Roeland J.W. Middelbeek

Brown adipose tissue regulates glucose homeostasis and insulin sensitivity

Brown adipose tissue (BAT) is known to function in the dissipation of chemical energy in response to cold or excess feeding, and also has the capacity to modulate energy balance. To test the hypothesis that BAT is fundamental to the regulation of glucose homeostasis, we transplanted BAT from male donor mice into the visceral cavity of age- and sex-matched recipient mice. By 8-12 weeks following transplantation, recipient mice had improved glucose tolerance, increased insulin sensitivity, lower body weight, decreased fat mass, and a complete reversal of high-fat diet-induced insulin resistance. Increasing the quantity of BAT transplanted into recipient mice further improved the metabolic effects of transplantation. BAT transplantation increased insulin-stimulated glucose uptake in vivo into endogenous BAT, white adipose tissue (WAT), and heart muscle but, surprisingly, not skeletal muscle. The improved metabolic profile was lost when the BAT used for transplantation was obtained from Il6-knockout mice, demonstrating that BAT-derived IL-6 is required for the profound effects of BAT transplantation on glucose homeostasis and insulin sensitivity. These findings reveal a previously under-appreciated role for BAT in glucose metabolism.

Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations

Regular physical activity and exercise training have long been known to cause adaptations to white adipose tissue (WAT), including decreases in cell size and lipid content and increases in mitochondrial proteins. In this article, we discuss recent studies that have investigated the effects of exercise training on mitochondrial function, the “beiging” of WAT, regulation of adipokines, metabolic effects of trained adipose tissue on systemic metabolism, and depot-specific responses to exercise training. The major WAT depots in the body are found in the visceral cavity (vWAT) and subcutaneously (scWAT). In rodent models, exercise training increases mitochondrial biogenesis and activity in both these adipose tissue depots. Exercise training also increases expression of the brown adipocyte marker uncoupling protein 1 (UCP1) in both adipose tissue depots, although these effects are much more pronounced in scWAT. Consistent with the increase in UCP1, exercise training increases the presence of brown-like adipocytes in scWAT, also known as browning or beiging. Training results in changes in the gene expression of thousands of scWAT genes and an altered adipokine profile in both scWAT and vWAT. Transplantation of trained scWAT in sedentary recipient mice results in striking improvements in skeletal muscle glucose uptake and whole-body metabolic homeostasis. Human and rodent exercise studies have indicated that exercise training can alter circulating adipokine concentration as well as adipokine expression in adipose tissue. Thus, the profound changes to WAT in response to exercise training may be part of the mechanism by which exercise improves whole-body metabolic health.

A Novel Role for Subcutaneous Adipose Tissue in Exercise-Induced Improvements in Glucose Homeostasis

Exercise training improves whole-body glucose homeostasis through effects largely attributed to adaptations in skeletal muscle; however, training also affects other tissues, including adipose tissue. To determine whether exercise-induced adaptations to adipose tissue contribute to training-induced improvements in glucose homeostasis, subcutaneous white adipose tissue (scWAT) from exercise-trained or sedentary donor mice was transplanted into the visceral cavity of sedentary recipients. Remarkably, 9 days post-transplantation, mice receiving scWAT from exercise-trained mice had improved glucose tolerance and enhanced insulin sensitivity compared with mice transplanted with scWAT from sedentary or sham-treated mice. Mice transplanted with scWAT from exercise-trained mice had increased insulin-stimulated glucose uptake in tibialis anterior and soleus muscles and brown adipose tissue, suggesting that the transplanted scWAT exerted endocrine effects. Furthermore, the deleterious effects of high-fat feeding on glucose tolerance and insulin sensitivity were completely reversed if high-fat–fed recipient mice were transplanted with scWAT from exercise-trained mice. In additional experiments, voluntary exercise training by wheel running for only 11 days resulted in profound changes in scWAT, including the increased expression of ∼1,550 genes involved in numerous cellular functions including metabolism. Exercise training causes adaptations to scWAT that elicit metabolic improvements in other tissues, demonstrating a previously unrecognized role for adipose tissue in the beneficial effects of exercise on systemic glucose homeostasis.

Insulin stimulation regulates AS160 and TBC1D1 phosphorylation sites in human skeletal muscle.

INTRODUCTION:Individuals with obesity and type 2 diabetes (T2D) are typically insulin resistant, exhibiting impaired skeletal muscle glucose uptake. Animal and cell culture experiments have shown that site-specific phosphorylation of the Rab-GTPase-activating proteins AS160 and TBC1D1 is critical for GLUT4 translocation facilitating glucose uptake, but their regulation in human skeletal muscle is not well understood.METHODS:Here, lean, obese and T2D subjects underwent a euglycemic-hyperinsulinemic clamp, and vastus lateralis muscle biopsies were obtained before, and at 30 and 180 min post insulin infusion.RESULTS:Obese and T2D subjects had higher body mass indexes and fasting insulin concentrations, and T2D subjects showed insulin resistance. Consistent with the clamp findings, T2D subjects had impaired insulin-stimulated phosphorylation of AS160 Thr642, a site previously shown to be important in glucose uptake in rodents. Interestingly, insulin-stimulated phosphorylation of TBC1D1 Thr590, a site shown to be regulated by insulin in rodents, was only increased in T2D subjects, although the functional significance of this difference is unknown.CONCLUSION:These data show that insulin differentially regulates AS160 and TBC1D1 phosphorylation in human skeletal muscle. Impaired insulin-stimulated glucose uptake in T2D subjects is accompanied by dysregulation of AS160 and TBC1D1 phosphorylation in skeletal muscle, suggesting that these proteins may regulate glucose uptake in humans.

Mechanisms of weight loss and improved metabolism following bariatric surgery

Bariatric surgery is increasingly recognized as one of the most effective interventions to help patients achieve significant and sustained weight loss, as well as improved metabolic and overall health. Unfortunately, the cellular and physiological mechanisms by which bariatric surgery achieves weight loss have not been fully elucidated, yet are critical to understanding the central role of the intestinal tract in whole‐body metabolism and to developing novel strategies for the treatment of obesity. In this review, we provide an overview of potential mechanisms contributing to weight loss, including effects on regulation of energy balance and both central and peripheral nervous system regulation of appetite and metabolism. Moreover, we highlight the importance of the gastrointestinal tract, including alterations in bile acid physiology, secretion of intestinally derived hormones, and the microbiome, as a potent mediator of improved metabolism in postbariatric patients.

Decreased insulin-stimulated brown adipose tissue glucose uptake after short-term exercise training in healthy middle aged men

To test the hypothesis that high‐intensity interval training (HIIT) and moderate‐intensity continuous training (MICT) improve brown adipose tissue (BAT) insulin sensitivity.

Gastric Bypass Surgery in Severely Obese Women With Type 1 Diabetes: Anthropometric and Cardiometabolic Effects at 1 and 5 Years Postsurgery

While the benefits of gastric bypass (GB) surgery in type 2 diabetes are well established, few studies have evaluated the long-term effects of GB in patients with type 1 diabetes (1,2), and these studies demonstrate conflicting effects on glycemic control. This is clinically important given the increasing prevalence of obesity in patients with type 1 diabetes (3). We studied 10 severely obese women with confirmed type 1 diabetes, as previously described (4), and evaluated outcomes prior to GB and at 1 and 5 years following surgery. Mean age at GB was 39.6 ± 8.4 years, mean duration of type 1 diabetes 24.6 ± 10.1 years, and mean age at diagnosis 16.0 ± 8.3 years. Six subjects used continuous subcutaneous insulin infusion. BMI decreased by 33% from baseline at 1 year postoperatively (from 43.5 ± 7.5 to 29.3 ± 5.4 kg/m2, P < 0.0001) but …

Diabetes, prediabetes, and glycemic control in the United States: challenges and opportunities.

Over the past several decades, U.S. obesity rates have increased dramatically. Today, more than one third of U.S. adults are obese (1). This increase has been attributed to many factors (most notably, dietary changes and lack of physical activity). A concomitant increase in type 2 diabetes parallels the increased incidence of obesity. Type 2 diabetes represents more than 90% of all diabetes cases and is associated with many complications, including neuropathy, retinopathy, nephropathy, and cardiovascular and cerebrovascular disease. The cost of diabetes and its complications was estimated to be

Concurrent Intrathyroidal Thyroid Cancer and Thyroid Cancer in Struma Ovarii: A Case Report and Literature Review

245 billion in 2012, representing approximately 9% of the health care costs in the United States (2). In this issue, Selvin and colleagues (3) examine the prevalence of diabetes and prediabetes as well as glycemic control in 43439 adults followed in NHANES (National Health and Nutrition Examination Survey) from 1988 to 1994 and 1999 to 2010, based on calibrated hemoglobin A1c (HbA1c) and fasting plasma glucose levels. Diabetes was either self-reported (previously diagnosed) or defined by a single HbA1c level of 6.5% or greater or a fasting plasma glucose level of 7.0 mmol/L or greater (126 mg/dL). During the study, the total prevalence of diabetes (diagnosed and undiagnosed) increased from 5.5% to 9.3%, corresponding to nearly 21 million U.S. adults. Although the prevalence of previously diagnosed diabetes increased, the percentage of persons with undiagnosed diabetes decreased to 11%. Similar increases were seen in the prevalence of prediabetes: Of interest, when defined by HbA1c levels (5.7% to 6.4%), the prediabetes prevalence increased from 5.8% to 12.4%; when based on fasting blood glucose levels (5.6 to 6.9 mmol/L [100 to 125 mg/dL]), the prevalence was significantly greater and increased from 25.2% to 28.7% (from 19881994 to 20052010). This difference may be related to the fact that a single measurement of HbA1c or glucose level was used for diagnostic purposes in the study and that the fasting glucose level is more variable than the HbA1c level. The increase in prevalence of diabetes and prediabetes was not equally distributed among all ethnicities and racial groups. A proportionally greater increase in diagnosed and undiagnosed diabetes was seen in non-Hispanic blacks and Mexican Americans. Selvin and colleagues also reviewed glycemic control in persons with diagnosed diabetes. Although the percentage of participants with an HbA1c level less than 7% increased from 50.9% to 58.8%, this improvement in persons achieving adequate glycemic control (based on national standards criteria) was not seen in minority groups. The overall observed improvements in glycemic control were probably related to increased use of medications, including combination therapy with insulin. Indeed, the number of patients not taking any antidiabetes medications decreased by nearly 50%. What can we learn from these findings? Similar to the increased rates of obesity seen in the U.S. population over the past decades, the NHANES data confirm a similar trend for diabetes and prediabetes. The decrease in the percentage of persons with undiagnosed diabetes suggests an increased awareness of the problem and easier methods of diagnosing diabetes. Indeed, the American Diabetes Associations decision in 2010 to include HbA1c levels of 6.5% or greater in the diagnostic criteria has probably further facilitated easier and earlier diagnosis of diabetes (4). However, the use of the HbA1c level as a single diagnostic criterion may not diagnose as many patients with diabetes or prediabetes as the fasting plasma glucose level (5). Further, we need to be aware that, by definition, the diagnosis of diabetes or prediabetes should be made if the biochemical findings are confirmed on a second sample. There has been an improvement in overall glycemic control in persons with diabetes over the past 2 decades. The advent of several new pharmacologic treatment options for type 2 diabetes in the mid-2000s, increased awareness of the severity of diabetes, and easier diagnosis have all probably contributed to the increased use of medications, including the combination of insulin with other medications. However, nearly 40% of persons are not at the goal, and this percentage is greater in minority groups who have a greater prevalence of diabetes-related complications (6). Clinical inertia is still a problem (7). We need to identify methods to help those not at the goal (and in particular, minority groups). The alarming increase in obesity and diabetes rates not only shifts the focus on further improving diabetes treatment but underscores the ongoing need to prevent type 2 diabetes. This study shows an increase in average body mass index and HbA1c level in adults without diabetes or prediabetes, as compared with a healthy, younger subset. However, the clinical consequences of this increase remain to be determined. We know from the Diabetes Prevention Program that an intensive lifestyle change effectively prevents or delays the onset of diabetes (8). Public policy should focus on increasing physical activity and optimizing and improving access to healthy food choices for adults as well as children (9, 10). Although the Centers for Disease Control and Prevention is actively engaged in adapting the Diabetes Prevention Program model for the community, we need to ensure that adequate resources are allocated to target these issues at the individual, societal, and environmental levels. Indeed, the public and private sectors need to work closely together to tackle this immense problem. Such collaboration may be the only way to prevent further increases in the prevalence of obesity and diabetes in the next decades and reduce the human and health care costs associated with these conditions.

Erratum. Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations. Diabetes 2015;64:2361–2368

Context: The presence of differentiated thyroid cancer in mature cystic teratomas in the ovaries is rare, and usually incidentally found on surgical pathology specimens. We present a case of simultaneous intrathyroidal thyroid cancer and thyroid cancer within a struma ovarii, presenting specific diagnostic challenges. Case Description: A 55-year-old woman had an intrathyroidal, encapsulated 1.2-cm papillary thyroid carcinoma, follicular variant, which was resected. Laboratory studies showed an elevated thyroglobulin level of 35 ng/mL while on suppressive levothyroxine therapy. During preparation for radioactive iodine ablation, thyroglobulin increased dramatically to 3490 ng/mL. A pretreatment whole-body scan showed residual tracer uptake in the thyroid bed and increased radiotracer uptake in the pelvis that raised concern for a pelvic metastasis, given the marked thyroglobulin elevation. After ablation, the posttreatment scan showed intense focal uptake in the pelvis. Single-photon emission computed tomography–computed tomography confirmed that the tracer uptake corresponded to a right adnexal mass. The patient underwent a laparoscopic bilateral salpingo-oophorecotomy with pelvic washings. The final pathology of the right ovary showed papillary thyroid carcinoma arising in a mature cystic teratoma. In addition, there was abundant normal thyroid tissue with colloid surrounding the carcinoma, indicating a source for the dramatic rise in thyroglobulin levels and suggesting that the ovarian papillary thyroid cancer arose within the teratoma and was not metastatic disease. Thyroglobulin measurements have been undetectable for 5 years since surgery and radioiodine treatment. Conclusions: Concurrent intrathyroidal thyroid cancer and differentiated thyroid cancer in struma ovarii are very rare, but can often be distinguished on clinical grounds.