Michael C. Riddell

The effects of glucocorticoids on adipose tissue lipid metabolism

Glucocorticoids (GCs) have long been accepted as being catabolic in nature, liberating energy substrates during times of stress to supply the increased metabolic demand of the body. The effects of GCs on adipose tissue metabolism are conflicting, however, because patients with elevated GCs present with central adiposity. We performed an extensive literature review of the effects of GCs on adipose tissue metabolism. The contradictory effects of GCs on lipid metabolism occur through a number of different mechanisms, some of which are well defined and others remain to be elucidated. Firstly, through increases in caloric and dietary fat intake, along with increased hydrolysis of circulating triglycerides (chylomicrons, very low-density lipoproteins) by lipoprotein lipase activity, GCs increase the amount of fatty acids in circulation, which are then available for ectopic fat distribution (liver, muscle, and central adipocytes). Glucocorticoids also increase de novo lipid production in hepatocytes through increased expression of fatty acid synthase. There is some controversy as to whether these same mechanisms occur in adipocytes, thereby contributing to adipose hypertrophy. Glucocorticoids promote preadipocyte conversion to mature adipocytes, causing hyperplasia of the adipose tissue. Glucocorticoids also have acute antilipolytic effect on adipocytes, whereas their genomic actions facilitate increased lipolysis after about 48 hours of exposure. The acute and long-term effects of GCs on adipose tissue lipolysis remain unclear. Although considerable evidence supports the notion that GCs increase lipolysis through glucocorticoid-induced increases of lipase expression, they clearly have antilipolytic effects within these same tissues and cell line models.

Physical Activity/Exercise and Diabetes: A Position Statement of the American Diabetes Association

The adoption and maintenance of physical activity are critical foci for blood glucose management and overall health in individuals with diabetes and prediabetes. Recommendations and precautions vary depending on individual characteristics and health status. In this Position Statement, we provide a clinically oriented review and evidence-based recommendations regarding physical activity and exercise in people with type 1 diabetes, type 2 diabetes, gestational diabetes mellitus, and prediabetes. Physical activity includes all movement that increases energy use, whereas exercise is planned, structured physical activity. Exercise improves blood glucose control in type 2 diabetes, reduces cardiovascular risk factors, contributes to weight loss, and improves well-being (1,2). Regular exercise may prevent or delay type 2 diabetes development (3). Regular exercise also has considerable health benefits for people with type 1 diabetes (e.g., improved cardiovascular fitness, muscle strength, insulin sensitivity, etc.) (4). The challenges related to blood glucose management vary with diabetes type, activity type, and presence of diabetes-related complications (5,6). Physical activity and exercise recommendations, therefore, should be tailored to meet the specific needs of each individual. Physical activity recommendations and precautions may vary by diabetes type. The primary types of diabetes are type 1 and type 2. Type 1 diabetes (5%–10% of cases) results from cellular-mediated autoimmune destruction of the pancreatic β-cells, producing insulin deficiency (7). Although it can occur at any age, β-cell destruction rates vary, typically occurring more rapidly in youth than in adults. Type 2 diabetes (90%–95% of cases) results from a progressive loss of insulin secretion, usually also with insulin resistance. Gestational diabetes mellitus occurs during pregnancy, with screening typically occurring at 24–28 weeks of gestation in pregnant women not previously known to have diabetes. Prediabetes is diagnosed when blood glucose levels are above the normal range but not high enough to be classified as …

Adipogenic and lipolytic effects of chronic glucocorticoid exposure

Glucocorticoids have been proposed to be both adipogenic and lipolytic in action within adipose tissue, although it is unknown whether these actions can occur simultaneously. Here we investigate both the in vitro and in vivo effects of corticosterone (Cort) on adipose tissue metabolism. Cort increased 3T3-L1 preadipocyte differentiation in a concentration-dependent manner, but did not increase lipogenesis in adipocytes. Cort increased lipolysis within adipocytes in a concentration-dependent manner (maximum effect at 1-10 μM). Surprisingly, removal of Cort further increased lipolytic rates (∼320% above control, P < 0.05), indicating a residual effect on basal lipolysis. mRNA and protein expression of adipose triglyceride lipase and phosphorylated status of hormone sensitive lipase (Ser563/Ser660) were increased with 48 h of Cort treatment. To test these responses in vivo, Sprague-Dawley rats were subcutaneously implanted with wax pellets with/without Cort (300 mg). After 10 days, adipose depots were removed and cultured ex vivo. Both free fatty acids and glycerol concentrations were elevated in fed and fasting conditions in Cort-treated rats. Despite increased lipolysis, Cort rats had more visceral adiposity than sham rats (10.2 vs. 6.9 g/kg body wt, P < 0.05). Visceral adipocytes from Cort rats were smaller and more numerous than those in sham rats, suggesting that adipogenesis occurred through preadipocyte differentiation rather than adipocyte hypertrophy. Visceral, but not subcutaneous, adipocyte cultures from Cort-treated rats displayed a 1.5-fold increase in basal lipolytic rates compared with sham rats (P < 0.05). Taken together, our findings demonstrate that chronic glucocorticoid exposure stimulates both lipolysis and adipogenesis in visceral adipose tissue but favors adipogenesis primarily through preadipocyte differentiation.

Exercise in children and adolescents with diabetes

Kenneth Robertsona, Peter Adolfssonb, Gary Scheinerc, Ragnar Hanasd and Michael C Riddelle aRoyal Hospital for Sick Children, Yorkhill, Glasgow, Scotland; bThe Queen Silvia Children’s Hospital, Gothenburg, Sweden; eIntegrated Diabetes Services, Philadelphia, PA, USA; dDepartment of Pediatrics, Uddevalla Hospital, Uddevalla, Sweden; eSchool of Kinesiology and Health Science, Muscle Health Research Centre, Faculty of Health, York University, Toronto, Canada

Physical activity, sport, and pediatric diabetes

Abstract:  The benefits derived from regular physical activity include improved cardiovascular fitness, increased lean mass, improved blood lipid profile, enhanced psychosocial well‐being, and decreased body adiposity. The benefits for children with diabetes may also include blood glucose control and enhanced insulin sensitivity. However, for these children, engagement in vigorous physical activity and sport must be properly controlled through modifications in insulin therapy and nutritional intake so that the benefits of exercise outweigh the risks. The following review describes the various physiological and metabolic factors which occur both during exercise and during sport while describing specific recommendations to control glucose excursions by proper insulin management and diet.

Adiponectin is expressed by skeletal muscle fibers and influences muscle phenotype and function

Adiponectin (Ad) is linked to various disease states and mediates antidiabetic and anti-inflammatory effects. While it was originally thought that Ad expression was limited to adipocytes, we demonstrate here that Ad is expressed in mouse skeletal muscles and within differentiated L6 myotubes, as assessed by RT-PCR, Western blot, and immunohistochemical analyses. Serial muscle sections stained for fiber type, lipid content, and Ad revealed that muscle fibers with elevated intramyocellular Ad expression were consistently type IIA and IID fibers with detectably higher intramyocellular lipid (IMCL) content. To determine the effect of Ad on muscle phenotype and function, we used an Ad-null [knockout (KO)] mouse model. Body mass increased significantly in 24-wk-old KO mice [+5.5 +/- 3% relative to wild-type mice (WT)], with no change in muscle mass observed. IMCL content was significantly increased (+75.1 +/- 25%), whereas epididymal fat mass, although elevated, was not different in the KO mice compared with WT (+35.1 +/- 23%; P = 0.16). Fiber-type composition was unaltered, although type IIB fiber area was increased in KO mice (+25.5 +/- 6%). In situ muscle stimulation revealed lower peak tetanic forces in KO mice relative to WT (-47.5 +/- 6%), with no change in low-frequency fatigue rates. These data demonstrate that the absence of Ad expression causes contractile dysfunction and phenotypical changes in skeletal muscle. Furthermore, we demonstrate that Ad is expressed in skeletal muscle and that its intramyocellular localization is associated with elevated IMCL, particularly in type IIA/D fibers.

Type 1 Diabetes and Vigorous Exercise: Applications of Exercise Physiology to Patient Management

Special considerations are needed for the physically active individual with type 1 diabetes mellitus. Although regular activity is beneficial for all patients, vigorous exercise can cause major disturbances in blood glucose.The glycemic response depends largely on the type, intensity and duration of the activity, as well as the circulating insulin and glucose counterregulatory hormone concentrations. This review highlights a number of strategies to optimize blood glucose levels in patients with type 1 diabetes who exercise vigorously.

Physical Activity and Diabetes

• Moderate to high levels of physical activity and cardiorespiratory fitness are associated with substantially lower morbidity and mortality in people with diabetes. • Both aerobic and resistance exercise are beneficial, and it is optimal to do both types of exercise. At least 150 minutes per week of aerobic exercise and at least 2 sessions per week of resistance exercise are recommended, though smaller amounts of activity still provide some health benefits. • A number of strategies that increase self-efficacy and motivation can be employed to increase physical activity uptake and maintenance, such as setting specific physical activity goals, using self-monitoring tools (pedometers or accelerometers) and developing strategies to overcome anticipated barriers. • For people with type 2 diabetes, supervised exercise programs have been particularly effective in improving glycemic control, reducing the need for noninsulin antihyperglycemic agents and insulin, and producing modest but sustained weight loss. • Habitual, prolonged sitting is associated with increased risk of death and major cardiovascular events.

Physical activity, exercise and diabetes.

During physical activity, whole-body oxygen consumption may increase by as much as 20-fold, and even greater increases may occur in the working muscles. To meet its energy needs under these circumstances, skeletal muscle uses, at a greatly increased rate, its own stores of glycogen and triglycerides, as well as free fatty acids (FFAs) derived from the breakdown of adipose tissue triglycerides and glucose released from the liver. To preserve central nervous system function, blood glucose levels are remarkably well maintained during physical activity. Hypoglycemia during physical activity rarely occurs in nondiabetic individuals. The metabolic adjustments that preserve normoglycemia during physical activity are in large part hormonally mediated. A decrease in plasma insulin and the presence of glucagon appear to be necessary for the early increase in hepatic glucose production during physical activity, and during prolonged exercise, increases in plasma glucagon and catecholamines appear to play a key role. These hormonal adaptations are essentially lost in insulin-deficient patients with type 1 diabetes. As a consequence, when such individuals have too little insulin in their circulation due to inadequate therapy, an excessive release of counterinsulin hormones during physical activity may increase already high levels of glucose and ketone bodies and can even precipitate diabetic ketoacidosis. Conversely, the presence of high levels of insulin, due to exogenous insulin administration, can attenuate or even prevent the increased mobilization of glucose and other substrates induced by physical activity, and hypoglycemia may ensue. Similar concerns exist in patients with type 2 diabetes on insulin or sulfonylurea therapy; however, in general, hypoglycemia during physical activity tends to be less of a problem in this population. Indeed, in patients with type 2 diabetes, physical activity may improve insulin sensitivity and assist in diminishing elevated blood glucose levels into the normal range. The purpose of this position statement is to update and crystallize current thinking on the role of physical activity in patients with types 1 and 2 diabetes. With the publication of new clinical reviews, it is becoming increasingly clear that physical activity may be a therapeutic tool in a variety of patients with, or at risk for diabetes, but that like any therapy its effects must be thoroughly understood (1–3). From a practical point of view, this means that the diabetes health care team will be required to understand how to analyze the risks and benefits of physical activity in a given patient. Furthermore, the team, consisting of but not limited to the physician, nurse, dietitian, mental health professional, and patient, will benefit from working with an individual with knowledge and training in exercise physiology. Finally, it has also become clear that it will be the role of this team to educate primary care physicians and others involved in the care of a given patient.

Effects of Performing Resistance Exercise Before Versus After Aerobic Exercise on Glycemia in Type 1 Diabetes

OBJECTIVE To determine the effects of exercise order on acute glycemic responses in individuals with type 1 diabetes performing both aerobic and resistance exercise in the same session. RESEARCH DESIGN AND METHODS Twelve physically active individuals with type 1 diabetes (HbA1c 7.1 ± 1.0%) performed aerobic exercise (45 min of running at 60% V̇o2peak) before 45 min of resistance training (three sets of eight, seven different exercises) (AR) or performed the resistance exercise before aerobic exercise (RA). Plasma glucose was measured during exercise and for 60 min after exercise. Interstitial glucose was measured by continuous glucose monitoring 24 h before, during, and 24 h after exercise. RESULTS Significant declines in blood glucose levels were seen in AR but not in RA throughout the first exercise modality, resulting in higher glucose levels in RA (AR = 5.5 ± 0.7, RA = 9.2 ± 1.2 mmol/L, P = 0.006 after 45 min of exercise). Glucose subsequently decreased in RA and increased in AR over the course of the second 45-min exercise bout, resulting in levels that were not significantly different by the end of exercise (AR = 7.5 ± 0.8, RA = 6.9 ± 1.0 mmol/L, P = 0.436). Although there were no differences in frequency of postexercise hypoglycemia, the duration (105 vs. 48 min) and severity (area under the curve 112 vs. 59 units ⋅ min) of hypoglycemia were nonsignificantly greater after AR compared with RA. CONCLUSIONS Performing resistance exercise before aerobic exercise improves glycemic stability throughout exercise and reduces the duration and severity of postexercise hypoglycemia for individuals with type 1 diabetes.