Low-dose Insulin Infusion Research Articles

Implementation of perioperative blood glucose monitoring and insulin infusion protocol can decrease postoperative infection rate in diabetic patients undergoing elective craniotomy: An observational study

BackgroundSevere perioperative hyperglycemia (SH) is a proven risk factor for postoperative complications after craniotomy. To reduce this risk, it has been proposed to implement the standardized clinical protocol for scheduled perioperative blood glucose concentration (BGC) monitoring. This would be followed by intravenous (IV) insulin infusion to keep BGC below 180 mg/dl in the perioperative period. The aim of this prospective observational study was to assess the impact of this type of protocol on the postoperative infection rate in patients undergoing elective craniotomy. MethodsA total of 42 patients were prospectively enrolled in the study. Protocol included scheduled BGC monitoring in the perioperative period and rapid-acting insulin IV infusion when intraoperative SH was detected. The diagnosis of infection (wound, pulmonary, blood stream, urinary tract infection or central nervous system infection) was established according to CDC criteria within the first postoperative week. A previously enrolled group of patients with sporadic BGC monitoring and subcutaneous insulin injections for SH management was used as a control group. ResultsAn infectious complication (i.e., pneumonia) was diagnosed only in one patient (2 %) in the prospective group. In comparison with the control group, a decrease in the risk of postoperative infection was statistically significant with OR = 0.08 [0.009 – 0.72] (p = 0.02). Implementation of the perioperative BGC monitoring and the correction protocol prevented both severe hyperglycemia and hypoglycemia with BGC < 70 mg/dl. ConclusionScheduled BGC monitoring and the use of low-dose insulin infusion protocol can decrease the postoperative infection rate in patients undergoing elective craniotomy. Future studies are needed to prove the causality of the implementation of such a protocol with an improved outcome.

1521-P: Healthy, Nonobese South Asian Men Have Both Greater Peripheral and Hepatic Insulin Resistance than Chinese Men

Introduction: South Asian individuals, despite a healthy weight, are at a greater risk of type 2 diabetes mellitus than Chinese individuals. This may be secondary to higher peripheral and/or hepatic insulin resistance (IR). Using the 2-stepped hyperinsulinemic-euglycemic clamp, we examined the differences in peripheral and hepatic insulin resistance between healthy and non-obese South Asian and Chinese men. Bioimpedance analysis was performed to assess body composition. Methods: A 2-stepped hyperinsulinemic-euglycemic clamp was performed together with a “pancreatic” clamp by infusing somatostatin. A low-dose insulin (10 mU/m2/min) was infused for 2 hours, followed by high-dose insulin infusion (40 mU/m2/min) for 2 hours. Intravenous 20% glucose was infused to maintain euglycemia (blood glucose = 95-100 mg/dl) for the clamp duration. A higher M value (mg glucose per kg bodyweight per minute) during low-dose insulin infusion reflects lower hepatic IR while a higher M value during high-dose insulin infusion reflects lower peripheral IR. Results: The 2 groups (26 South Asian and 26 Chinese men) had similar age (27.3 vs 26.2 years, p = 0.338), but the South Asian group had slightly higher BMI (24.6 vs 22.9 kg/m2, p = 0.027) and body fat % (23.9 vs. 20.6%, p &amp;lt; 0.05). During low-dose step, the M-value was lower among South Asians compared to Chinese (0.8 ± 0.58 vs. 1.1 ± 0.55 mg/kg/min, p = 0.027). During high-dose step, the M-value was also lower among South Asians compared to Chinese (3.2 ± 2.6 vs. 5.2 ± 3.3 mg/kg/min, p = 0.015). The differences in the M-values between South Asian and Chinese individuals remained significant after correcting for body weight and fat-free mass. Conclusion: Despite a healthy weight, young South Asians have both greater hepatic and peripheral muscle IR than Chinese. Disclosure A.Y.L.Lim: None. H.Tan: None. C.Khoo: None. Funding National Medical Research Council of Singapore (MOH-CNIG19NOV-0002)

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Insulin Infusion Dosing in Pediatric Diabetic Ketoacidosis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

We searched MEDLINE, EMBASE, PubMed, and Cochrane from inception to April 1, 2022. We included randomized controlled trials (RCTs) of children with DKA comparing intravenous insulin infusion administered at 0.05 units/kg/hr (low dose) versus 0.1 units/kg/hr (standard dose). We extracted data independently and in duplicate and pooled using a random effects model. We assessed the overall certainty of evidence for each outcome using the Grading Recommendations Assessment, Development and Evaluation approach. We included four RCTs (n = 190 participants). In children with DKA, low-dose compared with standard-dose insulin infusion probably has no effect on time to resolution of hyperglycemia (mean difference [MD], 0.22 hr fewer; 95% CI, 1.19 hr fewer to 0.75 hr more; moderate certainty), or time to resolution of acidosis (MD, 0.61 hr more; 95% CI, 1.81 hr fewer to 3.02 hr more; moderate certainty). Low-dose insulin infusion probably decreases the incidence of hypokalemia (relative risk [RR], 0.65; 95% CI, 0.47-0.89; moderate certainty) and hypoglycemia (RR, 0.37; 95% CI, 0.15-0.80; moderate certainty), but may have no effect on rate of change of blood glucose (MD, 0.42 mmol/L/hr slower; 95% CI, 1 mmol/L/hr slower to 0.18 mmol/L/hr faster; low certainty). In children with DKA, the use of low-dose insulin infusion is probably as efficacious as standard-dose insulin, and probably reduces treatment-related adverse events. Imprecision limited the certainty in the outcomes of interest, and the generalizability of the results is limited by all studies being performed in a single country.

Efficacy and Safety of Low Dose Insulin Infusion against Standard Dose Insulin Infusion in Children with Diabetic Ketoacidosis- An Open Labelled Randomized Controlled Trial.

Objective:To compare the efficacy and safety of low dose insulin infusion (0.05 U/kg/h) against the standard dose insulin infusion (0.1 U/kg/h) in children with diabetic ketoacidosis.Method:Children (age <12 years, n = 30) presenting with diabetic ketoacidosis were enrolled and randomised to receive insulin infusion either as 0.05 U/kg/h (low dose) or 0.1 U/kg/h (standard dose) as an open labelled randomised controlled trial. The rest of the management was identical in both groups. The time taken for resolution of acidosis (pH ≥7.3 and HCO3 ≥15) was the primary outcome variable. The secondary outcome variables included the time taken until a decline in blood glucose to 250 mg/dl, the proportion of children developing hypoglycemia and hypokalemia, and any treatment failure.Results:The two groups were similar with respect to mean age, weight and gender distribution. New-onset diabetes was diagnosed on 24/30. The mean ± SD time for resolution of acidosis was similar between the groups; 27.0 ± 6.1 hours in the low dose group vs 23.4 ± 7.3 hours in standard dose group, P = 0.16. The mean time for the decline in blood glucose to 250 mg/dl was 13.0 ± 5.9 hours in low dose vs 11.6 ± 6.0 hours in standard dose group, P = 0.52. A lesser proportion of participants developed hypoglycemia and hypokalemia in the low dose group, though not statistically significant. There was no incidence of treatment failure in either group.Conclusion:Low dose insulin infusion is equally effective and safe as standard dose insulin infusion in children with diabetic ketoacidosis.

Differential insulin sensitivity of NMR-based metabolomic measures in a two-step hyperinsulinemic euglycemic clamp study

BackgroundInsulin is the key regulator of glucose metabolism, but it is difficult to dissect direct insulin from glucose-induced effects. We aimed to investigate the effects of hyperinsulemia on metabolomic measures under euglycemic conditions in nondiabetic participants.MethodsWe assessed concentrations of 151 metabolomic measures throughout a two-step hyperinsulinemic euglycemic clamp procedure. We included 24 participants (50% women, mean age = 62 [s.d. = 4.2] years) and metabolomic measures were assessed under baseline, low-dose (10 mU/m2/min) and high-dose (40 mU/m2/min) insulin conditions. The effects of low- and high-dose insulin infusion on metabolomic measures were analyzed using linear mixed-effect models for repeated measures.ResultsAfter low-dose insulin infusion, 90 metabolomic measures changed in concentration (p < 1.34e−4), among which glycerol (beta [Confidence Interval] = − 1.41 [− 1.54, − 1.27] s.d., p = 1.28e−95) and three-hydroxybutyrate (− 1.22 [− 1.36, − 1.07] s.d., p = 1.44e−61) showed largest effect sizes. After high-dose insulin infusion, 121 metabolomic measures changed in concentration, among which branched-chain amino acids showed the largest additional decrease compared with low-dose insulin infusion (e.g., Leucine, − 1.78 [− 1.88, − 1.69] s.d., P = 2.7e−295). More specifically, after low- and high-dose insulin infusion, the distribution of the lipoproteins shifted towards more LDL-sized particles with decreased mean diameters.ConclusionMetabolomic measures are differentially insulin sensitive and may thus be differentially affected by the development of insulin resistance. Moreover, our data suggests insulin directly affects metabolomic measures previously associated with increased cardiovascular disease risk.

921-P: Do Glucose and Lipid Metabolism Differ by Adiposity in Adolescents with Type 1 Diabetes (T1D)? Preliminary Results of a 2-Step Clamp Study

Puberty is a known stage of insulin resistance in lean adolescents with or without T1D. Moreover, 25% of adolescents with T1D in clinical practice are overweight, which may further contribute to insulin resistance. The present study examines whether higher body fat aggravates insulin resistance in the liver, muscle, and adipose tissue in pubertal adolescents with T1D by performing a 2-step, 8 and 80 mU/m2/min hyperinsulinemic euglycemic clamp. Body Composition was measured by DEXA, abdominal fat by MRI and hepatic fat by MRI-proton density fat fraction (PDFF). Endogenous glucose production and glycerol turnover were traced with [6,6-2H2] glucose and [2H5]-glycerol (Figure). Participants (mean age 14.4±1.2 years, A1c 7.6±0.5%) with lower (22.9) and higher (36.7) mean % body fat had mean weights of 61.6 and 68.1 kg, BMI% 68.3 and 84.8, and PDFF 1.4 and 1.7%, respectively. Endogenous glucose production was partially suppressed across the body fat spectrum during the low dose insulin infusion. In contrast, those with higher body fat tended to have diminished suppression of glucose production during the high dose insulin infusion. Rates of lipolysis appear to be unaffected. Hence our preliminary findings suggest that on the spectrum of increasing body fat in pubertal adolescents with T1D, we start to see metabolic inflexibility in youth with a moderate degree of adiposity. Disclosure M. A. Van name: None. S. Siebel: None. E. M. Tichy: None. S. Caprio: None. W. V. Tamborlane: Consultant; Self; Medtronic, Sanofi, Other Relationship; Self; Tolerion, Inc. N. Santoro: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK115894-01A1)

Low-Dose (0.05 Unit/kg/hour) vs Standard-Dose (0.1 Unit/kg/hour) Insulin in the Management of Pediatric Diabetic Ketoacidosis: A Randomized Double-Blind Controlled Trial

To compare the efficacy of insulin infusion of 0.05 Unit/kg/hour vs 0.1 Unit/kg/hour in the management of pediatric diabetic ketoacidosis (DKA). Randomized, double-blind controlled clinical trial. Pediatric critical care division of a tertiary care hospital from October, 2014 to July, 2018. Children aged 12 years or younger with a diagnosis of DKA. Children with septic shock and those who had received insulin before enrollment were excluded. Low-dose (0.05 Unit/kg/hour) vs. Standard-dose (0.1 Unit/kg/hour) insulin infusion. The primary endpoint was time for resolution of DKA (pH ≥7.3, bicarbonate ≥15 mEq/L, beta-hydroxybutyrate <1 mmol/L). Secondary outcomes were the rate of fall in blood glucose until 250 mg/dL or less and the rate of complications (hypokalemia, hypoglycemia, and cerebral edema). Sixty patients were analyzed on an intention-to-treat basis (Low-dose group: n=30; Standard-dose group: n=30). Mean (SD) time taken for the resolution of ketoacidosis was similar in both groups [22 (12) vs 23 (18.5) hours; P=0.92]. The adjusted hazard ratio (95% CI) of the resolution of ketoacidosis was lower in the low-dose group [0.40 (0.19 to 0.85); P=0.017]. Mean (SD) rate of blood glucose decrease until 250 mg/dL or less reached [56 (41) vs 64 (65) mg/dL/hour; P=0.41] and time to achieve the target [4.2 (3.1) vs 4.8 (3.3) hours; P=0.44] were similar in both groups. Hypokalemia [30% vs 43.3%; P=0.28] and hypoglycemia [3.3% vs 13.3%; P=0.35] were lower in low-dose group. No child had cerebral edema, and no mortality occurred. Time for resolution of ketoacidosis was similar in the low-dose and standard-dose insulin with a lower rate of therapy-related complications in the low-dose group. Hence, low-dose insulin infusion can be a safer approach in the management of pediatric DKA.

Sodium-glucose cotransporter 2 inhibition does not reduce hepatic steatosis in overweight, insulin-resistant patients without type 2 diabetes.

Background and AimNon‐alcoholic fatty liver disease (NAFLD) is rapidly becoming the leading indication for liver transplant and is associated with increased cardiovascular and liver mortality, yet there are no licensed therapies. Sodium‐glucose cotransporter 2 (SGLT2) inhibitors are widely used for their glucose‐lowering effects in patients with type 2 diabetes (T2D). Preclinical models have suggested a beneficial impact on NAFLD, but clinical data are limited, and there are currently no data on patients without T2D. We aimed to investigate the impact of SGLT2 inhibition on NAFLD in overweight, nondiabetic patients and establish the effect these agents may have on the processes that regulate hepatic steatosis in vivo.MethodsWe conducted an open‐label, experimental medicine pilot study on insulin‐resistant overweight/obese individuals (n = 10) using gold‐standard noninvasive assessments of NAFLD phenotype, including magnetic resonance spectroscopy, two‐step hyperinsulinemic euglycemic clamps, and stable isotope tracers to assess lipid and glucose metabolism. Investigations were performed before and after a 12‐week treatment with the SGLT2 inhibitor, dapagliflozin.ResultsDespite a body weight reduction of 4.4 kg, hepatic steatosis was unchanged following treatment. Hepatic glucose production increased, and there was impairment of glucose disposal during the low‐dose insulin infusion. Although circulating, nonesterified, fatty acid levels did not change, the ability of insulin to suppress lipolysis was reduced.ConclusionsSGLT2 inhibition for 12 weeks does not improve hepatic steatosis in patients without T2D. Additional studies in patients with established T2D or impairments of fasting or postprandial glucose homeostasis are needed to determine whether SGLT2 inhibition represents a viable therapeutic strategy for NAFLD. (http://clinicaltrials.gov Number NCT02696941).

Iatrogenic Hyperinsulinemia, Not Hyperglycemia, Drives Insulin Resistance in Type 1 Diabetes as Revealed by Comparison With GCK-MODY (MODY2).

Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is uncertain. We therefore determined the relative contributions of hyperglycemia and iatrogenic hyperinsulinemia to insulin resistance using hyperinsulinemic-euglycemic clamps in three participant groups (n = 10/group) with differing insulinemia and glycemia: healthy control subjects (euinsulinemia and euglycemia), glucokinase–maturity-onset diabetes of the young (GCK-MODY; euinsulinemia and hyperglycemia), and type 1 diabetes (hyperinsulinemia and hyperglycemia matching GCK-MODY). We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes. Hemoglobin A1c was normal in control subjects and similarly elevated for type 1 diabetes and GCK-MODY. Basal insulin levels in control subjects and GCK-MODY were nearly equal but were 2.5-fold higher in type 1 diabetes. Low-dose insulin infusion suppressed endogenous glucose production similarly in all groups and suppressed nonesterified fatty acids similarly between control subjects and GCK-MODY, but to a lesser extent for type 1 diabetes. High-dose insulin infusion stimulated glucose disposal similarly in control subjects and GCK-MODY but was 29% and 22% less effective in type 1 diabetes, respectively. Multivariable linear regression showed that insulinemia—but not glycemia—was significantly associated with muscle insulin sensitivity. These data suggest that iatrogenic hyperinsulinemia predominates in driving insulin resistance in type 1 diabetes.

Insulin Requirements and Management in Trans-Catheter vs. Surgical Aortic Valve Replacement

Objective: Trans-catheter Aortic Valve Replacement/Aortic Valve Implantation (TAVR) are increasingly performed today. We compared insulin requirements between TAVR and Surgical Aortic Valve Replacement (SAVR) patients with and without diabetes mellitus (DM) to determine optimal glucose management strategies during the perioperative period (POP). Methods: Charts of consecutive patients undergoing aortic procedures were retrospectively reviewed for glucose ranges, insulin requirements and routes of insulin administration (subcutaneous vs. intravenous) for patients with and without DM to maintain BG < 180 mg/dl and compared between the surgical and trans-catheter groups. Results: Patients with SAVRs without DM and A1C < 6.5%, needed low dose insulin infusions and could be transitioned to subcutaneous insulin by 1.5 postoperative days. Patients with SAVR and DM had higher insulin requirements and were transitioned by 2.5 postoperative days. Patients with TAVR with no known DM did not need an insulin infusion in the perioperative period. Patients with TAVR with DM and an HbA1C < 6.5% did not require insulin infusions during the procedure but only postoperatively for short periods. Patients with DM and A1C ≥ 6.5%, required higher doses of insulin infusion and transitioned to subcutaneous insulin by postoperative day 1. Conclusions: TAVR patients have different insulin requirements compared to SAVRs (p < 0.05). This information helps build a glucose management algorithm for a procedure which is increasingly performed.

Insulin Acutely Regulates Gene Expression in Brain–A New Potential Major Level of Control of Metabolism and Neurotransmission

While the brain is now recognized as an insulin sensitive tissue, and impaired insulin signaling in brain can lead to many metabolic and behavioral abnormalities, effects of insulin on gene expression in the brain remain largely unknown. To understand now this aspect of insulin action may impact physiology in vivo, we performed hyperinsulinemic-euglycemic clamps at low (4 mU/kg/min) and high (12 mU/kg/min) physiological doses of insulin in C57BL/6 mice, and after 3 hours collected different brain regions and analyzed their transcriptomes using RNA Seq. In response to low dose insulin infusion, 1851 genes were up- or down-regulated in the hypothalamus by at least 50% (all P &amp;lt; 0.01). This was more than 4-fold as the number of genes regulated in liver or muscle under the same conditions. Other regions showed different responses with 2significantly regulated by at least 50% in hippocampus and 131 regulated in nucleus accumbens. The most upregulated pathway in all three regions was that for very long chain fatty acyl-CoA synthesis, indicating an important role of insulin action on brain fatty acid metabolism. Most other insulin responsive genes in these three brain regions were distinct. In the hypothalamus, insulin played a key role in modulating genes involved in neurotransmission in the hypothalamus, including enhancing the GABA-A receptor signaling pathway and suppressing neuropeptide signaling pathways. Insulin also modulated metabolism in the hypothalamus by suppressing the glycolysis and pentose phosphate pathways, while increasing the pyruvate dehydrogenase complex and cholesterol biosynthesis. Thus, insulin action in the brain acutely and potently regulates expression of genes involved in brain metabolism, neurotransmission and neuromodulation. In this way, insulin re-routes the carbon source to the biogenesis of plasma membrane for neuronal and glial function and synaptic remodeling. Disclosure W. Cai: None. A. Ramirez: None. J. Dreyfuss: None. T.M. Batista: None. R. Garcia Martin: None. H. Pan: None. M.E. Li: None. B.T. O'Neill: None. J.K. Kim: None. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.

Hyperinsulinemic Normoglycemia during Cardiac Surgery Reduces a Composite of 30-day Mortality and Serious In-hospital Complications: A Randomized Clinical Trial.

Hyperinsulinemic normoglycemia augments myocardial glucose uptake and utilization. We tested the hypothesis that hyperinsulinemic normoglycemia reduces 30-day mortality and morbidity after cardiac surgery. This dual-center, parallel-group, superiority trial randomized cardiac surgical patients between August 2007 and March 2015 at the Cleveland Clinic, Cleveland, Ohio, and Royal Victoria Hospital, Montreal, Canada, to intraoperative glycemic management with (1) hyperinsulinemic normoglycemia, a fixed high-dose insulin and concomitant variable glucose infusion titrated to glucose concentrations of 80 to 110 mg · dl; or (2) standard glycemic management, low-dose insulin infusion targeting glucose greater than 150 mg · dl. The primary outcome was a composite of 30-day mortality, mechanical circulatory support, infection, renal or neurologic morbidity. Interim analyses were planned at each 12.5% enrollment of a maximum 2,790 patients. At the third interim analysis (n = 1,439; hyperinsulinemic normoglycemia, 709, standard glycemic management, 730; 52% of planned maximum), the efficacy boundary was crossed and study stopped per protocol. Time-weighted average glucose concentration (means ± SDs) with hyperinsulinemic normoglycemia was 108 ± 20 versus 150 ± 33 mg · dl with standard glycemic management, P < 0.001. At least one component of the composite outcome occurred in 49 (6.9%) patients receiving hyperinsulinemic normoglycemia versus 82 (11.2%) receiving standard glucose management (P < efficacy boundary 0.0085); estimated relative risk (95% interim-adjusted CI) 0.62 (0.39 to 0.97), P = 0.0043. There was a treatment-by-site interaction (P = 0.063); relative risk for the composite outcome was 0.49 (0.26 to 0.91, P = 0.0007, n = 921) at Royal Victoria Hospital, but 0.96 (0.41 to 2.24, P = 0.89, n = 518) at the Cleveland Clinic. Severe hypoglycemia (less than 40 mg · dl) occurred in 6 (0.9%) patients. Intraoperative hyperinsulinemic normoglycemia reduced mortality and morbidity after cardiac surgery. Providing exogenous glucose while targeting normoglycemia may be preferable to simply normalizing glucose concentrations.

Acute interaction between hydrocortisone and insulin alters the plasma metabolome in humans

With the aim of identifying biomarkers of glucocorticoid action and their relationship with biomarkers of insulin action, metabolomic profiling was carried out in plasma samples from twenty healthy men who were administered either a low or medium dose insulin infusion (n = 10 each group). In addition, all subjects were given metyrapone (to inhibit adrenal cortisol secretion) + /− hydrocortisone (HC) in a randomised crossover design to produce low, medium and high glucocorticoid levels. The clearest effects of insulin were to reduce plasma levels of the branched chain amino acids (BCAs) leucine/isoleucine and their deaminated metabolites, and lowered free fatty acids and acylcarnitines. The highest dose of hydrocortisone increased plasma BCAs in both insulin groups but increased free fatty acids only in the high insulin group, however hydrocortisone did not affect the levels of acyl carnitines in either group. The clearest interaction between HC and insulin was that hydrocortisone produced an elevation in levels of BCAs and their metabolites which were lowered by insulin. The direct modulation of BCAs by glucocorticoids and insulin may provide the basis for improved in vivo monitoring of glucocorticoid and insulin action.

Review of Evidence for Adult Diabetic Ketoacidosis Management Protocols.

Diabetic ketoacidosis (DKA) is an endocrine emergency with associated risk of morbidity and mortality. Despite this, DKA management lacks strong evidence due to the absence of large randomised controlled trials (RCTs). To review existing studies investigating inpatient DKA management in adults, focusing on intravenous (IV) fluids; insulin administration; potassium, bicarbonate, and phosphate replacement; and DKA management protocols and impact of DKA resolution rates on outcomes. Ovid Medline searches were conducted with limits "all adult" and published between "1973 to current" applied. National consensus statements were also reviewed. Eligibility was determined by two reviewers' assessment of title, abstract, and availability. A total of 85 eligible articles published between 1973 and 2016 were reviewed. The salient findings were (i) Crystalloids are favoured over colloids though evidence is lacking. The preferred crystalloid and hydration rates remain contentious. (ii) IV infusion of regular human insulin is preferred over the subcutaneous route or rapid acting insulin analogues. Administering an initial IV insulin bolus before low-dose insulin infusions obviates the need for supplemental insulin. Consensus-statements recommend fixed weight-based over "sliding scale" insulin infusions although evidence is weak. (iii) Potassium replacement is imperative although no trials compare replacement rates. (iv) Bicarbonate replacement offers no benefit in DKA with pH > 6.9. In severe metabolic acidosis with pH < 6.9, there is lack of both data and consensus regarding bicarbonate administration. (v) There is no evidence that phosphate replacement offers outcome benefits. Guidelines consider replacement appropriate in patients with cardiac dysfunction, anaemia, respiratory depression, or phosphate levels <0.32 mmol/L. (vi) Upon resolution of DKA, subcutaneous insulin is recommended with IV insulin infusions ceased with an overlap of 1-2 h. (vii) DKA resolution rates are often used as end points in studies, despite a lack of evidence that rapid resolution improves outcome. (viii) Implementation of DKA protocols lacks strong evidence for adherence but may lead to improved clinical outcomes. There are major deficiencies in evidence for optimal management of DKA. Current practice is guided by weak evidence and consensus opinion. All aspects of DKA management require RCTs to affirm or redirect management and formulate consensus evidence-based practice to improve patient outcomes.

Methods for quantifying adipose tissue insulin resistance in overweight/obese humans.

Insulin resistance of adipose tissue is an important feature of obesity-related metabolic disease. However, assessment of lipolysis in humans requires labor-intensive and expensive methods, and there is limited validation of simplified measurement methods. We aimed to validate simplified methods for the quantification of adipose tissue insulin resistance against the assessment of insulin sensitivity of lipolysis suppression during hyperinsulinemic-euglycemic clamp studies. We assessed the insulin-mediated suppression of lipolysis by tracer-dilution of [1,1,2,3,3-2H5]glycerol during hyperinsulinemic-euglycemic clamp studies in 125 overweight or obese adults (85 men, 40 women; age 50±11 years; body mass index 38±7 kg m-2). Seven indices of adipose tissue insulin resistance were validated against the reference measurement method. Low-dose insulin infusion resulted in suppression of the glycerol rate of appearance ranging from 4% (most resistant) to 85% (most sensitive), indicating a good range of adipose tissue insulin sensitivity in the study population. The reference method correlated with (1) insulin-mediated suppression of plasma glycerol concentrations (r=0.960, P<0.001), (2) suppression of plasma non-esterified fatty acid (NEFA) concentrations (r=0.899, P<0.001), (3) the Adipose tissue Insulin Resistance (Adipo-IR) index (fasting plasma insulin-NEFA product; r=-0.526, P<0.001), (4) the fasting plasma insulin-glycerol product (r=-0.467, P<0.001), (5) the Adipose Tissue Insulin Resistance Index (fasting plasma insulin-basal lipolysis product; r=0.460, P<0.001), (6) the Quantitative Insulin Sensitivity Check Index (QUICKI)-NEFA index (r=0.621, P<0.001), and (7) the QUICKI-glycerol index (r=0.671, P<0.001). Bland-Altman plots showed no systematic errors for the suppression indices but proportional errors for all fasting indices. Receiver-operator characteristic curves confirmed that all indices were able to detect adipose tissue insulin resistance (area under the curve ⩾0.801, P<0.001). Adipose tissue insulin sensitivity (that is, the antilipolytic action of insulin) can be reliably quantified in overweight and obese humans by simplified index methods. The sensitivity and specificity of the Adipo-IR index and the fasting plasma insulin-glycerol product, combined with their simplicity and acceptable agreement, suggest that these may be most useful in clinical practice.

Consumption of red and processed meat and refined grains for 4 weeks decreases insulin sensitivity in insulin-resistant adults: A randomized crossover study

BackgroundRed and processed meat and refined grains are associated with an increased risk of type 2 diabetes. Interventions are limited. We hypothesized that a diet high in red and processed meat and refined grains (HMD) would decrease insulin sensitivity compared to a diet high in whole grains, nuts, dairy and legumes with no red meat (HWD). MethodsForty-nine subjects without diabetes [15 men and 34 women, age, 35.6±15.7 years, body mass index (BMI), 27±5.9kg/m2] underwent two 4-week weight-stable dietary interventions in a randomized crossover design. The insulin sensitivity index (ISI) was calculated from the last 30min of a continuous low-dose insulin (25mU/kg·h) and glucose (4mg/kg·min) infusion test (LDIGIT 120–150min) at the end of each diet. ResultsThe population fell into two very discrete groups: those with a very low insulin response in the LDIGIT 120–150min on HMD (Group 1<56pmol/L, n=24), and those with relatively normal insulin responses (Group 2>56pmol/L, n=25). Group 2 had significantly higher insulin concentrations [(median and interquartile range) 153, 180 for HMD vs. 123, 149pmol/L for HWD; P=0.019] and glucose concentrations [(mean±standard deviation) 7.4±1.3 for HMD vs.6.7±1.2mmol/L for HWD; P=0.05], resulting in a significantly decreased ISI [(median and interquartile range) 21.1, 34.2 for HMD vs. 31.6, 39.4 for HWD; P=0.014] compared to HWD. Log ISI after HMD was significantly correlated with BMI (r=−0.5; P=0.009), fat mass (r=−0.55; P=0.004) and self-reported activity levels (r=−0.45; P=0.024). ConclusionsA dietary pattern high in red and processed meat and refined grains decreased insulin sensitivity compared to a dietary pattern high in whole grains, nuts, dairy products and legumes only in relatively insulin-resistant adults.

Challenging the One-Dose-Fits-All Model for Insulin in the Acute Treatment of Pediatric Diabetic Ketoacidosis. A Critical Appraisal of "Low-Dose Versus Standard-Dose Insulin in Pediatric Diabetic Ketoacidosis: A Randomized Clinical Trial" by Nallasamy et al (JAMA Pediatrics 2014; 168:999-1005).

To review the findings and discuss the implications of the use of low-dose insulin infusions in pediatric diabetic ketoacidosis compared with standard-dose insulin. A search of the electronic PubMed database was used to perform the clinical query as well as to search for additional relevant literature. The article by Nallasamy K et al "Low-Dose vs Standard-Dose Insulin in Pediatric Diabetic Ketoacidosis: A Randomized Clinical Trial. JAMA Pediatrics 2014; 17:e477-e480" was selected for critical appraisal and literature review. The authors performed a randomized controlled trial among 50 consecutive patients of 0-12 years old presenting to the emergency department in diabetic ketoacidosis. They found that low-dose (0.05 U/kg/hr) insulin infusion was noninferior to standard-dose (0.1 U/kg/hr) insulin in terms of resolution of hyperglycemia and acidosis with a trend toward lower rates of therapy-related complications in the low-dose group. Low-dose insulin infusion is noninferior to standard-dose insulin in the treatment of younger pediatric patients with diabetic ketoacidosis and may lead to fewer therapy-related complications.

PP.10.03] SUCCESSFUL RENAL DENERVATION FOR RESISTANT HYPERTENSION FAILS TO IMPROVE INSULIN RESISTANCE AS ASSESSED BY HYPERINSULINEMIC EUGLYCEMIC STEP-CLAMP AND GLUCOSE TRACER INFUSION

Objective: The purpose of this study was to determine whether insulin sensitivity is improved after successful renal denervation (RDN) treatment for resistant hypertension. Design and method: Non-randomized, prospective study of 23 non-diabetic patients with resistant hypertension undergoing a two-step hyperinsulinemic euglycemic clamp with glucose tracer and labeled glucose infusion (HEC) as well as an oral glucose tolerance test (OGTT) before and 6 months after RDN. Whole body glucose disposal (WGD) and endoogenous glucose release (EGR) were calculated. Results: Eighteen of the 23 patients had metabolic syndrome at baseline, and body mass index (32 ± 5 kg/m2 at baseline) was stable during the study. At baseline, fasting plasma glucose was 5.9 ± 0.7 mmol/L, plasma insulin was 147 ± 93 pmol/L and plasma c-peptide was 1456 ± 502 pmol/L. No significant changes in these parameters were observed after 6 months. Basal glu-cose turnover rate and glucose infusion rate during two-step clamping remained unchanged. Suppression of endogenous glucose release during low-dose insulin infusion decreased from 0.9 ± 0.4 to 0.8 ± 0.4 mg/kg/min (p = 0.02), but remained unchanged during high insulin infu-sion. Area under the curve 0–120 min for glucose and insulin during OGTT, homeostasis model assessment-insulin resistance (HOMA-IR), Quantitative Insulin Sensitivity Check Index (ISQUICKI), the Simple Index assessing Insulin Sensitivity oral glucose tolerance (SIisOGTT) did not change significantly. Whole body glucose disposal did not change from basal levels at follow-up (Figure 1).Conclusions: Despite a significant effect on blood pressure, RDN treatment did not improve peripheral or hepatic insulin sensitivity, in this group of non-diabetic patients with resistant hypertension, as assessed by two-step HEC with glucose tracer infusion as well as indices derived from OGTT and fasting blood samples 6 months after RDN.

Aromatase Inhibition Reduces Insulin Sensitivity in Healthy Men.

Context:Deficiency of aromatase, the enzyme that catalyzes the conversion of androgens to estrogens, is associated with insulin resistance in humans and mice.Objective:We hypothesized that pharmacological aromatase inhibition results in peripheral insulin resistance in humans.Design:This was a double-blind, randomized, controlled, crossover study.Setting:The study was conducted at a clinical research facility.Participants:Seventeen healthy male volunteers (18–50 y) participated in the study.Intervention:The intervention included oral anastrozole (1 mg daily) and placebo, each for 6 weeks with a 2-week washout period.Main Outcome Measure:Glucose disposal and rates of lipolysis were measured during a stepwise hyperinsulinemic euglycemic clamp. Data are mean (SEM).Results:Anastrozole therapy resulted in significant estradiol suppression (59.9 ± 3.6 vs 102.0 ± 5.7 pmol/L, P = < .001) and a more modest elevation of total T (25.8 ± 1.2 vs 21.4 ± 0.7 nmol/L, P = .003). Glucose infusion rate, during the low-dose insulin infusion, was lower after anastrozole administration (12.16 ± 1.33 vs 14.15 ± 1.55 μmol/kg·min, P = .024). No differences in hepatic glucose production or rate of lipolysis were observed.Conclusion:Aromatase inhibition reduces insulin sensitivity, with respect to peripheral glucose disposal, in healthy men. Local generation and action of estradiol, at the level of skeletal muscle, is likely to be an important determinant of insulin sensitivity.