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CONTEXT: Studies in heterogenous groups of people with respect to sex, body mass index (BMI), and glycemic status (normoglycemia, impaired glucose tolerance, diabetes), indicate no relationship between liver fat accumulation and pancreatic insulin secretion. OBJECTIVE: To better understand the association of liver fat with insulin secretion. METHODS: Cross-sectional analysis of 61 men with abdominal obesity who had high liver fat (HLF, ≥5.6% by magnetic resonance spectroscopy, n=28) or low liver fat (LLF, n=33), but were balanced on BMI, total body fat, visceral adipose tissue (VAT), and pancreatic fat. A frequently sampled 5-hour oral glucose tolerance test with 11 samples, in conjunction with mathematical modeling, was used to compute indices of insulin sensitivity and insulin secretion (oral minimal model). RESULTS: Compared to subjects with LLF, those with HLF had significantly greater fasting glucose, insulin, C-peptide, and triglyceride; lower high-density lipoprotein-cholesterol; but similar glycated hemoglobin. Areas under the 5-hour curve for glucose, insulin, and C-peptide were greater in the HLF group than the LLF group (by â¼10%, â¼38%, and â¼28%, respectively); fasting and total postprandial insulin secretion rates were â¼37% and â¼50% greater, respectively (all P<0.05); whereas the insulinogenic index was not different. HLF subjects had lower whole-body and hepatic insulin sensitivity, disposition index, and total insulin clearance than LLF subjects (all P<0.05). CONCLUSION: Accumulation of liver fat is associated with increased insulin secretion independently of total adiposity, abdominal fat distribution, and pancreatic fat. Thereby, hyperinsulinemia in fatty liver disease is partly because of insulin hypersecretion and partly because of impaired insulin clearance.
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AIM: To test the effect of the glucagon-like peptide-1 receptor agonist, liraglutide, on residual beta-cell function in adults with newly diagnosed type 1 diabetes. MATERIALS AND METHODS: In a multicentre, double-blind, parallel-group trial, adults with newly diagnosed type 1 diabetes and stimulated C-peptide of more than 0.2 nmol/L were randomized (1:1) to 1.8-mg liraglutide (Victoza) or placebo once daily for 52 weeks with 6 weeks of follow-up with only insulin treatment. The primary endpoint was the between-group difference in C-peptide area under the curve (AUC) following a liquid mixed-meal test after 52 weeks of treatment. RESULTS: Sixty-eight individuals were randomized. After 52 weeks, the 4-hour AUC C-peptide response was maintained with liraglutide, but decreased with placebo (P = .002). Six weeks after end-of-treatment, C-peptide AUCs were similar for liraglutide and placebo. The average required total daily insulin dose decreased from 0.30 to 0.23 units/kg/day with liraglutide, but increased from 0.29 to 0.43 units/kg/day in the placebo group at week 52 (P < .001). Time without the need for insulin treatment was observed in 13 versus two patients and lasted for 22 weeks (from 3 to 52 weeks) versus 6 weeks (from 4 to 8 weeks) on average for liraglutide and placebo, respectively. Patients treated with liraglutide had fewer episodes of hypoglycaemia compared with placebo-treated patients. The adverse events with liraglutide were predominantly gastrointestinal and transient. CONCLUSIONS: Treatment with liraglutide improves residual beta-cell function and reduces the dose of insulin during the first year after diagnosis. Beta-cell function was similar at 6 weeks postliraglutide treatment.
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INTRODUCTION: The cornerstone in the management of type 2 diabetes (T2D) is lifestyle modification including a healthy diet, typically one in which carbohydrate provides 45%-60% of total energy intake (E%). Nevertheless, systematic reviews and meta-analyses of trials with low carbohydrate diets (which are increased in protein and/or fat) for T2D have found improved glycaemic control in the first months relative to comparator diets with higher carbohydrate content. Studies lasting ≥1 year are inconclusive, which could be due to decreased long-term dietary adherence. We hypothesise that glucometabolic benefits can be achieved following 12 months of carbohydrate-restricted dieting, by maximising dietary adherence through delivery of meal kits, containing fresh, high-quality ingredients for breakfast, dinner and snacks, combined with nutrition education and counselling. METHODS AND ANALYSIS: This protocol describes a 12-month investigator-initiated randomised controlled, open-label, superiority trial with two parallel groups that will examine the effect of a carbohydrate-reduced high-protein (CRHP) diet compared with a conventional diabetes (CD) diet on glucometabolic control (change in glycated haemoglobin being the primary outcome) in 100 individuals with T2D and body mass index (BMI) >25 kg/m2. Participants will be randomised 1:1 to receive either the CRHP or the CD diet (comprised 30/50 E% from carbohydrate, 30/17 E% from protein and 40/33 E% from fat, respectively) for 12 months delivered as meal kits, containing foods covering more than two-thirds of the participants' estimated daily energy requirements for weight maintenance. Adherence to the allocated diets will be reinforced by monthly sessions of nutrition education and counselling from registered clinical dietitians. ETHICS AND DISSEMINATION: The trial has been approved by the National Committee on Health Research Ethics of the Capital Region of Denmark. The trial will be conducted in accordance with the Declaration of Helsinki. Results will be submitted for publication in international peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT05330247. PROTOCOL VERSION: The trial protocol was approved on 9 March 2022 (study number: H-21057605). The latest version of the protocol, described in this manuscript, was approved on 23 June 2023.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/dietoterapia , Dinamarca , Ensaios Clínicos Controlados Aleatórios como Assunto , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/metabolismo , Refeições , Masculino , Glicemia/metabolismo , Glicemia/análise , Feminino , Adulto , Dieta Rica em Proteínas/métodos , Dieta com Restrição de Carboidratos/métodos , Pessoa de Meia-Idade , Dieta Rica em Proteínas e Pobre em Carboidratos/métodos , Populações Escandinavas e NórdicasRESUMO
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 â¼6% 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.
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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.
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Laticínios , Leite , Masculino , Humanos , Animais , Dieta , Fezes , Iogurte , MetabolomaRESUMO
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).
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Produtos Fermentados do Leite , Obesidade Abdominal , Masculino , Humanos , Animais , Fatores de Risco , Obesidade/metabolismo , Laticínios , Leite , Fígado/metabolismo , IogurteRESUMO
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.
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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).
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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.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Controle Glicêmico , Glicemia/metabolismo , Hemoglobinas Glicadas , Peso Corporal/fisiologia , Redução de PesoRESUMO
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.
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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).
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Obesidade , Redução de Peso , Adulto , Biomarcadores , Índice de Massa Corporal , Peso Corporal , Humanos , Lipídeos , Obesidade/terapia , Sobrepeso/terapiaRESUMO
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.
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Diabetes Mellitus Tipo 2 , Adulto , Cognição , Diabetes Mellitus Tipo 2/complicações , Carboidratos da Dieta , Humanos , Qualidade de Vida , Redução de PesoRESUMO
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.
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Diabetes Mellitus Tipo 2 , Adulto , Glicemia/metabolismo , Automonitorização da Glicemia , Diabetes Mellitus Tipo 2/terapia , Carboidratos da Dieta , Controle Glicêmico , Humanos , Fígado/metabolismo , Masculino , Redução de PesoRESUMO
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.
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Diabetes Mellitus Tipo 2 , Metformina , DNA , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes , Insulina , RNARESUMO
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.
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Diabetes Mellitus Tipo 2/dietoterapia , Dieta Rica em Proteínas e Pobre em Carboidratos/métodos , Preferências Alimentares/psicologia , Idoso , Apolipoproteínas/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Culinária , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Dieta Rica em Proteínas e Pobre em Carboidratos/psicologia , Jejum/sangue , Ácidos Graxos não Esterificados/sangue , Feminino , Seguimentos , Fatores de Risco de Doenças Cardíacas , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Estudos Prospectivos , Triglicerídeos/sangueRESUMO
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.
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Diabetes Mellitus Tipo 2 , Dieta Rica em Proteínas e Pobre em Carboidratos , Glicemia , Automonitorização da Glicemia , Peso Corporal , Carboidratos da Dieta , Humanos , Insulina , Fatores de RiscoRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/metabolismo , Dieta com Restrição de Carboidratos , Hormônios Gastrointestinais/metabolismo , Glucose/metabolismo , Hiperglicemia/metabolismo , Células Secretoras de Insulina/metabolismo , Resposta de Saciedade , Adulto , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/psicologia , Dieta com Restrição de Carboidratos/efeitos adversos , Proteínas Alimentares , Feminino , Esvaziamento Gástrico , Humanos , Secreção de Insulina , Masculino , Proinsulina/sangue , Resultado do TratamentoRESUMO
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).