Blood Glucose Excursions Research Articles

Estrogen Protects Against Olanzapine‐induced Hyperglycemia

Olanzapine is a second‐generation antipsychotic (SGA) used frequently in the treatment of schizophrenia and a growing list of off‐label conditions. Though effective in reducing psychoses, acute olanzapine treatment causes rapid increases in blood glucose that are mediated by increases in liver glucose output, skeletal muscle insulin resistance, and beta cell dysfunction. We recently reported that female, compared to male, mice are protected against acute olanzapine‐induced hyperglycemia. To date the mechanism by which female sex confers protection against olanzapine‐induced excursions in blood glucose have not been identified. The purpose of this study was to determine if the protective effects of the female sex against acute olanzapine‐induced hyperglycemia are due, in part, to female sex hormones and if this is mediated by GLP1 signalling. Ovariectomized (OVX) C57BL/6J mice or sham‐operated female controls were treated with olanzapine (5 mg/ kg, IP) or vehicle and blood glucose was measured at baseline, 15, 30, 60, 90, and 120 minutes post‐treatment. These experiments were repeated in female OVX mice following 2‐days of estradiol (E2) treatment (80 ug/kg/day; I.P.) compared to OVX or SHAM mice treated with vehicle. OVX exacerbated the effects of olanzapine on blood glucose, while the add back of E2 rescued olanzapine‐induced impairments in glucose homeostasis in OVX mice. Serum GLP1 concentrations were increased in female compared to male mice and thus, we wanted to determine if GLP1 signaling could be involved in the protective effects of female sex. Female mice were co‐treated with olanzapine and the GLP1 antagonist Exendin 9–39 (25 nmol/kg BW). GLP1 antagonism in female mice exacerbated olanzapine‐induced hyperglycemia. Given the evidence of E2 and GLP1 conferring a protective effect against olanzapine induced hyperglycemia in female mice, we co‐treated male mice with the GLP1 receptor agonist liraglutide (0.4 mg/kg BW) and olanzapine (5 mg/kg, IP). GLP1 agonism protected male mice from olanzapine‐induced hyperglycemia. Taken together, we provide evidence that the protection conferred by female sex on the hyperglycemic effects of olanzapine is due, at least in part, to E2 and GLP1 and that the protective effects of female sex can be recapitulated in male mice treated with liraglutide. Future work will be needed to determine if the protection afforded by female sex hormones on olanzapine‐induced hyperglycemia are dependent on GLP1 and the importance of this proposed mechanism in humans to provide insight into new adjunct treatments to offset the metabolic side effects of SGA treatment.

Mechanism of glucose-lowering by metformin in type 2 diabetes: Role of bile acids.

Type 2 diabetes mellitus (T2DM) is an increasingly prevalent chronic condition, characterized by abnormally elevated blood glucose concentrations and, as a consequence, increased risk of micro- and macrovascular complications. Metformin is usually the first-line glucose-lowering medication in T2DM; however, despite being used for more than 60 years, the mechanism underlying the glucose-lowering action of metformin remains incompletely understood. Although metformin reduces hepatic glucose production, there is persuasive evidence that the gastrointestinal tract is crucial in mediating this effect, particularly via secretion of the incretin hormone glucagon-like peptide 1 (GLP-1). It is now well recognized that bile acids, in addition to their established function in fat digestion and absorption, are important regulators of glucose metabolism. Exposure of the small and large intestine to bile acids induces GLP-1 secretion, modulates the composition of the gut microbiota, and reduces postprandial blood glucose excursions in humans with and without T2DM. Metformin reduces intestinal bile acid resorption substantially, such that intraluminal bile acids may, at least in part, account for its glucose-lowering effect. The present review focuses on the conceptual shift in our understanding as to how metformin lowers blood glucose in T2DM, with a particular emphasis on the role of intestinal bile acids.

Female mice are protected against acute olanzapine-induced hyperglycemia

Olanzapine is a second-generation antipsychotic (SGA) used frequently in the treatment of schizophrenia and a growing list of off-label conditions. Though effective in reducing psychoses, acute olanzapine treatment causes rapid increases in blood glucose that are believed to be mediated by increases in liver glucose output, skeletal muscle insulin resistance, and beta cell dysfunction. Further, the acute lipidemic response to olanzapine has been largely unexplored. While females have been reported to be more susceptible to olanzapine-induced weight gain, there is little known about the impact of sex on the acute response to SGAs. The purpose of this study was to determine if the acute effects of SGAs on glucose and lipid metabolism display a sexually dimorphic response in C57BL/6 J mice and examine potential mechanisms mediating this effect. Age matched male and female C57BL/6 J mice were treated with olanzapine (5 mg/ kg, IP) or vehicle control and blood glucose was measured at baseline, 15, 30, 60, 90, and 120 min post-treatment and tissues and serum harvested. These experiments were repeated, and mice underwent an insulin (0.5 IU/kg) or pyruvate tolerance test (2 g/kg) following 60 min of olanzapine treatment. Females were protected against olanzapine-induced increases in blood glucose and pyruvate intolerance compared to male mice, and this occurred despite the development of severe insulin resistance. In male mice olanzapine increased the glucagon:insulin ratio whereas in females this ratio was reduced. When challenged with exogenous glucagon (1 mg/kg IP), females were less responsive than males. Male and female mice displayed similar increases in whole body fatty acid oxidation, serum fatty acids and liver triglyceride accumulation. Our findings provide evidence that while there are no apparent sex differences in the lipid metabolism response to olanzapine, that females are protected from acute olanzapine-induced excursions in blood glucose. This is likely due in part to reductions in the glucagon:insulin ratio and glucagon responsiveness which could impact olanzapine induced increases in liver glucose production.

Independent Association of Glucose Variability With Hospital Mortality in Adult Intensive Care Patients: Results From the Australia and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation Binational Registry.

Retrospective, registry data analyses of outcomes. Large, binational registry (Australia and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation Adult Patient Database repository) of 176 ICUs across Australia and New Zealand. We used 10-year data on nonhyperglycemic patients registered in the Australia and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation Adult Patient Database repository (n = 290,966). None. Glucose variability was captured using glucose width defined as the difference between highest and lowest blood glucose concentration within first 24 hours of ICU admission. We used hierarchical, mixed effects logistic regression models that accounted for ICU variation and several fixed-effects covariates. Glucose width was specifically and independently associated with hospital mortality. The association of blood glucose variability with mortality remained significant (odds ratio for highest vs lowest quartile of glucose, 1.43; 95% CI, 1.32-1.55; p < 0.001) even after adjusting for the baseline risk of mortality, midpoint blood glucose level, occurrence of hypoglycemia and inter-ICU variation. Mixed effects modeling showed that there was a statistically significant variation in this association across ICUs. Our study demonstrates that glucose variability is independently associated with hospital mortality in critically ill adult patients. Inclusion of correction for glucose variability in glycemic control protocols needs to be investigated in future studies.

Longitudinal evaluation of gastric emptying in type 2 diabetes

AimsTo evaluate the natural history of gastric emptying in type 2 diabetes. Methods12 patients with type 2 diabetes (7 female; age 65.6 ± 1.2 years; duration of known diabetes 22.9 ± 1.5 years) were invited to return for repeat measurements of gastric emptying using the same dual-labelled solid and liquid meal, a mean of 14.0 ± 0.5 years after their initial study. Blood glucose levels, glycated haemoglobin, upper gastrointestinal symptoms and autonomic nerve function at baseline and follow up were also compared. ResultsGastric emptying of solids was more rapid at follow up than at baseline (period effect P < 0.05), while emptying of liquids was comparable at baseline and follow up (period effect P = 0.2). Gastric emptying of the solid component was abnormally slow (based on T100min) in 6 subjects at baseline and 1 subject at follow up. Liquid emptying was abnormally slow in 6 subjects at baseline, and 5 subjects at follow up. Two patients were insulin treated at baseline, and 6 at follow up. HbA1c was higher at follow up (P < 0.05); however, fasting blood glucose (P = 0.6), postprandial blood glucose excursions (P = 0.07), autonomic nerve function (P > 0.999), and total upper gastrointestinal symptom score (P = 0.1) did not differ. ConclusionsIn patients with long-term type 2 diabetes, gastric emptying of solids and liquids does not usually become more delayed over time, and abnormally slow gastric emptying of solids may improve.

1060-P: Effect of Dulaglutide and Long-Acting Insulin Combination Therapy in Patients with Type 2 Diabetes

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1-RA) are assumed to decrease the number of injections and improve blood glucose control in patients with type 2 diabetes (T2D). We aimed to evaluate the effects of switching from multiple daily insulin injection therapy (MDI) to combination therapy involving a long-acting GLP-1-RA, dulaglutide, and long-acting insulin on glycemic control. Methods: We examined patients with T2D who admitted to our department and underwent blood glucose management with MDI, followed by flash glucose monitoring. The treatment was subsequently switched to dulaglutide + long-acting insulin combination therapy. We evaluated the blood glucose excursion after MDI and 1 and 24 weeks after dulaglutide + long-acting insulin combination therapy. Furthermore, we evaluated hemoglobin A1c (HbA1c) after 12 and 24 weeks of dulaglutide + long-acting insulin combination therapy. Results: We enrolled 20 patients (mean age: 68.6 ± 11.7 years; HbA1c value: 10.1% ± 2.8%; previous MDI: n = 4). Mean blood glucose levels after MDI and 1 and 24 weeks after dulaglutide + long-acting insulin combination therapy were 124.8 ± 35.6, 122.5 ± 30.4, and 119 ± 21.3 mg/dl, respectively. Blood glucose level was significantly lower 24 weeks after dulaglutide + long-acting insulin combination therapy than shortly after MDI (P = 0.0048). Furthermore, blood glucose excursion tended to decrease after switching to dulaglutide + long-acting insulin combination therapy. After 12 and 24 weeks of the switch, HbA1c value significantly decreased (−3.6% ± 0.78%, P = 0.0003 and −3.7% ± 0.78%, P = 0.0002, respectively). Conclusions: The switch from MDI to dulaglutide + long-acting insulin combination therapy resulted in better blood glucose control, with reductions in blood glucose excursion and the number of self-injections; moreover, the effects continued for 24 weeks. Disclosure K. Ito: None. S. Satoh: None. Y. Kondo: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.

74-LB: Impact of Mild and Moderate High Blood Glucose Excursions on Daily Living in Adults with Type 1 Diabetes

Introduction: Severe hyperglycemic events and diabetic ketoacidosis (DKA) have significant effects on daily activity however, the effect of mild and moderate glucose excursions on functioning and quality of life (QoL) remains unknown. This study aimed to assess the impact of these excursions on well-being in a well-managed population with type 1 diabetes (T1D) using survey and CGM data. Methods: Adults with T1D (N = 71), 68.6% female, 93.2% white, aged 44.11 years, average A1c 6.51%, with diabetes for 26.65 years, completed an online survey through T1D Exchange Glu and uploaded CGM data via Tidepool. Results: Moderate high blood glucose (HBG) excursions were most strongly related to QoL (WHO-5) and happiness (Subjective Happiness Scale, SHS). Participants with fewer mild (&amp;gt; 180 mg/dL) HBG excursions had higher WHO-5 scores indicating better QoL when controlling for income and duration of diabetes. Participants who had longer durations in the same range, regardless if it was time in range or mild or moderate hyperglycemia, had higher SHS scores indicating greater happiness when controlled for income and duration of diabetes. Conclusions: This study illustrates the impact of mild HBG excursions and glycemic variability on QoL in people with T1D. HBG excursions were related to QoL and glycemic variability was related to happiness further supporting the urgency to decrease the amount of time hyperglycemic. These results indicate the need to increase time in range and decrease overall blood glucose variability. A limitation includes convenience sampling in a very well-managed population. Future research should further investigate the relationships of these factors in a diverse sample. Disclosure A. Hughes: None. J. Bispham: None. C. Garey: None. J. Liu: None. L. Fuller: None. E.T. Nykaza: None. J.A. Meno: None. A. McAuliffe-Fogarty: None.

867-P: The Impact of Diabetes on Daily Life: Highlights from People with T1D and Their Caregivers

People with type 1 diabetes (T1D) and caregivers of minors with T1D experience significant impact to many aspects of daily life. The impact of diabetes is not limited to monetary costs assessed by healthcare and economic data, but also includes the “cost” of sacrifices, such as sleep disruption and time lost. Limited research exists regarding daily disruptions and missed opportunities due to T1D. This study aimed to identify other aspects that are impacted by T1D in patients and caregivers living in the U.S. Six focus groups were conducted based on previously identified themes regarding finances, missed opportunities, and disruptions in daily activities from patients, caregivers and health care provider interviews. The current study conducted focus groups with people with T1D, ages 23-72 (n=17) and caregivers ages 34-55 (n=14), of minors with T1D. Five focus groups were conducted online and one was conducted in-person (San Diego, CA) with a total of 31 participants. All participants were recruited from T1D Exchange Glu (www.myglu.org), an online community for individuals living with T1D. Focus groups were audio-recorded, transcribed, and thematically analyzed. Participants reported issues with sleep, finance, health insurance (including obtaining supplies), and disruptions in work and school as most impacted by T1D. Overall, the majority of participants reported that their sleep was most impacted. Patients and caregivers experienced substantial amounts of sleep loss due to device alarms and night time blood glucose excursions as well as taking preventative actions to avoid excursions. People with T1D reported time dedicated to managing diabetes had a greater impact on life, while caregivers reported financial and employment sacrifices had the most impact. This study provides insight into the real-world impact of diabetes beyond the more commonly studied healthcare costs. Disclosure J. Bispham: None. A. Hughes: None. M. Perez-Nieves: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. L. Fan: Employee; Self; Lilly Diabetes. Stock/Shareholder; Self; Lilly Diabetes. A. McAuliffe-Fogarty: None.

2299-PUB: Liraglutide-Based Therapy Attained A1C Target with Little Risk of Hypoglycemia: Optimization by Average Daily Risk Range Measurement

Objective: Attainment of appropriate A1C target is indispensable to reduce the risk of diabetes complications in type 2 diabetic (T2D) patients. The aim of this study is to evaluate the ability of GLP-1 receptor agonist, liraglutide (Lira), to achieve A1C &amp;lt;7.0% without increase of hypoglycemia risk. Methods: A total of 194 patients (65.5±12.6 year-old) on Lira-based therapy (LBT) with T2D were included in the analysis. Effectiveness was compared before and after introduction of LBT. Glycaemic variability was evaluated by calculating hypoglycemia-sensitive ADRR score in patients who did self-blood glucose monitoring (SMBG). To avoid hypoglycemia, basal insulin was reduced when fasting blood glucose level reached &amp;lt;80mg/dL. Results: 1) Before change to LBT, even on insulin based basal-bolus therapy (BBT) (n=21) only 23.8% of the patients achieved the target, and on pre-mixed insulin therapy (MIX) (n=34), 20.6%. 2) Change to LBT improved the average of A1C from 9.7% to 7.1%, and the target was achieved in 55.7% of all patients (n=108/194). 3) Further, all patients were analyzed after divided into 3 groups by the treatment: Lira mono-injection (n=71), Lira+basal insulin (n=106), Lira+BBT/MIX therapy (n=17) group. In Lira mono-injection group, A1C was markedly improved from 10.1% to 6.6%, although the duration of diabetes was shortest (6.7±8.0 years) among 3 groups. The proportion of patients who achieved the target was 69.0%, 50.0%, and 35.3%, respectively. 4) 61.8% of patients at age of 70s also achieved the target by LBT. 5) To optimize blood glucose excursion, SMBG was done in 59.3% of patients. In patients who achieved A1C &amp;lt;7.0%, 82.2% (37/45) showed ADRR scores less than 10. Moreover, in patients who achieved more stringent A1C &amp;lt;6.0%, 73.3% (11/15) of patients showed much lower ADRR scores less than 5, indicating marked reduction of hypoglycemia risk. Conclusion: LBT makes it easier to achieve lower A1C target without risking hypoglycemia in all ages. Disclosure K. Kashima: None. H. Shimizu: None. M. Yamada: None.

Effects of Nicorandil and Chronic Physical Exercise on Glycemia in Diabetic Rats Induced by Streptozotocin

Diabetes is a chronic metabolic disease characterized by persistent hyperglycemia caused by a decrease or deficiency of insulin secretion and/or peripheral insulin resistance. Regular physical exercise could improves glucose metabolism and insulin sensitivity, which is essential for preventing diabetic complications. Moreover, there is evidence that the opening of ATP sensitive potassium (KATP) channels contributes to cytoprotective effects under metabolic stress, therefore KATP channels could be a therapeutic target in this disease. Thus, the purpose of this study was to assess the impact of the potential effects of nicorandil (KATP channel opener) after a chronic exercise training program on levels glicemic in diabetic rats.Male Wistar rats (23–25 days old) were randomly divided into six groups, among them: sedentary control, trained control, sedentary diabetic, trained diabetic, sedentary diabetic plus nicorandil, trained diabetic plus nicorandil. Diabetes was induced by a single streptozotocin injection (100 mg/kg body weight), animals with fasting blood glucose levels ≥ 250 mg/dL were considered as diabetic. Training comprised 8 weeks of treadmill running (30 minutes daily, 5 days/week); at week 4, nicorandil (3 mg/kg) was administered for to 4 weeks. Fasting blood glucose (FBG) level was recorded every week for 8 consecutive weeks. At the end of experimental protocol, insulin tolerance test (ITT) was evaluated in all groups, rats received a application of insulin (0.75UI/kg body weight), with blood samples drawn after 0, 30, 60, 90 and 120 min postinjection. Blood glucose response to ITT was calculated as area under the curve (AUC‐ITT) of the blood glucose excursion along 120 minutes after intra‐peritoneal insulin injection and correlated with the corresponding fasting values according to the trapezoidal method.Treatment with nicorandil and the chronic exercise exerted remarkable effects on hyperglycemic status in diabetic rats by decreases FBG levels (47.51± 10.2 %) and inducing significant increases in the insulin sensitivity (P&lt; 0.05) compared with sedentary diabetic rats and trained diabetic rats. Our results suggest than opening KATP channels by nicorandil mediates potential benefits the chronic physical exercise on glycemic in diabetes.Support or Funding InformationWe thank Universidad de Guanajuato, Campus León. We acknowledge the financing PRODEP (Programa para el Desarrollo Profesional Docente en Educación Superior, ESD (511‐6/18‐8876).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A performance bound for optimal insulin infusion in individuals with Type 1 diabetes ingesting a meal with slow postprandial response

Recent work, Goodwin et al. (2015, 2018), has established that, subject to an assumption regarding the relative blood glucose response times of meal and insulin, it is optimal for the minimisation of the peak blood glucose excursion to apply a bolus of insulin at the time of (or slightly prior to) meal ingestion. A key assumption underlying this result is that the impact of an impulse of insulin “lasts longer” than the impact of an impulse of food. The result is consistent with clinical trials reported in Lopez et al. (2014). In the current paper we consider the converse situation where the response of the meal lasts longer than the response of an insulin impulse. The latter situation is known to arise in certain circumstances e.g., when low glycaemic index and/or hi-fat/hi-protein meals are consumed (Bell et al., 2015; Lodefalk et al., 2008; van der Hoogt et al., 2017). We consider the same set-up as in Goodwin et al. (2015). However, here we show that, when the response of the meal lasts longer than the response of an insulin impulse, it is optimal to use an open-loop policy combining an insulin bolus (applied with the meal) and a specific form of decaying insulin flow thereafter. This gives support to results for clinical trials, reported in Lopez et al. (2017). However, as far as we are aware, no earlier work has given a methodology to quantify the best insulin flow after the initial bolus nor the best split between bolus and post-bolus insulin flow. In support of the theory, we apply the results to a model obtained from clinical trials on a real subject with Type 1 diabetes and include a discussion of open-loop versus closed-loop policies.

Glycaemic variability is associated with severity of coronary artery disease in patients with poorly controlled type 2 diabetes and acute myocardial infarction

BackgroundIn patients with type 2 diabetes (T2D), glycaemic variability (GV), another component of glycaemic abnormalities, is a novel potentially aggravating factor for coronary artery disease (CAD).Objectives: The aim of our study was to identify interactions between GV and severity of CAD in diabetes patients admitted for acute myocardial infarction (AMI). MethodsAll patients with T2D admitted to our university hospital for AMI from March 2015 to February 2017 who received intravenous (IV) insulin therapy and underwent coronary angiography were included. GV was assessed by mean amplitude of blood glucose excursion (MAGE) values taken within 2 days of admission. Patients with higher GV (highest MAGE tertile) were compared with those with lower GV (first and second MAGE tertiles). ResultsA total of 204 patients were included: median age was 72 (61–81) years; 32% were female; HbA1c was 7.3% (6.4–8.2%); diabetes duration was 10 (2–17.5) years; and MAGE value was 0.65 (0.43–0.92) g/L. Compared with those with lower GV, patients with the highest GV were more often women, treated with previous insulin, and had higher blood glucose and HbA1c levels. In addition, patients with elevated GV had significantly higher SYNTAX scores: 17 (10–28) vs. 12 (6–22) (P = 0.009). Indeed, SYNTAX scores (OR: 1.05, 95% CI: 1.02–1.08; P = 0.001) remained independently associated with high GV beyond HbA1c levels (OR: 1.51, 95% CI: 1.2–1.89; P < 0.001). ConclusionIn AMI patients with poorly controlled diabetes, GV is associated with CAD severity beyond chronic hyperglycaemia. Although no causality can be determined from our observational study, the results suggest that, in AMI, early evaluation of GV might contribute to the identification of those diabetes patients at high risk, and serve as a therapeutic target for both primary and secondary prevention.

Glucose Response during the Night Is Suppressed by Wheat Albumin in Healthy Participants: A Randomized Controlled Trial.

Postprandial blood glucose excursions are important for achieving optimal glycemic control. In normal-weight individuals, glucose tolerance is diminished in the evening compared to glucose tolerance in the morning. Wheat albumin (WA) has the potential to suppress the postprandial glucose response with a relatively small dose, compared to the dose required when using dietary fiber. In the present study, the effect of WA on glycemic control during the night was investigated after a late evening meal. A randomly assigned crossover trial involving a single oral ingestion in healthy male participants was performed in a double-blind placebo-controlled manner. The participants ingested the placebo (PL) tablets or the WA (1.5 g)-containing tablets 3 min before an evening meal at 22:00 hour, and blood samples were drawn during the night until 07:00 hour using an intravenous cannula. The participants slept from 00:30 hour to 06:30 hour. Glucose response, as a primary outcome during the night, was suppressed significantly by the WA treatment compared to the PL treatment, but the insulin response was not. Plasma glucose-dependent insulinotropic polypeptide concentration during the night was lowered significantly by the WA treatment compared to the PL treatment. In conclusion, WA may be a useful food constituent for glycemic control during the night.

Comparison of a twice daily injection of insulin aspart 50 with insulin aspart 30 in patients with poorly controlled type 2 diabetes

Objective: To compare the efficacy and safety of a twice daily injection of insulin aspart (BIAsp) 30 and BIAsp50 in patients with type 2 diabetes mellitus (T2DM) poorly controlled with oral hypoglycemic agents (OHAs).Methods: In this 12 week prospective, randomized, parallel trial, a total of 80 T2DM patients, 59 ± 10 years old with a disease duration of 9.3 ± 6.6 years and HbA1c >7% despite large doses of metformin and sulfonylurea administration, were randomized to receive BIAsp30 (n = 40) or BIAsp50 (n = 40). The primary endpoint was a change in HbA1c at week 12.Results: The changes in HbA1c from baseline were −2.5% ± 1.0% in the BIAsp50 group and −2.5% ± 1.2% in the BIAsp30 group (p = .897). No difference was observed in the rate of HbA1c target achievement (<7.0%) between BIAsp50 (42.5%) and BIAsp30 (32.5%) (p = .495). The change in fasting plasma glucose (FPG) in the BIAsp50 group was lower than that in the BIAsp30 group (p < .001), while the change in two-hour postprandial blood glucose (2hPBG) was higher and blood glucose excursion was lower in the BIAsp50 group than that in the BIAsp30 group (p < .001, p < .001). A significant improvement in HbA1c was observed with BIAsp50 in subgroups with baseline blood glucose excursion >7.8 mmol/L or 2hPBG >17.6 mmol/L compared with BIAsp30. There were no differences in hypoglycemia or body weight between groups.Conclusions: Compared with BIAsp30, BIAsp50 showed greater efficacy in patients with baseline BG excursion >7.8 mmol/L or 2hPBG >17.6 mmol/L as well as good safety for hypoglycemia.Trial registration: Chinese Clinical Trial Registry identifier: ChiCTR-IIR-16008958.

Effect of Methylphenidate on Blood Glucose Profile in an Adolescent Male with Type 1 Diabetes Mellitus, A Case Report

Introduction: Attention deficit/hyperactivity disorder (ADHD) is the commonest childhood neuro-developmental disorder. Methylphenidate (MPH) is a psychostimulant commonly prescribed in clinical practice to treat patients with ADHD. Comorbidity of Type 1Diabetes mellitus (T1D) and ADHD in children can be encountered in clinical practice. However, the impact of MPH on the blood glucose profile is scarcely addressed in the literature. Methods: Multiple blood glucose concentrations (BGCs) obtained from a 12 years old male with T1D (under treatment with continuous insulin infusion) and comorbid ADHD have been evaluated after having received 2 dose levels (5 mg and 7.5 mg) methylphenidate (MPH). BGCs were assessed at 6 time points, over 3 weeks period. During the assessment periods, the patient had similar daily feeding en activity conditions and unchanged background insulin infusion The means of the values obtained after each dose level were compared with each other and with those obtained before commencement of MPH treatment. Results: Three clinically relevant findings were encountered. The mean values of fasting Blood glucose levels (BGLs) obtained during MPH treatment periods were lower than that obtained before MPH use, respectively -28% and -23% below BL for the 5 and 7.5 mg dose levels. The means of other post-MPH treatment values obtained, through the day, were higher than that obtained before treatment, respectively +39% and +40% above Base line (BL). In addition, increasing MPH dose level was associated with increased BGL at all assessment time points. Conclusion: Methylphenidate seems to dysregulate blood glucose levels in patients with type 1 diabetes mellitus. This might lead to serious consequences, including both microvascular and macrovascular diseases, particularly in vulnerable subjects such as those who receive medication for a long period of time. Commencement of treatment with and up-titration of MPH dose in ADHD patients with comorbid T1D requires close monitoring of blood glucose concentrations to avoid potential blood glucose excursions that might lead to unwanted complications.

Glucose-responsive oral insulin delivery for postprandial glycemic regulation

Controlling postprandial glucose levels for diabetic patients is critical to achieve the tight glycemic control that decreases the risk for developing long-term micro- and macrovascular complications. Herein, we report a glucose-responsive oral insulin delivery system based on Fc receptor (FcRn)-targeted liposomes with glucose-sensitive hyaluronic acid (HA) shell for postprandial glycemic regulation. After oral administration, the HA shell can quickly detach in the presence of increasing intestinal glucose concentration due to the competitive binding of glucose with the phenylboronic acid groups conjugated with HA. The exposed Fc groups on the surface of liposomes then facilitate enhanced intestinal absorption in an FcRn-mediated transport pathway. In vivo studies on chemically-induced type 1 diabetic mice show this oral glucose-responsive delivery approach can effectively reduce postprandial blood glucose excursions. This work is the first demonstration of an oral insulin delivery system directly triggered by increasing postprandial glucose concentrations in the intestine to provide an on-demand insulin release with ease of administration.

Low glycaemic index diets as an intervention for obesity: a systematic review and meta-analysis.

Low glycaemic index (GI) diets may aid in weight loss by reducing postprandial blood glucose excursions, leading to more stable blood glucose concentrations and therefore a reduction in hunger. To test this hypothesis, we conducted a systematic review and meta-analysis of randomized controlled trials comparing low GI diets with other diet types. We included 101 studies involving 109 study arms and 8,527 participants. We meta-analysed the studies using a random-effects model and conducted subgroup analyses and meta-regression based on control diet, blood glucose control, baseline BMI and dietary GI. Low GI diets resulted in small but significant improvements in body weight, BMI, LDL and total cholesterol overall, although no individual control diet was significantly different from low GI diets. Studies in people with normal blood glucose who achieved a difference in GI of 20 points or more resulted in a larger reduction in body weight (SMD=-0.26; 95% CIs [-0.43, -0.09]), and total cholesterol (SMD=-0.24; 95% CIs [-0.42, -0.05]) than studies that only achieved a smaller reduction in GI. Low GI diets, especially diets achieving a substantial decrease in GI, were moderately effective in lowering body weight. However, efforts should be made to increase compliance with low GI diets, in order for them to be effective in people with overweight and obesity.

Blood glucose profiles in East Asian and Caucasian injection-naive patients with type 2 diabetes inadequately controlled on oral medication: a pooled analysis.

AimThe primary objective of this study was to compare blood glucose (BG) excursions between East Asian and Caucasian patients with type 2 diabetes mellitus (T2DM) who were injection‐naive, had inadequate glycemic control with oral antihyperglycemic medications, and who required initiation with injectable therapy.MethodsThis retrospective pooled analysis included individual patient data from completed clinical trials (Insulin lispro injection/dulaglutide development programs, first patient visit ≥1997). All included patients were ≥18 years, were East Asian or Caucasian, and had data for self‐monitored BG at baseline. The primary outcome, BG excursion at baseline (least‐squares mean, standard error), was compared between patient groups using an analysis of covariance with race as the fixed effect. Independent covariates included baseline body weight, baseline HbA1c, age, and duration of T2DM.ResultsCaucasian (n = 6779) and East Asian (n = 1638) patients from 21 trials were included. BG excursions were significantly higher for East Asian than Caucasian patients at breakfast (4.03 [0.075] vs 2.59 [0.045] mmol/L), lunch (3.37 [0.080] vs 1.43 [0.049] mmol/L), and dinner (3.16 [0.080] vs 1.74 [0.047] mmol/L) (P < 0.001 adjusted analyses). Similar findings were observed for the unadjusted analyses. At each time point, postprandial BG was significantly higher for East Asian than Caucasian patients (with adjusted and unadjusted analyses).ConclusionThese findings suggest that BG excursion and postprandial BG are higher among East Asian patients with T2DM than Caucasian patients. In addition, these findings may help clinicians select appropriate treatments for East Asian patients with T2DM who require injection therapy.

Role of Intestinal Bitter Sensing in Enteroendocrine Hormone Secretion and Metabolic Control.

The gastrointestinal tract stores ingested nutrients in the stomach which are then delivered to the small intestine at a controlled rate to optimize their digestion and absorption. The interaction of nutrients with the small and large intestine generates feedback that slows gastric emptying, induces satiation, and reduces postprandial glycemic excursions. The mechanisms underlying these nutrient-gut interactions are complex; it has only recently been appreciated that the gut has the capacity to detect intraluminal contents in much the same way as the tongue, via activation of specific G-protein-coupled receptors, and that ensuing signaling mechanisms modulate the release of an array of gut hormones that influence gastrointestinal motility, appetite and glycemia. Interestingly, evidence from preclinical models supports a functional link between intestinal bitter taste receptor (BTRs) and gastrointestinal hormone secretion, and the outcomes of recent studies indicate that stimulation of intestinal BTRs may be used to modulate gastrointestinal function, to diminish energy intake and limit postprandial blood glucose excursions in humans. This review summarizes current evidence about the expression and function of intestinal BTRs in relation to enteroendocrine hormone release and discusses the clinical implications of this pathway for the management of obesity and type 2 diabetes.

Design, synthesis and biological evaluation of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as potent and orally active SGLT dual inhibitors

A new series of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C5-fluoro-lactones 3 and 4, which are key intermediates to the C5-fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC50 = 43 nM for SGLT1 and IC50 = 9 nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10 mg/kg.