Nature Reviews Endocrinology最新文献

Insulin resistance is a key component of the pathogenesis and progression of obesity-associated type 2 diabetes mellitus (T2DM). The insulin receptor is expressed in endothelial cells and insulin acts on blood vessels to increase blood flow to metabolic tissues. Endothelial insulin resistance was already known to be reduced in people with T2DM compared with healthy individuals, but the mechanisms of this insulin resistance and its contribution to T2DM development were unclear. Now, a paper in Science has determined that the peptide hormone adrenomedullin has a role in inducing vascular insulin resistance in the context of obesity.

Adrenomedullin was found to inhibit insulin signalling, thereby preventing insulin-induced eNOS phosphorylation, a process that leads to vasodilation. Under healthy conditions, this vasodilation increases blood perfusion of metabolic tissues such as the skeletal muscle, adipose tissue and liver, enabling increased delivery of oxygen and nutrients. Inhibition of insulin signalling was mediated by the G protein subunit Gα_s and protein kinase A (PKA), which increased activity of PTP1B, a key regulator of insulin sensitivity, via insulin receptor dephosphorylation. Knockout of adrenomedullin, knockdown of Gα_s or chemical inhibition of PKA all led to increased insulin receptor phosphorylation and subsequent increased insulin signalling.

Interorgan communication between bone and skeletal muscle is central to human health. A dysregulation of bone–muscle crosstalk is implicated in several age-related diseases. Ageing-associated changes in endocrine, inflammatory, nutritional and biomechanical stimuli can influence the differentiation capacity, function and survival of mesenchymal stem cells and bone-forming and muscle-forming cells. Consequently, the secretome phenotype of bone and muscle cells is altered, leading to impaired crosstalk and, ultimately, catabolism of both tissues. Adipose tissue acts as a third player in the bone–muscle interaction by secreting factors that affect bone and muscle cells. Physical exercise remains the key biological stimulus for bone–muscle crosstalk, either directly via the release of cytokines from bone, muscle or adipocytes, or indirectly through extracellular vesicles. Overall, bone–muscle crosstalk is considered an inherent process necessary to maintain the structure and function of both tissues across the life cycle. This Review summarizes the latest biomedical advances in bone–muscle crosstalk as it pertains to human ageing and disease. We also outline future research priorities to accommodate the understanding of this rapidly emerging field.

Type 2 diabetes mellitus (T2DM) is associated with retinopathy, which can cause vision loss. A new study suggests that damage to the intestinal lining caused by neutrophil extracellular traps (NETs) might promote retinopathy in people with T2DM by releasing antigens from the gut into the blood and causing systemic inflammation.

The researchers then investigated whether inhibiting NETosis (NET release) could reduce intestinal injury and retinal damage in db/db mice, which are genetically engineered to have T2DM. The team pharmacologically inhibited NETosis in one group of these mice and gave a control group saline alone as a vehicle control. Next, the scientists administered fluorescent dextran to the mice via oral gavage, then measured how much leaked from the small intestine into the plasma. Transgenic mice that had received the NETosis inhibitor showed considerably lower intestinal permeability than control mice. There was also slightly less retinal damage in the mice that had been treated with the inhibitor than in the control mice.

Tumour cells are well known to have an altered metabolic profile and are more able to obtain and metabolize nutrients than surrounding cells. Several existing cancer therapies target tumour metabolism. A new study in Nature Biotechnology reports the development of a cell-based therapy using engineered adipocytes to reduce tumour cell growth by altering tumour metabolism.

The researchers used CRISPR activation to upregulate UCP1, PPARGC1A or PRDM16 in adipocytes, leading to browning and increased glucose and lipid metabolism. These engineered adipocytes were then co-cultured with breast, pancreatic, colon or prostate cancer cell lines, which suppressed cancer cell proliferation and resulted in decreased glucose uptake, glycolysis and fatty acid oxidation in the cancer cells.

In people with diabetes mellitus, the heart is metabolically characterized by the excessive use of fatty acids and diminished oxidation of glucose. These changes are implicated in decreased cardiac efficiency, vulnerability to ischaemic insults and an increased risk of heart failure. Interestingly, these alterations have been observed even in the absence of any impairments in cardiac insulin signalling, which suggests a role for direct substrate competition — a concept that was first described by Philip Randle and colleagues in a 1963 Lancet paper. The principle of reciprocal substrate competition between fatty acids and glucose for ATP generation laid out in this landmark publication formed the basis for our present understanding of cardiac metabolism in physiology and in response to metabolic stress.

Randle et al. showed that provision of exogenous fatty acids to isolated heart and diaphragm preparations or the presence of increased circulating levels of nonesterified fatty acids following adipose tissue lipolysis promotes fatty acid oxidation (FAO) and inhibits glucose utilization independent of hormonal control. The authors proposed that inhibition of pyruvate dehydrogenase (PDH; the mitochondrial enzyme that catalyses the conversion of pyruvate to acetyl-CoA) by acetyl-CoA derived from FAO is the primary mechanism by which fatty acids inhibit glucose utilization. By contrast, when glucose is abundant, utilization of glucose in adipose tissue inhibits lipolysis and the release of nonesterified fatty acids, which results in reduced fatty acid utilization by oxidative tissues and hence completes a ‘glucose–fatty acid cycle’ (now better known as the Randle cycle).

In rodents, the endocrine pancreas consists of islets of Langerhans scattered throughout the exocrine acinar tissue and accounts for a minor fraction of the organ’s total volume. This anatomical configuration, combined with the small size of the islets and the fact that they are embedded within enzyme-rich exocrine tissue, has historically made isolating intact and functional islets a considerable challenge, particularly for metabolic studies that require pure islet tissue.

Early efforts in the 1960s used free-hand microdissection to isolate small numbers of islets from rodent pancreas tissue and primarily targeted hypertrophic islets in obese rodents, in which surface islets are fairly accessible. Another method involved inducing pancreatic atrophy by ligating one of the main pancreatic ducts to facilitate islet dissection. However, these techniques were associated with notable pathological conditions, such as spontaneous hyperglycaemia in animals with hypertrophic islets and fibrosis or atrophy of the pancreas following duct ligation. Although these techniques provided foundational insights, their limited scalability and the pathological states associated with them highlighted the need for more advanced methods to reliably isolate intact islets.

Depression is linked to an altered stress response, as measured by elevated levels of cortisol and systemic inflammation. Many individuals become resistant to pharmacological treatments; however, non-pharmacological treatments, such as increased physical activity and exercise training, can reduce symptoms of depression in some patients. A decade ago, a key paper helped to define the mechanisms that underlie the effect of non-pharmacological treatments.

In a study published in 2014, Agudelo and colleagues sought to elucidate how stress, inflammation and depression were linked to the therapeutic benefits of exercise on symptoms of depression. The authors focused on tryptophan degradation via the kynurenine pathway, given the sensitivity of the first rate-limiting enzymes (tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase) to cortisol and inflammatory cytokines. At the time, kynurenine (a neurotoxic metabolite) and kynurenic acid (a neuroprotective metabolite) were the only kynurenine-pathway metabolites that had been implicated in mental health disorders, including depression. Kynurenine, but not kynurenic acid, can readily cross the blood–brain barrier. Thus, most kynurenine found in the brain comes from the peripheral circulation.