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Impact of Endurance Exercise Training in the Fasted State on Muscle Biochemistry and Metabolism in Healthy Subjects: Can These Effects be of Particular Clinical Benefit to Type 2 Diabetes Mellitus and Insulin-Resistant Patients?

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Abstract

Exercise training intervention is a cornerstone in the care of type 2 diabetes mellitus (T2DM) and insulin resistance (IR), and it is pursued in order to optimize exercise interventions for these patients. In this regard, the nutritional state of patients during exercise (being in the fed or fasted state) can be of particular interest. The aim of the present review is to describe the impact of endurance exercise (training) in the fasted versus fed state on parameters of muscle biochemistry and metabolism linked to glycemic control or insulin sensitivity in healthy subjects. From these data it can then be deduced whether exercise training in the fasted state may be relevant to patients with T2DM or IR. In healthy subjects, acute endurance exercise in the fasted state is accompanied by lower blood insulin and elevated blood free fatty acid concentrations, stable blood glucose concentrations (in the first 60–90 min), superior intramyocellular triacylglycerol oxidation and whole-body lipolysis, and muscle glycogen preservation. Long-term exercise training in the fasted state in healthy subjects is associated with greater improvements in insulin sensitivity, basal muscle fat uptake capacity, and oxidation. Therefore, promising results of exercise (training) in the fasted state have been found in healthy subjects on parameters of muscle biochemistry and metabolism linked to insulin sensitivity and glycemic control. Whether exercise training intervention in which exercise sessions are organized in the fasted state may be more effective in improving insulin sensitivity or glycemic control in T2DM patients and insulin-resistant individuals warrants investigation.
REVIEW ARTICLE
Impact of Endurance Exercise Training in the Fasted State
on Muscle Biochemistry and Metabolism in Healthy Subjects: Can
These Effects be of Particular Clinical Benefit to Type 2 Diabetes
Mellitus and Insulin-Resistant Patients?
Dominique Hansen
1,2
Dorien De Strijcker
3
Patrick Calders
3
Published online: 26 July 2016
ÓSpringer International Publishing Switzerland 2016
Abstract Exercise training intervention is a cornerstone in
the care of type 2 diabetes mellitus (T2DM) and insulin
resistance (IR), and it is pursued in order to optimize exercise
interventions for these patients. In this regard, the nutritional
state of patients during exercise (being in the fed or fasted
state) can be of particular interest. The aim of the present
review is to describe the impact of endurance exercise
(training) in the fasted versus fed state on parameters of
muscle biochemistry and metabolism linked to glycemic
control or insulin sensitivity in healthy subjects. From these
data it can then be deduced whether exercise training in the
fasted state may be relevant to patients with T2DM or IR. In
healthy subjects, acute endurance exercise in the fasted state
is accompanied by lower blood insulin and elevated blood
free fatty acid concentrations, stable blood glucose concen-
trations (in the first 60–90 min), superior intramyocellular
triacylglycerol oxidation and whole-body lipolysis, and
muscle glycogen preservation. Long-term exercise training
in the fasted state in healthy subjects is associated with
greater improvements in insulin sensitivity, basal muscle fat
uptake capacity, and oxidation. Therefore, promising results
of exercise (training) in the fasted state have been found in
healthy subjects on parameters of muscle biochemistry and
metabolism linked to insulin sensitivity and glycemic con-
trol. Whether exercise training intervention in which
exercise sessions are organized in the fasted state may be
more effective in improving insulin sensitivity or glycemic
control in T2DM patients and insulin-resistant individuals
warrants investigation.
Key Points
Exercise training intervention is a cornerstone in the
care of type 2 diabetes mellitus (T2DM) and insulin
resistance, and the optimization of exercise
interventions for these patients should be pursued by,
for example, manipulating the nutritional state
during exercise (training).
In healthy subjects, acute endurance exercise and
exercise training in the fasted state are accompanied
by significantly greater beneficial adaptations that
lead to improvements in insulin sensitivity.
Whether exercise training intervention in which
exercise sessions are organized in the fasted state
may be more effective in improving insulin
sensitivity or glycemic control in T2DM patients and
insulin-resistant individuals warrants further
investigation.
1 Introduction
Structured exercise intervention is a cornerstone in the care
of type 2 diabetes mellitus (T2DM) patients as it leads to
an *0.7 % reduction in blood glycated hemoglobin
(HbA
1c
) content, even when these patients already take
&Dominique Hansen
Dominique.hansen@uhasselt.be
1
Faculty of Medicine and Life Sciences, Rehabilitation
Research Center, Hasselt University, REVAL, Agoralaan,
Building A, 3590, Diepenbeek, Belgium
2
Heart Centre Hasselt, Jessa Hospital, Hasselt, Belgium
3
Department of Rehabilitation Sciences and Physiotherapy,
Ghent University, Ghent, Belgium
123
Sports Med (2017) 47:415–428
DOI 10.1007/s40279-016-0594-x
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Contrary to the ongoing trend towards exercise in the fasted state and the assumption that this approach might lead to lower blood insulin and beneficial changes in lipid metabolism [30], the postprandial glucose values obtained in this meta-analysis point towards the opposite direction. One of the included studies analyzed glycemic response and additional metabolic outcomes and reported a larger favorable effect of post-meal exercise on insulin secretion and blood triacylglycerol levels [17]. ...
... Contrary to these findings, a study of the effects of premeal exercise compared to multiple post-meal exercise bouts reported favorable effects on postprandial lipoprotein metabolism only for pre-meal exercise [31]. To explain the discrepancies between research on fasted exercise [30] and our data on pre-and post-meal exercise, differences in study design and especially in dietary stimuli have to be considered. A number of studies included in the review by Hansen et al. [30] included a standardized meal only in the study arm with postprandial exercise. ...
... To explain the discrepancies between research on fasted exercise [30] and our data on pre-and post-meal exercise, differences in study design and especially in dietary stimuli have to be considered. A number of studies included in the review by Hansen et al. [30] included a standardized meal only in the study arm with postprandial exercise. Consequently, these studies compared the metabolic response to exercise in the fasted state over a standardized timeframe (during which the participants continued fasting) with the response to exercise after meal ingestion over an identical amount of time in the postprandial state. ...
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Background The most effective way to cope with high blood sugar spikes is to engage in physical activity in temporal proximity to food intake. However, so far, it is unclear as to whether there is an optimal time for physical activity around food intake. Objectives We aimed to identify the impact of pre- and post-meal exercise on postprandial glucose excursions in humans with and without type 2 diabetes mellitus. Methods We conducted a systematic review with meta-analysis, PROSPERO registration number: CRD42022324070. We screened MEDLINE/PubMed, Cochrane/CINAHL/EMBASE, and Web of Knowledge until 1 May, 2022. We used the risk of bias rating with the crossover extension of the Cochrane risk of bias assessment tool II. Standardized mean differences (SMDs, Hedges’ g) with 95% confidence intervals (CIs) were calculated as pooled effect estimates of a random-effects meta-analysis. Eligibility criteria included three-armed randomized controlled trials comparing the acute effects of pre- and post-meal exercise to a no-exercise control in humans. Results Eight randomized controlled trials (crossover trials, high risk of bias) with 30 interventions in 116 participants (47 diagnosed with type 2 diabetes, 69 without type 2 diabetes) were eligible. Exercise after meal ingestion (real food or meal replacement drinks) led to a reduction in postprandial glucose excursions compared with exercise before eating (15 effect sizes; SMD = 0.47 [95% CI 0.23, 0.70]) and an inactive control condition (15 effect sizes; SMD = 0.55 [95% CI 0.34, 0.75]. Pre-meal exercise did not lead to significantly lower postprandial glucose compared to an inactive control (15 effect sizes; SMD = − 0.13 [95% CI − 0.42, 0.17]). The time between meal and exercise (estimate = − 0.0151; standard error = 0.00473; Z = − 3.19; p = 0.001; 95% CI − 0.024, − 0.006) had a moderating influence on postprandial glucose excursions. Conclusions Exercise, i.e., walking, has a greater acute beneficial impact on postprandial hyperglycemia when undertaken as soon as possible after a meal rather than after a longer interval or before eating. Clinical Trial Registration The review was pre-registered in the PROSPERO database (CRD42022324070). The date of submission was 07.04.2022, with the registration on 08.05.2022.
... Possui duração prolongada, com menores níveis de contração muscular. Sua principal fonte de energia encontra-se nos carboidratos (com moderada utilização de gorduras, e pouca utilização de proteínas), obtendo oxidação dentro das mitocôndrias musculares, o chamado metabolismo aeróbico (SBD, 2019;NETTO et al., 2020;HANSEN et al., 2017). ...
... Simplificando: o uso de glicose pelo músculo é um estímulo para geração de mais glicose pelo próprio organismo (o que o ocorre pelo aumento do glucagon), que é gerada e será usada pelo músculo, sem a necessidade de insulina, pois os receptores GLUT musculares são sensíveis à contração. Dessa forma, há uma queda dos níveis de insulina numa pessoa sem diabetes para garantir uma homeostase glicêmica (KARSTOF & PEDERSEN, 2016;SELLAMI et al., 2019;HANSEN et al., 2017;AMANAT et al., 2020). ...
... Devido a isso, além dos mecanismos de glicogenólise e gliconeogênese, que também ocorrem no exercício aeróbico, neles ocorrem aumento das catecolaminas. Elas, a noradrenalina e a adrenalina, também são hormônios contrarreguladores, porém muito mais potentes, pois elevam a glicemia sete vezes mais que o glucagon (SBD, 2019;NETTO et al., 2020;SELLAMI et al., 2019;HANSEN et al., 2017). ...
Chapter
A Editora Pasteur apresenta com muito prazer a 6ª edição da coletânea de capítulos sobre Saúde Pública. Essa é uma área de interesse internacional, onde comunidades com realidades diversas trocam experiências com o objetivo de reduzir custos e prestar a melhor cobertura possível em políticas públicas que atendam o maior número de pessoas. Por ser tratar de uma área multidisciplinar, nossas edições sempre contam com a participação de profissionais e estudantes das áreas de Biomedicina, Enfermagem, Farmácia, Fisioterapia, Fonoaudiologia, Medicina, Odontologia e Psicologia. A leitura deste material destina-se a todos os profissionais, estudantes, pesquisadores e interessados na área de Saúde Pública. A compreensão dos problemas e de projetos dentro deste campo proporciona ampliar os horizontes sobre novos projetos que podem ser implantados em suas regiões ou mesmo em locais carentes de iniciativas eficientes. Promoção à saúde e prevenção de doenças, políticas implementadas, estudos epidemiológicos e de gestão em saúde poderão ser encontrados nesta nova edição. Esperamos que tenham uma leitura agradável e parabenizamos os autores por suas pesquisas e redações.
... Fasting before exercise may be used to increase the proportion of fat metabolism and to lose weight, but the effect is not obvious in the long term [28]. Additionally, past research has shown that fasting before exercise can improve insulin sensitivity [29,30]. However, previous studies lacked an investigation of exercise after fasting for less than 12 h. ...
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The effects of fasting and different exercise intensities on lipid metabolism were investigated in 12 male students aged 19.9 ± 1.4 years, with maximal oxygen consumption (VO2max) of 50.33 ± 4.0 mL/kg/min, using a counterbalanced design. Each participant ran on a treadmill at 45% and 65% VO2max continuously for 20 min, followed by running at 85% VO2max for 20 min (or until exhaustion) under a fed or fasted state (6 h). The respiratory exchange ratio (RER), blood glucose (BGLU), blood lactate (BLA), and blood triglyceride (TG) were analyzed during exercise. The results showed that the intensity of exercise did not significantly affect the BGLU and TG in the fed state. The levels of both RER and BLA increased as the intensity of exercise increased from low to high (45, 65, and 85% VO2max), and more energy was converted from fat into glucose at a high intensity of exercise. In the fasted state of 6 h, the BGLU level increased parallel to the intensity of exercise. The RER was close to 1.0 at a high intensity of exercise, indicating that more energy was converted from glycogen. At the intensities of 45 and 65% VO2max, the RER and concentration of TG were both lower in the fasted than in the fed state, showing that a higher percentage of energy comes from fat than in the fed state at 45 and 65% VO2max. When running at 85% VO2max, the BGLU concentration was higher in the fasted than in the fed state, indicating that the liver tissues release more BGLU for energy in the fasted state. Therefore, in the fasted state, running at 45% and 65% of VO2max significantly affects lipid metabolism. On the contrary, the higher RER and BGLU concentrations when running at 85% VO2max revealed no significant difference between the two probes. This study suggests that medium- and low-intensity exercise (45 and 65% VO2max) in the fasted state enhances lipid metabolism.
... Aktifitas fisik yang memadahi dihubungkan dengan potensi perbaikan respons insulin. 26,27 Sebuah review melaporkan jenis olahraga aerobic seperti jalan kaki, meningkatkan kualitas hidup pasien melalui penurunan gula darah yang terjadi. 28 Hasil penelitian ini menunjukkan hubungan yang tidak signifikan antara HbA1C dengan usia, aktifitas fisik, dan kebiasaan makan pasien (p > 0,01). ...
... The key is to understand the potential mechanism that a combined diet and exercise strategy may prevent metabolic diseases (Figure 2). Several studies have elucidated that exercise in the fasted state generated advantageous metabolic adaptations, accompanying by stable blood glucose concentrations and elevated blood FFA concentrations, which may be more effective in improving insulin sensitivity and controlling glycemic in insulinresistant individuals [95,96]. From the GM perspective, combining physical exercise and diet tempers intestinal barrier dysfunction, reserving mucous thickness and intestinal permeability. ...
Article
Full-text available
Background: Unhealthy diet and sedentary lifestyle have contributed to the rising incidence of metabolic diseases, which is also accompanied by the shifts of gut microbiota architecture. The gut microbiota is a complicated and volatile ecosystem and can be regulated by diet and physical exercise. Extensive research suggests that diet alongside physical exercise interventions exert beneficial effects on metabolic diseases by regulating gut microbiota, involving in the changes of the energy metabolism, immune regulation, and the microbial-derived metabolites. Objective: In this review, we present the latest evidence in the modulating role of diet and physical exercise in the gut microbiota and its relevance to metabolic diseases. We also summarize the research from animal and human studies on improving metabolic diseases through diet-plus-exercise interventions, and new targeted therapies that might provide a better understanding of the potential mechanisms. Methods: A systematic and comprehensive literature search was performed in PubMed/Medline and Web of Science in October 2022. The key terms used in the searches included "combined physical exercise and diet", "physical exercise, diet and gut microbiota", "physical exercise, diet and metabolic diseases" and "physical exercise, diet, gut microbiota and metabolic diseases". Conclusions: Combined physical exercise and diet offer a more efficient approach for preventing metabolic diseases via the modification of gut microbiota, abating the burden related to longevity.
... The reason may be that FAE improved the biological effect of insulin, indirectly suggesting that FAE may improve the mechanism of insulin receptor or post-receptor action. 27 Maughan 28 believe that the body's response to fasting involves increased fat mobilization and decreased re-esterification of free fatty acids (FFA), and that fasting exercise causes an increase in blood FFA levels, which in turn causes an increase in FFA utilization by muscle tissue. INS is the most potent lipolysis inhibitory hormone secreted by islet beta cells in the pancreas, Low concentrations in the body during starvation and exercise induce an increase in the rate of lipolysis, 29 and higher levels of INS will inhibit lipolysis during exercise after carbohydrate intake. ...
Article
Full-text available
Background/Objective: The effects of fasted aerobic exercise on body composition and whether it causes adverse effects remain controversial. This study was to compare the effects of fasted and non-fasted aerobic exercise on body shape and blood biochemical indexes in overweight and obese young adult males, and observe whether FAE triggers adverse reactions. Methods: Thirty overweight and obese young adult males were randomly divided into fasted aerobic exercise (FAE) group, non-fasted aerobic exercise (NFAE) group, and control group. They were subjected to indoor treadmill intervention five days a week combined with diet control for six weeks. The FAE group had breakfast 0.5 h after exercise, and the NFAE group exercised 1 h after breakfast. Both groups filled out adverse reaction questionnaires during exercise, and the control group did not have any intervention. Height, weight, body mass index (BMI), and body fat percentage of the three groups of subjects before and after the experiment were measured by the GAIA KIKO bio-resistance antibody composition analyzer in Korea; waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were measured by the tape measure method; fasting plasma glucose (FPG), fasting insulin (FINs), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein (VLDL), and HDL-C/LDL-C were measured by Roche C8000 automatic biochemical analysis instrument. Results: Weight, BMI, body fat percentage, WC, HC, WHR, WHtR, TG, TC, LDL-C and VLDL decreased very significantly (P
... Exercise might not be sufficient as a stand-alone treatment, as suboptimal diets are the primary lifestyle factors for insulin resistance. However, there were evidence showing significant beneficial impact of exercise on the insulin resistant state [41]. ...
Chapter
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Abundant evidence proved that the amount of habitual exercise and the level of cardiorespiratory fitness (CRF) are inversely related to the risk of cardiovascular morbidity and mortality. In this chapter, you can learn about the cardiorespiratory benefits of exercise, involving: (1) delay the development of cardiovascular disease (CVD) affecting many of the standard cardiorespiratory diseases risk factors, such as plasma lipids, especially high-density lipoprotein cholesterol, fasting glucose levels, blood and hypertension control; (2) improve the cardiac output (CO) and the CRF of different ages. However, certain kind of exercise might not be applicable to cardiac patients, since high-intensity, high-volume exercise may increase all-cause mortality among these patients. At present, the American College of Sports Medicine (ACSM) recommends that aerobic exercise (AE) and resistance exercise (RE) two or three times a week is related to better physical function at different ages, improvement of muscle strength, body composition and, especially, CRF.
... Prior research suggests that fat oxidation during exercise is related to insulin resistance, although the results have been mixed [9][10][11][12]. We tested this relationship in our cohort because exercise regimes aimed at increasing fat oxidation might have beneficial effects on glycemic control [33]. In accordance with results in other cohorts [10,11,13], we found no associations between PFO and glucose tolerance in women with prior GDM. ...
Article
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Aims We sought to identify self-reported exercise and objectively measured fitness variables associated with glucose tolerance and metabolic health 6–10 years after gestational diabetes (GDM) Methods Women (n=84) underwent oral glucose tolerance testing (OGTT), body composition measurements, and lifestyle questionnaires 6 and 10 years after GDM. In a subset (n=45), peak oxygen uptake (VO2peak), peak fat oxidation, and maximal isometric strength of five muscle groups were tested Results At 10 years, 41 women (49%) had impaired glucose metabolism or type 2 diabetes (T2D). VO2peak and muscle strength were lowest in the T2D group. In a regression analysis, VO2peak and all strength measurements were associated negatively with HbA1c and waist-hip ratio and positively with high-density lipoprotein cholesterol. However, only muscle strength was associated with fasting and area-under-the-curve glucose. For changes between the 6- and 10-year follow-ups, only muscle strength was associated with HbA1c change, whereas both VO2peak and strength were associated with high-density lipoprotein level and changes in waist-hip ratio. Peak fat oxidation and self-reported physical activity showed no or weak relationships with glycemic variables Conclusion Objectively measured fitness variables, particularly muscle strength, were strongly associated with glycemic and other metabolic outcomes in a high-risk group after GDM.
... Therefore, mTORC1 is known as a key regulator in the control of skeletal muscle mass after contraction and hypertrophy due to mechanical load [19]. In this way, it seems regular physical activity (PA) can increase the synthesis of proteins in the skeletal muscles [20]. Sports activities are strong stimulations that can cause changes in signal transduction and cellular metabolism that vary depending on the intensity, type, and timing of exercise. ...
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Abstract Purpose: In people with diabetes, one of the problems for patients is muscle wasting and inhibition of the protein synthesis pathway. This study aimed to evaluate the effects of HIIT on protein expression in two skeletal muscles, flexor hallucis longus (FHL) and soleus (SOL) in rats with type 2 diabetes mellitus (T2DM). Materials and Methods: Diabetes initially was induced by streptozotocin (STZ) and nicotinamide. Rats with type 2 diabetes were randomly and equally divided into control (n=6) and HIIT groups (n=6). After 8 weeks of training, the content of total and phosphorylated proteins of serine/threonine-protein kinases (AKT1), mammalian target of rapamycin (mTOR), P70 ribosomal protein S6 kinase 1 (P70S6K1), and 4E (eIF4E)-binding protein 1 (4E-BP1) in FHL and SOL muscles were measured by Western blotting. While body weight and blood glucose were also controlled. Results: In the HIIT training group, compared to the control group, a significant increase in the content of AKT1 (0.003) and mTOR (0.001) proteins was observed in the FHL muscle. Also, after 8 weeks of HIIT training, protein 4E-BP1 (0.001) was increased in SOL muscle. However, there was no significant change in other proteins in FHL and SOL muscle. Conclusion: In rats with type 2 diabetes appear to HIIT leading to more protein expression of fast-twitch muscles than slow-twitch muscles. thus likely HIIT exercises can be an important approach to increase protein synthesis and prevent muscle atrophy in people with type 2 diabetes.
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This study determined if the suppression of lipolysis after preexercise carbohydrate ingestion reduces fat oxidation during exercise. Six healthy, active men cycled 60 min at 44 ± 2% peak oxygen consumption, exactly 1 h after ingesting 0.8 g/kg of glucose (Glc) or fructose (Fru) or after an overnight fast (Fast). The mean plasma insulin concentration during the 50 min before exercise was different among Fast, Fru, and Glc (8 ± 1, 17 ± 1, and 38 ± 5 μU/ml, respectively; P< 0.05). After 25 min of exercise, whole body lipolysis was 6.9 ± 0.2, 4.3 ± 0.3, and 3.2 ± 0.5 μmol ⋅ kg-1⋅ min-1and fat oxidation was 6.1 ± 0.2, 4.2 ± 0.5, and 3.1 ± 0.3 μmol ⋅ kg-1⋅ min-1during Fast, Fru, and Glc, respectively (all P < 0.05). During Fast, fat oxidation was less than lipolysis ( P < 0.05), whereas fat oxidation approximately equaled lipolysis during Fru and Glc. In an additional trial, the same subjects ingested glucose (0.8 g/kg) 1 h before exercise and lipolysis was simultaneously increased by infusing Intralipid and heparin throughout the resting and exercise periods (Glc+Lipid). This elevation of lipolysis during Glc+Lipid increased fat oxidation 30% above Glc (4.0 ± 0.4 vs. 3.1 ± 0.3 μmol ⋅ kg-1⋅ min-1; P < 0.05), confirming that lipolysis limited fat oxidation. In summary, small elevations in plasma insulin before exercise suppressed lipolysis during exercise to the point at which it equaled and appeared to limit fat oxidation.
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Background Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. Methods 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or. glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. in the conventional group, the aim was the best achievable FPG with diet atone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye,or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. Findings Over 10 years, haemoglobin A(1c) (HbA(1c)) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group-an 11% reduction. There was no difference in HbA(1c) among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). Interpretation Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.
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