Caspase-2 deficiency enhances whole-body carbohydrate utilisation and prevents high-fat diet-induced obesity

Published online 26 October 2017Caspase-2 has been shown to be involved in metabolic homeostasis. Here, we show that caspase-2 deficiency alters basal energy metabolism by shifting the balance in fuel choice from fatty acid to carbohydrate usage. At 4 weeks of age, whole-body carbohydrate utilisation was increased in Casp2-/- mice and was maintained into adulthood. By 17 weeks of age, Casp2-/- mice had reduced white adipose mass, smaller white adipocytes decreased fasting blood glucose and plasma triglycerides but maintained normal insulin levels. When placed on a 12-week high-fat diet (HFD), Casp2-/- mice resisted the development of obesity, fatty liver, hyperinsulinemia and insulin resistance. In addition, HFD-fed Casp2-/- mice had reduced white adipocyte hypertrophy, apoptosis and expansion of both subcutaneous and visceral adipose depots. Increased expression of UCP1 and the maintenance of adiponectin levels in white adipose tissue of HFD-fed Casp2-/- mice indicated increased browning and adipocyte hyperplasia. We found that while the preference for whole-body carbohydrate utilisation was maintained, HFD-fed Casp2-/- mice were not impaired in their ability to switch to utilising fats as a fuel source. Our findings suggest that caspase-2 impacts basal energy metabolism by regulating adipocyte biology and fat expansion, most likely via a non-apoptotic function. Furthermore, we show that caspase-2 deficiency shifts the balance in fuel choice towards increased carbohydrate utilisation and propose that this is due to mild energy stress. As a consequence, Casp2-/- mice show an adaptive remodelling of adipose tissue that protects from HFD-induced obesity and improves glucose homeostasis while paradoxically increasing their susceptibility to oxidative stress induced damage and premature ageing.Claire H Wilson, Andrej Nikolic, Stephen J Kentish, Marianne Keller, George Hatzinikolas, Loretta Dorstyn, Amanda J Page and Sharad Kuma

Sex-specific alterations in glucose homeostasis and metabolic parameters during ageing of caspase-2-deficient mice

Gender-specific differences are commonly found in metabolic pathways and in response to nutritional manipulation. Previously, we identified a role for caspase-2 in age-related glucose homeostasis and lipid metabolism using male caspase-2-deficient (Casp2 (-/-) ) mice. Here we show that the resistance to age-induced glucose tolerance does not occur in female Casp2 (-/-) mice and it appears to be independent of insulin sensitivity in males. Using fasting (18 h) as a means to further investigate the role of caspase-2 in energy and lipid metabolism, we identified sex-specific differences in the fasting response and lipid mobilization. In aged (18-22 months) male Casp2 (-/-) mice, a significant decrease in fasting liver mass, but not total body weight, was observed while in females, total body weight, but not liver mass, was reduced when compared with wild-type (WT) animals. Fasting-induced lipolysis of adipose tissue was enhanced in male Casp2 (-/-) mice as indicated by a significant reduction in white adipocyte cell size, and increased serum-free fatty acids. In females, white adipocyte cell size was significantly smaller in both fed and fasted Casp2 (-/-) mice. No difference in fasting-induced hepatosteatosis was observed in the absence of caspase-2. Further analysis of white adipose tissue (WAT) indicated that female Casp2 (-/-) mice may have enhanced fatty acid recycling and metabolism with expression of genes involved in glyceroneogenesis and fatty acid oxidation increased. Loss of Casp2 also increased fasting-induced autophagy in both male and female liver and in female skeletal muscle. Our observations suggest that caspase-2 can regulate glucose homeostasis and lipid metabolism in a tissue and sex-specific manner.CH Wilson, A Nikolic, SJ Kentish, S Shalini, G Hatzinikolas, AJ Page, L Dorstyn and S Kuma

Effects of substitution, and adding of carbohydrate and fat to whey-protein on energy intake, appetite, gastric emptying, glucose, insulin, ghrelin, cck and glp-1 in healthy older men - a randomized controlled trial

Protein-rich supplements are used widely for the management of malnutrition in the elderly. We reported previously that the suppression of energy intake by whey protein is less in older than younger adults. The aim was to determine the effects of substitution, and adding of carbohydrate and fat to whey protein, on ad libitum energy intake from a buffet meal (180-210 min), gastric emptying (3D-ultrasonography), plasma gut hormone concentrations (0-180 min) and appetite (visual analogue scales), in healthy older men. In a randomized, double-blind order, 13 older men (75 ± 2 years) ingested drinks (~450 mL) containing: (i) 70 g whey protein (280 kcal; 'P₂₈₀'); (ii) 14 g protein, 28 g carbohydrate, 12.4 g fat (280 kcal; 'M₂₈₀'); (iii) 70 g protein, 28 g carbohydrate, 12.4 g fat (504 kcal; 'M₅₀₄'); or (iv) control (~2 kcal). The caloric drinks, compared to a control, did not suppress appetite or energy intake; there was an increase in total energy intake (drink + meal, p < 0.05), which was increased most by the M₅₀₄-drink. P₂₈₀- and M₅₀₄-drink ingestion were associated with slower a gastric-emptying time (n = 9), lower ghrelin, and higher cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) than M₂₈₀ (p < 0.05). Glucose and insulin were increased most by the mixed-macronutrient drinks (p < 0.05). In conclusion, energy intake was not suppressed, compared to a control, and particularly whey protein, affected gastric emptying and gut hormone responses.Caroline Giezenaar, Yonta van der Burgh, Kylie Lange, Seva Hatzinikolas, Trygve Hausken, Karen L. Jones, Michael Horowitz, Ian Chapman, and Stijn Soene

Acute Administration of the GLP-1 Receptor Agonist Lixisenatide Diminishes Postprandial Insulin Secretion in Healthy Subjects But Not in Type 2 Diabetes, Associated with Slowing of Gastric Emptying

Published online 22 April 2022Introduction: It is uncertain whether lixisenatide has postprandial insulinotropic effects when its effect on slowing gastric emptying is considered, in healthy subjects and type 2 diabetes mellitus (T2DM). We evaluated the effects of single administration of 10 lg sc lixisenatide on glycaemia, insulin secretion and gastric emptying (GE), measured using the ‘gold standard’ technique of scintigraphy following an oral glucose load (75 g glucose). Methods: Fifteen healthy subjects (nine men, six women; age 67.2 ± 2.3 years) and 15 patients with T2DM (nine men, six women; age 61.9 ± 2.3 years) had measurements of GE, plasma glucose, insulin and C-peptide for 180 min after a radiolabeled 75 g glucose drink on two separate days. All subjects received lixisenatide (10 lg sc) or placebo in a randomised, double-blind, crossover fashion 30 min before the drink. Insulin secretory response (ISR) was determined using the C-peptide deconvolution method. Results: GE was markedly slowed by lixisenatide compared with placebo in both healthy subjects (1.45 ± 0.10 kcal/min for placebo vs. 0.60 ± 0.14 kcal/min for lixisenatide) and diabetes (1.57 ± 0.06 kcal/min for placebo vs. 0.75 ± 0.13 kcal/min for lixisenatide) (both P\0.001) with no difference between the two groups (P = 0.42). There was a moderate to strong inverse correlation between the early insulin secretory response calculated at 60 min and gastric retention at 60 min with lixisenatide treatment in healthy subjects (r = - 0.8, P = 0.0003) and a trend in type 2 diabetes (r = - 0.4, P = NS), compared with no relationships in the placebo arms (r = - 0.02, P = NS, healthy subjects) and (r = - 0.16, P = NS, type 2 diabetes). Conclusion: The marked slowing of GE of glucose induced by lixisenatide is associated with attenuation in the rise of postprandial glucose in both healthy subjects and diabetes and early insulin secretory response in healthy subjects.Chinmay S. Marathe . Hung Pham . Tongzhi Wu . Laurence G. Trahair . Rachael S. Rigda . Madeline D. M. Buttfield . Seva Hatzinikolas . Kylie Lange . Christopher K. Rayner . Andrea Mari . Michael Horowitz . Karen L. Jone

Antecedent hypoglycemia does not attenuate the acceleration of gastric emptying by hypoglycemia

Context: Acute hypoglycemia accelerates gastric emptying and increases cardiac contractility. However, antecedent hypoglycemia attenuates counterregulatory hormonal responses to subsequent hypoglycemia. Objective: To determine the effect of antecedent hypoglycemia on gastric and cardiac responses to subsequent hypoglycemia in health. Design: A prospective, single-blind, randomized, crossover study (performed at the Royal Adelaide Hospital, Adelaide, South Australia, Australia). Patients: Ten healthy young men 18 to 35 years of age were studied for 36 hours on two occasions. Interventions: Participants were randomly assigned to either antecedent hypoglycemia [three 45-minute periods of strict hypoglycemia (2.8 mmol/L] or control [three 45-minute periods of strict euglycemia (6 mmol/L)] during the initial 12-hour period. Participants were monitored overnight, and the following morning blood glucose was clamped at 2.8 mmol/L for 60 minutes and then at 6 mmol/L for 120 minutes. At least 6 weeks later participants returned for the alternative intervention. Gastric emptying and cardiac fractional shortening were measured with scintigraphy and two-dimensional echocardiography, respectively, on the morning of all 4 study days. Results: A single, acute episode of hypoglycemia accelerated gastric emptying (P = 0.01) and augmented fractional shortening (P < 0.01). Gastric emptying was unaffected by antecedent hypoglycemia (P = 0.74) whereas fractional shortening showed a trend to attenuation (P = 0.06). The adrenaline response was diminished (P < 0.05) by antecedent hypoglycemia Conclusions: In health, the acceleration of gastric emptying during hypoglycemia is unaffected by antecedent hypoglycemia, whereas the increase in cardiac contractility may be attenuated.Palash Kar, Karen L Jones, Mark P Plummer, Yasmine Ali Abdelhamid, Emma J Giersch, Matthew J Summers, Seva Hatzinikolas, Simon Heller, Michael Horowitz, Adam M Dean

Effects of sitagliptin on gastric emptying of, and the glycaemic and blood pressure responses to, a carbohydrate meal in type 2 diabetes

AIMS:To determine the effects of the dipeptidyl peptidase-4 inhibitor, sitagliptin, on gastric emptying of a high carbohydrate meal and associated glycaemic and blood pressure responses in type 2 diabetes mellitus. MATERIALS AND METHODS:Fourteen patients with type 2 diabetes (9 male, 5 female; age: 67.8±1.5 years; BMI: 31.2±0.9 kg/m2 ; diabetes duration: 4.2±0.9 years; HbA1 c: 46±1.8 mmol/mol (6.4±0.2%), managed by diet and/or metformin, underwent concurrent measurements of gastric emptying, blood pressure and plasma glucose for 240 min after ingestion of a radiolabelled a mashed potato meal after receiving sitagliptin (100 mg) or placebo in randomised, double-blind, crossover fashion on two consecutive days. RESULTS:Sitagliptin reduced postprandial plasma glucose (P<0.005), without affecting gastric emptying (P=0.88). The magnitude of the glucose-lowering effect (change in iAUC0-240 min from placebo to sitagliptin) was related to gastric emptying (kcal/min) on placebo (r=0.68, P=0.008) There was a comparable fall in systolic blood pressure (P=0.80) following the meal without any difference between the two days. CONCLUSIONS:In type 2 diabetes, while sitagliptin has no effect on either gastric emptying or postprandial blood pressure, it's effects to lower postprandial glucose is dependent on the basal rate of gastric emptying. This article is protected by copyright. All rights reserved.Julie E. Stevens, Madeline Buttfield, Tongzhi Wu, Seva Hatzinikolas, Hung Pham, Kylie Lange, Christopher K. Rayner, Michael Horowitz, Karen L. Jone

Effects of sitagliptin on gastric emptying of, and the glycaemic and blood pressure responses to, a carbohydrate meal in type 2 diabetes

AIMS To determine the effects of the dipeptidyl peptidase‐4 inhibitor, sitagliptin, on gastric emptying of a high carbohydrate meal and associated glycaemic and blood pressure responses in type 2 diabetes mellitus. MATERIALS AND METHODS Fourteen patients with type 2 diabetes (9 male, 5 female; age: 67.8±1.5 years; BMI: 31.2±0.9 kg/m2; diabetes duration: 4.2±0.9 years; HbA1c: 46±1.8 mmol/mol (6.4±0.2%), managed by diet and/or metformin, underwent concurrent measurements of gastric emptying, blood pressure and plasma glucose for 240 min after ingestion of a radiolabelled a mashed potato meal after receiving sitagliptin (100 mg) or placebo in randomised, double‐blind, crossover fashion on two consecutive days. RESULTS Sitagliptin reduced postprandial plasma glucose (P&lt;0.005), without affecting gastric emptying (P=0.88). The magnitude of the glucose‐lowering effect (change in iAUC0‐240 min from placebo to sitagliptin) was related to gastric emptying (kcal/min) on placebo (r=0.68, P=0.008) There was a comparable fall in systolic blood pressure (P=0.80) following the meal without any difference between the two days. CONCLUSIONS In type 2 diabetes, while sitagliptin has no effect on either gastric emptying or postprandial blood pressure, it&#039;s effects to lower postprandial glucose is dependent on the basal rate of gastric emptying

Autonomic function, postprandial hypotension and falls in older adults at one year after critical illness

OBJECTIVE: Postprandial hypotension occurs frequently in older survivors of critical illness at 3 months after discharge. We aimed to determine whether postprandial hypotension and its predictors - gastric dysmotility and cardiovascular autonomic dysfunction - persist or resolve as older survivors of critical illness recover, and whether postprandial hypotension after intensive care unit (ICU) discharge is associated with adverse outcomes at 12 months. DESIGN: Prospective observational study. SETTING: Tertiary medical-surgical ICU. PARTICIPANTS: Older adults (aged ≥ 65 years) who had been studied 3 months after ICU discharge and who returned for a follow-up study at 12 months after discharge. MAIN OUTCOME MEASURES: On both occasions after fasting overnight, participants consumed a 300 mL drink containing 75 g glucose, radiolabelled with 20 MBq 99mTcphytate. Blood pressure, heart rate, blood glucose concentration and gastric emptying rate were measured concurrently before and after ingestion of the drink. Falls, quality of life, hospitalisation and mortality rates were also quantified. RESULTS: Out of 35 older adults studied at 3 months, 22 returned for the follow-up study at 12 months. Postprandial hypotension was evident in 29% of participants (95% CI, 14-44%) at 3 months and 10% of participants (95% CI, 1-30%) at 12 months. Postprandial hypotension at 3 months was associated with a more than threefold increase in the risk of falls in the year after ICU discharge (relative risk, 3.7 [95% CI, 1.6-8.8]; P = 0.003). At 12 months, gastric emptying was normal (mean time taken for 50% of gastric contents to empty, 101.6 [SD, 33.3] min) and cardiovascular autonomic dysfunction prevalence was low (9% [95% CI, 1-29%]). CONCLUSIONS: In older adults who were evaluated 3 and 12 months after ICU discharge, postprandial hypotension at 3 months was associated with an increased risk of subsequent falls, but the prevalence of postprandial hypotension decreased with time

Postprandial hypotension in older survivors of critical illness

Abstract not availableThu Anh Ngoc Nguyen, Yasmine Ali Abdelhamid, Luke M. Weinel, Seva Hatzinikolas, Palash Kar, Matthew J. Summers, Liza K. Phillips, Michael Horowitz, Karen L. Jones, Adam M. Dean

Effects of a guar/whey preload on gastric emptying and glycaemic responses to oral glucose in healthy older people

International audienceBackground and aims: A whey protein/guar preload (Omniblend Innovation) has been developed recently to reduce postprandial glycaemia. The preload comprises 5g guar, 20g (whey) protein and 3g lactose (total 90kcal) in a sachet, which is added to a ‘shake and take’ cup containing 150ml water. Our previous trial suggested that this supplement slowed gastric emptying (GE), but the latter was assessed using a stable isotope breath test technique which limits the capacity to discriminate between slowing of GE and a delay in intestinal absorption. Our aim was to determine the effects of this guar/whey protein preload on GE (using the ‘gold standard’ technique, scintigraphy), and the glycaemic/ insulinaemic responses to an oral glucose load in healthy older people. Materials and methods: Ten healthy older participants (6F, 4M; age: 74.0 ± 1.6 yr; BMI: 26.0 ± 0.7 kg/m2) with normal glucose tolerance underwent concurrent measurements of GE, plasma glucose and insulin for 180 min on two occasions. Participants were studied after an overnight fast, were seated with their back against a gamma camera and a cannula inserted into an antecubital vein for blood sampling. In random order, each received a test drink comprising 50g glucose made up to 300ml with water containing 20MBq 99mTc-calcium-phytate with or without the guar/whey protein preload (90kcal) made up to 150ml with water, ingested 15 min before the test drink. Blood samples were taken immediately before the preload, before the glucose test drink and at 15-30 min intervals thereafter until t=180 min. The early insulin secretory response was estimated by the ratio of the change in insulin (ΔI0-30) to that of glucose at 30 min (ΔG0-30) represented as ΔI0-30/ΔG0-30. Data are mean values ± SEM. Results: The guar/whey protein preload reduced both the iAUC0-120 (PConclusion: In healthy older people, the glucose-lowering effect of the whey protein/guar preload appears unrelated to changes in GE and may reflect increased insulin secretion and/or slowing of small intestinal absorption