Novel aspects of insulin resistance: focus on the brain. Studies using positron emission tomography

We are currently facing a global epidemic of obesity, which poses a great challenge for the global health. Insulin resistance is the common soil that links obesity and type 2 diabetes. Whereas most lifestyle interventions fail, bariatric surgery has been a powerful weapon in the battle against obesity. Preclinical data have shown that the brain may directly control the determinants of glucose tolerance, namely insulin sensitivity and insulin secretion. We used positron emission tomography, to study whether brain metabolism assessed as brain glucose and/or brain fatty acid uptake is related to the endogenous glucose production (EGP), and ß-cell function. Moreover, we addressed whether there are differences in brain fatty acid uptake between morbidly obese and lean individuals as well as the effect of significant weight loss induced by bariatric surgery. Finally, we investigated whether brain substrate handling predicted any metabolic outcome at follow-up. We found that in morbidly obese subjects brain glucose uptake (BGU) correlated positively with EGP, and that this association remained significant also six months after surgery. On the contrary, there was no such association in the lean subjects. In 52 non-diabetic subjects to whom ß-cell modeling was performed, insulin-stimulated BGU correlated also with the basal insulin secretion, total insulin output and potentiation of glucose-stimulated insulin secretion. Contrastingly, in 15 patients with type 2 diabetes BGU and insulin secretion did not correlate, but there was a significant inverse correlation between BGU and potentiation. Cross-sectionally in 34 studied women, brain fatty acid uptake (BFAU) also correlated negatively with potentiation, and similar trends were seen both in non-diabetics and diabetics. Finally, we found that, unlike in lean individuals, BFAU is increased in morbidly obese subjects, and that six months after bariatric surgery, BFAU remained unchanged. Baseline BGU and baseline BFAU predicted worse glucose control at two-year follow-up after bariatric surgery. In conclusion, this thesis work shows that brain substrate handling differs in obese and lean individuals and that brain metabolism may be a direct way of controlling whole-body homeostasis in humans. Moreover, in two different datasets, increased brain substrate uptake at baseline predicted worse metabolic outcome after bariatric surgery

Hepatic Positron Emission Tomography: Applications in Metabolism, Haemodynamics and Cancer

Evaluating in vivo the metabolic rates of the human liver has been a challenge due to its unique perfusion system. Positron emission tomography (PET) represents the current gold standard for assessing non-invasively tissue metabolic rates in vivo. Here, we review the existing literature on the assessment of hepatic metabolism, haemodynamics and cancer with PET. The tracer mainly used in metabolic studies has been [F-18]2-fluoro-2-deoxy-D-glucose (F-18-FDG). Its application not only enables the evaluation of hepatic glucose uptake in a variety of metabolic conditions and interventions, but based on the kinetics of F-18-FDG, endogenous glucose production can also be assessed. 14(R,S)-[F-18]fluoro-6-thia-Heptadecanoic acid (F-18-FTHA), C-11-Palmitate and C-11-Acetate have also been applied for the assessment of hepatic fatty acid uptake rates (F-18-FTHA and C-11-Palmitate) and blood flow and oxidation (C-11-Acetate). Oxygen-15 labelled water (O-15-H2O) has been used for the quantification of hepatic perfusion. F-18-FDG is also the most common tracer used for hepatic cancer diagnostics, whereas C-11-Acetate has also shown some promising applications in imaging liver malignancies. The modelling approaches used to analyse PET data and also the challenges in utilizing PET in the assessment of hepatic metabolism are presented

Pleiotropic Effects of Secretin: A Potential Drug Candidate in the Treatment of Obesity?

Secretin is the first hormone that has been discovered, inaugurating the era and the field of endocrinology. Despite the initial focus, the interest in its actions faded away over the decades. However, there is mounting evidence regarding the pleiotropic beneficial effects of secretin on whole-body homeostasis. In this review, we discuss the evidence from preclinical and clinical studies based on which secretin may have a role in the treatment of obesity.</p

Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline-Does Insulin Have Anything to Do with It? A Narrative Review

Imaging brain glucose metabolism with fluorine-labelled fluorodeoxyglucose ([F-18]-FDG) positron emission tomography (PET) has long been utilized to aid the diagnosis of memory disorders, in particular in differentiating Alzheimer's disease (AD) from other neurological conditions causing cognitive decline. The interest for studying brain glucose metabolism in the context of metabolic disorders has arisen more recently. Obesity and type 2 diabetes-two diseases characterized by systemic insulin resistance-are associated with an increased risk for AD. Along with the well-defined patterns of fasting [F-18]-FDG-PET changes that occur in AD, recent evidence has shown alterations in fasting and insulin-stimulated brain glucose metabolism also in obesity and systemic insulin resistance. Thus, it is important to clarify whether changes in brain glucose metabolism are just an epiphenomenon of the pathophysiology of the metabolic and neurologic disorders, or a crucial determinant of their pathophysiologic cascade. In this review, we discuss the current knowledge regarding alterations in brain glucose metabolism, studied with [F-18]-FDG-PET from metabolic disorders to AD, with a special focus on how manipulation of insulin levels affects brain glucose metabolism in health and in systemic insulin resistance. A better understanding of alterations in brain glucose metabolism in health, obesity, and neurodegeneration, and the relationships between insulin resistance and central nervous system glucose metabolism may be an important step for the battle against metabolic and cognitive disorders

The Beneficial Effects of Bariatric-Surgery-Induced Weight Loss on Renal Function

Obesity represents an independent risk factor for the development of chronic kidney disease (CKD), leading to specific histopathological alterations, known as obesity-related glomerulopathy. Bariatric surgery is the most effective means of inducing and maintaining sustained weight loss. Furthermore, in the context of bariatric-surgery-induced weight loss, a reduction in the proinflammatory state and an improvement in the adipokine profile occur, which may also contribute to the improvement of renal function following bariatric surgery. However, the assessment of renal function in the context of obesity and following marked weight loss is difficult, since the formulas adopted to estimate glomerular function use biomarkers whose production is dependent on muscle mass (creatinine) or adipose tissue mass and inflammation (cystatin-c). Thus, following bariatric surgery, the extent to which reductions in plasma concentrations reflect the actual improvement in renal function is not clear. Despite this limitation, the available literature suggests that in patients with hyperfiltration at baseline, GFR is reduced following bariatric surgery, whereas GFR is increased in patients with decreased GFR at baseline. These findings are also confirmed in the few studies that have used measured rather than estimated GFR. Albuminuria is also decreased following bariatric surgery. Moreover, bariatric surgery seems superior in achieving the remission of albuminuria and early CKD than the best medical treatment. In this article, we discuss the pathophysiology of renal complications in obesity, review the mechanisms through which weight loss induces improvements in renal function, and provide an overview of the renal outcomes following bariatric surgery

Underlying Kidney Diseases and Complications for COVID-19: A Review

There is mounting evidence supporting that patients with kidney diseases are particularly vulnerable to coronavirus disease-2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The review was conducted to examine the risk and complications of COVID-19 among patients with confirmed cases of underlying kidney disease. A search of Google Scholar, PubMed and Science direct databases to August 2020 was conducted using search terms pertaining to kidney diseases, renal insufficiency, kidney injury, angiotensin receptors, hemodialysis, and kidney transplant. We briefly reviewed COVID-19 in the context of kidney diseases. A significant proportion of hospitalized patients for COVID-19 have acute kidney injury, which further deteriorates their prognosis. COVID-19 increases morbidity and mortality among people already diagnosed with kidney disorders and obesity due to multiple organ injury caused by the SARS-CoV-2. This review supports the need for clinicians to carefully manage and monitor all patients with renal disorders in order to minimize acute kidney injuries. Although some therapeutic drugs have been suggested by some studies, treatment should be administered cautiously not to worsen the condition of the kidney. Further studies are required to highlight the efficient management of patients with underlying kidney diseases, who are infected with SARS-CoV-2. With proactive systematic screening and triaging, close monitoring and prompt management of coexisting other infections, the COVID-19 disease burden among these patients could be reduced

The utilization of positron emission tomography in the evaluation of renal health and disease

Purpose: Positron emission tomography (PET) is a nuclear imaging technique that uses radiotracers to visualize metabolic processes of interest across different organs, to diagnose and manage diseases, and monitor therapeutic response. This systematic review aimed to characterize the value of PET for the assessment of renal metabolism and function in subjects with non-oncological metabolic disorders. Methods: This review was conducted and reported in accordance with the PRISMA statement. Research articles reporting “kidney” or “renal” metabolism evaluated with PET imaging between 1980 and 2021 were systematically searched in Medline/PubMed, Science Direct, and the Cochrane Library. Search results were exported and stored in RefWorks, the duplicates were removed, and eligible studies were identified, evaluated, and summarized. Results: Thirty reports met the inclusion criteria. The majority of the studies were prospective (73.33%, n = 22) in nature. The most utilized PET radiotracers were 15O-labeled radio water (H215O, n = 14) and 18F-fluorodeoxyglucose (18F-FDG, n = 8). Other radiotracers used in at least one study were 14(R,S)-(18)F-fluoro-6-thia-heptadecanoic acid (18F-FTHA), 18F-Sodium Fluoride (18F-NaF), 11C-acetate, 68-Gallium (68Ga), 13N-ammonia (13N-NH3), Rubidium-82 (82Rb), radiolabeled cationic ferritin (RadioCF), 11C‐para-aminobenzoic acid (11C-PABA), Gallium-68 pentixafor (68Ga-Pentixafor), 2-deoxy-2-F-fluoro-d-sorbitol (F-FDS) and 55Co-ethylene diamine tetra acetic acid (55Co-EDTA). Conclusion: PET imaging provides an effective modality for evaluating a range of metabolic functions including glucose and fatty acid uptake, oxygen consumption and renal perfusion. Multiple positron emitting radiolabeled racers can be used for renal imaging in clinical settings. PET imaging thus holds the potential to improve the diagnosis of renal disorders, and to monitor disease progression and treatment response