Dietary carbohydrate restriction augments weight loss-induced improvements in glycaemic control and liver fat in individuals with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Lifestyle modification and weight loss are cornerstones of type 2 diabetes management. However, carbohydrate restriction may have weight-independent beneficial effects on glycaemic control. This has been difficult to demonstrate because low-carbohydrate diets readily decrease body weight. We hypothesised that carbohydrate restriction enhances the beneficial metabolic effects of weight loss in type 2 diabetes. METHODS: This open-label, parallel RCT included adults with type 2 diabetes, HbA1c 48-97 mmol/mol (6.5-11%), BMI >25 kg/m2, eGFR >30 ml min-1 [1.73 m]-2 and glucose-lowering therapy restricted to metformin or dipeptidyl peptidase-4 inhibitors. Participants were randomised by a third party and assigned to 6 weeks of energy restriction (all foods were provided) aiming at ~6% weight loss with either a carbohydrate-reduced high-protein diet (CRHP, percentage of total energy intake [E%]: CH30/P30/F40) or a conventional diabetes diet (CD, E%: CH50/P17/F33). Fasting blood samples, continuous glucose monitoring and magnetic resonance spectroscopy were used to assess glycaemic control, lipid metabolism and intrahepatic fat. Change in HbA1c was the primary outcome; changes in circulating and intrahepatic triacylglycerol were secondary outcomes. Data were collected at Copenhagen University Hospital (Bispebjerg and Herlev). RESULTS: Seventy-two adults (CD 36, CRHP 36, all white, 38 male sex) with type 2 diabetes (mean duration 8 years, mean HbA1c 57 mmol/mol [7.4%]) and mean BMI of 33 kg/m2 were enrolled, of which 67 (CD 33, CRHP 34) completed the study. Body weight decreased by 5.8 kg (5.9%) in both groups after 6 weeks. Compared with the CD diet, the CRHP diet further reduced HbA1c (mean [95% CI] -1.9 [-3.5, -0.3] mmol/mol [-0.18 (-0.32, -0.03)%], p = 0.018) and diurnal mean glucose (mean [95% CI] -0.8 [-1.2, -0.4] mmol/l, p < 0.001), stabilised glucose excursions by reducing glucose CV (mean [95% CI] -4.1 [-5.9, -2.2]%, p < 0.001), and augmented the reductions in fasting triacylglycerol concentration (by mean [95% CI] -18 [-29, -6]%, p < 0.01) and liver fat content (by mean [95% CI] -26 [-45, 0]%, p = 0.051). However, pancreatic fat content was decreased to a lesser extent by the CRHP than the CD diet (mean [95% CI] 33 [7, 65]%, p = 0.010). Fasting glucose, insulin, HOMA2-IR and cholesterol concentrations (total, LDL and HDL) were reduced significantly and similarly by both diets. CONCLUSIONS/INTERPRETATION: Moderate carbohydrate restriction for 6 weeks modestly improved glycaemic control, and decreased circulating and intrahepatic triacylglycerol levels beyond the effects of weight loss itself compared with a CD diet in individuals with type 2 diabetes. Concurrent differences in protein and fat intakes, and the quality of dietary macronutrients, may have contributed to these results and should be explored in future studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT03814694. FUNDING: The study was funded by Arla Foods amba, The Danish Dairy Research Foundation, and Copenhagen University Hospital Bispebjerg Frederiksberg.

Effects of carbohydrate restriction on postprandial glucose metabolism, ß-cell function, gut hormone secretion, and satiety in patients with Type 2 diabetes.

Dietary carbohydrate restriction may improve the phenotype of Type 2 diabetes (T2D) patients. We aimed to investigate 6 wk of carbohydrate restriction on postprandial glucose metabolism, pancreatic α- and ß-cell function, gut hormone secretion, and satiety in T2D patients. Methods In a crossover design, 28 T2D patients (mean HbA1c: 60 mmol/mol) were randomized to 6 wk of carbohydrate-reduced high-protein (CRHP) diet and 6 wk of conventional diabetes (CD) diet (energy-percentage carbohydrate/protein/fat: 30/30/40 vs. 50/17/33). Twenty-four-hour continuous glucose monitoring (CGM) and mixed-meal tests were undertaken and fasting intact proinsulin (IP), 32,33 split proinsulin concentrations (SP), and postprandial insulin secretion rates (ISR), insulinogenic index (IGI), ß-cell sensitivity to glucose (Bup), glucagon, and gut hormones were measured. Gastric emptying was evaluated by postprandial paracetamol concentrations and satiety by visual analog scale ratings. A CRHP diet reduced postprandial glucose area under curve (net AUC) by 60% (P < 0.001), 24 h glucose by 13% (P < 0.001), fasting IP and SP concentrations (both absolute and relative to C-peptide, P < 0.05), and postprandial ISR (24%, P = 0.015), while IGI and Bup improved by 31% and 45% (both P < 0.001). The CRHP diet increased postprandial glucagon net AUC by 235% (P < 0.001), subjective satiety by 18% (P = 0.03), delayed gastric emptying by 15 min (P < 0.001), decreased gastric inhibitory polypeptide net AUC by 29% (P < 0.001), but had no significant effect on glucagon-like-peptide-1, total peptide YY, and cholecystokinin responses. A CRHP diet reduced glucose excursions and improved ß-cell function, including proinsulin processing, and increased subjective satiety in patients with T2D.

Body weight and metabolic risk factors in patients with type 2 diabetes on a self-selected high-protein low-carbohydrate diet.

PURPOSE: We previously reported beneficial glucoregulatory effects of a fully provided carbohydrate-reduced, high-protein (CRHP) diet in patients with type 2 diabetes mellitus (T2DM) in a crossover 2 × 6-week trial, in which patients maintained their body weight. Here, we investigated physiological changes during an additional 6-month period on a self-selected and self-prepared CRHP diet. METHODS: Twenty-eight patients with T2DM were instructed to consume a CRHP diet (30% of energy from carbohydrate and 30% from protein) for 24 weeks, after an initial 2 × 6-week trial when all food was prepared and provided to them. Patients received dietary advice every 2 weeks. At weeks 0, 6, 12 and 36, they underwent a 3-h intravenous glucose tolerance test, a 4-h mixed meal test, and a 48-h continuous glucose monitoring. Liver, muscle, pancreas, and visceral fat contents were measured by magnetic resonance imaging. RESULTS: During the 24-week self-selected diet period (weeks 12-36), body weight, visceral fat, liver fat, and glycated haemoglobin were maintained at the same levels achieved at the end of the fully provided diet period, and were still lower than at baseline (P < 0.05). Postprandial insulinaemia and insulin secretion were significantly greater (P < 0.05). At week 36, fasting insulin and C-peptide levels increased (P < 0.01) and daily glycaemia decreased further (P < 0.05) when compared with the end of the fully provided diet period. CONCLUSION: Substituting dietary carbohydrate for protein and fat has metabolic benefits in patients with T2DM. These beneficial effects are maintained or augmented over the next 6 months when patients self-select and self-prepare this diet in a dietitian-supported setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02764021.

Effects of a highly controlled carbohydrate-reduced high-protein diet on markers of oxidatively generated nucleic acid modifications and inflammation in weight stable participants with type 2 diabetes; a randomized controlled trial.

Carbohydrate-restricted diets are increasingly recognized as options for dietary management of type 2 diabetes mellitus (T2DM). We investigated the effects of a carbohydrate-reduced high-protein (CRHP) and a conventional diabetes (CD) diet on oxidative stress and inflammation in weight stable individuals with T2DM. We hypothesized that the CRHP diet would improve markers of oxidatively generated RNA and DNA modifications as well as inflammatory parameters. Thirty participants with T2DM were randomized to 6 weeks of CRHP or CD dietary treatment (30/50 energy percentage (E%) carbohydrate, 30/17E% protein, 40/33E% fat), followed by a cross-over to the opposite diet for a subsequent 6-week period. All meals were provided during the study and body weight was controlled. Diurnal urine samples were collected after 4 weeks on each diet and oxidatively generated RNA and DNA modifications were measured as 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), respectively. Fasting concentrations of soluble urokinase plasminogen activator receptor, high-sensitivity C-reactive protein, tumor necrosis factor alpha and interleukin-6 were measured before and after 6 weeks of interventions. Compared with the CD diet, the CRHP diet increased 24-hour urinary excretion of 8-oxoGuo by 9.3% (38.6 ± 12.6 vs. 35.3 ± 11.0 nmol/24 h, p = .03), whereas 8-oxodG did not differ between diets (24.0 ± 9.5 vs. 24.8 ± 11.1 nmol/24 h, p = .17). Changes in plasma inflammatory parameters did not differ between CRHP and CD diets, all p ≥ .2. The clinical implications of increased RNA oxidation following a CRHP diet as well as long-term effects of carbohydrate-restriction on markers of oxidatively generated nucleic acid modifications should be a field of future study.

A carbohydrate-reduced high-protein diet improves HbA1c and liver fat content in weight stable participants with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Dietary recommendations for treating type 2 diabetes are unclear but a trend towards recommending a diet reduced in carbohydrate content is acknowledged. We compared a carbohydrate-reduced high-protein (CRHP) diet with an iso-energetic conventional diabetes (CD) diet to elucidate the effects on glycaemic control and selected cardiovascular risk markers during 6 weeks of full food provision of each diet. METHODS: The primary outcome of the study was change in HbA1c. Secondary outcomes reported in the present paper include glycaemic variables, ectopic fat content and 24 h blood pressure. Eligibility criteria were: men and women with type 2 diabetes, HbA1c 48-97 mmol/mol (6.5-11%), age >18 years, haemoglobin >6/>7 mmol/l (women/men) and eGFR >30 ml min-1 (1.73 m)-2. Participants were randomised by drawing blinded ballots to 6 + 6 weeks of an iso-energetic CRHP vs CD diet in an open label, crossover design aiming at body weight stability. The CRHP/CD diets contained carbohydrate 30/50 energy per cent (E%), protein 30/17E% and fat 40/33E%, respectively. Participants underwent a meal test at the end of each diet period and glycaemic variables, lipid profiles, 24 h blood pressure and ectopic fat including liver and pancreatic fat content were assessed at baseline and at the end of each diet period. Data were collected at Copenhagen University Hospital, Bispebjerg and Copenhagen University Hospital, Herlev. RESULTS: Twenty-eight participants completed the study. Fourteen participants carried out 6 weeks of the CRHP intervention followed by 6 weeks of the CD intervention, and 14 participants received the dietary interventions in the reverse order. Compared with a CD diet, a CRHP diet reduced the primary outcome of HbA1c (mean ± SEM: -6.2 ± 0.8 mmol/mol (-0.6 ± 0.1%) vs -0.75 ± 1.0 mmol/mol (-0.1 ± 0.1%); p < 0.001). Nine (out of 37) pre-specified secondary outcomes are reported in the present paper, of which five were significantly different between the diets, (p < 0.05); compared with a CD diet, a CRHP diet reduced the secondary outcomes (mean ± SEM or medians [interquartile range]) of fasting plasma glucose (-0.71 ± 0.20 mmol/l vs 0.03 ± 0.23 mmol/l; p < 0.05), postprandial plasma glucose AUC (9.58 ± 0.29 mmol/l × 240 min vs 11.89 ± 0.43 mmol/l × 240 min; p < 0.001) and net AUC (1.25 ± 0.20 mmol/l × 240 min vs 3.10 ± 0.25 mmol/l × 240 min; p < 0.001), hepatic fat content (-2.4% [-7.8% to -1.0%] vs 0.2% [-2.3% to 0.9%]; p < 0.01) and pancreatic fat content (-1.7% [-3.5% to 0.6%] vs 0.5% [-1.0% to 2.0%]; p < 0.05). Changes in other secondary outcomes, i.e. 24 h blood pressure and muscle-, visceral- or subcutaneous adipose tissue, did not differ between diets. CONCLUSIONS/INTERPRETATION: A moderate macronutrient shift by substituting carbohydrates with protein and fat for 6 weeks reduced HbA1c and hepatic fat content in weight stable individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02764021. FUNDING: The study was funded by grants from Arla Food for Health; the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen; the Department of Clinical Medicine, Aarhus University; the Department of Nutrition, Exercise and Sports, University of Copenhagen; and Copenhagen University Hospital, Bispebjerg.

Effect of liraglutide on estimates of lipolysis and lipid oxidation in obese patients with stable coronary artery disease and newly diagnosed type 2 diabetes: A randomized trial.

Elevated levels of non-esterified fatty acids (NEFA) play a role in insulin resistance, impaired beta-cell function and they are a denominator of the abnormal atherogenic lipid profile that characterizes obese patients with type 2 diabetes (T2DM). We hypothesized that the GLP-1 receptor agonist liraglutide, in combination with metformin, would reduce lipolysis. In a randomized, double-blind, placebo-controlled, cross-over trial, 41 T2DM patients with coronary artery disease were randomized and treated with liraglutide-metformin vs placebo-metformin during 12- + 12-week periods with a wash-out period of at least 2 weeks before and between the intervention periods. NEFA kinetics were estimated using the Boston Minimal Model of NEFA metabolism, with plasma NEFA and glucose levels measured during a standard 180-minute frequently sampled intravenous glucose tolerance test. Liraglutide-metformin reduced estimates of lipolysis. Furthermore, placebo-metformin increased estimates of lipid oxidation, while treatment with liraglutide eliminated this effect. We conclude that liraglutide exerts a clinically relevant reduction in estimates of lipolysis and lipid oxidation which is explained, in part, by improved insulin secretion, as revealed by an intravenous glucose tolerance test.

A carbohydrate-reduced high-protein diet acutely decreases postprandial and diurnal glucose excursions in type 2 diabetes patients.

The aim of the study was to assess whether a simple substitution of carbohydrate in the conventionally recommended diet with protein and fat would result in a clinically meaningful reduction in postprandial hyperglycaemia in subjects with type 2 diabetes mellitus (T2DM). In all, sixteen subjects with T2DM treated with metformin only, fourteen male, with a median age of 65 (43-70) years, HbA1c of 6·5 % (47 mmol/l) (5·5-8·3 % (37-67 mmol/l)) and a BMI of 30 (sd 4·4) kg/m2 participated in the randomised, cross-over study. A carbohydrate-reduced high-protein (CRHP) diet was compared with an iso-energetic conventional diabetes (CD) diet. Macronutrient contents of the CRHP/CD diets consisted of 31/54 % energy from carbohydrate, 29/16 % energy from protein and 40/30 % energy from fat, respectively. Each diet was consumed on 2 consecutive days in a randomised order. Postprandial glycaemia, pancreatic and gut hormones, as well as satiety, were evaluated at breakfast and lunch. Compared with the CD diet, the CRHP diet reduced postprandial AUC of glucose by 14 %, insulin by 22 % and glucose-dependent insulinotropic polypeptide by 17 % (all P<0·001), respectively. Correspondingly, glucagon AUC increased by 33 % (P<0·001), cholecystokinin by 24 % (P=0·004) and satiety scores by 7 % (P=0·035), respectively. A moderate reduction in carbohydrate with an increase in fat and protein in the diet, compared with an energy-matched CD diet, greatly reduced postprandial glucose excursions and resulted in increased satiety in patients with well-controlled T2DM.

The acute effects of dietary carbohydrate reduction on postprandial responses of non-esterified fatty acids and triglycerides: a randomized trial.

BACKGROUND: Postprandial non-esterified fatty acid (NEFA) and triglyceride (TG) responses are increased in subjects with type 2 diabetes mellitus (T2DM) and may impair insulin action and increase risk of cardiovascular disease and death. Dietary carbohydrate reduction has been suggested as non-pharmacological therapy for T2DM, but the acute effects on NEFA and TG during subsequent meals remain to be investigated. METHODS: Postprandial NEFA and TG responses were assessed in subjects with T2DM by comparing a carbohydrate-reduced high-protein (CRHP) diet with a conventional diabetes (CD) diet in an open-label, randomized, cross-over study. Each diet was consumed on two consecutive days, separated by a wash-out period. The iso-caloric CRHP/CD diets contained 31/54 E% from carbohydrate, 29/16 E% energy from protein and 40/30 E% from fat, respectively. Sixteen subjects with well-controlled T2DM (median HbA1c 47 mmol/mol, (37-67 mmol/mol) and BMI 30 ± 4.4 kg/m2) participated in the study. NEFA and TG were evaluated following breakfast and lunch. RESULTS: NEFA net area under curve (AUC) was increased by 97 ± 38 µmol/Lx270 min (p = 0.024) after breakfast but reduced by 141 ± 33 µmol/Lx180 min (p < 0.001) after lunch on the CRHP compared with CD diet. Likewise, TG net AUC was increased by 80 ± 28 µmol/Lx270 min (p = 0.012) after breakfast but reduced by 320 ± 60 µmol/Lx180 min (p < 0.001) after lunch on the CRHP compared with CD diet. CONCLUSIONS: In well-controlled T2DM a modest reduction of dietary carbohydrate with a corresponding increase in protein and fat acutely reduced postprandial serum NEFA suppression and increased serum TG responses after a breakfast meal but had the opposite effect after a lunch meal. The mechanism behind this second-meal phenomenon of CRHP diet on important risk factors for aggravating T2DM and cardiovascular disease awaits further investigation. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov ID: NCT02472951. https://clinicaltrials.gov/ct2/show/NCT02472951 . Registered June 16, 2015.

Effect of a 6-Week Carbohydrate-Reduced High-Protein Diet on Levels of FGF21 and GDF15 in People With Type 2 Diabetes.

Context: Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are increased in type 2 diabetes and are potential regulators of metabolism. The effect of changes in caloric intake and macronutrient composition on their circulating levels in patients with type 2 diabetes are unknown. Objective: To explore the effects of a carbohydrate-reduced high-protein diet with and without a clinically significant weight loss on circulating levels of FGF21 and GDF15 in patients with type 2 diabetes. Methods: We measured circulating FGF21 and GDF15 in patients with type 2 diabetes who completed 2 previously published diet interventions. Study 1 randomized 28 subjects to an isocaloric diet in a 6 + 6-week crossover trial consisting of, in random order, a carbohydrate-reduced high-protein (CRHP) or a conventional diabetes (CD) diet. Study 2 randomized 72 subjects to a 6-week hypocaloric diet aiming at a ∼6% weight loss induced by either a CRHP or a CD diet. Fasting plasma FGF21 and GDF15 were measured before and after the interventions in a subset of samples (n = 24 in study 1, n = 66 in study 2). Results: Plasma levels of FGF21 were reduced by 54% in the isocaloric study (P < .05) and 18% in the hypocaloric study (P < .05) in CRHP-treated individuals only. Circulating GDF15 levels increased by 18% (P < .05) following weight loss in combination with a CRHP diet but only in those treated with metformin. Conclusion: The CRHP diet significantly reduced FGF21 in people with type 2 diabetes independent of weight loss, supporting the role of FGF21 as a "nutrient sensor." Combining metformin treatment with carbohydrate restriction and weight loss may provide additional metabolic improvements due to the rise in circulating GDF15.

Markers of Glucagon Resistance Improve With Reductions in Hepatic Steatosis and Body Weight in Type 2 Diabetes.

Context: Hyperglucagonemia may develop in type 2 diabetes due to obesity-prone hepatic steatosis (glucagon resistance). Markers of glucagon resistance (including the glucagon-alanine index) improve following diet-induced weight loss, but the partial contribution of lowering hepatic steatosis vs body weight is unknown. Objective: This work aimed to investigate the dependency of body weight loss following a reduction in hepatic steatosis on markers of glucagon resistance in type 2 diabetes. Methods: A post hoc analysis was conducted from 2 previously published randomized controlled trials. We investigated the effect of weight maintenance (study 1: isocaloric feeding) or weight loss (study 2: hypocaloric feeding), both of which induced reductions in hepatic steatosis, on markers of glucagon sensitivity, including the glucagon-alanine index measured using a validated enzyme-linked immunosorbent assay and metabolomics in 94 individuals (n = 28 in study 1; n = 66 in study 2). Individuals with overweight or obesity with type 2 diabetes were randomly assigned to a 6-week conventional diabetes (CD) or carbohydrate-reduced high-protein (CRHP) diet within both isocaloric and hypocaloric feeding-interventions. Results: By design, weight loss was greater after hypocaloric compared to isocaloric feeding, but both diets caused similar reductions in hepatic steatosis, allowing us to investigate the effect of reducing hepatic steatosis with or without a clinically relevant weight loss on markers of glucagon resistance. The glucagon-alanine index improved following hypocaloric, but not isocaloric, feeding, independently of macronutrient composition. Conclusion: Improvements in glucagon resistance may depend on body weight loss in patients with type 2 diabetes.

Weight loss improves ß-cell function independently of dietary carbohydrate restriction in people with type 2 diabetes: A 6-week randomized controlled trial.

Background: Carbohydrate restriction may benefit ß-cell function and glucose metabolism in type 2 diabetes (T2D) but also leads to weight loss which in itself is beneficial. Methods: In order to determine the additional effect of carbohydrate restriction in addition to a fixed body weight loss, we randomly assigned 72 adults with T2D and obesity (mean ± SD HbA1c 7.4 ± 0.7%, BMI 33 ± 5 kg/m2) to a carbohydrate-reduced high-protein diet (CRHP; energy percent from carbohydrate/protein/fat: 30/30/40) or an isocaloric conventional diabetes diet (CD; 50/17/33) for 6 weeks. All foods were provided free of charge and total energy intake was tailored individually, so both groups lost 6% of baseline body weight. Results: Despite significantly greater reductions in HbA1c (mean [95% CI] -1.9 [-3.5, -0.3] mmol/mol) after 6 weeks, the CRHP diet neither improved glucose tolerance, ß-cell response to glucose, insulin sensitivity, during a 4-h oral glucose tolerance test, nor basal proinsulin secretion when compared to the CD diet, but increased C-peptide concentration and insulin secretion rate (area under the curve [AUC] and peak) significantly more (~10%, P ≤ 0.03 for all). Furthermore, compared with the CD diet, the CRHP diet borderline increased basal glucagon concentration (16 [-0.1, 34]%, P = 0.05), but decreased glucagon net AUC (-2.0 [-3.4, -0.6] mmol/L ×240 min, P < 0.01), decreased basal triglyceride and total AUC (~20%, P < 0.01 for both), and increased gastric inhibitory polypeptide total AUC (14%, P = 0.01). Conclusion: A moderately carbohydrate-restricted diet for 6 weeks decreased HbA1c but did not improve ß-cell function or glucose tolerance beyond the effects of weight loss when compared with a conventional diabetes diet in people with T2D. Clinical trials registration: www.Clinicaltrials.gov, Identifier: NCT02472951.

Effects of Carbohydrate Restriction on Body Weight and Glycemic Control in Individuals with Type 2 Diabetes: A Randomized Controlled Trial of Efficacy in Real-Life Settings.

A fully provided, hypocaloric, carbohydrate-reduced high-protein (CRHP) diet compared to a hypocaloric conventional diabetes (CD) diet for 6 weeks improved glycemic control to a greater extent in face of an intended 6% weight loss in individuals with type 2 diabetes mellitus (T2DM). The present 24-week extension of that study reports on the efficacy of CRHP and CD diets in a real-life setting. Sixty-five individuals with T2DM who completed the initial 6-week fully provided diet period (% energy from carbohydrate, protein, and fat was 30/30/40 in CRHP, and 50/17/33 in CD) continued a free-living, dietician guided 24-week period of which 59 individuals completed. The CRHP compared to CD group reported a 4% lower carbohydrate intake and had higher urea excretion by 22% (both p ≤ 0.05) at week 30, suggesting less difference in carbohydrate and protein intake between groups during the 24-week extension compared to week 6. The loss of body weight during the initial 6 weeks was maintained in both groups during the 24-week extension (-5.5 ± 4.5 and -4.6 ± 4.8 kg) as well as HbA1c (-8.4 ± 6.2 and -8.4 ± 6.9 mmol/mol) with no significant differences between groups. The additional benefits on glucoregulation harnessed by carbohydrate restriction under full diet provision for 6 weeks combined with titrated weight loss could not be maintained in a real-life setting of self-prepared diet aiming on similar diets for 6 months.

Weight-loss induced by carbohydrate restriction does not negatively affect health-related quality of life and cognition in people with type 2 diabetes: A randomised controlled trial.

BACKGROUND & AIMS: We evaluated the effect of weight loss induced by dietary carbohydrate restriction on health-related quality of life (HRQoL) and cognition in type 2 diabetes (T2D). METHODS: In this randomised parallel trial, 72 adults with T2D and overweight/obesity (mean ± SD, HbA1c: 57 ± 8 mmol/mol and BMI: 33 ± 5 kg/m2) were randomly assigned to a carbohydrate-reduced high-protein diet (CRHP: C30E%-P30E%-F40E%) or conventional diabetes diet (CD: C50E%-P17E%-F33E%) for 6 weeks, targeting a 6% weight loss. HRQoL was assessed from the short form 36 (SF-36) questionnaire, including physical and mental component summary (PCS and MCS) scores; global cognition, verbal memory, attention and psychomotor speed, and executive function were assessed from a neuropsychological test battery. RESULTS: Both diet groups achieved a 5.8 kg weight loss and improved PCS (median [25th;75th percentiles], CD: 2.7 [1.1; 4.2] vs. CRHP: 2.1 [0.7; 3.7]), with no difference between diets. The CRHP diet resulted in a clinically relevant improvement of MCS, albeit non-significantly different compared with the change after the CD diet (2.0 [-0.7; 4.8], p = 0.15). Global cognition, attention, and verbal memory were unaffected by the CRHP diet, which selectively worsened the Symbol Digit Modality Test assessing psychomotor speed when compared with the CD diet (-4.1 [-7.2;-1.1], p < 0.01). CONCLUSION: Physical health improved by weight loss independently of macronutrient distribution, while mental health and cognition may be affected by the amount of carbohydrate, protein and fat in the diet. Collectively, our data suggest that weight loss through moderate carbohydrate restriction has no clinically important impact on HRQoL and global cognition in patients with T2D. Registered under ClinicalTrials.gov Identifier no. NCT03814694.

Effects of a Self-Prepared Carbohydrate-Reduced High-Protein Diet on Cardiovascular Disease Risk Markers in Patients with Type 2 Diabetes.

We previously observed beneficial effects of a carbohydrate-reduced, high-protein (CRHP) diet on cardiovascular risk markers in patients with type 2 diabetes mellitus (T2DM) in a crossover 2 × 6-week trial, when all food was provided to subjects as ready-to-eat meals. Here, we report the results from a 6-month open label extension: 28 patients with T2DM were instructed to self-prepare the CRHP diet with dietetic guidance. At weeks 0, 6, 12, and 36, fasting and postprandial (4-h meal test) blood samples were collected for measurements of total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triacylglycerol (TG), apolipoproteins A1 and B, non-esterified fatty acids (NEFA), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6. Diurnal blood pressure and heart rate were also assessed. At the end of the study (week 36), concentrations of fasting total and LDL-cholesterol, fasting and postprandial NEFA and TG, and fasting apolipoprotein-B, CRP and TNF-α concentrations were significantly lower compared with week 0 (p < 0.05). A significant decrease in diurnal heart rate was also observed. From week 12 to 36, an increase in HDL-cholesterol and apolipoprotein-A1 concentrations and a further reduction in fasting and postprandial NEFA (p < 0.05) were found. These changes were independent of minor fluctuations in body weight. We conclude that the substitution of dietary carbohydrate for protein and fat has beneficial effects on several cardiovascular risk markers in patients with T2DM, which are maintained or augmented over the next 6 months when patients select and prepare the CRHP diet on their own in a dietitian-supported setting.

The clinical effects of a carbohydrate-reduced high-protein diet on glycaemic variability in metformin-treated patients with type 2 diabetes mellitus: A randomised controlled study.

BACKGROUND & AIMS: High glycaemic variability (GV) is associated with late complications in type 2 diabetes (T2D). We hypothesised that a carbohydrate-reduced high-protein (CRHP) diet would reduce GV acutely in patients with T2D compared with a conventional diabetes (CD) diet. METHODS: In this controlled, randomised crossover study, 16 patients with metformin-treated T2D (median (IQR) age: 64.0 (58.8-68.0) years; HbA1c: 47 (43-57) mmol/mol; duration of T2D: 5.5 (2.8-10.3) years) were assigned to an energy-matched CRHP diet and CD diet (31E%/54E% carbohydrate, 29E%/16E% protein and 40E%/30E% fat, respectively) for two separate 48-h intervention periods. Interstitial continuous glucose monitoring (CGM) was performed to assess accepted measures of glycaemic variability, i.e. standard deviation (SD) around the sensor glucose level; coefficient of variation in percent (CV); mean amplitude of glucose excursions (MAGE); continuous overlapping net glycaemic action (CONGA1, CONGA4) of observations 1 and 4 h apart; and mean absolute glucose (MAG) change. RESULTS: All indices of glycaemic variability (mean ± SD) were significantly reduced during CRHP diet compared with CD diet; including SD (1.0 ± 0.3 (CRHP) vs 1.6 ± 0.5 mmol/L (CD)), CV (12.3 ± 3.8 vs 19.3 ± 5.5%), MAGE (2.3 ± 0.9 vs 4.2 ± 1.3 mmol/L), CONGA1 (0.8 ± 0.3 vs 1.5 ± 0.4 mmol/L), CONGA4 (1.4 ± 0.5 vs 2.5 ± 0.8 mmol/L), and MAG change (0.9 ± 0.3 vs 1.4 ± 0.4 mmol/L/h) (p < 0.001 for all). Compared with the CD diet, the CRHP diet improved the diurnal glucose profile by reducing 24-h mean sensor glucose (7.7 ± 1.6 vs 8.6 ± 2.0 mmol/L). CONCLUSIONS: In T2D patients treated with diet and metformin, two days of iso-energetic replacement of dietary carbohydrates by protein and fat reduced all indices of glycaemic variability by 36%-45% when compared with a conventional diabetes diet. These data may support reduction of carbohydrates as dietary advice for T2D patients. CLINICALTRIALS. GOV IDENTIFIER: NCT02472951.

Mechanisms of action of a carbohydrate-reduced, high-protein diet in reducing the risk of postprandial hypoglycemia after Roux-en-Y gastric bypass surgery.

BACKGROUND: Postprandial hypoglycemia is a risk after Roux-en-Y gastric bypass (RYGB). OBJECTIVES: We speculated that a carbohydrate-reduced, high-protein (CRHP) diet might reduce the risk of hypoglycemia and therefore compared the acute effects of a conventionally recommended (CR) diet and CRHP diet [55/30 energy percent (E%) carbohydrate and 15/30 E% protein, respectively] in RYGB patients. METHODS: Ten individuals (2 males, 8 females, mean ± SD age 47 ± 7 y; stable body mass index 31 ± 6 kg/m2; 6 ± 3 y post-RYGB) with recurrent postprandial hypoglycemia documented by plasma glucose (PG) ≤3.4 mmol/L were examined on 2 d with isoenergetic CRHP or CR diets comprising a breakfast and subsequent lunch meal. RESULTS: Peak PG was significantly reduced on the CRHP diet after breakfast and lunch by 11% and 31% compared with the CR diet. Nadir PG increased significantly on CRHP (by 13% and 9%). Insulin secretion was reduced, and glucagon secretion increased on the CRHP diet after both meals. Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide secretion were lower after lunch but unaltered after breakfast on CRHP; ß-cell function and insulin clearance were unchanged. CONCLUSIONS: The CRHP diet lowered glucose excursions and reduced insulin secretion and incretin hormone responses, but enhanced glucagon responses compared with the CR diet. Taken together, the results may explain the decreased glucose variability and lower risk of postprandial hypoglycemia. This study was registered at clinicaltrials.gov as NCT02665715.

Liraglutide in combination with metformin may improve the atherogenic lipid profile and decrease C-reactive protein level in statin treated obese patients with coronary artery disease and newly diagnosed type 2 diabetes: A randomized trial.

BACKGROUND AND AIMS: Atherosclerosis in obesity and type 2 diabetes (T2DM) is associated with low-grade inflammation (LGI) and dyslipidemia, where especially small, dense lipoprotein particles are atherogenic. The glucagon-like peptide-1 receptor agonist, liraglutide, reduces cardiovascular events by poorly understood mechanisms. We investigated the effect of liraglutide combined with metformin on LGI and lipoprotein density profiles in patients with stable coronary artery disease (CAD) and newly diagnosed T2DM. METHODS: We conducted a randomized, double-blind, placebo-controlled, cross-over trial over a 12 + 12-week period, with ≥2-week wash-out. INTERVENTION: liraglutide/metformin vs. placebo/metformin. Lipoproteins were separated by continuous density gradient ultracentrifugation, and LDL divided into five subfractions between 226 and 270 Å, considering particle size ≤255 Šas the atherogenic pattern. Plasma C-reactive protein and tumor necrosis factor-α were assessed by the enzyme-linked immunosorbent-assay. RESULTS: 28 out of 41 randomized patients completed all visits. Intention-to-treat analysis was performed but one patient had statin dosage and was excluded from the analysis. 95% of the patients were on statin therapy. Overall, liraglutide did not affect lipid subfractions or markers of LGI compared to placebo. The combination of liraglutide and metformin reduced the total LDL subfractions, primarily by reducing the most atherogenic subfraction LDL5, and reduced CRP but not TNF-α. Explorative analyses suggested that the subfraction LDL5 during the wash-out period rebounded significantly at least in a per-protocol analysis of the sub-group of patients starting the liraglutide therapy. CONCLUSIONS: In patients with CAD and newly diagnosed T2DM on stable statin therapy, liraglutide combined with metformin may improve the atherogenic LDL lipid profile and CRP.

Acute Effects of Dietary Carbohydrate Restriction on Glycemia, Lipemia and Appetite Regulating Hormones in Normal-Weight to Obese Subjects.

Postprandial responses to food are highly dependent on the macronutrient composition of the diet. We investigated the acute effects of transition from the recommended moderately high carbohydrate (HC) diet towards a carbohydrate-reduced high-protein (CRHP) diet on postprandial glycemia, insulinemia, lipemia, and appetite-regulating hormones in non-diabetic adults. Fourteen subjects, including five males (Mean ± SD: age 62 ± 6.5; BMI 32 ± 7.6 kg/m²; hemoglobin A1c (HbA1c) 40 ± 3.0 mmol/mol; HOMA2-IR 2.1 ± 0.9) were included in this randomized, cross-over study. Iso-caloric diets were consumed for two consecutive days with a median wash-out period of 21 days (range 2⁻8 weeks) between diets (macronutrient energy composition: CRHP/HC; 31%/54% carbohydrate, 29%/16% protein, 40%/30% fat). Postprandial glucose, insulin secretion rate (ISR), triglycerides (TGs), non-esterified fatty acids (NEFAs), and satiety ratings were assessed after ingestion of breakfast (Br) and lunch (Lu), and gut hormones and glucagon were assessed after ingestion of Br. Compared with the HC diet, the CRHP diet reduced peak glucose concentrations (Br 11%, p = 0.024; Lu 11%, p < 0.001), glucose excursions (Br 80%, p = 0.20; Lu 85%, p < 0.001), and ISR (Br 31%; Lu 64%, both p < 0.001) whereas CRHP, as compared with HC, increased glucagon-like peptide-1 (Br 27%, p = 0.015) and glucagon values (Br 249%, p < 0.001). NEFA and TG levels increased in the CRHP diet as compared with the HC diet after Br, but no difference was found after Lu (NEFA Br 22%, p < 0.01; TG Br 42%, p = 0.012). Beta-cell glucose sensitivity, insulin clearance, cholecystokinin values, and subjective satiety ratings were unaffected. It is possible to achieve a reduction in postprandial glycemia and insulin without a deleterious effect on beta-cell glucose sensitivity by substituting part of dietary carbohydrate with iso-caloric protein and fat in subjects without type 2 diabetes mellitus (T2DM). The metabolic effects are more pronounced after the second meal.

Bronchoschopy should always be performed in children on suspicion of foreign body aspiration.

INTRODUCTION: Foreign body aspiration (FBA) can have a fatal outcome, and the diagnosis is challenging since symptoms and signs may vary. We therefore investigated whether it was possible to identify predictors indicating the presence of a foreign body. MATERIAL AND METHODS: The medical records of children undergoing bronchoscopy at Odense University Hospital for suspected FBA in the period from 1977 to 2010 were reviewed and analyzed. RESULTS: A total of 143 children underwent bronchoscopy due to suspected FBA. The medical records of 137 of these children were accessible. Their median age was 1.84 years, 62.8% were male and foreign bodies were found in 76 cases (55.5%). The only variable that statistically significantly predicted the presence of a foreign body was a radiologic finding (any abnormal chest X-ray or fluoroscopy) (p = 0.023). A foreign body was found in 22 out of 47 (46.8%) patients with no radiologic findings and in three of 11 (27%) patients with neither symptoms at admission nor radiologic or physical findings. CONCLUSION: Parental suspicion of an FBA indicates acute bronchoscopy in children regardless of signs, symptoms and findings.