Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms.

INTRODUCTION: Glucagon receptor agonism is currently explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The metabolic effects of glucagon receptor agonism may in part be mediated by increases in circulating levels of Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor 15 (GDF15). The effect of glucagon agonism on FGF21 and GDF15 levels remains uncertain, especially in the context of elevated insulin levels commonly observed in metabolic diseases. METHODS: We investigated the effect of a single bolus of glucagon and a continuous infusion of glucagon on plasma concentrations of FGF21 and GDF15 in conditions of endogenous low or high insulin levels. The studies included individuals with overweight with and without MASLD, healthy controls (CON) and individuals with type 1 diabetes (T1D). The direct effect of glucagon on FGF21 and GDF15 was evaluated using our in-house developed isolated perfused mouse liver model. RESULTS: FGF21 and GDF15 correlated with plasma levels of insulin, but not glucagon, and their secretion was highly increased in MASLD compared with CON and T1D. Furthermore, FGF21 levels in individuals with overweight with or without MASLD did not increase after glucagon stimulation when insulin levels were kept constant. FGF21 and GDF15 levels were unaffected by direct stimulation with glucagon in the isolated perfused mouse liver. CONCLUSION: The glucagon-induced secretion of FGF21 and GDF15 is augmented in MASLD and may depend on insulin. Thus, glucagon receptor agonism may augment its metabolic benefits in patients with MASLD through enhanced secretion of FGF21 and GDF15.

Autonomic Nerve Function Predicts Risk of Early Death after Discharge in Acute Medical Disease.

BACKGROUND: Heart rate variability, a marker of autonomic function, has shown promising prognostic results in specific populations, but has not been tested in a general medical population. We hypothesized that heart rate variability identifies high-risk medical patients early after admission to the hospital. METHODS: This was a single-center prospective cohort study of acutely admitted medical patients aged ≥18 years with a life expectancy ≥3 months, included between 2019-2023. Unstable patients needing direct admission to the intensive care unit were excluded. Heart rate variability was recorded within 24 hours of admission for 10 minutes. The standard deviation of normal-normal beats (SDNN) was the primary heart rate variability marker. Low SDNN was defined as the lowest tertile (≤22 ms). The primary outcome was 30-day all-cause mortality. The secondary outcome was 30-day readmission or mortality. RESULTS: Among 721 patients included, low SDNN carried an 8-fold greater risk of 30-day mortality in univariate analysis (hazard ratio [HR] 8.3; P = .001); in multivariate analyses a 4-fold greater risk (HR 3.8; P = .037). Low SDNN was associated with the combined outcome of 30-day mortality or readmission (HR 1.5; P = .03) in multivariate analysis. In receiver operating characteristics analyses, low SDNN improved the predictive accuracy of early warning score for 30-day mortality or readmission from 0.63 to 0.71 (P = .008) but did not improve the accuracy for 30-day mortality alone. CONCLUSIONS: In patients admitted due to acute medical illness, low heart rate variability predicted 30-day mortality and readmission, suggesting heart rate variability as a tool to identify patients at high and low risk of relevant endpoints.

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.

Incidence and Characteristics of the Hyperosmolar Hyperglycemic State: A Danish Cohort Study.

OBJECTIVE: The hyperosmolar hyperglycemic state (HHS) is a rare and life-threatening complication of diabetes. We aimed to estimate the incidence of HHS and describe the clinical and biomarker profiles of patients with HHS, including subgroups with acidosis and acute kidney injury. RESEARCH DESIGN AND METHODS: This nationwide, descriptive cohort study used Danish registry data during years 2016-2018 to identify acutely admitted patients fulfilling the hyperglycemia and hyperosmolarity criteria of HHS (glucose ≥33 mmol/L and osmolarity [2 × sodium + glucose] ≥320 mmol/L). RESULTS: We identified 634 patients (median age, 69 years (first quartile; third quartile: 58; 79) who met the criteria of HHS among 4.80 million inhabitants aged ≥18 years. The incidence rates were 16.5 and 3.9 per 10,000 person-years among people with known type 1 (n = 24,196) and type 2 (n = 251,357) diabetes, respectively. Thirty-two percent of patients with HHS were not previously diagnosed with diabetes. Patients were categorized as pure HHS (n = 394) and combined HHS and diabetic ketoacidosis (HHS-DKA; n = 240). The in-hospital mortality rate for pure HHS was 17% and 9% for HHS-DKA. CONCLUSIONS: The incidence of HHS was higher among patients with type 1 diabetes compared with type 2 diabetes. HHS is a spectrum of hyperglycemic crises and can be divided in pure HHS and HHS-DKA. In one-third of patients, HHS was the debut of their diabetes diagnosis.

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.

Perioperative optimization and profitability (POP) in a high-volume bariatric surgery center.

BACKGROUND: Currently, bariatric surgery is the most effective long-term treatment of obesity. Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) are the primary types of bariatric surgery performed worldwide. To minimize the risks of surgical complications and optimize cost-effectiveness, it is essential to develop fast-track protocols and patient logistics. At Aleris Hospitals in Denmark, a fast-track methodology in bariatric surgery has been implemented and continuously optimized over the last 15 years. The main objective was to demonstrate timelines recorded during one consecutive year in a fast-track, high-volume bariatric surgery setting after logistic optimization. METHODS: This study included 949 consecutive patients who had undergone primary bariatric surgery in 2021. The primary outcomes were length of hospital stay and perioperative timeline recordings that were prospectively collected. The secondary outcomes were mortality, complication rates, and weight loss data. RESULTS: The vast majority of our patients (99.1%) were discharged from the hospital within the day after surgery. The median total surgery time was 30 min, after 12 min of patient preparation and with a turnover time between patients of seven min. The median knife-to-knife time in one operating room was 56 min. Mortality was zero, 30-day reoperation rate was 1.2%, and 30-day readmission rate was 0.8%. SG and RYGB patients had an excess weight loss after four months of 45.6% and 57.9%, respectively. CONCLUSION: Implementation of fast-track principles in the clinical practice of bariatric surgery allows for an optimized, cost-effective surgical organization supporting the quality of procedures and patient safety.

Complications in Patients Undergoing Laparoscopic Bariatric Surgery in an ERABS-optimized, High-Volume, Single Center During 2020 and 2021.

PURPOSE: Complication rates after fast-track optimization in bariatric surgery are varying. The aim of this study was to identify short-term complications in patients undergoing laparoscopic sleeve gastrectomy (SG) in an ERABS (enhanced recovery after bariatric surgery) optimized setup. MATERIALS AND METHODS: This study is an observational analysis of a consecutive cohort of 1600 patients undergoing SG at an ERABS-optimized, private hospital during 2020 and 2021. Primary outcomes were length of stay, mortality, readmissions, reoperations, and complications according to the Clavien-Dindo classification (CDC) within postoperative day (POD) 30 and 90. Secondary outcomes were weight loss and quality of life (QoL) according to Moorehead-Ardelt questionnaires during the first postoperative year. RESULTS: Primary outcomes: 99.1% of patients were discharged within POD 1. The 90-day mortality rate was zero. There were 1% readmissions and 1.2% reoperations within POD 30. Total 30-day complication rate was 4.6%, where 3.4% accounted for CDC grades ≤ II, and 1.3% accounted for CDC grade III. There were zero grade IV-V complications. SECONDARY OUTCOMES: One year after surgery, weight loss was substantial (p < 0.001), with an excess weight loss of 71.9%, and QoL had significantly increased (p < 0.001). CONCLUSION: This study demonstrates that the use of an ERABS protocol in bariatric surgery does not compromise neither safety nor efficacy. Complication rates were low, and weight loss was significant. This study thus provides strong arguments that ERABS programs are beneficial in bariatric surgery.

Development of a glucagon sensitivity test in humans: Pilot data and the GLUSENTIC study protocol.

A physiological feedback system exists between hepatocytes and the alpha cells, termed the liver-alpha cell axis and refers to the relationship between amino acid-stimulated glucagon secretion and glucagon-stimulated amino acid catabolism. Several reports indicate that non-alcoholic fatty liver disease (NAFLD) disrupts the liver-alpha cell axis, because of impaired glucagon receptor signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans. The objective was to develop an experimental test to determine glucagon sensitivity with respect to amino acid and glucose metabolism in humans. The proposed glucagon sensitivity test (comprising two elements: 1) i.v. injection of 0.2 mg glucagon and 2) infusion of mixed amino acids 331 mg/hour/kg) is based on nine pilot studies which are presented. Calculation of a proposed glucagon sensitivity index with respect to amino acid catabolism is also described. Secondly, we describe a complete study protocol (GLUSENTIC) according to which the glucagon sensitivity test will be applied in a cross-sectional study currently taking place. 65 participants including 20 individuals with a BMI 18.6-25 kg/m2, 30 individuals with a BMI ≥ 25-40 kg/m2, and 15 individuals with type 1 diabetes with a BMI between 18.6 and 40 kg/m2 will be included. Participants will be grouped according to their degree of hepatic steatosis measured by whole-liver magnetic resonance imaging (MRI). The primary outcome measure will be differences in the glucagon sensitivity index between individuals with and without hepatic steatosis. Developing a glucagon sensitivity test and index may provide insight into the physiological and pathophysiological mechanism of glucagon action and glucagon-based therapies.

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.

Parasympathetic tonus in type 2 diabetes and pre-diabetes and its clinical implications.

Autonomic imbalance reflected by higher resting heart rate and reduced parasympathetic tone may be driven by low-grade inflammation (LGI) and impaired glycemic control in type 2 diabetes mellitus (T2DM) and pre-diabetes. We examined the interaction of parasympathetic components of heart rate variability (HRV), variables of LGI, and glucose metabolism in people with T2DM, pre-diabetes, and normal glucose metabolism (NGM). We recorded HRV by Holter (48 h) in 633 community-dwelling people of whom T2DM n = 131, pre-diabetes n = 372, and NGM n = 130 and mean HbA1c of 7.2, 6.0 and 5.3%, respectively. Age was 55-75 years and all were without known cardiovascular disease except from hypertension. Fasting plasma glucose, fasting insulin, HOMA-IR, HbA1c and LGI (CRP, Interleukin-18 (IL-18), and white blood cells) were measured. Root-mean-square-of-normal-to-normal-beats (RMSSD), and proportion of normal-to-normal complexes differing by more than 50 ms (pNN50) are accepted measures of parasympathetic activity. In univariate analyses, RMSSD and pNN50 were significantly inversely correlated with level of HbA1c and CRP among people with T2DM and pre-diabetes, but not among NGM. RMSSD and pNN50 remained significantly inversely associated with level of HbA1c after adjusting for age, sex, smoking, and BMI among people with T2DM (ß = - 0.22) and pre-diabetes (ß = - 0.11); adjustment for LGI, HOMA-IR, and FPG did not attenuate these associations. In backward elimination models, age and level of HbA1c remained associated with RMSSD and pNN50. In people with well controlled diabetes and pre-diabetes, a lower parasympathetic activity was more related to age and HbA1c than to markers of LGI. Thus, this study shows that the driver of parasympathetic tonus may be more the level of glycemic control than inflammation in people with prediabetes and well controlled 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.

Profiling Bispebjerg Acute Cohort: Database Formation, Acute Contact Characteristics of a Metropolitan Hospital, and Comparisons to Urban and Rural Hospitals in Denmark.

Purpose: To present a metropolitan cohort, Bispebjerg acute cohort (BAC), and compare patient characteristics and outcomes with patients from urban and rural hospitals in Denmark. Patients and Methods: We linked data from seven Danish nationwide registries and included all acute contacts to non-psychiatric hospitals in the years 2016-2018. Acute hospital contacts to Bispebjerg and Frederiksberg Hospital constituted BAC, representing a solely metropolitan/urban catchment area. Patient characteristics and outcomes were compared to the rest of Denmark in an urban cohort (UrC) and a rural cohort (RuC), stratified by visit and hospitalization contact types. Results: We identified 4,063,420 acute hospital contacts in Denmark and BAC constituted 8.4% (n=343,200) of them. BAC had a higher proportion of visits (65.1%) compared with UrC (52.1%) and RuC (45.3%). Patients in BAC more often lived alone (visits: BAC: 34.8%, UrC: 30.6%, RuC: 29.2%; hospitalizations: BAC: 50.8%, UrC: 36.7%, RuC: 37.2%) and had temporary CPR number (visits: BAC: 4.4%, UrC: 1.9%, RuC: 1.6%; hospitalizations: BAC: 1.5%, UrC: 0.9%, RuC: 0.8%). Visit patients in BAC were younger (BAC: 36, UrC: 42, RuC: 45 years, median), more often students (BAC: 18.0%, UrC: 14.0%, RuC: 12.5%), and had more contacts due to infectious diseases (BAC: 19.8%, UrC: 14.1%, RuC: 6.2%) but less due to injuries (BAC: 40.0%, UrC: 43.8%, RuC: 60.7%). Hospitalized patients in BAC had higher median age (BAC: 64, UrC: 61, RuC: 64 years) and fewer were in employment than in UrC (BAC: 26.1%, UrC: 32.1%, RuC: 28.1%). BAC Hospitalizations had a lower death rate within 30 days than in RuC (BAC: 3.0% [2.9-3.1%], UrC: 3.1% [3.0-3.1%], RuC: 3.4% [3.3-3.4%]), but a higher readmission-rate (BAC: 20.5% [20.3-20.8%], UrC: 17.3% [17.2-17.4%], RuC: 17.5% [17.5-17.6%]). Conclusion: Significant differences between BAC, urban, and rural cohorts may be explained by differences in healthcare structure and sociodemographics of the catchment areas.

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 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.

The effect of sodium-glucose transport protein 2 inhibitors on mortality and heart failure in randomized trials versus observational studies.

AIM: Randomized clinical trials (RCTs) allocating type 2 diabetes patients to treatment with sodium-glucose transport protein 2 (SGLT-2) inhibitors or placebo have found significant effects on the risk of heart failure and modest effects on mortality. In the wake of the first trials, a number of observational studies have been conducted, some of these reporting a mortality reduction of 50% compared to active comparators. In this review, we systematically assess and compare the results on all-cause mortality, cardiovascular mortality and heart failure hospitalization observed in RCTs with the results obtained in observational studies. METHOD: We performed a systematic bibliographical search including cardiovascular outcome trials and observational studies assessing the effect of SGLT-2 inhibitors on mortality and heart failure. RESULTS: Seven RCTs and 23 observational studies were included in the current review. The observed heterogeneity between study results for all-cause mortality (p-interaction < 0.001) and cardiovascular mortality (p-interaction < 0.001) was explained by study type, whereas this was not the case for heart failure (p-interaction = 0.18). CONCLUSION: Methodological considerations such as the omission of important confounders, immortal-time bias and residual confounding such as unmeasured social economic inequality may be the cause of the inflated results observed in observational studies and that calls for caution when observational studies are used to guide treatment of patients with type 2 diabetes.

Night-time heart rate variability identifies high-risk people among people with uncomplicated type 2 diabetes mellitus.

BACKGROUND: Low heart rate variability (HRV) reflects cardiac autonomic neuropathy, which is associated with increased cardiovascular mortality in people with type 2 diabetes mellitus (T2DM). Measuring HRV is challenged by environmental noise, mental stress and physical activity during daytime. Night-time HRV during sleep may be a more valid tool to measure cardiac autonomic neuropathy and therefore may improve prediction of cardiovascular (CV) events in low-risk people with T2DM. METHODS: Copenhagen Holter Study included 678 community-dwelling participants aged 55-75 years who were free of previous CV disease. Day and night-time HRV were available for 653 participants. The population included 133 people with well-controlled T2DM and newly recognized T2DM (mean HbA1c 55 mmol/mol [7.2%]). HRV is defined as standard deviation for the mean value of normal-to-normal complexes (SDNN). Night-time HRV measurements were pre-defined from 2:00 to 2:15 AM. Cardiovascular events were defined as CV death, myocardial infarction, stroke or coronary revascularization. RESULTS: Median follow-up time was 14.4 years. During this period, 245 death and 149 CV events (CV death 36, myocardial infarction 42, revascularisation procedures 46, stroke 70) occurred in total. Among people with T2DM, 41 CV events were observed (CV death 13, myocardial infarction 13, revascularisation procedures 17, stroke 18). Night-time SDNN was inversely associated with CV events in people with T2DM, (hazard ratio [HR]: 0.74 95% confidence interval [CI]:0.61-0.89) for each 10-millisecond increment in SDNN after adjustment for the conventional risk factors sex, age, LDL cholesterol, smoking, systolic blood pressure and by also including glucose CRP and NT-proBNP in adjustment. Twenty-four-hour HRV was not associated with CV events, but associated with all-cause mortality in people with T2DM. Conventional risk factors had a receiver operating characteristic (ROC) value of 0.704 (95% CI 0.602-0.806) to predict CV events in people with T2DM. The prediction of CV events by conventional risk factors was improved in people with T2DM by the addition of night-time SDNN; ROC 0.765 (95% CI 0.669-0.862), p = 0.037, but ROC was not improved by addition of CRP and NT-proBNP in the model. In people with T2DM and night-time SDNN ≤30 ms, the 10-year risk of CV death and CV event rate was 12% and 45%, respectively, which re-allocated them to a 'very high-risk' group according to current guidelines. CONCLUSION: Reduced night-time HRV predicts increased risk of CV events in people with well-controlled T2DM, thus night-time HRV may add to traditional risk factors in predicting CV events in people with T2DM.

Effects of liraglutide on diastolic function parameters in patients with type 2 diabetes and coronary artery disease: a randomized crossover study.

BACKGROUND: Diastolic dysfunction is highly prevalent in patients with type 2 diabetes mellitus (T2DM) and is associated with overweight, glucose dysregulation and coronary artery disease (CAD). The GLP-1 receptor agonist, liraglutide, has shown to induce weight loss and improve metabolic factors, thus modulating factors associated with diastolic dysfunction. We have previously reported the effects of liraglutide on systolic function, and in this current study we explore the effects of liraglutide on diastolic function parameters in patients with stable CAD, preserved left ventricular ejection fraction (LVEF), and newly diagnosed T2DM. METHODS: Thirty subjects were randomized to liraglutide or placebo intervention for 12 + 12-weeks in this double-blind cross-over study. 2D-echocardiography using tissue velocity imaging was used for assessment of diastolic function parameters. Early diastolic filling velocity (E), late atrial filling velocity (A), E-wave deceleration time (EDT) and E/A ratio was assessed from the pulse wave (PW)-Doppler velocity recording of the mitral inflow. Peak early diastolic annular velocities (e') was measured from color tissue doppler images. RESULTS: Liraglutide, when compared to placebo, induced a significant reduction in average e' and lateral e' velocities (- 0.57 cm/s [- 1.05 to - 0.08] and -0.74 cm/s [-1.32 to -0.15], respectively). Adjusted for the concomitant increase in HR (+ 6.16 bpm [0.79 to 11.54], the changes were not significant. No significant changes in other diastolic function parameters were observed. CONCLUSIONS: Liraglutide therapy did not improve any diastolic function parameters in subjects with T2DM, CAD, and preserved LVEF. Instead, a deterioration in e' was observed, which was associated to an increase in heart rate induced by liraglutide therapy. Trial registration Clinical Trial Registration: http://www.clinicaltrials.gov (unique identifier: NCT01595789) (first submitted May 8, 2012).

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.