Insulin Excursions Research Articles

Effects of night-to-night variations in objectively measured sleep on blood glucose in healthy university students.

We examined associations between daily variations in objectively measured sleep and blood glucose in a sample of non-diabetic young adults to complement laboratory studies on how sleep affects blood glucose levels. 119 university students underwent sleep measurement using an Oura Ring 2 and continuous glucose monitoring (CGM) for up to 14 days. In 69 individuals who consumed a standardised diet across the study, multilevel models examined associations between sleep duration, timing and efficiency and daily CGM profiles. Separately, in 58 individuals, multilevel models were used to evaluate postprandial glycaemic responses to a test meal challenge on 7 days. Participants also underwent oral glucose tolerance testing once after a night of ad libitum sleep, and again following a night of sleep restriction by 1-2 hours relative to that individual's habitual sleep duration. Between-condition glucose and insulin excursions, HOMA-IR and Matsuda index were compared. Nocturnal sleep did not significantly influence following-day CGM profiles, postprandial glucose, or nocturnal mean glucose levels (all Ps>0.05). Longer sleep durations were associated with lower same-night glucose variability (all Ps<0.001). However, the range of variation of sugar levels was small and unlikely to be of functional significance. Considering naps in the analysis did not alter the findings. Sleep restriction by an average of 1.73 hours (SD=0.97) did not significantly impact excursions in glucose or insulin or insulin sensitivity the following morning (all Ps>0.05). Glucose handling in young, healthy adults may be more resilient to real-life fluctuations in sleep patterns than previously thought.

Post Prandial Glucose Turnover Differs Between Adolescents & Adults with Type 1 Diabetes: Triple Tracer Mixed Meal Study.

Insulin sensitivity (SI) varies with age in Type 1 diabetes (T1D). To compare postprandial glucose turnover and insulin sensitivity between adolescents and adults with T1D. Cross-sectional comparison. Clinical Research Unit. 21 early adolescents with T1D (T1D-adol) [12F; age: 11.5 ± 0.5yrs.; BMI: 19 ± 2 kg/m2], 13 adults with T1D (T1D-adult) [5F; 37.8 ± 9.1yrs.; BMI: 27 ± 2 kg/m2] and 14 anthropometrically matched adults without diabetes (ND) [7F; 26.9 ± 7.0yrs.; BMI: 25 ± 2.5 kg/m2]. Triple-tracer mixed meal study and oral glucose models. SI between T1D-adol and T1D-adult. Post-prandial glucose excursions were not different in T1D-adol vs T1D-adult (p = 0.111) but higher than in ND (p < 0.01). Insulin excursions were also similar in T1D-adol vs. T1D-adult (p = 0.600) and they were both lower (p < 0.05) compared to ND, while glucagon excursions were lower (p < 0.01) in T1D-adol than in T1D-adult and ND. Integrated rates of endogenous glucose production and glucose disappearance were lower in T1D-adol than in T1D-adult and in ND vs. T1D-adult but did not differ between T1D-adol and ND. Meal glucose appearance did not differ between groups. Insulin sensitivity (SI) in T1D-adol vs ND was similar (p = 0.299). However, SI was higher in T1D-adol and ND vs. T1D-adult (p < 0.01). We report differences in parameters of postprandial glucose turnover and insulin sensitivity between adults and early adolescents with T1D that could, at least in part, be due to the shorter duration of diabetes among T1D-adol. These data support the concept that over time with T1D endogenous glucose production increases and SI deteriorates.

Post-Bariatric Hypoglycemia: an Impaired Metabolic Response to a Meal

Aims/HypothesisPost-bariatric hypoglycemia (PBH) is caused by postprandial hyperinsulinemia, due to anatomical alterations and changes in post-prandial metabolism after bariatric surgery. The mechanisms underlying the failing regulatory and compensatory systems are unclear. In this study, we investigated the differences in post-prandial hormones and metabolic profiles between patients with and without PBH.MethodsWe performed a mixed meal test (MMT) in 63 subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery. Blood was withdrawn at 0, 10, 20, 30, 60, and 120 min after ingestion of a standardized meal. Glucose, insulin, GLP-1, FGF-19, and FGF-21 were measured and untargeted metabolomics analysis was performed on blood plasma to analyze which hormonal and metabolic systems were altered between patients with and without PBH.ResultsOut of 63, a total of 21 subjects (33%) subjects developed PBH (glucose < 3.1 mmol/L) after surgery. Decreased glucose and increased insulin excursions during MMT were seen in PBH (p < 0.05). GLP-1, FGF-19, and FGF-21 were elevated after surgery (p < 0.001), but did not differ between PBH and non-PBH groups. We identified 20 metabolites possibly involved in carbohydrate metabolism which differed between the two groups, including increased carnitine and acylcholines in PBH.ConclusionOverall, 33% of the subjects developed PBH 1 year after RYGB surgery. While GLP-1, FGF-19, and FGF-21 were similar in PBH and non-PBH patients, metabolomics analysis revealed changes in carnitine and acyclcholines that are possibly involved in energy metabolism, which may play a role in the occurrence of PBH.Graphical

The effect of statin treatment on glucose homeostasis in prediabetic individuals: A prospective, randomized, controlled trial.

This study aimed to evaluate the effects of rosuvastatin and pravastatin on glucose homeostasis and other biomarkers in individuals at high risk of developing diabetes. This prospective, randomized, open-labeled, and controlled trial included prediabetic individuals with impaired fasting glucose and impaired glucose tolerance. The participants were randomized into three groups: rosuvastatin (10 mg), pravastatin (40 mg), or control. Biomarkers of diabetes and glucose and insulin responses to oral glucose tolerance tests were assessed at baseline and after 6 months of treatment. The primary outcomes were comparisons of glucose homeostasis and biomarkers of diabetes among groups at baseline and after 6 months of treatment. A total of 141 subjects with impaired fasting glucose (IFG) were screened and 41 participants were recruited. Twenty-two subjects were randomized to either the rosuvastatin or pravastatin group and 19 subjects were assigned to the control group. After 6 months of treatment, all groups had similar cholesterol and triglyceride levels. Likewise, HbA1c levels, glucose, and insulin excursions during oral glucose tolerance test, were similar among the three groups. However, compared to the other groups, the rosuvastatin group had higher homeostasis model assessment for insulin resistance (HOMA-IR) (insulin resistance) and a lower Matsuda index (insulin sensitivity). Among prediabetic individuals with IFG, rosuvastatin treatment was associated with increased insulin resistance and decreased insulin sensitivity compared to pravastatin and control groups. Further research is needed to elucidate the underlying mechanisms and clinical implications of these findings.

Canagliflozin or acarbose versus placebo to ameliorate post-bariatric hypoglycaemia - The HypoBar I randomized clinical trial protocol.

Post-bariatric hypoglycaemia (PBH) is a rare yet disabling clinical condition, mostly reported after Roux-en-Y gastric bypass (RYGB) surgery. RYGB is one of the most widely used and effective bariatric procedures. The pathophysiology of PBH remains unclear, and treatment options are limited in effectiveness and/or carry significant side effects. Acarbose slows carbohydrates digestion and absorption and is generally considered first-line pharmacological treatment for PBH but its gastrointestinal side effects limit patient compliance. Canagliflozin inhibits intestinal and renal sodium-dependent glucose absorption and reduces postprandial excursions of glucose, insulin and incretins after RYGB - effects that could be beneficial in ameliorating PBH. The trial aims to investigate how blood glucose levels are affected during daily living in subjects with PBH during treatment with canagliflozin or acarbose compared with placebo, and to study the meal-induced entero-endocrine mechanisms implied in the treatment responses. In a double-blinded, randomized, crossover clinical trial, HypoBar I will investigate the effectiveness in reducing the risk of PBH, safety, ambulatory glucose profile and entero-endocrine responses when PBH is treated with canagliflozin 300 mg twice daily during a 4-week intervention period, compared with acarbose 50 mg thrice daily or placebo. HypoBar I is approved by the Local regulatory entities. Results will be published in peer-reviewed journals. If effective, well-tolerated and safe, canagliflozin could be a novel treatment for people with PBH. HypoBar I might also unravel new mechanisms underlying PBH, potentially identifying new treatment targets. EudraCT number 2022-000157-87.

Role of human Kallistatin in glucose and energy homeostasis in mice

ObjectiveKallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown. MethodsKallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT) of 47 people with overweight to obesity of the clinical trial “Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)” was measured. Moreover, we studied transgenic mice systemically overexpressing human KST (hKST-TG) and wild type littermate control mice (WT) under normal chow (NCD) and high-fat diet (HFD) conditions. ResultsIn sWAT of people with overweight to obesity, KST mRNA increased after diet-induced weight loss. On NCD, we did not observe differences between hKST-TG and WT mice. Under HFD conditions, body weight, body fat and liver fat content did not differ between genotypes. Yet, during intraperitoneal glucose tolerance tests (ipGTT) insulin excursions and HOMA-IR were lower in hKST-TG (4.42 ± 0.87 AU, WT vs. 2.20 ± 0.27 AU, hKST-TG, p < 0.05). Hyperinsulinemic euglycemic clamp studies with tracer-labeled glucose infusion confirmed improved insulin sensitivity by higher glucose infusion rates in hKST-TG mice (31.5 ± 1.78 mg/kg/min, hKST-TG vs. 18.1 ± 1.67 mg/kg/min, WT, p < 0.05). Improved insulin sensitivity was driven by reduced hepatic insulin resistance (clamp hepatic glucose output: 7.7 ± 1.9 mg/kg/min, hKST-TG vs 12.2 ± 0.8 mg/kg/min, WT, p < 0.05), providing evidence for direct insulin sensitizing effects of KST for the first time. Insulin sensitivity was differentially affected in skeletal muscle and adipose tissue. Mechanistically, we observed reduced Wnt signaling in the liver but not in skeletal muscle, which may explain the effect. ConclusionsKST expression increases after weight loss in sWAT from people with obesity. Furthermore, human KST ameliorates diet-induced hepatic insulin resistance in mice, while differentially affecting skeletal muscle and adipose tissue insulin sensitivity. Thus, KST may be an interesting, yet challenging, therapeutic target for patients with obesity and insulin resistance.

Comparative Study of Insulin Sensitivity and Resistance and Their Correlation with Androgens in Lean and Obese Women with Polycystic Ovary Syndrome.

There is a lack of consensus on the optimal screening strategy for insulin resistance (IR), particularly in lean women with polycystic ovary syndrome (PCOS). Therefore, we conducted a cross-sectional study in 80 women with PCOS (28 lean/52 obese) and 80 age- and body mass index (BMI)-matched controls. Using a 5-point 75-g oral glucose tolerance test (OGTT) (0, 30, 60, 90, 120min), we examined glucose and insulin excursions, IR, insulin sensitivity, beta-cell function (ßF), and the effect of androgens on IR. Lean and obese women with PCOS had similar glucose but higher insulin (except fasting in lean women) and insulin AUC as compared to their respective controls (p < 0.05). Lean women with PCOS were equally insulin-resistant but more hyperinsulinemic than the obese controls (p < 0.05). Although ßF ([1st phase: 481.71 ± 263.53 vs. 430.56 ± 232.37], [2nd phase: 815.16 ± 447.12 vs. 752.66 ± 428.95]) was comparable in lean and obese women with PCOS, lean women had better insulin sensitivity (112.78 ± 66.26 vs. 75.49 ± 55.6) (p < 0.05). Dehydroepiandrosterone sulfate (DHEAS) and androstenedione decreased with increasing BMI in lean women, and this correlated with deteriorating insulin sensitivity and exaggerated hyperinsulinemia. In obese women with PCOS, sex hormone-binding globulin (SHBG) correlated negatively with BMI and hyperinsulinemia, and positively with insulin sensitivity. This data suggests that estimating only fasting insulin may miss IR in lean women with PCOS; hence, additional time points in OGTT will add value to screening for IR. DHEAS and androstenedione may have a beneficial effect on insulin sensitivity and may be used to screen IR in lean women, while SHBG can be used as a predictive marker for IR in obese women with PCOS.

774-P: Weight-Independent Effects of CT-868, a Signaling Biased Dual GLP-1/GIP Receptor Modulator, on Glucose Homeostasis in Overweight and Obese Adults with Type 2 Diabetes

GLP-1 and GIP can deliver complementary pharmacology when combined. CT-868 (CT) is a biased dual GLP-1 and GIP receptor modulator that exhibits no arrestin coupling or receptor internalization at either receptor. Its effects on insulin (INS) secretion via graded glucose infusion (GGI), glucose (GLUC) homeostasis in response to a mixed meal tolerance test (MMTT), gastric emptying (GE), and food intake (FI) were investigated in a randomized, double-blind crossover study in 20 overweight and obese adults with T2D split into 2 groups: CT vs placebo (PL), n=7 and CT vs PL vs liraglutide (LI), n = 13, the latter as a fixed 3rd period. Mean age and BMI were 52.2 years and 32.7 kg/m2 with 55% males. Treatments were administered for 4 days to minimize weight loss with 14 days washout between periods. GGI data showed robust INS secretion for CT-868 vs PL [change in ISR/GLUC at GIRmax (pmol/kg/min): CT 1.1 (0.1), PL 0.1 (0.2), LI 1.0 (0.3)]. MMTT based GLUC iAUC0-240 was significantly reduced for CT vs PL [72(46) vs 392(48)mmol/L*min] and numerically lower vs. LI [187(55) mmol/L*min] accompanied by significantly decreased INS iAUC0-240 vs both PL and LI: CT 1178(846), PL 5833(873), LI 4613(1253) mU/L*min. As both CT and LI had similar delayed GE vs PL, the reduced GLUC and INS excursion seen with CT suggests improved INS sensitivity or enhanced INS independent GLUC disposal. CT demonstrated minimal suppression of glucagon during MMTT vs LI that showed glucagon lowering. FI was lower for CT vs PL accompanied by reduction in hunger and appetite as assessed by VAS. There were no significant body weight changes in any treatment period. GI side effects were mostly mild and transient. This data supports a robust weight-independent effect of CT-868 (vs unbiased liraglutide) on glucose disposal with minimal suppression of glucagon. Further delineation of CT-868's longer term effects in overweight and obese patients with both T2D and T1D is underway. Disclosure M.Chakravarthy: Employee; Carmot Therapeutics, Inc. M.Hernandez: None. M.Elliott: Employee; Carmot Therapeutics, Inc. A.Macias: None. S.K.Hansen: Board Member; Carmot Therapeutics, Inc. M.Hompesch: Board Member; ProSciento, Consultant; Wiley-Blackwell, Employee; ProSciento, Stock/Shareholder; ProSciento.

1649-P: Biased GLP-1 Improves Weight Loss with Additional Benefits on Glucose Homeostasis via Biased GIP in Diabetic Rodent Models

GLP-1 and GIP when combined can deliver complementary pharmacology. CT-868 (CT) and CT-859 are biased dual GLP-1 and GIP receptor modulators with no β-arrestin coupling on either receptor. Effect of both compounds on weight loss (WL) and glucose (GLUC) homeostasis were assessed in relevant rodent models. At non-GIPR engaging doses in ob/ob mice, 30 nmol/kg CT achieved greater WL vs 200 nmol/kg Liraglutide (LI), an unbiased GLP-1RA (19.8% vs 11.5%, p=0.002), indicating biased GLP-1 improves WL vs unbiased GLP-1. GLUC tolerance test (GTT) in GIPR-/- mice showed similar reduction in AUCGLUC with LI and CT-859 at 20 nmol/kg 4h after dosing (53% vs 62%, p=NS), but only CT-859 maintained significant reduction after 24h and 48h, indicating biased GLP-1 induces a sustained GLUC lowering effect. After 14d of dosing in Akita mice with non-GIPR engaging doses of CT 20 nmol/kg, blood glucose (BG) decreased 30% vs LI 20 nmol/kg (p=0.01) indicating superior effect of biased GLP-1 on glycemic control. At GIPR engaging doses, CT 200 nmol/kg on background of insulin (INS) significantly lowered BG vs LI 200nmol/kg in Akita (↓35%, p=0.009) and DIO-STZ (↓32%, p&amp;lt;0.0001) mice. Akita mice treated for 14d with CT 300 nmol/kg + low INS normalized BG to same extent as vehicle + high INS, but with 68% lower INS levels (p &amp;lt; 0.0001). In GLP-1R-/- mice, CT 300 nmol/kg lowered AUCGLUC 38% vs vehicle (p&amp;lt;0.0001) without concomitant INS excursion, showing that GIP enhances INS independent GLUC disposal or INS sensitivity. In response to pyruvate challenge, CT 100 nmol/kg suppressed AUCGLUC 36% (p&amp;lt;0.05) and 14% (p=0.006) on a background of INS treatment in Akita and GLP-1R-/- mice, respectively, suggesting GIPR activation may contribute to suppression of endogenous GLUC production. Together, these data demonstrate that CT provides improved WL via biased GLP-1 with enhanced GLUC homeostasis via biased GIP relative to unbiased GLP-1 (LI). These findings have translated to T2D patients treated with CT-868. Disclosure R.Rodriguez: Employee; Carmot Therapeutics, Inc. T.Tracy: Employee; Carmot Therapeutics, Inc. M.Morales: None. A.Hergarden: Employee; Carmot Therapeutics, Inc. D.Lam: Employee; Carmot Therapeutics, Inc. S.Krishnan: Employee; Carmot Therapeutics, Inc. S.K.Hansen: Board Member; Carmot Therapeutics, Inc. M.Chakravarthy: Employee; Carmot Therapeutics, Inc.

LBSUN307 A Randomized Controlled Pilot Study Of The Food Order Behavioral Intervention In Prediabetes

Abstract Background and Objectives Ordering the ingestion of carbohydrate-rich foods after protein/vegetables (carbohydrate-last food order) significantly reduced postprandial glucose and insulin excursions over 180 min in patients with prediabetes and type 2 diabetes, compared with the reverse food order (carbohydrate-first) in previous research. We implemented a 16-week food order behavioral intervention, assessing its feasibility and impacts on glucose tolerance (GT), HbA1c, and weight (wt) in adults with prediabetes. Methods Participants with overweight/obesity and prediabetes (HbA1c 5.7-6.4%) were randomized to receive either standard nutritional counseling (control group) or standard nutritional counseling plus carbohydrate-last food order counseling (FO group). Participants were instructed to maintain their usual level of exercise throughout the study; this was assessed by the Godin Leisure-Time Exercise questionnaire at baseline and wk 16. Participants in both groups received 4 in-person brief counseling sessions at 1-month intervals. Due to the Covid-19 pandemic, later participants received some or all of their counseling via telemedicine. Oral GT was tested at baseline and week 16. Feasibility was assessed via a questionnaire. Results Of the 45 randomized subjects, 39 completed the study (control 21, FO 18). Demographics and baseline variables including wt (190.8 lbs vs 191.1 lbs) and HbA1c (6% vs 6%) were similar between groups. Exercise levels did not differ between groups at baseline and wk 16. Within FO group, body wt declined (-3.6 ±5.7 lbs, p=0. 017; -1.8% ±2.8, p=0. 012), and there was a trend towards improvement in HbA1c (-0.1 ±0.2, p=0. 054). Control group wt changed (-2.6 ±6.8 lbs, p=0.102; -1.6% ±3.5, p=0. 048) without altering HbA1c (-0. 03 ±0.3, p=0.605). Changes in wt, HbA1c, and GT were not significantly different between groups. At week 16, 17 FO group subjects (94%) reported high intervention adherence, 13 (74%) reported it was easy to eat protein/vegetables before carbohydrates, and 14 (78%) reported they would continue eating protein/vegetables before carbohydrates. Conclusions Carbohydrate-last food order is a feasible behavioral strategy in individuals with prediabetes. More research with a larger sample size and longer duration is needed to delineate its clinical impact. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Quantifying the contribution of triglycerides to metabolic resilience through the mixed meal model

SummaryDespite the pivotal role played by elevated circulating triglyceride levels in the pathophysiology of cardio-metabolic diseases many of the indices used to quantify metabolic health focus on deviations in glucose and insulin alone. We present the Mixed Meal Model, a computational model describing the systemic interplay between triglycerides, free fatty acids, glucose, and insulin. We show that the Mixed Meal Model can capture deviations in the post-meal excursions of plasma glucose, insulin, and triglyceride that are indicative of features of metabolic resilience; quantifying insulin resistance and liver fat; validated by comparison to gold-standard measures. We also demonstrate that the Mixed Meal Model is generalizable, applying it to meals with diverse macro-nutrient compositions. In this way, by coupling triglycerides to the glucose-insulin system the Mixed Meal Model provides a more holistic assessment of metabolic resilience from meal response data, quantifying pre-clinical metabolic deteriorations that drive disease development in overweight and obesity.

The bad rainbow of COVID-19 time: effects on glucose metabolism in children and adolescents with obesity and overweight.

BackgroundCOVID-19 restriction measurements have enhanced the obesity status in the pediatric population which might further contribute to obesity-related glucose-insulin metabolism alterations. Therefore, we retrospectively compared anthropometric and OGTT data on children with obesity during the 13 years before and during the COVID-19 pandemic.Subjects/methodsData from 741 children with obesity and overweight were retrieved and clustered into seven groups starting from year 2008–2009 until 2020–2021. Differences in anthropometric measurements and glucose/insulin metabolism were evaluated between the different groups.ResultsChildren with overweight and obesity in the COVID-19 restriction group did not present increased values of SDS­Body Mass Index (BMI). Significantly higher values for Waist Circumference (WC), SDS-WC, Waist/Height ratio (WHtR), and body mass fat were detected in these children (all P < 0.01). Fasting glycaemia, glucose, and insulin excursions were significantly higher compared to pre­ pandemic children (all P < 0.01). Insulin resistance was higher while insulin secretion was lower (all P < 0.01) determining a significantly higher percentage of impaired glucose tolerance in the COVID-19 restriction group (P < 0.002). Furthermore, High-Density Lipoprotein (HDL) cholesterol was significantly lower (P < 0.01) and SDS for systolic and diastolic blood pressure values were significantly higher (P = 0.03 and P = 0.02, respectively).ConclusionsCOVID-19 restriction measurements determined profound alterations in glucose and insulin metabolism in children with obesity and overweight. Urgent strategies are needed in order to reverse COVID-19 restriction measures’ effects on glucose and insulin metabolism.

Central NPFF signalling is critical in the regulation of glucose homeostasis

ObjectiveNeuropeptide FF (NPFF) group peptides belong to the evolutionary conserved RF-amide peptide family. While they have been assigned a role as pain modulators, their roles in other aspects of physiology have received much less attention. NPFF peptides and their receptor NPFFR2 have strong and localized expression within the dorsal vagal complex that has emerged as the key centre for regulating glucose homeostasis. Therefore, we investigated the role of the NPFF system in the control of glucose metabolism and the histochemical and molecular identities of NPFF and NPFFR2 neurons. MethodsWe examined glucose metabolism in Npff−/− and wild type (WT) mice using intraperitoneal (i.p.) glucose tolerance and insulin tolerance tests. Body composition and glucose tolerance was further examined in mice after 1-week and 3-week of high-fat diet (HFD). Using RNAScope double ISH, we investigated the neurochemical identity of NPFF and NPFFR2 neurons in the caudal brainstem, and the expression of receptors for peripheral factors in NPFF neurons. ResultsLack of NPFF signalling in mice leads to improved glucose tolerance without significant impact on insulin excursion after the i.p. glucose challenge. In response to an i.p. bolus of insulin, Npff−/− mice have lower glucose excursions than WT mice, indicating an enhanced insulin action. Moreover, while HFD has rapid and potent detrimental effects on glucose tolerance, this diet-induced glucose intolerance is ameliorated in mice lacking NPFF signalling. This occurs in the absence of any significant impact of NPFF deletion on lean or fat masses, suggesting a direct effect of NPFF signalling on glucose metabolism. We further reveal that NPFF neurons in the subpostrema area (SubP) co-express receptors for peripheral factors involved in glucose homeostasis regulation such as insulin and GLP1. Furthermore, Npffr2 is expressed in the glutamatergic NPFF neurons in the SubP, and in cholinergic neurons of the dorsal motor nucleus of the vagus (DMV), indicating that central NPFF signalling is likely modulating vagal output to innervated peripheral tissues including those important for glucose metabolic control. ConclusionsNPFF signalling plays an important role in the regulation of glucose metabolism. NPFF neurons in the SubP are likely to receive peripheral signals and mediate the control of whole-body glucose homeostasis via centrally vagal pathways. Targeting NPFF and NPFFR2 signalling may provide a new avenue for treating type 2 diabetes and obesity.

Exercise-nutrient interactions for improved postprandial glycemic control and insulin sensitivity.

Type 2 diabetes (T2D) is a rapidly growing yet largely preventable chronic disease. Exaggerated increases in blood glucose concentration following meals is a primary contributor to many long-term complications of the disease that decrease quality of life and reduce lifespan. Adverse health consequences also manifest years prior to the development of T2D due to underlying insulin resistance and exaggerated postprandial concentrations of the glucose-lowering hormone insulin. Postprandial hyperglycemic and hyperinsulinemic excursions can be improved by exercise, which contributes to the well-established benefits of physical activity for the prevention and treatment of T2D. The aim of this review is to describe the postprandial dysmetabolism that occurs in individuals at risk for and with T2D, and highlight how acute and chronic exercise can lower postprandial glucose and insulin excursions. In addition to describing the effects of traditional moderate-intensity continuous exercise on glycemic control, we highlight other forms of activity including low-intensity walking, high-intensity interval exercise, and resistance training. In an effort to improve knowledge translation and implementation of exercise for maximal glycemic benefits, we also describe how timing of exercise around meals and post-exercise nutrition can modify acute and chronic effects of exercise on glycemic control and insulin sensitivity. Novelty: Exaggerated postprandial blood glucose and insulin excursions are associated with disease risk. Both a single session and repeated sessions of exercise improve postprandial glycemic control in individuals with and without T2D. The glycemic benefits of exercise can be enhanced by considering the timing and macronutrient composition of meals around exercise.

Insulin signaling in AgRP neurons regulates meal size to limit glucose excursions and insulin resistance.

The importance of hypothalamic insulin signaling on feeding and glucose metabolism remains unclear. We report that insulin acts on AgRP neurons to acutely decrease meal size and thereby limit postprandial glucose and insulin excursions. The promotion of insulin signaling in AgRP neurons decreased meal size without altering total caloric intake, whereas the genetic ablation of the insulin receptor had the opposite effect. The promotion of insulin signaling also decreased the intake of sucrose-sweetened water or high-fat food over standard chow, without influencing food-seeking and hedonic behaviors. The ability of heightened insulin signaling to override the hedonistic consumption of highly palatable high-fat food attenuated the development of systemic insulin resistance, without affecting body weight. Our findings define an unprecedented mechanism by which insulin acutely influences glucose metabolism. Approaches that enhance insulin signaling in AgRP neurons may provide a means for altering feeding behavior in a nutrient-dense environment to combat the metabolic syndrome.

Effects of D-allulose on glucose tolerance and insulin response to a standard oral sucrose load: results of a prospective, randomized, crossover study

IntroductionCurrent dietary guidelines recommend limiting sugar intake for the prevention of diabetes mellitus (DM). Reduction in sugar intake may require sugar substitutes. Among these, D-allulose is a non-calorie rare monosaccharide...

Can Metabolite and Hormone Profiles Provide a Rationale for Choosing Between Bariatric Procedures?

There are no formal guidelines for choosing among different bariatric surgery procedures for obesity treatment. So, our aim was to evaluate whether post-absorptive metabolite and hormone profiles could aid the surgeon decision when considering bariatric surgery interventions. Subjects (N=38) previously submitted to biliopancreatic diversion with duodenal switch (BPD-DS, n=9), single anastomosis duodenal-ileum bypass with sleeve gastrectomy (SADI-S, n= 9), long biliopancreatic limb Roux-en-Y gastric bypass (RYGB-M, n= 11), and classic RYGB (RYGB-C, n= 9) underwent a mixed meal test to evaluate post-absorptive glucose, total amino acid (AA), insulin, and GLP-1 profiles. Glucose, AA, insulin, and GLP-1 excursions were lower after BPD-DS when compared to other surgeries. SADI-S resulted in lower glucose but similar AA and insulin excursions when compared to RYGB-M. The highest GLP-1 excursion was observed after RYGB-M. There were no significant differences in glucose or AA post-prandial excursions between RYGB procedures, yet insulin excursion was higher after RYGB-C when compared to RYGB-M. Post-prandial metabolite excursions diverge across bariatric procedures being lowest after BPD-DS, intermediate after SADI-S, and highest after RYGB, in parallel with the anti-diabetic efficacy and malabsorption risk reported for each type of intervention. SADI-S and RYGB-M seem to elicit similar post-prandial hormonal profiles, with potentially lower risk of protein malnutrition when compared to BPD-DS. Post-absorptive metabolite and hormone profiles could provide a rationale as decision-aid when choosing among bariatric surgery interventions, as long as these findings are validated in future trials.

Uncoupling protein gene UCP1-3826A/G, UCP2 Ins/Del and UCP3-55C/T polymorphisms in obese Turkish children.

Mitochondrial uncoupling proteins (UCP) 1, 2 and 3 are members of the anion carrier protein family located in the inner mitochondrial membrane. There are various controversial reports on UCP genotypes and obesity in adults and children. This study aims to investigate the link between mostly studied UCP polymorphisms (UCP1-3826A/G, UCP2 Insertion/Deletion (Ins/Del) polymorphism of exon 8, and UCP3-55C/T Polymorphisms) and obesity in Turkish children. Furthermore, the relationships of UCP polymorphisms are also analyzed within the scope of metabolic parameters of obese children. Molecular screening of the UCP1, UCP2, and UCP3 gene polymorphisms was carried out in 189 children aged 6 to 18 years, 102 of who had exogenous obesity (54 girls) and 87 of whom were healthy controls (48 girls). In the obese group, fasting lipids, glucose and insulin levels were measured. In 60 obese children, an oral glucose tolerance test (OGTT) was performed with 0, 30, 60, 90 and 120 minutes of sampling for plasma glucose and insulin levels. The frequency of UCP polymorphisms was similar in obese and non-obese children. In obese children, fasting lipids, glucose and insulin levels were not different among the UCP 1, 2 and 3 genotypes. While no relationship was found between the UCP 1 and 3 genotypes and glucose/insulin levels during OGTT, carriers of the Insertion allele with UCP2 Ins/Del polymorphism had significantly higher 30-minute insulin levels (p=0.018). Polymorphisms of the UCP1-3826A/G, UCP2 Ins/Del, and UCP3-55C/T are not associated with obesity and related pathologies in Turkish children. However, the presence of the Ins allele of the UCP2 gene has been found to have an unfavorable influence on early insulin excursion after glucose loading.

Breakfast consumption modulates postprandial glycaemic, insulinaemic and NEFA response in pre-diabetic Asian males.

Breakfast consumption is associated with a variety of nutritional and lifestyle-related health outcomes. The objective of the present study was to investigate how the consumption of breakfast affected blood glucose, insulin and NEFA profiles. A lower postprandial blood glucose, insulin and NEFA response is associated with a lower risk of development of metabolic diseases. In a randomised crossover non-blind design, thirteen pre-diabetic Chinese adult males (BMI 26·7 (sd 4·2) kg/m2) attended two sessions where they either consumed a high-glycaemic index breakfast or no breakfast consumption. Changes in glycaemic response over 27 h periods were measured using the Medtronic MiniMed iProTM2 continuous glucose monitoring system. Blood samples were collected using a peripheral venous catheter at fixed intervals for 3 h after the test meal and 3 h after standardised lunch consumption. Postprandial glucose, insulin and NEFA response was calculated as total AUC and incremental AUC using the trapezoidal rule that ignored the area under the baseline. It was found that breakfast consumption significantly decreased postprandial glucose, insulin and NEFA excursion response at lunch time (P = 0·001). Consumption of breakfast attenuated blood glucose profiles by minimising glycaemic excursions and reduced both insulinaemic and NEFA responses in pre-diabetic Asian males during the second meal. This simple dietary intervention may be a novel approach to help improve subsequent lunch glycaemic responses in Asians at high risk of developing diabetes.

Biliopancreatic Diversion Induces Greater Metabolic Improvement Than Roux-en-Y Gastric Bypass

Diabetes remission is greater after biliopancreatic diversion (BPD) than Roux-en-Y gastric bypass (RYGB) surgery. We used a mixed-meal test with ingested and infused glucose tracers and the hyperinsulinemic-euglycemic clamp procedure with glucose tracer infusion to assess the effect of 20% weight loss induced by either RYGB or BPD on glucoregulation in people with obesity (ClinicalTrials.gov number: NCT03111953). The rate of appearance of ingested glucose into the circulation was much slower, and the postprandial increases in plasma glucose and insulin concentrations were markedly blunted after BPD compared to after RYGB. Insulin sensitivity, assessed as glucose disposal rate during insulin infusion, was ∼45% greater after BPD than RYGB, whereas β cell function was not different between groups. These results demonstrate thatcompared with matched-percentage weight loss induced by RYGB, BPD has unique beneficial effects on glycemic control, manifested by slower postprandial glucose absorption, blunted postprandial plasma glucose and insulin excursions, and greater improvement in insulin sensitivity.