Low-dose Insulin Research Articles

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.

Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus—the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) trial

ObjectiveTo assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes.Design and settingInvestigator-initiated,...

Sensory Neurodegeneration in Diabetes: Beyond Glucotoxicity.

Diabetic polyneuropathy in humans is of gradual, sometimes insidious onset, and is more likely to occur if glucose control is poor. Arguments that the disorder arises chiefly from glucose toxicity however ignore the greater complexity of a unique neurodegenerative disorder. For example, sensory neurons regularly thrive in media with levels of glucose at or exceeding those of poorly controlled diabetic persons. Also, all of the linkages between hyperglycemia and neuropathy develop in the setting of altered insulin availability or sensitivity. Insulin itself is recognized as a potent growth, or trophic factor for adult sensory neurons. Low doses of insulin, insufficient to alter blood glucose levels, reverse features of diabetic neurodegeneration in animal models. Insulin resistance, as occurs in diabetic adipose tissue, liver, and muscle, also develops in sensory neurons, offering a mechanism for neurodegeneration in the setting of normal or elevated insulin levels. Other interventions that "shore up" sensory neurons prevent features of diabetic polyneuropathy from developing despite persistent hyperglycemia. More recently evidence has emerged that a series of subtle molecular changes in sensory neurons can be linked to neurodegeneration including epigenetic changes in the control of gene expression. Understanding the new complexity of sensory neuron degeneration may give rise to therapeutic strategies that have a higher chance of success in the clinical trial arena.

Assessment of a Key Message in Newly Diagnosed Type 2 Diabetes Mellitus Patients Considering Their Educational Program

Background: It is well known that therapeutic nutrition education provided to patients with new diagnosed type 2 diabetes mellitus is crucial in terms of subsequent adherence to a dedicated multi-factorial treatment. The patient could be empowered to act on insulin dose and/or on other aspects (calorie intake, therapeutically efforts and sleep schedule etc.) regarding the achievement of the final therapeutic targets. Objective: The aim of this retrospective study was to determine the impact of the message perceived by patients with new diagnosed type 2 diabetes mellitus on the means used in achieving metabolic control at 3 months of treatment after an initial educational program. Method: We performed a retrospective, case-control study of 143 patients with new diagnosed type 2 diabetes mellitus patients admitted to general hospital wards to investigate the relationship between remaining messages after attending our educational program with all methods to achieve adequate metabolic control. It was hypothesized that message have a great impact considering all methods to achieve this targets and are associated with a greater impact of dose insulin. Result: At the moment of evaluation we find that the dose of insulin is significantly different between the two lots: 0.43 ± 0.02 UI/Kgc vs. 0.13 ± 0.01 UI/Kgc, p <0.05; and the level of physical therapeutic effort is also significantly different 2.12 ± 0.35 MET/day vs. 3.51 ± 0.32 MET/day, p<0.05. At the same time weight loss, as well as HbA1c levels that the groups reached, have statistical significance (p<0.05). Conclusion: We could say at the final of our study that the main message of our program is associated with a lower dose of insulin used for treatment of type 2 diabetes mellitus patients.

A Rare Cause of Polyuria and Polydipsia in a Patient With Cystic Renal Disease: Maturity-Onset Diabetes of the Young Type 5

Hepatocyte nuclear factor-1beta (HNF-1beta) is a transcription factor that is responsible for the development of kidney, pancreas, liver and genitourinary tract. Affected individuals may present a variety of renal developmental abnormalities and/or maturity-onset diabetes of the young type 5 (MODY 5). Here we report a boy with autosomal recessive polycystic kidney disease (ARPKD) diagnosed in neonatal period who developed insulin-dependent diabetes at the age of 11. He presented with poliuria and polydipsia. The diagnosis of ARPKD was made in neonatal period based on the findings of large hyperechogenic kidneys in antenatal ultrasound and no history of renal disease in parents. Laboratory investigations revealed hyperglycemia, glycosuria, and a reduced glomerular filtration rate (GFR). Based on autoantibody-negative diabetes and low-dose insulin requirement in addition to renal anomalies, he was suspected to have MODY 5. Genetic studies identified a known heterozygous HNF1B gene mutation (S148L) compatible with an MODY 5 phenotype. As a result, MODY 5 should be considered in children with developmental kidney disease and hyperglycemia. Also HNF-1beta mutations should be suspected in patients with undefined cystic kidney disease especially when associated with other systemic findings as in our case. World J Nephrol Urol. 2016;5(3):67-70 doi: http://dx.doi.org/10.14740/wjnu272w

Dissociation between exercise-induced reduction in liver fat and changes in hepatic and peripheral glucose homoeostasis in obese patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is associated with multi-organ (hepatic, skeletal muscle, adipose tissue) insulin resistance (IR). Exercise is an effective treatment for lowering liver fat but its effect on IR in NAFLD is unknown. We aimed to determine whether supervised exercise in NAFLD would reduce liver fat and improve hepatic and peripheral (skeletal muscle and adipose tissue) insulin sensitivity. Sixty nine NAFLD patients were randomized to 16 weeks exercise supervision (n=38) or counselling (n=31) without dietary modification. All participants underwent MRI/spectroscopy to assess changes in body fat and in liver and skeletal muscle triglyceride, before and following exercise/counselling. To quantify changes in hepatic and peripheral insulin sensitivity, a pre-determined subset (n=12 per group) underwent a two-stage hyperinsulinaemic euglycaemic clamp pre- and post-intervention. Results are shown as mean [95% confidence interval (CI)]. Fifty participants (30 exercise, 20 counselling), 51 years (IQR 40, 56), body mass index (BMI) 31 kg/m(2) (IQR 29, 35) with baseline liver fat/water % of 18.8% (IQR 10.7, 34.6) completed the study (12/12 exercise and 7/12 counselling completed the clamp studies). Supervised exercise mediated a greater reduction in liver fat/water percentage than counselling [Δ mean change 4.7% (0.01, 9.4); P<0.05], which correlated with the change in cardiorespiratory fitness (r=-0.34, P=0.0173). With exercise, peripheral insulin sensitivity significantly increased (following high-dose insulin) despite no significant change in hepatic glucose production (HGP; following low-dose insulin); no changes were observed in the control group. Although supervised exercise effectively reduced liver fat, improving peripheral IR in NAFLD, the reduction in liver fat was insufficient to improve hepatic IR.

Reestablishment of the hyperglycemia to the normal levels seems not to be essential to the anxiolytic-like effect induced by insulin.

Diabetes is a chronic metabolic disease accompanied by several comorbidities, including neuropsychiatric conditions. Since the hyperglycemia appears to be the primary factor involved in diabetic conditions, we examined the effect of insulin treatment in diabetic rats on behavioral responses related to anxiety and aversive memory extinction. For this, normoglycemic (NGL) or streptozotocin-diabetic (DBT) rats were submitted to the elevated T maze (ETM) and the contextual conditioned fear (CCF) tests. Therefore, animals were subjected to the prolonged treatment with insulin (6IU/day, s.c.) to investigate the effect of the treatment on distinct behaviors. When anxiety-like responses such as the inhibitory avoidance (IA) on the ETM and the time of freezing in the first session of the CCF test were evaluated, our data showed a more pronounced anxiogenic-like behavior in DBT animals when compared to NGL ones. In addition, an increased freezing time was observed in DBT animals exposed to the CCF test (sessions 2 and 3) when compared to the NGL group, suggestive of an impairment in the extinction of aversive memory. Insulin treatment induced an anxiolytic-like effect when IA and freezing time (session 1) was evaluated, but did not alter the impaired extinction of aversive memory (sessions 2 and 3). To better understand the involvement of a rigorous control of glycaemia, we also investigated the effect of a lower dose of insulin (3IU/day, s.c.), unable to reestablish the hyperglycemia to the normal levels, on the same behavioral parameters. Our data show that independent of the dose of insulin, the same effects were observed when animals were evaluated in the ETM and CCF tests. However, only the highest dose of insulin was able to reduce the hyperglycemia to the normal levels. To conclude, our data suggest that a severe glycemic control by insulin treatment seems to be important, but not essential in improving diabetes-induced anxiety.

Acute Management of Pediatric Diabetic Ketoacidosis

OPEN ACCESSSeptember 29, 2015Acute Management of Pediatric Diabetic Ketoacidosis Janine Zee-Cheng, MD, Alexander Djuricich, MD, Emily Webber, MD, Samer Abu-Sultaneh, MD Janine Zee-Cheng, MD Indiana University School of Medicine Google Scholar More articles by this author , Alexander Djuricich, MD Indiana University School of Medicine Google Scholar More articles by this author , Emily Webber, MD Indiana University School of Medicine Google Scholar More articles by this author , Samer Abu-Sultaneh, MD Indiana University School of Medicine Google Scholar More articles by this author https://doi.org/10.15766/mep_2374-8265.10219 SectionsAbout ToolsDownload Citations ShareFacebookTwitterEmail Abstract Introduction: This educational tool is a PowerPoint presentation that allows providers to quickly access guidelines for acute management of pediatric diabetic ketoacidosis (DKA). It was created after a chart review of pediatric patients with DKA determined that guidelines of DKA management were being incompletely followed. Methods: The resource contains recommendations from the American Diabetes Association guidelines, as well as a learning module consisting of a case scenario and three questions, each of which highlights important aspects of the care of pediatric patients with DKA. Session length should be no longer than 15 minutes. Results: Data are currently being collected on the reach of this educational tool. Discussion: The resource is limited by its short duration. It was deliberately designed to be readily accessible in a time-limited situation for initial care. Part of the education focuses on the complexity of pediatric patients with DKA, in the process making it clear that the three questions highlight only the most immediate clinical need. As a tool to be used in an acute care setting, this resource is adequate; however, a more comprehensive module with more detailed recommendations could be constructed for learners with less clinical experience. Educational Objectives By the end of this session, learners will be able to: Utilize an educational module and quick reference for established guidelines for pediatric diabetic ketoacidosis (DKA).Evaluate their knowledge and management of pediatric DKA. ReferencesBarrios EK, Hageman J, Lyons E, et al. Current variability of clinical practice management of pediatric diabetic ketoacidosis in Illinois pediatric emergency departments, Pediatr Emerg Care.2012;28(12):1307–1313.Medline, Google ScholarBohn D, Daneman D. Diabetic ketoacidosis and cerebral edema, Curr Opin Pediatr.2002;14(3):287–291. http://dx.doi.org/10.1097/00008480-200206000-00001Medline, Google ScholarClark MG, Dalabih A. Variability of DKA management among pediatric emergency room and critical care providers: a call for more evidence-based and cost-effective care?J Clin Res Pediatr Endocrinol.2014;6(3):190–191. http://dx.doi.org/10.4274/jcrpe.1434Medline, Google ScholarEdge JA, Hawkins MM, Winter DL, Dunger DB. The risk and outcome of cerebral oedema developing during diabetic ketoacidosis, Arch Dis Child.2001;85(1):16–22. http://dx.doi.org/10.1136/adc.85.1.16Medline, Google ScholarEdge JA, Jakes R, Ray Y, et al. The UK prospective study of cerebral oedema complicating diabetic ketoacidosis, Arch Dis Child.2005;90(suppl 2):A2–A3.Medline, Google ScholarGlaser N, Barnett P, McCaslin I, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis, N Eng J Med.2001;344(4):264–269. http://dx.doi.org/10.1056/NEJM200101253440404Medline, Google ScholarGlaser NS, Kuppermann N, Yee CKJ, Schwartz DL, Styne DM. Variation in the management of pediatric diabetic ketoacidosis by specialty training, Arch Pediatr Adolesc Med.1997;151(11):1125–1132. http://dx.doi.org/10.1001/archpedi.1997.02170480055008Medline, Google ScholarLawrence SE, Cummings EA, Gaboury I, Daneman D. Population-based study of incidence and risk factors for cerebral edema in pediatric diabetic ketoacidosis, J Pediatr.2005;146(5):688–692. http://dx.doi.org/10.1016/j.jpeds.2004.12.041Medline, Google ScholarLindsay R, Bolte RG. The use of an insulin bolus in low-dose insulin infusion for pediatric diabetic ketoacidosis, Pediatr Emerg Care.1989;5(2):77–79. http://dx.doi.org/10.1097/00006565-198906000-00001Medline, Google ScholarRewers A, Dong F, Slover RH, Klingensmith GJ, Rewers M. Incidence of diabetic ketoacidosis at diagnosis of type 1 diabetes in Colorado youth, 1998-2012, JAMA.2015;313(15):1570–1572. http://dx.doi.org/10.1001/jama.2015.1414Medline, Google ScholarWatts W, Edge JA. How can cerebral edema during treatment of diabetic ketoacidosis be avoided?Pediatr Diabetes.2014;15(4):271–276. http://dx.doi.org/10.1111/pedi.12155Medline, Google ScholarWolfsdorf J, Craig ME, Daneman D, et al. Diabetic ketoacidosis in children and adolescents with diabetes, Pediatr Diabetes.2009;10(suppl 12):118–133. http://dx.doi.org/10.1111/j.1399-5448.2009.00569.xMedline, Google ScholarWolfsdorf J, Glaser N, Sperling MA. Diabetic ketoacidosis in infants, children, and adolescents: a consensus statement from the American Diabetes Association, Diabetes Care.2006;29(5):1150–1159. http://dx.doi.org/10.2337/dc06-9909Medline, Google Scholar Sign up for the latest publications from MedEdPORTAL Add your email below FILES INCLUDEDReferencesRelatedDetails FILES INCLUDED Included in this publication: Pediatric DKA Instructor's Guide.pdf Pediatric DKA Module.pptx To view all publication components, extract (i.e., unzip) them from the downloaded .zip file. Download editor’s noteThis publication may contain technology or a display format that is no longer in use. CitationZee-Cheng J, Djuricich A, Webber E, Abu-Sultaneh S. Acute Management of Pediatric Diabetic Ketoacidosis. MedEdPORTAL. 2015;11:10219. https://doi.org/10.15766/mep_2374-8265.10219 Copyright & Permissions© 2015 Zee-Cheng et al. This is an open-access publication distributed under the terms of the Creative Commons Attribution-NonCommercial license.KeywordsDiabetic KetoacidosisDKAPediatricsEmergency Medical ServicesPediatric DKADiabetesEndocrinology Disclosures None to report. Funding/Support None to report. tabs.loading

Incidence of Hypoglycemia in Patients With Low eGFR Treated With Insulin and Dextrose for Hyperkalemia.

Hyperkalemia is a potentially life-threatening condition that is common in kidney disease patients. Insulin is used to treat hyperkalemia, but may cause hypoglycemia, especially in kidney disease when insulin may be metabolized more slowly. We compared the rates of hypoglycemia in patients with low estimated glomerular filtration rate (eGFR) using high versus low doses of insulin for hyperkalemia to determine if lower doses of insulin would decrease the incidence of hypoglycemia. This was a retrospective study of hospitalized patients receiving intravenous insulin for hyperkalemia during a 6-month period. Patients with low eGFR were analyzed based on how much insulin they received: high dose (10 units, n = 78) versus low dose (5 units, n = 71). Postdose nadir blood glucose values were examined for up to 8 hours after the dose. The percentage of hypoglycemia (blood glucose ≤70 mg/dl) and a subset of severe hypoglycemia (blood glucose <50 mg/dl) were then reported for each dose group. A total of 149 doses were identified in patients with low eGFR. The rates of hypoglycemia were 16.7% and 19.7% (P = 0.79), respectively, among high-dose (n = 78) and low-dose (n = 71) groups. Rates of severe hypoglycemia were 8.9% and 7.0%, respectively (P = 0.90). More than 28% of hypoglycemic episodes with high doses occurred after 4 hours (median = 2.5 hours) compared with 14.3% with low doses (median = 2.38 hours). There was no difference in the rate of hypoglycemia or severe hypoglycemia between high or low doses of insulin in patients with low eGFR. We recommend monitoring up to 6 hours after insulin use in hyperkalemia.

Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis

Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH. Fourteen patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomised, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes. Liraglutide reduced BMI (-1.9 vs. +0.04kg/m(2); p<0.001), HbA1c (-0.3 vs. +0.3%; p<0.01), cholesterol-LDL (-0.7 vs. +0.05mmol/L; p<0.01), ALT (-54 vs. -4.0IU/L; p<0.01) and serum leptin, adiponectin, and CCL-2 (all p<0.05). Liraglutide increased hepatic insulin sensitivity (-9.36 vs. -2.54% suppression of hepatic endogenous glucose production with low-dose insulin; p<0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (-24.9 vs. +54.8pmol/L insulin required to ½ maximally suppress serum non-esterified fatty acids; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic de novo lipogenesis in vivo (-1.26 vs. +1.30%; p<0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01). Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.

Phenotypic Characterization of Insulin-Resistant and Insulin-Sensitive Obesity.

Whereas insulin resistance and obesity coexist, some obese individuals remain insulin sensitive. We examined phenotypic and metabolic factors associated with insulin sensitivity in both muscle and liver in obese individuals. Sixty-four nondiabetic obese adults (29 males) underwent hyperinsulinemic (15 and 80 mU/m(2) · min)-euglycemic clamps with deuterated glucose. Top tertile subjects for glucose infusion rate during the high-dose insulin clamp were assigned Musclesen and those in the lower two tertiles were assigned Muscleres. Secondarily, top tertile subjects for endogenous glucose production suppression during the low-dose insulin clamp were deemed Liversen and the remainder Liverres. Clinical and laboratory parameters and visceral, subcutaneous, liver, and pancreatic fat were compared. Musclesen and Muscleres had similar body mass index and total fat (P > .16), but Musclesen had lower glycated hemoglobin (P < .001) and systolic (P = .01) and diastolic (P = .03) blood pressure (BP). Despite similar sc fat (P = 1), Musclesen had lower visceral (P < .001) and liver (P < .001) fat. Liversen had lower visceral (P < .01) and liver (P < .01) fat and C-reactive protein (P = .02) than Liverres. When subjects were grouped by both glucose infusion rate during the high-dose insulin clamp and endogenous glucose production suppression, insulin sensitivity at either muscle or liver conferred apparent protection from the adverse metabolic features that characterized subjects insulin resistant at both sites. High-density lipoprotein-cholesterol, 1-hour glucose, systolic BP, and triglycerides explained 54% of the variance in muscle insulin sensitivity. Obese subjects who were insulin sensitive at muscle and/or liver exhibited favorable metabolic features, including lower BP, liver and visceral adiposity. This study identifies factors associated with, and possibly contributing to, insulin sensitivity in obesity.

Role of PKCδ in Insulin Sensitivity and Skeletal Muscle Metabolism

Protein kinase C (PKC)δ has been shown to be increased in liver in obesity and plays an important role in the development of hepatic insulin resistance in both mice and humans. In the current study, we explored the role of PKCδ in skeletal muscle in the control of insulin sensitivity and glucose metabolism by generating mice in which PKCδ was deleted specifically in muscle using Cre-lox recombination. Deletion of PKCδ in muscle improved insulin signaling in young mice, especially at low insulin doses; however, this did not change glucose tolerance or insulin tolerance tests done with pharmacological levels of insulin. Likewise, in young mice, muscle-specific deletion of PKCδ did not rescue high-fat diet–induced insulin resistance or glucose intolerance. However, with an increase in age, PKCδ levels in muscle increased, and by 6 to 7 months of age, muscle-specific deletion of PKCδ improved whole-body insulin sensitivity and muscle insulin resistance and by 15 months of age improved the age-related decline in whole-body glucose tolerance. At 15 months of age, M-PKCδKO mice also exhibited decreased metabolic rate and lower levels of some proteins of the OXPHOS complex suggesting a role for PKCδ in the regulation of mitochondrial mass at older age. These data indicate an important role of PKCδ in the regulation of insulin sensitivity and mitochondrial homeostasis in skeletal muscle with aging.

Early Clinical Detection of Pharmacologic Response in Insulin Action in a Nondiabetic Insulin-Resistant Population

BackgroundInsulin resistance heightens the risk for type 2 diabetes mellitus and cardiovascular disease. Amelioration of insulin resistance may reduce this risk. The thiazolidinedone class of insulin sensitizers improves insulin action in individuals with insulin-resistant diabetes and nondiabetic individuals. However, there are few reports on the time of onset of such effects independent of reversal of glucotoxicity. ObjectiveThe goal of our study was to test whether the thiazolidinedione pioglitazone has prominent early metabolic effects that can be detected in an obese, nondiabetic, insulin-resistant population. MethodsWe conducted a randomized, double-blind, placebo-controlled, parallel-group trial in men with nondiabetic insulin resistance using a hyperinsulinemic euglycemic clamp technique (at low and high doses of insulin at 10 and 40 mU/m2/min, respectively). The patients were given 30 mg daily oral pioglitazone or placebo for 28 days. Patients underwent a baseline clamp before initiation of treatment, and again at 14 and 28 days of treatment. ResultsCompared with placebo, under high-dose hyperinsulinemia, pioglitazone led to significant increases in glucose disposal rates (GDR) of 1.29 mg/kg/min (90% CI, 0.43–2.15; 39%; P=0.008) that were detectable at 2 weeks of treatment and persisted at 4 weeks of treatment. Under low-dose hyperinsulinemia, significant increases in GDR of 0.40 mg/kg/min (90% CI, 0.17–0.62; 95%; P=0.003) were observed at 4 weeks of treatment. These responses were accompanied by robust suppression of free fatty acids under hyperinsulinemic conditions, and by significant increases in circulating basal total adiponectin at 2 and 4 weeks of treatment. ConclusionsSignificant changes in insulin action across multiple insulin-sensitive tissues can be detected within 2 weeks of initiation of insulin-sensitizing therapy with pioglitazone in obese patients with nondiabetic insulin resistance. ClinicalTrials.gov identifier: NCT01115712.

A randomized controlled trial comparing treatment with oral agents and basal insulin in elderly patients with type 2 diabetes in long-term care facilities

BackgroundManaging hyperglycemia and diabetes is challenging in geriatric patients admitted to long-term care (LTC) facilities.MethodsThis randomized control trial enrolled patients with type 2 diabetes (T2D) with blood glucose (BG) >180...

The Mobile Insulin Titration Intervention (MITI) for Insulin Adjustment in an Urban, Low-Income Population: Randomized Controlled Trial.

BackgroundDiabetes patients are usually started on a low dose of insulin and their dose is adjusted or “titrated” according to their blood glucose levels. Insulin titration administered through face-to-face visits with a clinician can be time consuming and logistically burdensome for patients, especially those of low socioeconomic status (SES). Given the wide use of mobile phones among this population, there is the potential to use short message service (SMS) text messaging and phone calls to perform insulin titration remotely.ObjectiveThe goals of this pilot study were to (1) evaluate if our Mobile Insulin Titration Intervention (MITI) intervention using text messaging and phone calls was effective in helping patients reach their optimal insulin glargine dose within 12 weeks, (2) assess the feasibility of the intervention within our clinic setting and patient population, (3) collect data on the cost savings associated with the intervention, and (4) measure patient satisfaction with the intervention.MethodsThis was a pilot study evaluating an intervention for patients requiring insulin glargine titration in the outpatient medical clinic of Bellevue Hospital Center in New York City. Patients in the intervention arm received weekday SMS text messages from a health management platform requesting their fasting blood glucose values. The clinic’s diabetes nurse educator monitored the texted responses on the platform website each weekday for alarm values. Once a week, the nurse reviewed the glucose values, consulted the MITI titration algorithm, and called patients to adjust their insulin dose. Patients in the usual care arm continued to receive their standard clinic care for insulin titration. The primary outcome was whether a patient reached his/her optimal insulin glargine dose within 12 weeks.ResultsA total of 61 patients consented and were randomized into the study. A significantly greater proportion of patients in the intervention arm reached their optimal insulin glargine dose than patients in the usual care arm (88%, 29/33 vs 37%, 10/27; P<.001). Patients responded to 84.3% (420/498) of the SMS text messages requesting their blood glucose values. The nurse reached patients within 2 attempts or by voicemail 91% of the time (90/99 assigned calls). When patients traveled to the clinic, they spent a median of 45 minutes (IQR 30-60) on travel and 39 minutes (IQR 30-64) waiting prior to appointments. A total of 61% (37/61) of patients had appointment copays. After participating in the study, patients in the intervention arm reported higher treatment satisfaction than those in the usual care arm.ConclusionsMITI is an effective way to help low-SES patients reach their optimal insulin glargine dose using basic SMS text messaging and phone calls. The intervention was feasible and patients were highly satisfied with their treatment. The intervention was cost saving in terms of time for patients, who were able to have their insulin titrated without multiple clinic appointments. Similar interventions should be explored to improve care for low-SES patients managing chronic disease.Trial RegistrationClinicaltrials.gov NCT01879579; https://clinicaltrials.gov/ct2/show/NCT01879579 (Archived by WebCite at http://www.webcitation.org/6YZik33L3).

SGLT2 Inhibitors May Predispose to Ketoacidosis.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.

Strategies for preservation of memory function in patients with brain metastases.

Cognitive decline, particularly in memory, is a side effect seen in patients with brain metastases and when severe, can have a significant impact on their quality of life. It is most often the result of multiple intersecting etiologic factors, including the use of whole brain radiation therapy, effects of which, in part, are mediated by damage within the hippocampus. A variety of clinical factors and comorbidities may impact the likelihood and severity of this cognitive decline, and affected patients should be considered for evaluation in a comprehensive neuro-rehabilitation or "brain fitness" program. Avoiding WBRT is warranted for some patients with brain metastases; particularly those <50 years old. However, when WBRT is clinically indicated, hippocampal avoidance WBRT (HA-WBRT) has been shown to significantly reduce memory decline compared to historical controls without compromising treatment efficacy. Additionally, the NMDA receptor antagonist memantine and renin-angiotensin-aldosterone system (RAAS) blockers have shown promise as neuroprotective agents that could be used prophylactically with radiation. After the onset of neurocognitive decline the treatment is largely symptom-driven, however simply screening for and treating depression, fatigue, anxiety, cognitive slowing, and other processes may alleviate some impairment. Stimulants such as methylphenidate may be useful in treating symptoms of fatigue and cognitive slowing. Other treatments including donepezil and cognitive rehabilitation have been extensively tested in the population at risk for dementia, although they have not been adequately studied in patients following cranial radiotherapy. An innovative hypothetical approach is the use of intranasal metabolic stimulants such as low dose insulin, which could be valuable in improving cognition and memory, by reversing impaired brain metabolic activity. Prevention of neurocognitive decline in patients with brain metastases requires a multimodal approach tailored to each patient's need, avoiding WBRT in some, altering the WBRT plan in others, and/or using neuroprotective prophylaxis in those in whom avoidance cannot be utilized. Likewise treatment will require a personalized combination of strategies optimized to address the patient's symptoms.

Efficacy and safety of insulin degludec in Japanese patients with type1 and type2 diabetes: 24-week results from the observational study in routine clinical practice.

This is first observational prospective study of insulin degludec in routine clinical practice that we evaluated the effect on glycemic control and risk of hypoglycemia in basal‐bolus insulin therapy. We found that insulin degludec can maintain glycemic control at a lower insulin dose and frequency of hypoglycemia in type 1 diabetes, while it can improve glycemic control at equally insulin dose in type 2 diabetes.These results mean that insulin degludec is of use in routine clinical practice.

Insulin dosing in pediatric diabetic ketoacidosis: where to start?

The incidenceof type 1diabetesmellitus is increasing inpediatric populations.1 Although the degree of hyperglycemia and frequencyofketoacidosisat initialpresentationof thosewith type1diabetes have steadily declined,2 diabetic ketoacidosis (DKA) remains the leading cause of death in children and young people (aged <24 years) with type 1 diabetes mellitus.3,4 Cerebral edema can be difficult to recognize and manage in children and represents the major cause of the continuedmortality andmorbidity associatedwith DKA in this population.4 In a report in theNovember2014 issueof JAMAPediatrics, Nallasamy et al5 studied 50 children presenting with DKA after randomizing themto receive standard-dose insulin (0.1U/kg/h)or lowdose insulin (0.05 U/kg/h). The study was powered to detect noninferiority using the rate of decline in blood glucose, until a glucose level of 250 mg/dL or less was reached, as the primary outcome. Secondary outcomes included time to resolution of acidosis, episodesof treatment failure, and incidencesofhypokalemiaand hypoglycemia. The low-dose insulin strategy was found to be noninferior across all outcomemeasures in this open-label clinical trial. The authors used a straightforward study design and had a high recruitment rate, despite the inherent difficulties in performing a study of this nature, particularly in a pediatric population. The results are encouraging, suggesting that a low-dose insulin strategy is a viable treatment option in the treatment of pediatric DKA. Although this study excluded some of the sickest children (symptomatic cerebral edema, septic shock at presentation), JAMAPEDIATRICS

Update on insulin treatment for dogs and cats: insulin dosing pens and more.

Insulin therapy is still the primary therapy for all diabetic dogs and cats. Several insulin options are available for each species, including veterinary registered products and human insulin preparations. The insulin chosen depends on the individual patient’s requirements. Intermediate-acting insulin is usually the first choice for dogs, and longer-acting insulin is the first choice for cats. Once the insulin type is chosen, the best method of insulin administration should be considered. Traditionally, insulin vials and syringes have been used, but insulin pen devices have recently entered the veterinary market. Pens have different handling requirements when compared with standard insulin vials including: storage out of the refrigerator for some insulin preparations once pen cartridges are in use; priming of the pen to ensure a full dose of insulin is administered; and holding the pen device in place for several seconds during the injection. Many different types of pen devices are available, with features such as half-unit dosing, large dials for visually impaired people, and memory that can display the last time and dose of insulin administered. Insulin pens come in both reusable and disposable options. Pens have several benefits over syringes, including improved dose accuracy, especially for low insulin doses.