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Highlights Despite the common practice of switching patients from one medicine to another—to improve efficacy, safety, or tolerability—guidance on how to do so is uncommon. During this time of global shortage of glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) ± glucose‐dependent insulinotropic polypeptide (GIP) RA therapies, this research letter offers a quick clinical reference of rough equivalency between GLP‐1 ± GIP RA for A1c and body weight reduction in people with type 2 diabetes.

Stimulation of adipocyte β-adrenergic receptors (β-ARs) induces expression of uncoupling protein 1 (UCP1), promoting nonshivering thermogenesis. Association of β-ARs with a lysine-myristoylated form of A kinase-anchoring protein 12 (AKAP12, also known as gravin-α) is required for downstream signaling that culminates in UCP1 induction. Conversely, demyristoylation of gravin-α by histone deacetylase 11 (HDAC11) suppresses this pathway. Whether inhibition of HDAC11 in adipocytes is sufficient to drive UCP1 expression independently of β-ARs is not known. Here, we demonstrate that adipocyte-specific deletion of HDAC11 in mice leads to robust induction of UCP1 in adipose tissue (AT), resulting in increased body temperature. These effects are mimicked by treating mice in vivo or human AT ex vivo with an HDAC11-selective inhibitor, FT895. FT895 triggers biphasic, gravin-α myristoylation-dependent induction of UCP1 protein expression, with a noncanonical acute response that is posttranscriptional and independent of protein kinase A (PKA), and a delayed response requiring PKA activity and new Ucp1 mRNA synthesis. Remarkably, HDAC11 inhibition promotes UCP1 expression even in models of adipocyte catecholamine resistance where β-AR signaling is blocked. These findings define cell-autonomous, multimodal roles for HDAC11 as a suppressor of thermogenesis, and highlight the potential of inhibiting HDAC11 to therapeutically alter AT phenotype independently of β-AR stimulation.

Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Previously we showed that deficiency of coenzyme Q (CoQ) is necessary and sufficient for IR in adipocytes and skeletal muscle (Fazakerley et al., 2018). Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, CoQ deficiency, mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells result in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (mice, C57BL/6J) (under chow and high-fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial ceramide–CoQ–respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.

Smoking is the most common cause of preventable morbidity and mortality in the United States, in part because it is an independent risk factor for the development of insulin resistance and type 2 diabetes. However, mechanisms responsible for smoking-induced insulin resistance are unclear. In this study, we found smokers were less insulin sensitive compared with controls, which increased after either 1 or 2 weeks of smoking cessation. Improvements in insulin sensitivity after smoking cessation occurred with normalization of IRS-1ser636 phosphorylation. In muscle cell culture, nicotine exposure significantly increased IRS-1ser636 phosphorylation and decreased insulin sensitivity, recapitulating the phenotype of smoking-induced insulin resistance in humans. The two pathways known to stimulate IRS-1ser636 phosphorylation (p44/42 mitogen-activated protein kinase [MAPK] and mammalian target of rapamycin [mTOR]) were both stimulated by nicotine in culture. Inhibition of mTOR, but not p44/42 MAPK, during nicotine exposure prevented IRS-1ser636 phosphorylation and normalized insulin sensitivity. These data indicate nicotine induces insulin resistance in skeletal muscle by activating mTOR. Therapeutic agents designed to oppose skeletal muscle mTOR activation may prevent insulin resistance in humans who are unable to stop smoking or are chronically exposed to secondhand smoke.

Over-nutrition has fuelled the global epidemic of type 2 diabetes, but the role of individual macronutrients to the diabetogenic process is not well delineated. We aimed to examine the impact of dietary fatty acid intake on fasting and 2-hour plasma glucose concentrations, as well as tissue-specific insulin action governing each. Normoglycemic controls (n = 15), athletes (n = 14), and obese (n = 23), as well as people with prediabetes (n = 10) and type 2 diabetes (n = 11), were queried about their habitual diet using a Food Frequency Questionnaire. All subjects were screened by an oral glucose tolerance test (OGTT) and studied using the hyperinsulinemic/euglycemic clamp with infusion of 6,62H2-glucose. Multiple regression was performed to examine relationships between dietary fat intake and 1) fasting plasma glucose, 2) % suppression of endogenous glucose production, 3) 2-hour post-OGTT plasma glucose, and 4) skeletal muscle insulin sensitivity (glucose rate of disappearance (Rd) and non-oxidative glucose disposal (NOGD)). The %kcal from saturated fat (SFA) was positively associated with fasting (β = 0.303, P = 0.018) and 2-hour plasma glucose (β = 0.415, P<0.001), and negatively related to % suppression of hepatic glucose production (β = -0.245, P = 0.049), clamp Rd (β = -0.256, P = 0.001) and NOGD (β = -0.257, P = 0.001). The %kcal from trans fat was also negatively related to clamp Rd (β = -0.209, P = 0.008) and NOGD (β = -0.210, P = 0.008). In contrast, the %kcal from polyunsaturated fat (PUFA) was negatively associated with 2-hour glucose levels (β = -0.383, P = 0.001), and positively related to Rd (β = 0.253, P = 0.007) and NOGD (β = 0.246, P = 0.008). Dietary advice to prevent diabetes should consider the underlying pathophysiology of the prediabetic state.

Adipose tissue secretes an abundance of lipid and protein mediators, and this secretome is depot‐specific, with local and systemic effects on metabolic regulation. Intermuscular adipose tissue (IMAT) accumulates within the skeletal muscle compartment in obesity, and is associated with insulin resistance and metabolic disease. While the human IMAT secretome decreases insulin sensitivity in vitro, its composition is entirely unknown. The current study was conducted to investigate the composition of the human IMAT secretome, compared to that of the subcutaneous (SAT) and visceral adipose tissue (VAT) depots. IMAT, SAT, and VAT explants from individuals with obesity were used to generate conditioned media. Proteomics analysis of conditioned media was performed using multiplex proximity extension assays, and eicosanoid analysis using liquid chromatography–tandem mass spectrometry. Compared to SAT and/or VAT, IMAT secreted significantly more cytokines (IL2, IL5, IL10, IL13, IL27, FGF23, IFNγ and CSF1) and chemokines (MCP1, IL8, CCL11, CCL20, CCL25 and CCL27). Adipokines hepatocyte growth factor and resistin were secreted significantly more by IMAT than SAT or VAT. IMAT secreted significantly more eicosanoids (PGE2, TXB2, 5‐HETE, and 12‐HETE) compared to SAT and/or VAT. In the context of obesity, IMAT is a distinct adipose tissue with a highly immunogenic and inflammatory secretome, and given its proximity to skeletal muscle, may be critical to glucose regulation and insulin resistance. Intermuscular adipose tissue (IMAT) is interlaced within the muscle compartment and is negatively associated with the metabolic syndrome. This is the first report of the composition of the human IMAT secretome. In obesity, the IMAT secretome is highly immunogenic, secreting a distinct combination of cytokines, chemokines, adipokines and eicosanoids that are associated with insulin sensitivity. This study highlights the potential significance of crosstalk between IMAT and skeletal muscle in the development of type 2 diabetes.

Intermuscular adipose tissue (IMAT) is a distinct adipose depot described in early reports as a ‘fatty replacement’ or ‘muscle fat infiltration’ that was linked to ageing and neuromuscular disease. Later studies quantifying IMAT with modern in vivo imaging methods (computed tomography and magnetic resonance imaging) revealed that IMAT is proportionately higher in men and women with type 2 diabetes mellitus and the metabolic syndrome than in people without these conditions and is associated with insulin resistance and poor physical function with ageing. In parallel, agricultural research has provided extensive insight into the role of IMAT and other muscle lipids in muscle (that is, meat) quality. In addition, studies using rodent models have shown that IMAT is a bona fide white adipose tissue depot capable of robust triglyceride storage and turnover. Insight into the importance of IMAT in human biology has been limited by the dearth of studies on its biological properties, that is, the quality of IMAT. However, in the past few years, investigations have begun to determine that IMAT has molecular and metabolic features that distinguish it from other adipose tissue depots. These studies will be critical to further decipher the role of IMAT in health and disease and to better understand its potential as a therapeutic target.Understanding of intermuscular adipose tissue has expanded over the past few years. This Review discusses the specific role of intermuscular adipose tissue in metabolic diseases in humans and in animal models, with a particular emphasis on the quantity and biological properties of this unique adipose tissue.

Glucose sensing (eg. glucokinase activity) becomes impaired in the development of type 2 diabetes, the etiology of which is unclear. Estrogen can stimulate glucokinase activity, whereas the pervasive environmental pollutant bisphenol A (BPA) can inhibit estrogen action, hence we aimed to determine the effect of BPA on glucokinase activity directly. To evaluate a potential acute effect on hepatic glucokinase activity, BPA in water (n = 5) vs. water alone (n = 5) was administered at the EPA's purported \"safe dose\" (50 µg/kg) by gavage to lean 6-month old male C57BL/6 mice. Two hours later, animals were euthanized and hepatic glucokinase activity measured over glucose levels from 1-20 mmol/l in liver homogenate. To determine the effect of chronic BPA exposure on hepatic glucokinase activity, lean 6-month old male C57BL/6 mice were provided with water (n = 15) or water with 1.75 mM BPA (∼50 µg/kg/day; n = 14) for 2 weeks. Following the 2-week exposure, animals were euthanized and glucokinase activity measured as above. Hepatic glucokinase activity was signficantly suppressed after 2 hours in animals given an oral BPA bolus compared to those who received only water (p = 0.002-0.029 at glucose 5-20 mmol/l; overall treatment effect p<0.001). Exposure to BPA over 2 weeks also suppressed hepatic glucokinase activity in exposed vs. unexposed mice (overall treatment effect, p = 0.003). In both experiments, the Hill coefficient was higher and Vmax lower in mice treated with BPA. Both acute and chronic exposure to BPA significantly impair hepatic glucokinase activity and function. These findings identify a potential mechanism for how BPA may increase risk for diabetes.

Our objective was to interrogate mesenchymal stem cell (MSC) lipid metabolism and gestational exposures beyond maternal body mass that may contribute to child obesity risk. MSCs were cultured from term infants of mothers with obesity (n = 16) or normal weight (n = 15). In MSCs undergoing myogenesis in vitro, we used lipidomics to distinguish phenotypes by unbiased cluster analysis and lipid challenge (24-hour excess fatty acid [24hFA]). We measured MSC AMP-activated protein kinase (AMPK) activity and fatty acid oxidation (FAO), and a composite index of maternal glucose, insulin, triglycerides, free fatty acids, TNF-α, and high-density lipoprotein and total cholesterol in fasting blood from mid and late gestation (~17 and ~27 weeks, respectively). We measured child adiposity at birth (n = 29), 4-6 months (n = 29), and 4-6 years (n = 13). Three MSC clusters were distinguished by triacylglycerol (TAG) stores, with greatest TAGs in Cluster 2. All clusters increased acylcarnitines and TAGs with 24hFA, although Cluster 2 was more pronounced and corresponded to AMPK activation and FAO. Maternal metabolic markers predicted MSC clusters and child adiposity at 4-6 years (both highest in Cluster 3). Our data support the notion that MSC phenotypes are predicted by comprehensive maternal metabolic milieu exposures, independent of maternal BMI, and suggest utility as an at-birth predictor for child adiposity, although validation with larger longitudinal samples is warranted.

Endurance‐oriented exercise typically enhances insulin action in skeletal muscle; however, relatively little is known about the impact of resistance exercise. In the present study, insulin action was determined in primary human skeletal muscle stem cells (HSkMCs) isolated from habitual endurance and resistance exercisers and sedentary controls (N = 8–9/group). Insulin action was assessed by insulin‐stimulated glycogen synthesis and glucose oxidation using 14C‐labeled glucose and insulin signal transduction measured as phosphorylation of Akt (Ser473) and AS160 (Thr640). No differences were detected in basal and insulin‐stimulated glycogen synthesis, glucose oxidation, and insulin signal transduction between the endurance and resistance exercisers. When HSkMCs were challenged by a fatty‐acid treatment which induced insulin resistance, no differential protection was detected with either exercise training modality. When data from the habitual endurance and resistance exercise groups were combined (EX) and compared to sedentary controls, HSkMC from EX exhibited greater rates of insulin‐stimulated glycogen synthesis. However, Akt and AS160 phosphorylation were similar between EX and sedentary individuals. Exercise training provided no protection against fatty‐acid‐induced insulin resistance across any measure of insulin action. These data suggest that habitual exercise, including resistance training, improves insulin action in skeletal muscle but may not offer intrinsic protection against fatty‐acid‐induced insulin resistance.