In This Issue of Diabetes


By Max Bingham, PhD

Success With In Vivo Imaging of β-Cell Mass

The search for a noninvasive method to characterize β-cell mass continues with Eriksson et al. (p. 182) reporting an investigation into a radio-labeled small molecule GPR44 antagonist called [11C]AZ12204657 to visualize β-cells in vivo via positron electron tomography (PET). The authors say that taken together their data suggest the molecule is likely specific for GPR44 in pancreatic β-cells and as a result can be used as an imaging biomarker of β-cell mass in vivo. The study, which includes experiments in pigs, nonhuman primates, rodents, and in vitro cell cultures, uses the premise that the transmembrane G-protein–coupled GPR44 is highly restricted to β-cells in the human pancreas and thus might be targetable with a labeled molecule that can act as beacon when bound to β-cells. Initially focusing on human and animal pancreas sections from subjects with and without diabetes, they report that [11C]AZ12204657 did bind selectively to islets when assessed via autoradiography and insulin staining. Furthermore, in immunodeficient mice with transplanted human islets, the molecule also reportedly bound successfully and was detectable. They go on to show the molecule binding to islets from pancreas sections from both humans and pigs without diabetes specifically via a GPR44-mediated pathway. However, no binding took place in equivalent sections from donors with type 1 diabetes. Further in vivo experiments with nondiabetic pigs and nonhuman primates reportedly proved the molecule could bind specifically to GPR44 in pancreas. Dose-escalation studies designed to compete away the radio-labeled version of the molecule further demonstrated the specificity of the molecule. Author Olof Eriksson told Diabetes: “GPR44 targeting by PET imaging potentially offers highly selective measurement of β-cell mass in health and during progression of diabetes. High precision biomarkers of pancreatic β-cell mass, such as our new method, are urgently needed in development of the next generation of antidiabetic drugs.”

Representative parametric images of GPR44 imaging in pigs (color coded for VT) following [11C]AZ12204657 injection at baseline (A), at escalating mass doses (B and C), or following pretreatment by 5 mg/kg AZ8154 (D). The pancreas segmentation is indicated by a solid purple line in the yellow crosshairs.

Eriksson et al. In vivo visualization of β-cells by targeting of GPR44. Diabetes 2018;67:182–192

Glucocorticoids in Feedback Loop to Maintain Insulin Secretion in β-Cells

The role of endogenous glucocorticoids in the regulation of β-cell function is reported in the study by Fine et al. (p. 278), where they reveal that an enzyme-assisted, steroid-regulated feedback loop likely maintains normal insulin secretory output. The authors say that failure of the mechanism potentially contributes to diabetes in situations of glucocorticoid excess (e.g., Cushing syndrome), likely driving profound glucose intolerance and insulin resistance. Although it was known that systemic administration of glucocorticoids can induce failure in insulin secretion, the authors say that the role of glucocorticoids at physiological levels, particularly with respect to insulin secretion and signaling, is less well understood; hence, the investigation. They report that corticosterone and cortisol, along with two other less active glucocorticoids, appear to suppress Ca2+ channel functioning in both mice and human β-cells but that this did not appear to upset insulin secretion, energy regulation, or their appearance. In parallel however, they did see an upregulation of cAMP, which is a signaling molecule involved in a number of cellular processes including the regulation of glucose. They say that the effects induced by 11-dehydrocorticosterone (11-DHC) could be prevented through the addition of palmitate via lipotoxicity and that deletion of 11β-hydroxysteroid dehydrogenase type 1 normalized Ca2+ channel function and the generation of cAMP. Author David J. Hodson said: “High levels of glucocorticoid are generally thought to disrupt β-cell function and insulin release, which, together with their effects on lipid levels and insulin resistance, contribute to type 2 diabetes. Our recent data show that, contrary to belief, naturally secreted glucocorticoids such as cortisol are in fact protective of β-cell function, and it is the interaction with lipids that likely lowers insulin secretion and predisposes to type 2 diabetes. We are thus able to provide an updated model for glucocorticoid action at the β-cell that can be potentially targeted to treat type 2 diabetes in individuals with Cushing syndrome or, alternatively, exploited to boost insulin release in individuals without the syndrome.”


Glucocorticoids suppress cytosolic Ca2+ fluxes in response to glucose and glucose + KCl. Representative maximum intensity projection images showing impaired Ca2+ signaling in glucose-stimulated islets treated with control, 200 nmol/L of 11-DHC, and corticosterone (scale bar = 20 μm) (images cropped to show a single islet).

Fine et al. Glucocorticoids reprogram β-cell signaling to preserve insulin secretion. Diabetes 2018;67:278–290

Loss-of-Function Variant in AKT2 Results in Reduced Glucose Uptake in Multiple Tissues

Carriers of a partial loss-of-function AKT2 coding variant called p.Pro50Thr have reduced insulin-mediated glucose uptake in multiple insulin-sensitive tissues. As a consequence, Latva-Rasku et al. (p. 334) say this likely explains, at least in part, why such individuals have an increased risk of type 2 diabetes. The conclusions come from a large cross-sectional study of Finnish men investigating, among other things, low-frequency or rare genetic risk variants for type 2 diabetes. Already identified as a risk factor, the loss-of-function p.Pro50Thr variant of AKT2 is reportedly specific to the Finnish population and present at a rate of 1.1% of the population. To investigate the effects of the presence of the variant, the authors identified 20 carriers and 25 matched noncarriers as control subjects and invited them back for a positron emission tomography (PET) investigation that used [18F]-fluorodeoxyglucose to track glucose uptake. The scan was performed during a hyperinsulinemic-euglycemic clamp procedure. According to the authors, they found that carriers of the variant had a 39.4% reduction in whole-body glucose uptake and a 55.6% increase in endogenous glucose production. There were also significant reductions in glucose uptake in multiple tissues, including skeletal muscle, bone marrow, brown adipose tissue, and liver (36.4%, 32.9%, 29.7%, and 16.1%, respectively). Conversely, there were reportedly increases in glucose uptake in seven different brain areas. The authors say that although the changes in glucose uptake may explain some of the increased risk of type 2 diabetes that carriers of the p.Pro50Thr variant have, the study also demonstrates the value of genotype-based callback approach and that PET can be used as a noninvasive method to characterize the function of genetic variants. Author Markku Laakso commented: “Studies on population isolates, including the Finnish population, offer an excellent opportunity to investigate the significance of rare gene variants not found in other populations and help to reveal new mechanisms for the pathophysiology of type 2 diabetes.”


Brain regions in the PET study where insulin-stimulated glucose uptake was measured in carriers and noncarriers of the p.P50T/AKT2 variant.

Latva-Rasku et al. A partial loss-of-function variant in AKT2 is associated with reduced insulin-mediated glucose uptake in multiple insulin-sensitive tissues: a genotype-based callback positron emission tomography study. Diabetes 2018;67:334–342

Genetic Influences on BMI Throughout Adulthood

A genetic predisposition toward adiposity and increasing BMI is apparently persistent throughout adult life, according to Song et al. (p. 248). As a result, the authors say that understanding the genetic components of weight gain and adiposity should provide critical insights into the origins of obesity and ultimately pinpoint the optimal time frame(s) for intervention to modify risk. The study focuses on just under 1,700 women and men who have been tracked over many years as part of either the Nurses’ Health Study (NHS) or the Health Professionals Follow-Up Study (HPFS). All individuals provided BMI measurements over many years and also early on provided a blood sample for genotyping. Then based on a series of 97 single nucleotide polymorphisms linked to BMI, the authors calculated a genetic risk score (GRS) and examined the relationship with BMI. The GRS was positively associated with BMI across all ages, with slightly stronger associations in women than men. Specifically, the associations increased from early to mid-adulthood, peaking at 45 years of age in men and 60 years of age in women. The authors go on to detail specific changes in weight associated with GRS at different stages of adult life and specifically point out that the menopause is likely to modify weight gain in women. An overall pattern emerges of much less of an association in later life. They say that further studies are needed to understand the mechanisms and, importantly, to understand how environmental factors modify the genetic effects. Author Mingyang Song said: “In this large longitudinal study, we addressed the knowledge gap in the genetic influences on BMI trajectory across adulthood. Our findings support the biological evidence about the persistent effects of genetic susceptibility on body fat accumulation and have implications for the development of tailored obesity prevention strategies that may target genetically high-risk individuals at their most sensitive period of life for weight gain.”

Song et al. Longitudinal analysis of genetic susceptibility and BMI throughout adult life. Diabetes 2018;67:248–255

Source link

Products You May Like

Articles You May Like

Chemotherapy and hair loss: What to expect during treatment
The Best Soup Makers For Quick, Healthy, Hassle-Free Soups
What is the Relationship between Alcohol Consumption and Obesity? – Medical News Bulletin
How a combination of exercise and music helps us feel less pain — ScienceDaily
New Technique Creates Images from Brain Activity of Perceptions

Leave a Reply

Your email address will not be published. Required fields are marked *