Kristian Karstoft

The Effects of Free-Living Interval-Walking Training on Glycemic Control, Body Composition, and Physical Fitness in Type 2 Diabetic Patients A randomized, controlled trial

OBJECTIVE To evaluate the feasibility of free-living walking training in type 2 diabetic patients and to investigate the effects of interval-walking training versus continuous-walking training upon physical fitness, body composition, and glycemic control. RESEARCH DESIGN AND METHODS Subjects with type 2 diabetes were randomized to a control (n = 8), continuous-walking (n = 12), or interval-walking group (n = 12). Training groups were prescribed five sessions per week (60 min/session) and were controlled with an accelerometer and a heart-rate monitor. Continuous walkers performed all training at moderate intensity, whereas interval walkers alternated 3-min repetitions at low and high intensity. Before and after the 4-month intervention, the following variables were measured: VO2max, body composition, and glycemic control (fasting glucose, HbA1c, oral glucose tolerance test, and continuous glucose monitoring [CGM]). RESULTS Training adherence was high (89 ± 4%), and training energy expenditure and mean intensity were comparable. VO2max increased 16.1 ± 3.7% in the interval-walking group (P < 0.05), whereas no changes were observed in the continuous-walking or control group. Body mass and adiposity (fat mass and visceral fat) decreased in the interval-walking group only (P < 0.05). Glycemic control (elevated mean CGM glucose levels and increased fasting insulin) worsened in the control group (P < 0.05), whereas mean (P = 0.05) and maximum (P < 0.05) CGM glucose levels decreased in the interval-walking group. The continuous walkers showed no changes in glycemic control. CONCLUSIONS Free-living walking training is feasible in type 2 diabetic patients. Continuous walking offsets the deterioration in glycemia seen in the control group, and interval walking is superior to energy expenditure–matched continuous walking for improving physical fitness, body composition, and glycemic control.

Exercise and type 2 diabetes: focus on metabolism and inflammation.

Type 2 diabetes mellitus (T2DM) is associated with metabolic dysregulation and chronic inflammation, and regular exercise may provide a strong stimulus for improving both. In this review, we first discuss the link between inflammation and metabolism. Next, we give an update on the clinical metabolic effects of exercise in T2DM patients with special focus on which parameters to consider for optimizing metabolic improvements. We then discuss the mechanisms whereby exercise exerts its anti‐inflammatory and related metabolic effects. Evidence exists that interleukin (IL)‐1β is involved in pancreatic β‐cell damage, whereas tumor necrosis factor (TNF)‐α appears to be a key molecule in peripheral insulin resistance. Mechanistic studies in humans suggest that moderate acute elevations in IL‐6, as provoked by exercise, exert direct anti‐inflammatory effects by an inhibition of TNF‐α and by stimulating IL‐1ra (IL‐1 receptor antagonist), thereby limiting IL‐1β signaling. In addition, IL‐6 has direct impact on glucose and lipid metabolism. Moreover, indirect anti‐inflammatory effects of exercise may be mediated via improvements in, for example, body composition. While waiting for the outcome of long‐term randomized clinical training studies with hard end points, it should be emphasized that physical activity represents a natural strong anti‐inflammatory and metabolism‐improving strategy with minor side effects.

Pancreatic β-cell Function Is a Stronger Predictor of Changes in Glycemic Control After an Aerobic Exercise Intervention Than Insulin Sensitivity

CONTEXT Understanding intersubject variability in glycemic control following exercise training will help individualize treatment. OBJECTIVE Our aim was to determine whether this variability is related to training-induced changes in insulin sensitivity or pancreatic β-cell function. DESIGN, SETTING, AND PARTICIPANTS We conducted an observational clinical study of 105 subjects with impaired glucose tolerance or type 2 diabetes. INTERVENTIONS AND MAIN OUTCOME MEASURES Individual subject changes in fitness (VO2max), glycemia (glycosylated hemoglobin, fasting glucose, oral glucose tolerance test), insulin sensitivity (hyperinsulinemic-euglycemic clamp), oral glucose-stimulated insulin secretion (GSIS), and disposition index (DI) were measured following 12 to 16 weeks of aerobic exercise training. Regression analyses were used to identify relationships between variables. RESULTS After training, 86% of subjects increased VO2max and lost weight. Glycosylated hemoglobin, fasting glucose, and 2-hour oral glucose tolerance test were reduced in 69%, 62%, and 68% of subjects, respectively, while insulin sensitivity improved in 90% of the participants. Changes in glycemic control were congruent with changes in GSIS such that 66% of subjects had a reduction in first-phase GSIS, and 46% had reduced second-phase GSIS. Training increased first- and second-phase DI in 83% and 74% of subjects. Training-induced changes in glycemic control were related to changes in GSIS (P < .05), but not insulin sensitivity or DI, and training-induced improvements in glycemic control were largest in subjects with greater pretraining GSIS. CONCLUSIONS Intersubject variability in restoring glycemic control following exercise is explained primarily by changes in insulin secretion. Thus, baseline and training-induced changes in β-cell function may be a key determinant of training-induced improvements in glycemic control.

Examining the Effects of Hyperglycemia on Pancreatic Endocrine Function in Humans: Evidence for in Vivo Glucotoxicity

CONTEXT Investigating the impact of hyperglycemia on pancreatic endocrine function promotes our understanding of the pathophysiology of hyperglycemia-related disease. OBJECTIVE The objective of the study was to test the hypothesis that experimental hyperglycemia impairs insulin and glucagon secretion. DESIGN A randomized, crossover in healthy controls, compared with type 2 diabetic patients. SETTING The study was conducted at a university hospital. PARTICIPANTS Normal glucose-tolerant subjects (n = 10) and patients with type 2 diabetes (n = 10), individually matched by age, sex, and body mass index. INTERVENTIONS Normal glucose-tolerant subjects underwent 24 h of experimental hyperglycemia (+5.4 mm above basal). Subjects with type 2 diabetes did not undergo an intervention. MAIN OUTCOME MEASURES Insulin secretion, glucagon secretion, insulin sensitivity, disposition index, and endogenous glucose production (via [6,6-(2)H(2)]glucose infusion) were measured during hyperglycemic clamps combined with infusion of glucagon-like peptide (GLP)-1(7-36) (0.5 pmol/kg · min) and injection of arginine (5 g). RESULTS Insulin secretion was correlated with glucagon suppression in subjects with normal glucose tolerance only. Individuals with type 2 diabetes had lower insulin sensitivity (-33 ± 11%) and insulin secretory responses to glucose, GLP-1, and arginine (-40 ± 11, -58 ± 7, and -36 ± 13%, respectively) and higher plasma glucagon and endogenous glucose production compared with normal glucose-tolerant subjects (all P < 0.05). After 24 h of experimental hyperglycemia, insulin sensitivity (-29 ± 10%), disposition index (-24 ± 16%), and GLP-1- (-19 ± 7%) and arginine-stimulated (-15 ± 10%) insulin secretion were decreased in normal glucose-tolerant subjects (all P < 0.05). However, plasma glucagon responses were not affected. Furthermore, experimental hyperglycemia abolished the correlation between insulin secretion and glucagon suppression. CONCLUSIONS Experimental hyperglycemia impaired pancreatic β-cell function but did not acutely impair α-cell glucagon secretion in normal glucose-tolerant subjects.

The Acute Effects of Interval- Vs Continuous-Walking Exercise on Glycemic Control in Subjects With Type 2 Diabetes: A Crossover, Controlled Study

CONTEXT Glycemic control improves with physical activity, but the optimal exercise mode is unknown. OBJECTIVE The objective of the study was to determine whether interval-based exercise improves postprandial glucose tolerance and free-living glycemia more than oxygen consumption- and time duration-matched continuous exercise. DESIGN This was a crossover, controlled study with trials performed in randomized order. SETTING The study was conducted in hospitalized and ambulatory care. PATIENTS PATIENTS diagnosed with type 2 diabetes mellitus (n=10, no withdrawals) participated in the study. INTERVENTIONS Subjects performed three 1-hour interventions: 1) interval walking (IW; repeated cycles of 3 min of slow and fast walking); 2) continuous walking (CW); and 3) control (CON). Oxygen consumption (VO2) was measured continuously to match mean VO2 between exercise sessions (∼75% VO2peak). MAIN OUTCOME MEASURES A mixed-meal tolerance test (MMTT; 450 kcal, 55% carbohydrate) with stable glucose isotopic tracers was provided after each intervention, and glucose kinetics were measured during the following 4 hours. Free-living glycemic control was assessed for approximately 32 hours after the MMTT using continuous glucose monitoring. RESULTS VO2 was well matched between the exercise interventions. IW decreased the mean and maximal incremental plasma glucose during the MMTT when compared with the CON (mean 1.2 ± 0.4 vs 2.0 ± 0.5 mmol/L, P < .001; maximal 3.7 ± 0.6 vs 4.6 ± 0.7 mmol/L, P = .005) and mean when compared with CW (1.7 ± 0.4 mmol/L, P = .02). No differences in the mean or maximal incremental plasma glucose values were seen between the CW and CON. The metabolic clearance rate of glucose during the MMTT was increased in the IW compared with CW (P = .049) and CON (P < .001). Continuous glucose monitoring mean glucose was reduced in IW compared with CW for the rest of the intervention day (8.2 ± 0.4 vs 9.3 ± 0.7 mmol/L, P = .03), whereas no differences were found between IW and CW the following day. CONCLUSIONS One interval-based exercise session improves glycemic control in type 2 diabetes mellitus subjects when compared with an oxygen consumption- and time duration-matched continuous exercise session.

Increased shelterin mRNA expression in peripheral blood mononuclear cells and skeletal muscle following an ultra-long-distance running event

Located at the end of chromosomes, telomeres are progressively shortened with each replication of DNA during aging. Integral to the regulation of telomere length is a group of proteins making up the shelterin complex, whose tissue-specific function during physiological stress is not well understood. In this study, we examine the mRNA and protein levels of proteins within and associated with the shelterin complex in subjects (n = 8, mean age = 44 yr) who completed a physiological stress of seven marathons in 7 days. Twenty-two to 24 h after the last marathon, subjects had increased mRNA levels of DNA repair enzymes Ku70 and Ku80 (P < 0.05) in both skeletal muscle and peripheral blood mononuclear cells (PBMCs). Additionally, the PBMCs displayed an increment in three shelterin protein mRNA levels (TRF1, TRF2, and Pot-1, P < 0.05) following the event. Seven days of ultrarunning did not result in changes in mean telomere length, telomerase activity, hTert mRNA, or hterc mRNAs found in PBMCs. Higher protein concentrations of TRF2 were found in skeletal muscle vs. PBMCs at rest. Mean telomere length in skeletal muscle did not change and did not contain detectable levels of htert mRNA or telomerase activity. Furthermore, changes in the PBMCs could not be attributed to changes in the proportion of subtypes of CD4(+) or CD8(+) cells. We have provided the first evidence that, in humans, proteins within and associated with the shelterin complex increase at the mRNA level in response to a physiological stress differentially in PBMCs and skeletal muscle.

Normal physical activity obliterates the deleterious effects of a high-caloric intake

A high-caloric intake combined with a sedentary lifestyle is an important player in the development of type 2 diabetes mellitus (T2DM). The present study was undertaken to examine if the level of physical activity has impact on the metabolic effects of a high-caloric (+2,000 kcal/day) intake. Therefore, healthy individuals on a high-caloric intake were randomized to either 10,000 or 1,500 steps/day for 14 days. Step number, total energy expenditure, dietary records, neuropsychological tests, maximal oxygen uptake (Vo2max), whole body dual-energy X-ray absorptiometry (DXA) and abdominal magnetic resonance imaging (MRI) scans, continuous glucose monitoring (CGM), and oral glucose tolerance tests (OGTT) with stable isotopes were performed before and after the intervention. Both study groups gained the same amount of body weight. However, the inactive group accumulated significantly more visceral fat compared with the active group. Following the 2-wk period, the inactive group also experienced a poorer glycemic control, increased endogenous glucose production, decreased hepatic insulin extraction, increased baseline plasma levels of total cholesterol and LDL, and a decreased cognitive function with regard to capacity of attention. In conclusion, we find evidence to support that habitual physical activity may prevent pathophysiological symptoms associated with diet-induced obesity.

Skeletal muscle as a gene regulatory endocrine organ.

Purpose of reviewSkeletal muscle is gaining increased attention as an endocrine organ. Recently, novel myokines and new effects of already established myokines have been identified. The objective of this review is to give an update on the recent advances in the field. Recent findingsSeveral hundred putative myokines have been described, some of which are induced by contraction and differentially regulated between healthy and metabolically diseased individuals. Interleukin-6 (IL-6) is the prototype myokine, which was identified as a muscle-derived cytokine 15 years ago. Recently, IL-6 has been linked to &bgr;-cell survival and inhibition of cancer-cell growth. Moreover, trans-signaling appears to determine whether IL-6 acts as a proinflammatory or an anti-inflammatory cytokine. Irisin has been shown to be a secreted myokine, which contribute to circulating concentrations dependent on training status. IL-15 has been established as a cytokine mediating cross-talk between skeletal muscle and skin tissue, and decorin has been characterized as a contraction-induced myokine which apparently is differentially regulated between healthy and dysglycemic individuals. SummarySkeletal muscle is an endocrine organ which, by the release of myokines, may influence metabolism in virtually all organs in the body. This knowledge may potentially open up for the possibility of designing new drugs that mimic the effects of myokine signaling.

Association Between Cardiorespiratory Fitness and the Determinants of Glycemic Control Across the Entire Glucose Tolerance Continuum

OBJECTIVE Cardiorespiratory fitness (VO2max) is associated with glycemic control, yet the relationship between VO2max and the underlying determinants of glycemic control is less clear. Our aim was to determine whether VO2max is associated with insulin sensitivity, insulin secretion, and the disposition index, a measure of compensatory pancreatic β-cell insulin secretion relative to insulin sensitivity, in subjects representing the entire range of the glucose tolerance continuum. RESEARCH DESIGN AND METHODS A cohort of subjects (N = 313) with heterogeneous age, sex, BMI, and glycemic control underwent measurements of body composition, HbA1c, fasting glucose, oral glucose tolerance (OGTT), and VO2max. OGTT-derived insulin sensitivity (SiOGTT), glucose-stimulated insulin secretion (GSISOGTT), and the disposition index (DIOGTT) (the product of SiOGTT and GSISOGTT) were measured, and associations between VO2max and these determinants of glycemic control were examined. RESULTS A low VO2max was associated with high HbA1c (r = −0.33), high fasting glucose (r = −0.34), high 2-h OGTT glucose (r = −0.33), low SiOGTT (r = 0.73), and high early-phase (r = −0.34) and late-phase (r = −0.36) GSISOGTT. Furthermore, a low VO2max was associated with low early- and late-phase DIOGTT (both r = 0.41). Interestingly, relationships between VO2max and either glycemic control or late-phase GSISOGTT deteriorated across the glucose tolerance continuum. CONCLUSIONS The association between poor cardiorespiratory fitness and compromised pancreatic β-cell compensation across the entire glucose tolerance continuum provides additional evidence highlighting the importance of fitness in protection against the onset of a fundamental pathophysiological event that leads to type 2 diabetes.

Effect of an Intensive Lifestyle Intervention on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

Importance It is unclear whether a lifestyle intervention can maintain glycemic control in patients with type 2 diabetes. Objective To test whether an intensive lifestyle intervention results in equivalent glycemic control compared with standard care and, secondarily, leads to a reduction in glucose-lowering medication in participants with type 2 diabetes. Design, Setting, and Participants Randomized, assessor-blinded, single-center study within Region Zealand and the Capital Region of Denmark (April 2015-August 2016). Ninety-eight adult participants with non–insulin-dependent type 2 diabetes who were diagnosed for less than 10 years were included. Participants were randomly assigned (2:1; stratified by sex) to the lifestyle group (n = 64) or the standard care group (n = 34). Interventions All participants received standard care with individual counseling and standardized, blinded, target-driven medical therapy. Additionally, the lifestyle intervention included 5 to 6 weekly aerobic training sessions (duration 30-60 minutes), of which 2 to 3 sessions were combined with resistance training. The lifestyle participants received dietary plans aiming for a body mass index of 25 or less. Participants were followed up for 12 months. Main Outcomes and Measures Primary outcome was change in hemoglobin A1c (HbA1c) from baseline to 12-month follow-up, and equivalence was prespecified by a CI margin of ±0.4% based on the intention-to-treat population. Superiority analysis was performed on the secondary outcome reductions in glucose-lowering medication. Results Among 98 randomized participants (mean age, 54.6 years [SD, 8.9]; women, 47 [48%]; mean baseline HbA1c, 6.7%), 93 participants completed the trial. From baseline to 12-month follow-up, the mean HbA1c level changed from 6.65% to 6.34% in the lifestyle group and from 6.74% to 6.66% in the standard care group (mean between-group difference in change of −0.26% [95% CI, −0.52% to −0.01%]), not meeting the criteria for equivalence (P = .15). Reduction in glucose-lowering medications occurred in 47 participants (73.5%) in the lifestyle group and 9 participants (26.4%) in the standard care group (difference, 47.1 percentage points [95% CI, 28.6-65.3]). There were 32 adverse events (most commonly musculoskeletal pain or discomfort and mild hypoglycemia) in the lifestyle group and 5 in the standard care group. Conclusions and Relevance Among adults with type 2 diabetes diagnosed for less than 10 years, a lifestyle intervention compared with standard care resulted in a change in glycemic control that did not reach the criterion for equivalence, but was in a direction consistent with benefit. Further research is needed to assess superiority, as well as generalizability and durability of findings. Trial Registration clinicaltrials.gov Identifier: NCT02417012