PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families.

PURPOSE: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. METHODS: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. RESULTS: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. CONCLUSION: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.

Nocturnal Hypoglycemia in Patients With Diabetes Discharged From ICUs: A Prospective Two-Center Cohort Study.

OBJECTIVES: There is very limited information about glycemic control after discharge from the ICU. The aims of this study were to evaluate the prevalence of hypoglycemia in ICU survivors with type-2 diabetes and determine whether hypoglycemia is associated with cardiac arrhythmias. DESIGN: Prospective, observational, two-center study. Participants underwent up to 5 days of simultaneous blinded continuous interstitial glucose monitoring and ambulatory 12-lead electrocardiogram monitoring immediately after ICU discharge during ward-based care. Frequency of arrhythmias, heart rate variability, and cardiac repolarization markers were compared between hypoglycemia (interstitial glucose ≤ 3.5 mmol/L) and euglycemia (5-10 mmol/L) matched for time of day. SETTING: Mixed medical-surgical ICUs in two geographically distinct university-affiliated hospitals. PATIENTS: Patients with type-2 diabetes who were discharged from ICU after greater than or equal to 24 hours with greater than or equal to one organ failure and were prescribed subcutaneous insulin were eligible. MEASUREMENTS AND MAIN RESULTS: Thirty-one participants (mean ± sd, age 65 ± 13 yr, glycated hemoglobin 64 ± 22 mmol/mol) were monitored for 101 ± 32 hours post-ICU (total 3,117 hr). Hypoglycemia occurred in 12 participants (39%; 95% CI, 22-56%) and was predominantly nocturnal (40/51 hr) and asymptomatic (25/29 episodes). Participants experiencing hypoglycemia had 2.4 ± 0.7 discrete episodes lasting 45 minutes (interquartile range, 25-140 min). Glucose nadir was less than or equal to 2.2 mmol/L in 34% of episodes. The longest episode of nocturnal hypoglycemia was 585 minutes with glucose nadir less than 2.2 mmol/L. Simultaneous electrocardiogram and continuous interstitial glucose monitoring recordings were obtained during 44 hours of hypoglycemia and 991 hours of euglycemia. Hypoglycemia was associated with greater risk of bradycardia but did not affect atrial or ventricular ectopics, heart rate variability, or cardiac repolarization. CONCLUSIONS: In ICU survivors with insulin-treated type-2 diabetes, hypoglycemia occurs frequently and is predominantly nocturnal, asymptomatic, and prolonged.

Survivors of Intensive Care With Type 2 Diabetes and the Effect of Shared-Care Follow-Up Clinics: The SWEET-AS Randomized Controlled Pilot Study.

BACKGROUND: Follow-up clinics after ICU admission have demonstrated limited benefit. However, existing trials have evaluated heterogeneous cohorts and used physicians who had limited training in outpatient care. RESEARCH QUESTION: What are the effects of a "shared-care" intensivist-endocrinologist clinic for ICU survivors with type 2 diabetes on process measures and clinical outcomes 6 months after hospital discharge, and is it feasible to conduct a larger trial? STUDY DESIGN AND METHODS: This was a prospective, randomized, single-center pilot study with blinded outcome assessment. Patients with type 2 diabetes, who required ≥ 5 days of ICU care (mixed medical-surgical ICU) and survived to ICU discharge, were eligible. Participants were randomized to attendance at the shared-care clinic 1 month after hospital discharge or usual care. Six months after hospital discharge, participants were assessed for outcomes including glycated hemoglobin, neuropathy, nephropathy, quality of life, return to employment, frailty, and health-care use. The primary outcome was participant recruitment and retention. RESULTS: During an 18-month period, 42 of 82 eligible patients (51%) were recruited. Four participants (10%) withdrew before assessment at 6 months and 11 (26%) died. At 6 months, only 18 of 38 participants who did not withdraw (47%) were living independently without support, and 24 (63%) required at least one subsequent hospital admission. In the intervention group (n = 21), 16 (76%) attended the clinic. Point estimates did not indicate that the intervention improved glycated hemoglobin (+5.6 mmol/mol; 95% CI, -6.3 to 17; P = .36) or quality of life (36-Item Short Form Survey physical summary score, 32 [9] vs. 32 [7]; P = 1.0). INTERPRETATION: Outcomes for ICU survivors with type 2 diabetes are poor. Because of low participation and high mortality, a larger trial of a shared-care follow-up clinic in this cohort, using the present design, does not appear feasible. TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry (ANZCTR); No.: ACTRN12616000206426; URL: www.anzctr.org.au.

Effects of Sustained Treatment With Lixisenatide on Gastric Emptying and Postprandial Glucose Metabolism in Type 2 Diabetes: A Randomized Controlled Trial.

OBJECTIVE: Tachyphylaxis for slowing of gastric emptying is seen with continuous exposure to glucagon-like peptide 1 (GLP-1). We therefore aimed to establish whether prolonged use of a "short-acting" GLP-1 receptor agonist, lixisenatide, achieves sustained slowing of gastric emptying and reduction in postprandial glycemia. RESEARCH DESIGN AND METHODS: A total of 30 patients with metformin-treated type 2 diabetes underwent assessment of gastric emptying (scintigraphy) and glucose metabolism (dual tracer technique) after a 75-g glucose drink, before and after 8 weeks' treatment with lixisenatide (20 µg subcutaneously daily) or placebo, in a double-blind randomized parallel design. RESULTS: Gastric retention of the glucose drink was markedly increased after lixisenatide versus placebo (ratio of adjusted geometric means for area under the curve [AUC] over 240 min of 2.19 [95% CI 1.82, 2.64], P < 0.001), associated with substantial reductions in the rate of systemic appearance of oral glucose (P < 0.001) and incremental AUC for blood glucose (P < 0.001). Lixisenatide suppressed both glucagon (P = 0.003) and insulin (P = 0.032), but not endogenous glucose production, over 120 min after oral glucose intake. Postprandial glucose lowering over 240 min was strongly related to the magnitude of slowing of gastric emptying by lixisenatide (r = -0.74, P = 0.002) and to the baseline rate of emptying (r = 0.52, P = 0.048) but unrelated to ß-cell function (assessed by ß-cell glucose sensitivity). CONCLUSIONS: Eight weeks' treatment with lixisenatide is associated with sustained slowing of gastric emptying and marked reductions in postprandial glycemia and appearance of ingested glucose. Short-acting GLP-1 receptor agonists therefore potentially represent an effective long-term therapy for specifically targeting postprandial glucose excursions.

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.

Exenatide once weekly slows gastric emptying of solids and liquids in healthy, overweight people at steady-state concentrations.

AIMS: To evaluate the effects of 8 weeks' administration of exenatide (EXE) once weekly on gastric emptying of solids and liquids (using the "gold standard" technique, scintigraphy), glucose absorption and postprandial glycaemia in healthy people. MATERIAL AND METHODS: A total of 32 healthy participants were randomized to receive either EXE once weekly (2 mg/wk subcutaneously; six men, 10 women, mean age 59.9 ± 0.9 years, mean body mass index [BMI] 29.6 ± 0.6 kg/m2 ) or matching placebo (PBO; six men, 10 women, mean age 60.6 ± 1.2 years, mean BMI 29.5 ± 1.0 kg/m2 ) for 8 weeks. Gastric emptying, nausea (visual analogue scale), and plasma glucose, insulin, C-peptide and glucagon were measured for 120 min after a solid/liquid meal, comprising 100 g ground beef (radiolabelled with 20 MBq 99m Tc-sulphur colloid) and 150 mL 10% glucose (radiolabelled with 7 MBq 67 Ga-EDTA), and containing 5 g 3-O-methyl-glucose (3-OMG) as a marker of glucose absorption, at baseline and after 8 weeks' treatment. RESULTS: The study treatments were well tolerated. Scores for nausea were consistently low, with no difference between the EXE once weekly and PBO groups. EXE once weekly slowed gastric emptying of solids (area under the curve [AUC]0-120min : P < 0.05) and liquids (AUC0-120min : P = 0.01) substantially, and attenuated glucose absorption (3-OMG incremental AUC [iAUC]0-30min : P = 0.001) and the postprandial rise in plasma glucose (iAUC0-30min : P = 0.008). Plasma glucagon at 2 h was reduced by EXE once weekly (P = 0.001). The magnitude of the reduction in plasma glucose at t = 30 min from baseline to 8 weeks with EXE once weekly was related inversely to the 50% emptying time of the glucose drink (r = -0.55, P = 0.03). CONCLUSIONS: In healthy participants, 8 weeks' administration of the "long-acting" glucagon-like peptide-1 receptor agonist EXE, slowed gastric emptying of solids and liquids substantially, with consequent reductions in glucose absorption and postprandial glycaemia.

The relationship between plasma GIP and GLP-1 levels in individuals with normal and impaired glucose tolerance.

AIMS: Glucose-dependent insulinotropic polypeptide (GIP) is released primarily from the proximal small intestine and glucagon-like peptide-1 (GLP-1) from the more distal small intestine and colon. Their relative importance to the incretin effect in health has been contentious in the past, although it now appears that GIP has the dominant role. It is uncertain whether there is a relationship between GIP and GLP-1 secretion. We aimed to evaluate the relationship between plasma GIP and GLP-1 responses to a 75-g oral glucose load in individuals with normal (NGT) and impaired glucose tolerance (IGT). METHODS: One hundred healthy subjects had measurements of blood glucose, serum insulin, plasma GIP and GLP-1 concentrations for 240 min after a 300 mL drink containing 75 g glucose. RESULTS: Fifty had NGT and 41 IGT; 9 had type 2 diabetes and were excluded from analysis. In both groups, there were increases in plasma GIP and GLP-1 following the glucose drink, with no difference in the magnitude of the responses between t = 0-240 min. There was a weak relationship between the iAUC0-240 min for GIP and GLP-1 in the combined (r = 0.23, P = 0.015) and in the IGT (r = 0.34, P = 0.01), but not in the NGT (r = 0.15, P = 0.14) group. CONCLUSIONS: There is a weak relationship between oral glucose-induced GIP and GLP-1 secretions in non-diabetic subjects.

The Effects of a Whey Protein and Guar Gum-Containing Preload on Gastric Emptying, Glycaemia, Small Intestinal Absorption and Blood Pressure in Healthy Older Subjects.

A whey protein/guar gum preload reduces postprandial glycaemia in type 2 diabetes through slowing gastric emptying. However, gastric emptying has previously been assessed using a stable isotope breath test technique, which cannot discriminate between slowing of gastric emptying and small intestinal absorption. This preload also may be useful in the management of postprandial hypotension. We evaluated the effects of a whey protein/guar preload on gastric emptying, glucose absorption, glycaemic/insulinaemic and blood pressure (BP) responses to an oral glucose load. Eighteen healthy older participants underwent measurements of gastric emptying (scintigraphy), plasma glucose and insulin, glucose absorption, superior mesenteric artery (SMA) flow, BP and heart rate (HR) after ingesting a 50 g glucose drink, with or without the preload. The preload reduced plasma glucose (p = 0.02) and serum 3-O-methylglucose (3-OMG) (p = 0.003), and increased plasma insulin (p = 0.03). There was no difference in gastric emptying or BP between the two days. The reduction in plasma glucose on the preload day was related to the reduction in glucose absorption (r = 0.71, p = 0.002). In conclusion, the glucose-lowering effect of the preload may relate to delayed small intestinal glucose absorption and insulin stimulation, rather than slowing of gastric emptying.

The prevalence and impact of low faecal elastase-1 in community-based patients with type 2 diabetes.

AIMS: To determine the prevalence of low faecal elastase-1 (FE-1) (≤200 µg/g) in type 2 diabetes (T2DM), and to test the hypothesis that pancreatic enzyme replacement therapy (PERT) would reduce postprandial glycaemia after a high-fat, high-carbohydrate meal in T2DM subjects with low FE-1. METHODS: Of 109 community-based patients who submitted stool samples, 10 had low FE-1 and 8 were recruited (6 male, 2 female, 67.8 ±â€¯3.0 years). Participants were given a high-fat, high-carbohydrate meal (718 kcal) with either pancrelipase (50,000 units) or placebo in a randomised, double-blind, crossover fashion. The primary outcome was the difference in postprandial glycaemia following PERT vs placebo, as evaluated by the incremental area under the postprandial plasma glucose curve (iAUC). Secondary outcomes included differences in gastric half-emptying time (T50) measured using scintigraphy, and C-peptide iAUC. RESULTS: The prevalence of low FE-1 in T2DM was 9.2% (95% CI 3.8-14.6%). There was no difference in postprandial glycaemia iAUC (P = 0.38), gastric emptying T50 (P = 0.69) or C-peptide iAUC (P = 0.25) after PERT compared to placebo. CONCLUSIONS: Decreased FE-1 has a relatively low prevalence in community-based patients with T2DM, and PERT does not reduce postprandial glycaemia in these patients. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12617000349347.

Longitudinal Changes in Fasting and Glucose-Stimulated GLP-1 and GIP in Healthy Older Subjects.

CONTEXT: It is not known whether glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels correlate within individuals, nor whether levels change with age. Previous studies have all been cross-sectional in design. OBJECTIVE: To evaluate longitudinal changes in fasting and glucose-stimulated incretin hormone concentrations in healthy older subjects. PATIENTS AND DESIGN: Forty-one healthy older subjects had measurements of plasma GLP-1 and GIP while fasting and after a 75-g oral glucose load on two occasions separated by 5.9 ± 0.1 years [mean age at the initial study: 71.2 ± 3.8 (SD) years]. Breath samples were collected to calculate the gastric 50% emptying time (T50). RESULTS: For GLP-1, both fasting concentrations (P < 0.001) and area under the curve 0 to 120 minutes (P = 0.001) were decreased at followup. Fasting GIP was also lower (P = 0.03) at follow up, but there was no change in the area under the curve 0 to 120 minutes (P = 0.26). The gastric emptying T50 was slower at followup (P = 0.008). Neither the change in T50 nor the body mass index at the initial study was a determinant of the change in incretin responses. Between the two study days, fasting GIP (r = 0.72, P < 0.001) correlated well, but not fasting GLP-1 (r = 0.23, P = 0.18). However, both glucose-stimulated GLP-1 (r = 0.50, P = 0.002) and GIP (r = 0.60, P < 0.001) showed correlations between the initial and follow-up studies. CONCLUSIONS: Fasting GIP and glucose-stimulated GLP-1 and GIP concentrations correlate within individuals over a follow-up period of ∼5.9 years. Aging is associated with reductions in fasting GLP-1 and GIP, and glucose-stimulated GLP-1, which may predispose to the development of glucose intolerance and type 2 diabetes.

Acute Effects of Nutritive and Non-Nutritive Sweeteners on Postprandial Blood Pressure.

Postprandial hypotension (PPH) is under-recognised, but common, particularly in the elderly, and is of clear clinical importance due to both the independent association between PPH and an increase in mortality and lack of effective management for this condition. Following health concerns surrounding excessive consumption of sugar, there has been a trend in the use of low- or non-nutritive sweeteners as an alternative. Due to the lack of literature in this area, we conducted a systematic search to identify studies relevant to the effects of different types of sweeteners on postprandial blood pressure (BP). The BP response to ingestion of sweeteners is generally unaffected in healthy young subjects, however in elderly subjects, glucose induces the greatest decrease in postprandial BP, while the response to sucrose is less pronounced. The limited studies investigating other nutritive and non-nutritive sweeteners have demonstrated minimal or no effect on postprandial BP. Dietary modification by replacing high nutritive sweeteners (glucose, fructose, and sucrose) with low nutritive (d-xylose, xylitol, erythritol, maltose, maltodextrin, and tagatose) and non-nutritive sweeteners may be a simple and effective management strategy for PPH.

Longitudinal evaluation of gastric emptying in type 2 diabetes.

AIMS: To evaluate the natural history of gastric emptying in type 2 diabetes. METHODS: 12 patients with type 2 diabetes (7 female; age 65.6 ±â€¯1.2 years; duration of known diabetes 22.9 ±â€¯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 ±â€¯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. RESULTS: Gastric 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. CONCLUSIONS: In 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.

Gastric Emptying in Patients With Well-Controlled Type 2 Diabetes Compared With Young and Older Control Subjects Without Diabetes.

CONTEXT: Gastric emptying is a major determinant of postprandial glycemia and is often delayed in long-standing, complicated type 2 diabetes mellitus (T2DM). However, there is little information about gastric emptying in well-controlled T2DM. OBJECTIVE: To evaluate the rate of gastric emptying in community-based patients with relatively well-controlled T2DM compared with young and older control subjects without diabetes. PARTICIPANTS AND DESIGN: A total of 111 patients with T2DM managed by diet (n = 52) or metformin monotherapy (n = 59) (HbA1c 6.6 ± 0.1%/49.0 ± 0.9 mmol/mol), 18 age- and body mass index (BMI)-matched older subjects without diabetes, and 15 young healthy subjects consumed a standardized mashed potato meal (368.5 kcal) containing 100 µL 13C-octanoic acid. Gastric emptying (by breath test) and blood glucose were evaluated over 240 minutes. RESULTS: Gastric emptying was slower in the older than in the young subjects without diabetes (2.3 ± 0.1 vs 3.0 ± 0.1 kcal/min, P = 0.0008). However, relative to the age- and BMI-matched subjects without diabetes, gastric emptying (2.8 ± 0.1 kcal/min) was faster in patients with T2DM (P = 0.0005). Furthermore, gastric emptying was faster in the metformin-treated (3.0 ± 0.1 kcal/min) than in the diet-controlled (2.7 ± 0.1 kcal/min) patients with T2DM (P = 0.011), although there were no differences in age, BMI, HbA1c, or the duration of known diabetes. The increments in blood glucose (at t = 30 and 60 minutes and the incremental area under the curve during t = 0 to 120 minutes) after the meal were related directly to the rate of gastric emptying in the subjects with T2DM regardless of treatment with or without metformin (P < 0.05 each). CONCLUSIONS: Gastric emptying is slowed with aging but otherwise is relatively more rapid in patients with well-controlled T2DM. This provides a strong rationale for slowing gastric emptying to improve postprandial glycemic control in these patients.

Incident Diabetes in Survivors of Critical Illness and Mechanisms Underlying Persistent Glucose Intolerance: A Prospective Cohort Study.

OBJECTIVES: Stress hyperglycemia occurs in critically ill patients and may be a risk factor for subsequent diabetes. The aims of this study were to determine incident diabetes and prevalent prediabetes in survivors of critical illness experiencing stress hyperglycemia and to explore underlying mechanisms. DESIGN: This was a prospective, single center, cohort study. At admission to ICU, hemoglobin A1c was measured in eligible patients. Participants returned at 3 and 12 months after ICU admission and underwent hemoglobin A1c testing and an oral glucose tolerance test. Blood was also collected for hormone concentrations, whereas gastric emptying was measured via an isotope breath test. ß-cell function was modeled using standard techniques. SETTING: Tertiary-referral, mixed medical-surgical ICU. PATIENTS: Consecutively admitted patients who developed stress hyperglycemia and survived to hospital discharge were eligible. MEASUREMENTS AND MAIN RESULTS: Consent was obtained from 40 patients (mean age, 58 yr [SD, 10], hemoglobin A1c 36.8 mmol/mol [4.9 mmol/mol]) with 35 attending the 3-month and 26 the 12-month visits. At 3 months, 13 (37%) had diabetes and 15 (43%) had prediabetes. At 12 months, seven (27%) participants had diabetes, whereas 11 (42%) had prediabetes. Mean hemoglobin A1c increased from baseline during the study: +0.7 mmol/mol (-1.2 to 2.5 mmol/mol) at 3 months and +3.3 mmol/mol (0.98-5.59 mmol/mol) at 12 months (p = 0.02). Gastric emptying was not significantly different across groups at either 3 or 12 months. CONCLUSIONS: Diabetes and prediabetes occur frequently in survivors of ICU experiencing stress hyperglycemia. Based on the occurrence rate observed in this cohort, structured screening and intervention programs appear warranted.

A whey/guar "preload" improves postprandial glycaemia and glycated haemoglobin levels in type 2 diabetes: A 12-week, single-blind, randomized, placebo-controlled trial.

AIMS: To evaluate the effects of 12 weeks of treatment with a whey/guar preload on gastric emptying, postprandial glycaemia and glycated haemoglobin (HbA1c) levels in people with type 2 diabetes (T2DM). MATERIALS AND METHODS: A total of 79 people with T2DM, managed on diet or metformin (HbA1c 49 ± 0.7 mmol/mol [6.6 ± 0.1%]), were randomized, in single-blind fashion, to receive 150 mL flavoured preloads, containing either 17 g whey protein plus 5 g guar (n = 37) or flavoured placebo (n = 42), 15 minutes before two meals, each day for 12 weeks. Blood glucose and gastric emptying (breath test) were measured before and after a mashed potato meal at baseline (without preload), and after the preload at the beginning (week 1) and end (week 12) of treatment. HbA1c levels, energy intake, weight and body composition were also evaluated. RESULTS: Gastric emptying was slower (P < 0.01) and postprandial blood glucose levels lower (P < 0.05) with the whey/guar preload compared to placebo preload, and the magnitude of reduction in glycaemia was related to the rate of gastric emptying at both week 1 (r = -0.54, P < 0.001) and week 12 (r = -0.54, P < 0.0001). At the end of treatment, there was a 1 mmol/mol [0.1%] reduction in HbA1c in the whey/guar group compared to the placebo group (49 ± 1.0 mmol/mol [6.6 ± 0.05%] vs. 50 ± 0.8 mmol/mol [6.7 ± 0.05%]; P < 0.05). There were no differences in energy intake, body weight, or lean or fat mass between the groups. CONCLUSIONS: In patients with well-controlled T2DM, 12 weeks' treatment with a low-dose whey/guar preload, taken twice daily before meals, had sustained effects of slowing gastric emptying and reducing postprandial blood glucose, which were associated with a modest reduction in HbA1c, without causing weight gain.

Title: Differentiating the effects of whey protein and guar gum preloads on postprandial glycemia in type 2 diabetes.

BACKGROUND AND AIMS: Whey protein and guar gum have both been reported to reduce postprandial glycemia in health and type 2 diabetes, associated with stimulation of glucagon-like peptide-1 (GLP-1) and/or slowing of gastric emptying. Our aim was to evaluate, in type 2 diabetes, the acute effects of low dose "preloads" of whey and guar, given alone or in combination before a meal, on postprandial glycemia, insulin, GLP-1, and gastric emptying. METHODS: 21 patients with type 2 diabetes, managed by diet or metformin alone, were each studied on 4 days. They received a preload "shake" 15min before a mashed potato meal (368.5 kcal) labeled with 13C-octanoic-acid. The preloads comprised either (i) 17 g whey (W), (ii) 5 g guar (G), (iii) 17 g whey + 5 g guar (WG) each sweetened with 60 mg sucralose, and (iv) 60 mg sucralose alone (control; C), all dissolved in 150 mL water. Venous blood was sampled frequently for measurements of glucose, insulin, and GLP-1 concentrations. Gastric half-emptying time (T50) was calculated from breath 13CO2 excretion over 240 min. RESULTS: Postprandial blood glucose concentrations were lower with W and WG compared to C (each P < 0.0001, treatment × time interaction), and lower after G than C only at 30min. Insulin, GLP-1, and glucagon concentrations were higher after W than WG, G, or C (P < 0.05, treatment × time interaction), without differences between the latter three. Gastric emptying was slower with W (T50: 179.6 ± 6.1 min, P < 0.05) and WG (T50: 197.6 ± 9.7 min, P < 0.0001) when compared to C (T50: 162.9 ± 6.2 min), but did not differ between G (T50: 171.3 ± 7.0) and C (P > 0.99). CONCLUSION: Both whey and whey/guar preloads reduced postprandial glycemia, associated with slowing of gastric emptying. Low dose guar was less effective as a preload for glucose-lowering and did not slow gastric emptying. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: Australian and New Zealand Clinical Trials Registry, Trial ID ACTRN12615001272583, http://www.anzctr.org.au.

Effects of intraduodenal administration of the artificial sweetener sucralose on blood pressure and superior mesenteric artery blood flow in healthy older subjects.

Background: Postprandial hypotension (PPH) occurs frequently, particularly in older people and those with type 2 diabetes, and is associated with increased morbidity and mortality. The magnitude of the decrease in blood pressure (BP) induced by carbohydrate, fat, and protein appears to be comparable and results from the interaction of macronutrients with the small intestine, including an observed stimulation of mesenteric blood flow. It is not known whether artificial sweeteners, such as sucralose, which are widely used, affect BP. Objective: The aim of this study was to evaluate the effects of intraduodenal sucralose on BP and superior mesenteric artery (SMA) blood flow, compared with intraduodenal glucose and saline (control), in healthy older subjects. Design: Twelve healthy subjects (6 men, 6 women; aged 66-79 y) were studied on 3 separate occasions in a randomized, double-blind, crossover design. After an overnight fast, subjects had concurrent measurements of BP and heart rate (HR; automated device), SMA blood flow (Doppler ultrasound), and blood glucose (glucometer) during intraduodenal infusion of 1) glucose (25% wt:vol, ∼1400 mOsmol/L), 2) sucralose (4 mmol/L, ∼300 mOsmol/L), or 3) saline (0.9% wt:vol, ∼300 mOsmol/L) at a rate of 3 mL/min for 60 min followed by intraduodenal saline for a further 60 min. Results: There was a decrease in mean arterial BP (P < 0.001) during intraduodenal glucose [baseline (mean ± SEM): 91.7 ± 2.6 mm Hg compared with t = 60 min: 85.9 ± 2.8 mm Hg] but not during intraduodenal saline or intraduodenal sucralose. The HR (P < 0.0001) and SMA blood flow (P < 0.0001) also increased during intraduodenal glucose but not during intraduodenal saline or intraduodenal sucralose. As expected, blood glucose concentrations increased in response to glucose (P < 0.0001) but not saline or sucralose. Conclusions: In healthy older subjects, intraduodenal administration of the artificial sweetener sucralose was not associated with changes in BP or SMA blood flow. Further studies are therefore warranted to determine the potential role for artificial sweeteners as a therapy for PPH. This trial was registered at http://www.ANZCTR.org.au as ACTRN12617001249347.