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.

Changes in Plasma, Urine, and Fecal Metabolome after 16 Weeks of Consuming Dairy With Different Food Matrixes - A Randomized Controlled Trial.

SCOPE: Understanding the mode-of-action by which fermented dairy consumption influences health is of interest. The aim of this study is to elucidate the impact of the chemical-physical properties of the dairy matrix and postbiotic effects on the metabolomics response to fermented dairy consumption. METHODS AND RESULTS: Hundred males (Body Mass Index (BMI) 28.0-45.0 kg m-2, waist circumference ≥ 102 cm) are included in the study. During a 16-week intervention, the study subjects are instructed to consume 400 g per day of either 1) milk, 2) yogurt, 3) heat-treated yogurt, or 4) chemically acidified milk as part of their habitual diet. Nuclear Magnetic Resonance (NMR)-based metabolomics is conducted on plasma, urine, and fecal samples collected before and after the intervention. Both consumption of acidified milk and heat-treated yogurt resulted in changes in the fecal metabolome including decreases in the level of amino acids (leucine, valine, and threonine), and the branched-chain fatty acid (BCFA) isobutyrate that indicated an altered protein putrefaction, and proteolytic metabolism in the gut. In the plasma metabolome, an increased citrate is found for yogurt consumption. No difference in the urine metabolome is found. CONCLUSIONS: Our metabolomics analyses indicate that consumption of heat-treated yogurt and acidified milk exerted similar effects on the metabolic activity in the gut as yogurt consumption.

The effect of dairy products on liver fat and metabolic risk markers in males with abdominal obesity - a four-arm randomized controlled trial.

BACKGROUND & AIMS: In recent years, epidemiological studies have reported links between the consumption of fermented dairy products, such as yogurt, and health; however, evidence from human intervention trials is scarce and inconsistent. We aimed to investigate the effect of consumption of four different types of dairy products (two fermented and two non-fermented) on liver fat (primary outcome) and metabolic risk markers in males with abdominal obesity. METHODS: In this parallel randomized controlled trial with four arms, 100 males aged 30-70 years, with body mass index 28.0-45.0 kg/m2, and waist circumference ≥102 cm underwent a 16-weeks intervention where they were instructed to consume 400 g/day of either milk, yogurt, heat-treated yogurt, or acidified milk as part of their habitual diet. Liver fat was measured by magnetic resonance imaging. RESULTS: In the complete case analyses (n = 80), no effects of the intervention or differences between groups were detected in anthropometry or body composition including liver fat. Moreover, no effects were detected in inflammatory markers. Main effects of time were detected in blood pressure (decrease; P < 0.001), insulin (decrease; P < 0.001), C-peptide (decrease; P = 0.040), homeostatic model assessment for insulin resistance (decrease; P < 0.001), total cholesterol (decrease; P = 0.016), low-density lipoprotein (decrease; P = 0.033), high-density lipoprotein (decrease; P = 0.006), and alanine transaminase (decrease; P = 0.019). Interactions between group and time failed to reach significance. CONCLUSIONS: In conclusion, findings from our study do not confirm that fermented yogurt products are superior in reducing liver fat or improving metabolic risk markers compared to non-fermented milk products. In fact, all intervention products (both fermented yogurt products and non-fermented milk products) did not affect liver fat and caused largely similar modest favorable changes in some metabolic risk markers. The study was registered at www. CLINICALTRIALS: gov (# NCT04755530).

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.

Quality of life, patient satisfaction, and cardiovascular outcomes of the randomised 2 x 3 factorial Copenhagen insulin and Metformin therapy (CIMT) trial - A detailed statistical analysis plan.

Background: The evidence on the effects of metformin and insulin in type 2 diabetes patients on quality of life, patient satisfaction, and cardiovascular outcomes is unclear. Methods: The Copenhagen Insulin and Metformin Therapy (CIMT) trial is an investigator-initiated multicentre, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark. Participants with type 2 diabetes were randomised to metformin (n = 206) versus placebo (n = 206); in combination with open-label biphasic insulin aspart one to three times daily (n = 137) versus insulin aspart three times daily in combination with insulin detemir once daily (n = 138) versus insulin detemir once daily (n = 137).We present a detailed description of the methodology and statistical analysis of the clinical CIMT outcomes including a detailed description of tests of the assumptions behind the statistical analyses. The outcomes are quality of life (Short Form Health Survey (SF-36)), Diabetes Medication Satisfaction Questionnaire, and Insulin Treatment Satisfaction Questionnaire (assessed at entry and 18 months after randomisation) and cardiovascular outcomes including time to a composite of either myocardial infarction, stroke, peripheral amputation, coronary revascularisation, peripheral revascularisation, or death. Discussions: This statistical analysis plan ensure the highest possible quality of the subsequent post-hoc analyses. Trial registration: The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency (EudraCT: 2007-006665-33 CIMT), and registered within ClinicalTrials.gov (NCT00657943, 8th of April 2008).

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 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.

A double-blinded, randomized, parallel intervention to evaluate biomarker-based nutrition plans for weight loss: The PREVENTOMICS study.

BACKGROUND & AIMS: Growing evidence suggests that biomarker-guided dietary interventions can optimize response to treatment. In this study, we evaluated the efficacy of the PREVENTOMCIS platform-which uses metabolomic and genetic information to classify individuals into different 'metabolic clusters' and create personalized dietary plans-for improving health outcomes in subjects with overweight or obesity. METHODS: A 10-week parallel, double-blinded, randomized intervention was conducted in 100 adults (82 completers) aged 18-65 years, with body mass index ≥27 but <40 kg/m2, who were allocated into either a personalized diet group (n = 49) or a control diet group (n = 51). About 60% of all food was provided free-of-charge. No specific instruction to restrict energy intake was given. The primary outcome was change in fat mass from baseline, evaluated by dual energy X-ray absorptiometry. Other endpoints included body weight, waist circumference, lipid profile, glucose homeostasis markers, inflammatory markers, blood pressure, physical activity, stress and eating behavior. RESULTS: There were significant main effects of time (P < 0.01), but no group main effects, or time-by-group interactions, for the change in fat mass (personalized: -2.1 [95% CI -2.9, -1.4] kg; control: -2.0 [95% CI -2.7, -1.3] kg) and body weight (personalized: -3.1 [95% CI -4.1, -2.1] kg; control: -3.3 [95% CI -4.2, -2.4] kg). The difference between groups in fat mass change was -0.1 kg (95% CI -1.2, 0.9 kg, P = 0.77). Both diets resulted in significant improvements in insulin resistance and lipid profile, but there were no significant differences between groups. CONCLUSION: Personalized dietary plans did not result in greater benefits over a generic, but generally healthy diet, in this 10-week clinical trial. Further studies are required to establish the soundness of different precision nutrition approaches, and translate this science into clinically relevant dietary advice to reduce the burden of obesity and its comorbidities. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov registry (NCT04590989).

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.

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 18-months metformin versus placebo in combination with three insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes: A post-hoc analysis of a randomized clinical trial.

Formation of reactive oxygen species has been linked to the development of diabetes complications. Treatment with metformin has been associated with a lower risk of developing diabetes complications, including when used in combination with insulin. Metformin inhibits Complex 1 in isolated mitochondria and thereby decreases the formation of reactive oxygen species. Thus, we post-hoc investigated the effect of metformin in combination with different insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes. Four hundred and fifteen individuals with type 2 diabetes were randomized (1:1) to blinded treatment with metformin (1,000 mg twice daily) versus placebo and to (1:1:1) open-label biphasic insulin, basal-bolus insulin, or basal insulin therapy in a 2 × 3 factorial design. RNA and DNA oxidation were determined at baseline and after 18 months measured as urinary excretions of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), respectively. Urinary excretion of 8-oxoGuo changed by +7.1% (95% CI: 0.5% to 14.0%, P = 0.03) following metformin versus placebo, whereas changes in 8-oxodG were comparable between intervention groups. Biphasic insulin decreased urinary excretion of 8-oxoGuo (within-group: -9.6% (95% CI: -14.4% to -4.4%)) more than basal-bolus insulin (within-group: 5.2% (95% CI: -0.5% to 11.2%)), P = 0.0002 between groups, and basal insulin (within-group: 3.7% (95% CI: -2.0% to 9.7%)), P = 0.0007 between groups. Urinary excretion of 8-oxodG decreased more in the biphasic insulin group (within-group: -9.9% (95% CI: -14.4% to -5.2%)) than basal-bolus insulin (within group effect: -1.2% (95% CI: -6.1% to 3.9%)), P = 0.01 between groups, whereas no difference was observed compared with basal insulin. In conclusion, eighteen months of metformin treatment in addition to different insulin regimens increased RNA oxidation, but not DNA oxidation. Biphasic insulin decreased both RNA and DNA oxidation compared with other insulin regimens.

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.

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 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.

Metformin may adversely affect orthostatic blood pressure recovery in patients with type 2 diabetes: substudy from the placebo-controlled Copenhagen Insulin and Metformin Therapy (CIMT) trial.

BACKGROUND: Metformin has been shown to have both neuroprotective and neurodegenerative effects. The aim of this study was to investigate the effect of metformin in combination with insulin on cardiovascular autonomic neuropathy (CAN) and distal peripheral neuropathy (DPN) in individuals with type 2 diabetes (T2DM). METHODS: The study is a sub-study of the CIMT trial, a randomized placebo-controlled trial with a 2 × 3 factorial design, where 412 patients with T2DM were randomized to 18 months of metformin or placebo in addition to open-labelled insulin. Outcomes were measures of CAN: Changes in heart rate response to deep breathing (beat-to-beat), orthostatic blood pressure (OBP) and heart rate and vibration detection threshold (VDT) as a marker DPN. Serum levels of vitamin B12 and methyl malonic acid (MMA) were analysed. RESULTS: After 18 months early drop in OBP (30 s after standing) was increased in the metformin group compared to placebo: systolic blood pressure drop increased by 3.4 mmHg (95% CI 0.6; 6.2, p = 0.02) and diastolic blood pressure drop increased by 1.3 mmHg (95% CI 0.3; 2.6, p = 0.045) compared to placebo. Beat-to-beat variation decreased in the metformin group by 1.1 beats per minute (95% CI - 2.4; 0.2, p = 0.10). Metformin treatment did not affect VDT group difference - 0.33 V (95% CI - 1.99; 1.33, p = 0.39) or other outcomes. Changes in B12, MMA and HbA1c did not confound the associations. CONCLUSIONS: Eighteen months of metformin treatment in combination with insulin compared with insulin alone increased early drop in OBP indicating an adverse effect of metformin on CAN independent of vitamin B12, MMA HbA1c. Trial registration The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency and registered with ClinicalTrials.gov (NCT00657943).

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.

Prediction of carotid intima-media thickness and its relation to cardiovascular events in persons with type 2 diabetes.

AIMS: To investigate measures of carotid intima-media thickness (IMT) and conventional cardiovascular (CV) risk factors as predictors of future carotid IMT, and the prediction of CV events during follow-up based on measures of carotid IMT. METHODS: Observational longitudinal study including 230 persons with type 2 diabetes (T2D). RESULTS: Mean age at follow-up was 66.7 (SD 8.5) years, 30.5% were women and mean body mass index (BMI) was 31.8 (4.4) kg/m2. Carotid IMT was measured at baseline, after 18 months of intervention in the Copenhagen Insulin and Metformin Therapy (CIMT) trial and after a mean follow-up of 6.4 (1.0) years. Baseline carotid IMT, carotid IMT after 18 months' intervention, and CV risk factors (age, sex and baseline systolic blood pressure) gave the best prediction of carotid IMT (root mean-squared error of prediction of 0.106 and 95% prediction error probability interval of -0.160, 0.204). CONCLUSIONS: Measures of carotid IMT combined with CV risk factors at baseline predicts attained carotid IMT better than measures of carotid IMT or CV risk factors alone. Carotid IMT did not predict CV events, and the present results do not support the use of carotid IMT as a predictor of CV events in persons with T2D.

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.