%) patients in the iGlar group had baseline residual hyperglycemia. The proportion of patients with residual hyperglycemia at week 26 decreased to 15.7% in the iGlarLixi group, and increased to 36.9% in the iGlar group. Patients in the iGlarLixi group had significantly greater reductions in glycated hemoglobin compared with the iGlar group (-0.72% difference between groups; P < 0.0001). CONCLUSIONS: New data from this post-hoc analysis of the JP-L trial show that treatment with the fixed-ratio combination iGlarLixi reduced the proportion of Japanese patients with residual hyperglycemia from baseline to week 26 and significantly reduced glycated hemoglobin vs similar doses of iGlar alone.

Comparative clinical outcomes of insulin degludec and insulin glargine 300 U/mL after switching from other basal insulins in real-world patients with type 1 and type 2 diabetes.

AIMS/INTRODUCTION: To evaluate and compare the efficacy of insulin degludec (IDeg) and insulin glargine 300 U/mL (Gla300) 6 months after switching from other basal insulins by assessing the changes in glycated hemoglobin (HbA1c), body mass index (BMI), and insulin doses in patients with type 1 and type 2 diabetes in a real-world clinical setting. MATERIALS AND METHODS: A total of 307 patients with type 1 diabetes and 294 patients with type 2 diabetes with HbA1c >7.0% were studied. Adjusted mean changes in HbA1c, BMI, and insulin doses were compared between IDeg (IDeg group) and Gla300 (Gla300 group) switchers. Multivariable logistic regression analyses were carried out to examine whether the IDeg or Gla300 group was associated with HbA1c or insulin dose reduction and BMI gain. RESULTS: HbA1c was significantly decreased in both the IDeg and Gla300 groups. Adjusted mean changes in HbA1c (approximately -0.3% and -0.5% in type 1 diabetes and type 2 diabetes patients, respectively) and BMI were similar between both groups. The mean change in insulin dose was slightly larger for dose reduction in the IDeg group than in the Gla300 group. Multivariable logistic regression models showed that the IDeg group was significantly associated with insulin dose reduction after adjusting for basal insulin type, insulin dose, and number of basal insulin injections at baseline and other confounding factors. CONCLUSIONS: The current study suggested that IDeg and Gla300 have similar effects in reducing HbA1c and gaining BMI after switching from other basal insulins in Japanese patients with type 1 diabetes and type 2 diabetes. IDeg selection was associated with insulin dose reduction.

The effect of insulin pump combined with ulinastatin on the levels of PCT, TG, PTX-3, and CX3CL1 in patients with diabetic ketoacidosis and pancreatitis.

ABSTRACT: The aim of this research is to observe the effect of insulin pump combined with Ulinastatin on the levels of procalcitonin (PCT), triglycerides (TG), pentraxin-3(PTX-3), and C-X3-C motif chemokine ligand 1 (CX3CL1) in patients with diabetic ketoacidosis and pancreatitis.A total of 72 patients with diabetic ketoacidosis and pancreatitis who were admitted to our hospital from February 2016 to February 2020 were selected as the research subjects. They were divided into study groups (36 cases, given insulin pump combined Ulinastatin treatment) and control group (36 cases, given insulin pump treatment). Statistics of changes in blood amylase (AMS), blood glucose, blood ketones, glycosylated hemoglobin (HbA1c), PCT, TG, PTX-3, and chemokine CX3CL in pancreatic tissue before and after treatment.After treatment, the clinical efficacy of the study group was significantly higher than that of the control group (94.44% vs 75.00%), the difference was significant (P < .05). After treatment, the clinical symptoms (abdominal distension, abdominal pain, body temperature, blood sugar, HbA1c and blood amylase) in the study group were significantly less time-to-normal than in the control group, and the difference was significant (P < .05). After treatment, the AMS, blood sugar, HbA1c, and blood ketones of the 2 groups were all lower than before treatment, and the study group's AMS, blood sugar, HbA1c, and blood ketones were all lower In the control group, the difference was significant (P < .05). After treatment, the 2 groups of PCT, TG, PTX-3, and CX3CL were all lower than before treatment, among which the study group PCT, TG, PTX-3, and CX3CL1 were lower than the control group, the difference was significant (P < .05). After treatment, the total adverse reaction rate of the 2 groups was not significantly different (P > .05), but the total adverse reaction rate of the study group was lower than that of the control group.The combination of insulin pump and ulinastatin in the treatment of patients with diabetic ketoacidosis complicated with acute pancreatitis has a effect, which can shorten the recovery time of clinical symptoms, reduce the levels of PCT, TG, PTX-3, and CX3CL1, and has fewer adverse reactions. It is worthy of clinical application.

Impact of Insulin Treatment on Prognosis of non-B non-C Hepatocellular Carcinoma After Hepatectomy.

BACKGROUND/AIM: Several studies have reported that DM is closely associated with an increased incidence of hepatocellular carcinoma (HCC). To clarify the effects of diabetes mellitus (DM) and antidiabetic medications on the prognosis of patients with non-B non-C (NBNC) HCC following curative initial hepatectomy. PATIENTS AND METHODS: HCC patients (n=156) were divided into three groups according to the presence or absence of chronic viral hepatitis: hepatitis B virus (HBV) group, hepatitis C virus (HCV) group, and NBNC group. The clinical characteristics and survival outcomes were compared. In the NBNC group, univariate and multivariate analyses were conducted to determine prognostic factors. RESULTS: The NBNC group had a higher incidence of DM, ethanol intake, and large nodules than the other groups. Disease-free survival (DFS) was significantly worse in the NBNC group than in the HBV group. In the NBNC group, insulin treatment was an independent prognostic factor for DFS and overall survival (OS). CONCLUSION: Medications for DM that affect insulin resistance might be appropriate prognostic factors for NBNC-HCC.

Improving the treatment of patients with diabetes using insulin analogues: current findings and future directions.

Introduction: The aim of insulin replacement in insulin-deficient people (type 1 diabetes, pancreatic causes of diabetes, long-standing type 2 diabetes) is to approximate the physiologic insulin action profile as closely as possible. However, short-acting human insulins start too slow and act too long, causing postprandial hyperglycemia and delayed hypoglycemia, while the insulin action profile of long-acting human insulins is too variable in duration and strength of action, leading to insufficient basal insulin covering and peak insulin levels after injection causing early nocturnal hypoglycemia. Insulin analogues were designed to overcome these shortcomings. In insulin-resistant people (type 2 diabetes), insulin analogues contribute to more efficient and safer insulin supplementation. Areas covered: In this review, we describe the unmet needs for insulin therapy, the currently available short- and long-acting insulin analogues and some considerations on cardiovascular outcomes, use in special populations, and cost-effectiveness. Finally, we discuss what is new in the field of insulin analogues. Expert opinion: The development of insulin analogues is an important step in diabetes treatment. Despite many patients meeting their glycemic targets with the newest analogues, hypoglycemic episodes remain a major problem. More physiologic insulin regimens, with glucose-sensitive or organ-targeting insulin analogues may be the answer to these issues.

ISPAD Clinical Practice Consensus Guideline: Diabetic ketoacidosis in the time of COVID-19 and resource-limited settings-role of subcutaneous insulin.

The International Society for Pediatric and Adolescent Diabetes Clinical Practice Consensus Guideline 2018 for management of diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar state provide comprehensive guidance for management of DKA in young people. Intravenous (IV) infusion of insulin remains the treatment of choice for treating DKA; however, the policy of many hospitals around the world requires admission to an intensive care unit (ICU) for IV insulin infusion. During the coronavirus 2019 (COVID-19) pandemic or other settings where intensive care resources are limited, ICU services may need to be prioritized or may not be appropriate due to risk of transmission of infection to young people with type 1 or type 2 diabetes. The aim of this guideline, which should be used in conjunction with the ISPAD 2018 guidelines, is to ensure that young individuals with DKA receive management according to best evidence in the context of limited ICU resources. Specifically, this guideline summarizes evidence for the role of subcutaneous insulin in treatment of uncomplicated mild to moderate DKA in young people and may be implemented if administration of IV insulin is not an option.

Intense 99mTc-MDP Uptake in the Abdominal Soft Tissue Secondary to Subcutaneous Insulin Injection.

A 65-year-old woman with known breast cancer presented with lower back pain over 1 month. Multiple sclerotic foci of increased tracer uptake in the bones were noted on the Tc-MDP bone scintigraphy and SPECT/CT images, suggesting osteoblastic metastasis. Unexpectedly, symmetric Tc-MDP activity was visualized in the soft tissue near the umbilical area, corresponding to the sites of insulin injection.

Reducing the Burden of Diabetes Treatment: A Review of Low-cost Oral Hypoglycemic Medications.

BACKGROUND: The vast majority of individuals diagnosed with diabetes are low/middle income and may have access to only three of the 11 oral hypoglycemic medications (OHMs) due to cost: metformin intermediate release (IR) or extended release (ER), sulfonylureas (glimepiride, glipizide, glyburide), and pioglitazone. Sulfonylureas and pioglitazone have had significant controversy related to potential adverse events, but it remains unclear whether these negative outcomes are class, drug, or dose-related. OBJECTIVE: We conducted a narrative review of low-cost OHMs. METHODS: We evaluated the maximum recommended (MAX) compared to the most effective (EFF) daily dose, time-to-peak change in HbA1c levels, and adverse events of low-cost oral hypoglycemic medications. RESULTS: We found that the MAX was often greater than the EFF: metformin IR/ER (MAX: 2,550/2,000 mg, EFF: 1,500-2,000/1,500-2,000 mg), glipizide IR/ER (MAX: 40/20 mg, EFF: 20/5 mg), glyburide (MAX: 20 mg, EFF: 2.5-5.0 mg), pioglitazone (MAX: 45 mg, EFF: 45 mg). Time-to-peak change in HbA1c levels occurred at weeks 12-20 (sulfonylureas), 25-39 (metformin), and 25 (pioglitazone). Glimepiride was not associated with weight gain, hypoglycemia, or negative cardiovascular events relative to other sulfonylureas. Cardiovascular event rates did not increase with lower glyburide doses (p<0.05). Glimepiride and pioglitazone have been successfully used in renal impairment. CONCLUSION: Metformin, glimepiride, and pioglitazone are safe and efficacious OHMs. Prescribing at the EFF rather than the MAX may avoid negative dose-related outcomes. OHMs should be evaluated as individual drugs, not generalized as a class, due to different dosing and adverse-event profiles; Glimepiride is the preferred sulfonylurea since it is not associated with the adverse events as others in its class.

Towards in vitro in vivo correlation for modified release subcutaneously administered insulins.

Therapeutic proteins and peptides are mainly administrated by subcutaneous injection. In vitro release testing of subcutaneous injectables performed using methods that take the structure and environment of the subcutaneous tissue into account may improve predictability of the in vivo behavior and thereby facilitate establishment of in vitro in vivo correlations. The aim of the study was to develop a biopredictive flow-through in vitro release method with a gel-type matrix for subcutaneously administered formulations and to explore the possibility of establishing a level A in vitro in vivo correlation for selected insulin products. A novel gel-based flow-through method with the incorporation of an injection step was used to assess selected commercial insulin formulations with different duration of action (Actrapid®, Mixtard® 30, Insulatard®, Lantus®). The in vitro release method provided the correct rank ordering in relation to the in vivo performance. For the modified release insulins Insulatard® and Lantus®, an in vitro in vivo correlation using non-linear time scaling was established based on the in vitro release data and in vivo subcutaneous absorption data of the 125I-labeled insulins taken from literature. Predicted absorption profiles were constructed using the in vitro in vivo correlation and subsequently converted into simulated plasma profiles. The approach taken may be of wider utility in characterizing injectables for subcutaneous administration.

[Contact allergy due to insulin pumps and glucose sensor systems]. / Kontaktallergie auf Glukosemesssysteme und Insulinpumpen.

The design and development of insulin pumps and various glucose sensor systems has an enormous impact on life quality of diabetic patients. Surveillance and therapy of diabetes has improved due to the new diabetic devices, which are affixed to the patients' skin for several days. Since their introduction, irritant and allergic contact dermatitis have been frequently reported. Patients often acquire contact sensitization to isobornyl acrylate, N,N-dimethylacrylamide or formerly to 2­ethyl-cyanoacrylate. These contact allergens were found in the patch, in the glue to affix the box on the patch or in the casing of the system itself. Development of contact allergy to substances of these systems may result in the need to abandon modern diabetic devices.

Does Type 1 Diabetic Adolescents' Fear of Stigmatization Predict a Negative Perception Insulin Treatment?

The purpose of this study was to investigate stigmatization, sociodemographic/diabetes-related characteristics and parents-related characteristics as predictors of a negative perception of insulin treatment in adolescents with type 1 diabetes in Turkey. The study was carried out using a cross-sectional correlation design. The research sample included 80 adolescents with type 1 diabetes who volunteered to take part. A positive perception of insulin treatment (ß = -.38, p < .001), stigmatization (ß = -.24, p = .013), informing others about one's type 1 diabetes (ß = .24, p = .017) and only using insulin when alone in public places (ß = .19, p = .042) were significant predictors of a negative perception of insulin treatment, and these variables explained 35% of the common variance. Diabetes' nurses should take stigmatization into account during their training and plan appropriate measures. Entrepreneurial, randomized, and controlled studies should be conducted to decrease the negative influence of stigmatization on the perception of insulin treatment in individuals with type 1 diabetes.

Insulin-derived amyloidosis without a palpable mass at the insulin injection site: A report of two cases.

To date, almost all case reports of insulin-derived amyloidosis described the presence of a subcutaneous mass that was observable on physical examination. This report presents two cases of insulin-derived amyloidosis without palpable masses at insulin injection sites. In both cases, blood glucose concentrations improved, and the insulin dose could be reduced by an average of 45% after changing the insulin injection sites. The insulin absorption at the site was reduced to at most 40% of that at a normal site in one case. Magnetic resonance imaging and ultrasonography were useful to screen and differentiate insulin-derived amyloidosis without a palpable mass. This report showed that insulin-derived amyloidosis without a palpable mass can be present at the insulin injection site, and has similar clinical effects to insulin-derived amyloidosis with palpable masses.