The prevalence of type 2 diabetes (T2D) varies among populations of different races/ethnicities. The influence of genetically proxied LDL cholesterol lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA reductase (HMGCR) on T2D in non-European populations is not well established. A drug target Mendelian randomization approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and Europe (EUR). Our study did not find relationships between genetically proxied PCSK9 inhibition and T2D risk in the EAS (odds ratio [OR] 1.02; 95% CI 0.95-1.10), SAS (1.05; 0.97-1.14), HISP (1.03; 0.94-1.12), or EUR population (1.04; 0.98-1.11). However, in the AFR population, primary analyses suggested an increased risk of T2D resulting from PCSK9 inhibition (OR 1.53; 95% CI 1.058-2.22; P = 0.024), although this was not supported in sensitivity analyses. Genetically proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR 1.44; 95% CI 1.30-1.61; P = 9.8 × 10-12), EAS (1.36; 1.22-1.51; P = 4.2 × 10-10), and EUR populations (1.52; 1.21-1.90; P = 3.3 × 10-4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-EUR populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in SAS, EAS, and EUR cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases.

The ventromedial hypothalamic nucleus (VMN) maintains healthy metabolic function through several important roles. Collectively, homeostasis is maintained via intermingled cells within the VMN that raise blood glucose, lower blood glucose, and stimulate energy expenditure when needed. In this article I discuss the defining factors for the VMN cell types that govern distinct functions induced by the VMN, particularly in relation to energy balance and blood glucose levels. Special attention is given to distinct features of VMN cells responsible for these processes. Finally, these topics are reviewed in the context of research funded by the American Diabetes Association Pathway to Stop Diabetes initiative, with highlighting of key findings and current unresolved questions for future investigations.

There is evidence that 1-h plasma glucose (PG) concentration during the 75-g oral glucose tolerance test (OGTT) is superior to 2-h PG level in predicting diabetes. We investigated the characteristics of insulin sensitivity and β-cell function behind this observation. After age, sex, and BMI matching, 496 study participants selected from 3,965 individuals without diabetes who were at high risk of type 2 diabetes in a tertiary medical center were categorized into four groups in a 1:1:1:1 ratio based on OGTT results: 1) 1-h PG level <8.6 mmol/L and 2-h PG level <7.8 mmol/L (normal glucose tolerance [NGT]/1h-normal); 2) 1-h PG level ≥8.6 mmol/L and 2-h level <7.8 mmol/L (NGT/1h-high); 3) 1-h PG level <8.6 mmol/L and 2-h level ≥7.8 mmol/L (impaired glucose tolerance [IGT]/1h-normal); and 4) 1 h PG level ≥8.6 mmol/L and 2-h level ≥7.8 mmol/L. Compared with participants with IGT/1h-normal, those with NGT/1h-high had a similar extent of insulin resistance but lower early-phase insulin secretion. Additionally, participants with NGT/1h-high had a lower disposition index at both 0-30 min and 0-120 min than those with IGT/1h-normal. The fitted regression line relating PG to log-transformed disposition index (0-30 min and 0-120 min) was significantly steeper for 1-h than 2-h PG. In conclusion, 1-h PG seemed to be more sensitive to the deterioration in β-cell function than was 2-h PG. The use of 1-h PG may identify individuals at high risk of type 2 diabetes at an earlier stage.

Early, intensive glycemic control in patients with type 2 diabetes (T2D) is associated with long-term benefits in cardiovascular disease (CVD) development. Evidence on benefits of achieving HbA1c targets close to normal values is scant. Individuals with newly diagnosed T2D, without CVD at baseline, were identified in an Italian clinical registry (n = 251,339). We adopted three definitions of early exposure periods (0-1, 0-2, and 0-3 years). Mean HbA1c was categorized into HbA1c <5.7%, 5.7-6.4%, 6.5-7.0%, 7.1-8.0%, and >8.0%. The outcome was the incidence of major cardiovascular events. After a mean follow-up of 4.6 ± 2.9 years, at multivariate Cox regression analysis, compared with mean HbA1c <5.7% during the first year after diagnosis, the increase in the risk of CVD was 24%, 42%, 49%, and 56% for patients with HbA1c of 5.7-6.4%, 6.5-7.0%, 7.1-8.0%, and >8.0%, respectively. The same trend was documented in all exposure periods. In conclusion, our data support that an early achievement of stringent targets of HbA1c <5.7% is worthy for CVD prevention.

Lesioned fascicles (LFs) in the sciatic nerves of individuals with diabetic neuropathy (DN) correlate with clinical symptom severity. This study aimed to characterize the structural and molecular composition of these lesions to better understand DN pathogenesis. Sciatic nerves from amputees with and without type 2 diabetes (T2D) were examined using ex vivo magnetic resonance neurography, in vitro imaging, and proteomic analysis. Lesions were only found in T2D donors and exhibited significant structural abnormalities, including axonal degeneration, demyelination, and impaired blood-nerve barrier (BNB). Although non-LFs from T2D donors showed activation of neuroprotective pathways, LFs lacked this response and instead displayed increased complement activation via the classical pathway. The detection of liver-derived acute-phase proteins suggests that BNB disruption facilitates harmful interorgan communication between the liver and nerves. These findings reveal key molecular mechanisms contributing to DN and highlight potential targets for therapeutic intervention.

Exploring the mechanisms underlying abnormal glycemic traits is important for deciphering type 2 diabetes and characterizing novel drug targets. This study aimed to decipher the causal associations of circulating proteins with fasting glucose (FG), 2-h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) using large-scale proteome-wide Mendelian randomization (MR) analyses. Genetic data on plasma proteomes were obtained from 10 proteomic genome-wide association studies. Both cis-protein quantitative trait loci (pQTLs) and cis + trans-pQTLs MR analyses were conducted. Bayesian colocalization, Steiger filtering analysis, assessment of protein-altering variants, and mapping expression QTLs to pQTLs were performed to investigate the reliability of the MR findings. Protein-protein interaction, pathway enrichment analysis, and evaluation of drug targets were performed. Thirty-three proteins were identified with causal effects on FG, FI, or HbA1c but not 2hGlu in the cis-pQTL analysis, and 93 proteins had causal effects on glycemic traits in the cis + trans-pQTLs analysis. Most proteins were either considered druggable or drug targets. In conclusion, many novel circulating protein biomarkers were identified to be causally associated with glycemic traits. These biomarkers enhance the understanding of molecular etiology and provide insights into the screening, monitoring, and treatment of diabetes.

There are key differences between the central nervous system (CNS) (brain and spinal cord) and peripheral nervous system (PNS), such as glial cell types, whether there is protection by the blood-brain barrier, modes of synaptic connections, etc. However, there are many more similarities between these two arms of the nervous system, including neuronal structure and function, neuroimmune and neurovascular interactions, and, perhaps most essentially, the balance between neural plasticity (including processes like neuron survival, neurite outgrowth, synapse formation, gliogenesis) and neurodegeneration (neuronal death, peripheral neuropathies like axonopathy and demyelination). This article brings together current research evidence on shared mechanisms of nervous system health and disease between the CNS and PNS, particularly with metabolic diseases like obesity and diabetes. This evidence supports the claim that the two arms of the nervous system are critically linked and that previously understudied conditions of central neurodegeneration or peripheral neurodegeneration may actually be manifesting across the entire nervous system at the same time, through shared genetic and cellular mechanisms. This topic has been critically underexplored due to the research silos between studies of the brain and studies of peripheral nerves and an overemphasis on the brain in neuroscience as a field of study. There are likely shared and linked mechanisms for how neurons stay healthy versus undergo damage and disease among this one nervous system in the body-providing new opportunities for understanding neurological disease etiology and future development of neuroprotective therapeutics.

The brain coordinates the homeostatic defense of multiple metabolic variables, including blood glucose levels, in the context of ever-changing external and internal environments. The biologically defended level of glycemia (BDLG) is the net result of brain modulation of insulin-dependent mechanisms in cooperation with the islet, and insulin-independent mechanisms through direct innervation and neuroendocrine control of glucose effector tissues. In this article, we highlight evidence from animal and human studies to develop a framework for the brain's core homeostatic functions-sensory/afferent, integration/processing, and motor/efferent-that contribute to the normal BDLG in health and its elevation in diabetes.

Increased arcuate proopiomelanocortin (POMC) neuron activity improves glucose metabolism and reduces appetite, facilitating weight loss. We recently showed that arcuate POMC neurons are activated by exercise. However, the role of excitatory glutamatergic input in these neurons and the metabolic outcomes of exercise remains undefined. To investigate this, we developed a mouse model with NMDA receptors (NMDARs) selectively deleted from POMC neurons of adult mice. We performed metabolic assessments, including the monitoring of body weight, body composition analysis, and glucometabolic tolerance tests. We also examined the metabolic outcomes of these mice in response to exercise, including changes in arcuate POMC neuronal activity and insulin sensitivity. Loss of NMDARs in POMC neurons failed to alter body weight or body composition. Notably, however, we did observe a marked impairment in glucose tolerance and insulin sensitivity. Additionally, exercise resulted in activation of arcuate POMC neurons and a sustained improvement in insulin sensitivity, an effect that was abrogated in mice deficient for NMDARs in POMC neurons when compared with their respective sedentary controls. This underscores an important link among exercise, hypothalamic neuron function, and metabolic health. Moreover, this highlights an underappreciated role of hypothalamic POMC neurons in mediating beneficial effects of exercise on glucose metabolism.

Translocational regulation of proinsulin biosynthesis in pancreatic β-cells is unknown, although several studies have reported an important accessory role for the Translocon-Associated Protein complex to assist preproinsulin delivery into the endoplasmic reticulum via the heterotrimeric Sec61 translocon (comprising α, β, and γ subunits). The actual protein-conducting channel is the α-subunit encoded either by Sec61A1 or its paralog Sec61A2. Although the underlying channel selectivity for preproinsulin translocation is unknown, almost all studies of Sec61α to date have focused on Sec61α1. There is currently no evidence to suggest that this gene product plays a major role in proinsulin production, whereas genome-wide association studies indicate linkage of Sec61A2 with diabetes. Here, we report that evolutionary differences in mouse preproinsulin signal peptides affect proinsulin biosynthesis. Moreover, we find that, although some preproinsulin translocation can proceed through Sec61α1, Sec61α2 has a greater impact on proinsulin biosynthesis in pancreatic β-cells. Remarkably, Sec61α2 translocon deficiency exerts a significant inhibitory effect on the biosynthesis of preproinsulin itself, including a disproportionate increase of full-length nascent chain unreleased from ribosomes. This study not only reveals novel translocational regulation of proinsulin biosynthesis but also provides a rationale for genetic evidence suggesting an important role of Sec61α2 in maintaining blood glucose homeostasis.

Excessive iron accumulation in metabolic organs such as the adipose tissue, liver, and skeletal muscle is associated with increased diabetes risk. Tissue-resident macrophages serve multiple roles, including managing inflammatory tone and regulating parenchymal iron homeostasis, thus protecting against metabolic dysfunction upon iron overload. The scavenger receptor CD163 is uniquely present on tissue-resident macrophages and plays a significant role in iron homeostasis by clearing extracellular hemoglobin-haptoglobin complexes, thereby limiting oxidative damage caused by free hemoglobin in metabolic tissues. We show that the absence of CD163 exacerbates glucose intolerance and insulin resistance in male mice with obesity. Additionally, loss of CD163 reduced the expression of iron regulatory genes (Tfr1, Cisd1, Slc40a1) in adipose tissue macrophages and anti-inflammatory (M2-like) bone marrow-derived macrophages (BMDMs). Furthermore, CD163 deficiency mediated a proinflammatory shift and limited hemoglobin scavenging specifically in M2-like BMDMs. To this end, iron buffering was diminished in inguinal white adipose tissue (iWAT) macrophages in vivo, which culminated in iron spillover into adipocytes and CD45+ CD11B- nonmyeloid immune cells in iWAT. These findings show that CD163 on tissue-resident macrophages is critical for their anti-inflammatory and hemoglobin scavenging roles, and its absence results in impaired systemic insulin action in an obese setting.

Pancreatic β-cells in the islets of Langerhans are key to maintaining glucose homeostasis by secreting the peptide hormone insulin. Insulin is packaged within vesicles named insulin secretory granules (ISGs), which recently have been considered to have intrinsic structures and proteins that regulate insulin granule maturation, trafficking, and secretion. Previously, studies have identified a handful of novel ISG-associated proteins, using different separation techniques. The present study combines an optimized ISG isolation technique and mass spectrometry-based proteomics, with an unbiased protein correlation profiling and targeted machine-learning approach to uncover 211 ISG-associated proteins with confidence. Four of these proteins, syntaxin-7, synaptophysin, synaptotagmin-13, and Scamp3 have not been previously associated with ISG. Through colocalization analysis of confocal imaging, we validate the association of these proteins to the ISG in MIN6 and human β-cells. We further validate the role for one (Scamp3) in regulating insulin content and secretion from β-cells for the first time. Scamp3 knockdown INS-1 cells have reduced insulin content and dysfunctional insulin secretion. These data provide the basis for future investigation of Scamp3 in β-cell biology and the regulation of insulin secretion.

The prevalence of type 2 diabetes (T2D) poses a significant health challenge, yet the contribution of air pollutants to T2D epidemics remains under-studied. Several studies demonstrated a correlation between exposure to volatile organic compounds (VOCs) in indoor/outdoor environments and T2D. Here, we conducted the first meta-analysis, establishing a robust association between exposure to benzene, a prevalent airborne VOC, and insulin resistance in humans across all ages. We used a controlled benzene exposure system, continuous glucose monitoring approach, and indirect calorimetry in mice, to investigate the underlying mechanisms. Following exposure, disruptions in energy homeostasis, accompanied by modifications in the hypothalamic transcriptome and alterations in insulin and immune signaling, were observed exclusively in males, leading to a surge in blood glucose levels. In agreement, RNA sequencing of microglia revealed increased expression of genes associated with immune response and NF-κB signaling. Selective ablation of IKKβ in immune cells (Cx3cr1GFPΔIKK) or exclusively in microglia (Tmem119ERΔIKK) in adult mice alleviated benzene-induced gliosis, restored energy homeostasis and hypothalamic gene expression, and protected against hyperglycemia. We conclude that the microglial NF-κB pathway plays a critical role in chemical-induced metabolic disturbances, revealing a vital pathophysiological mechanism linking exposure to airborne toxicants and the onset of metabolic diseases.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and effective treatment modalities that fully address its molecular etiology are lacking. Prior studies support that the stress response protein REDD1 (regulated in development and DNA damage 1) contributes to the development of diabetes complications. This study investigated a potential role for REDD1 expression in podocytes in diabetes-induced podocyte loss and compromised glomerular filtration. Podocyte-specific REDD1 deletion protected against renal injury, as evidenced by reduced albuminuria, glomerular hypertrophy, and mesangial matrix deposition in streptozotocin (STZ)-induced diabetic mice. Podocyte-specific REDD1 expression was required for diabetes-induced reduction in slit diaphragm (SD) proteins podocin and nephrin. Notably, podocyte-specific REDD1 deletion protected against podocytopenia and preserved glomerular basement membrane and foot process architecture in diabetic mice. In the kidneys of diabetic mice and in human podocyte cultures exposed to hyperglycemic conditions, REDD1 was necessary for increased expression of the transient receptor potential canonical 6 (TRPC6) channel. More specifically, REDD1 promoted nuclear factor-κB-dependent transcription of TRPC6, intracellular calcium entry, and cytoskeletal remodeling under hyperglycemic conditions. Overall, the findings provide new insight into the role of podocyte-specific REDD1 expression in renal pathology and support the possibility that therapeutics targeting REDD1 in podocytes could be beneficial for DN.

Hypothalamic innate immune responses to dietary fats underpin the pathogenesis of obesity, in which microglia play a critical role. Progranulin (PGRN) is an evolutionarily conserved secretory protein containing seven and a half granulin (GRN) motifs. It is cleaved into GRNs by multiple proteases. In the central nervous system, PGRN is highly expressed in microglia. To investigate the role of microglia-derived PGRN in metabolism regulation, we established a mouse model with a microglia-specific deletion of the Grn gene, which encodes PGRN. Mice with microglia-specific Grn depletion displayed diet-dependent metabolic phenotypes. Under normal diet-fed conditions, microglial Grn depletion produced adverse outcomes, such as fasting hyperglycemia and aberrant activation of hypothalamic microglia. However, when fed a high-fat diet (HFD), these mice exhibited beneficial effects, including less obesity, glucose dysregulation, and hypothalamic inflammation. These differing phenotypes appeared to be linked to increased extracellular cleavage of anti-inflammatory PGRN into proinflammatory GRNs in the hypothalamus during overnutrition. In support of this, inhibiting PGRN cleavage attenuated HFD-induced hypothalamic inflammation and obesity progression. Our results suggest that the extracellular cleavage of microglia-derived PGRN plays a significant role in promoting hypothalamic inflammation and obesity during periods of overnutrition. Therefore, therapies that inhibit PGRN cleavage may be beneficial for combating diet-induced obesity.

Type 1 diabetes (T1D) is a consequence of autoimmune destruction of β-cells, and macrophages (MΦs) have a central role in initiating processes that lead to β-cell demise. We reported that Ca2+-independent phospholipase A2β (iPLA2β)-derived lipid (iDL) signaling contributes to β-cell death. Because MΦs express iPLA2β, we assessed its role in T1D development. We find that selective reduction of myeloid-iPLA2β in spontaneously diabetes-prone NOD mice 1) decreases proinflammatory eicosanoid production by MΦs, 2) favors the anti-inflammatory (M2-like) MΦ phenotype, and 3) diminishes activated CD4+ and CD8+ T-cells phenotype in the pancreatic infiltrate, prior to T1D onset. These outcomes are associated with a significant reduction in T1D. Further, inhibition of select proinflammatory lipid signaling pathways reduces M1-like MΦ polarization and adoptive transfer of M2-like MΦs reduces NOD T1D incidence, suggesting a mechanism by which iDLs impact T1D development. These findings identify MΦ-iPLA2β as a critical contributor to T1D development and potential target to counter T1D onset.

Human genetic and transgenic mouse studies have highlighted a potential liver-adipose tissue endocrine axis, involving activin C (Act-C) and/or Act-E and ALK7, influencing fat distribution and systemic metabolism. We investigated the bidirectional effects between circulating INHBC, which homodimerizes into Act-C, and adiposity traits, insulin resistance, inflammation, and cardiometabolic disease risk. Additionally, we examined whether Act-C is an ALK7 ligand in human adipocytes. We used Mendelian randomization and in vitro studies in immortalized human abdominal and gluteal adipocytes. Circulating INHBC was causally linked to reduced lower-body fat, dyslipidemia, and increased risks of coronary artery disease (CAD) and nonalcoholic fatty liver disease (NAFLD). Conversely, upper-body fat distribution, obesity, hypertriglyceridemia, subclinical inflammation, and type 2 diabetes positively impacted plasma INHBC levels. Mechanistically, an atherogenic lipid profile may partly explain the INHBC-CAD link, while inflammation and hypertriglyceridemia may partly explain how adiposity traits affect circulating INHBC. Phenome-wide Mendelian randomization showed weak causal relationships between higher plasma INHBC and impaired kidney function and higher gout risk. In human adipocytes, recombinant Act-C activated SMAD2/3 signaling via ALK7 and suppressed lipolysis. In summary, INHBC influences systemic metabolism by activating ALK7 in adipose tissue and may serve as a drug target for atherogenic dyslipidemia, CAD, and NAFLD.

Our objective was to test a single dose of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib as a tool for acute modeling of insulin resistance in healthy volunteers. This single-center double-blind phase 1 clinical trial randomly assigned healthy adults to a single oral dose of 300 mg alpelisib (n = 5) or placebo (n = 6) at bedtime, followed by measurement of glucose, insulin, and C-peptide levels after an overnight fast and during a 3-h 75-g oral glucose tolerance test (OGTT). Fasting plasma glucose trended higher with alpelisib (mean ± SD 93 ± 11 mg/dL) versus placebo (84 ± 5 mg/dL); mean fasting serum insulin increased nearly fivefold (23 ± 12 vs. 5 ± 3 μU/mL, respectively), and HOMA of insulin resistance (IR) scores were 5.4 ± 3.1 for alpelisib and 1.1 ± 0.6 for placebo. During OGTT, incremental area under the curve (AUC) for insulin was more than fourfold greater with alpelisib (22 ± 15 mU/mL × min) than with placebo (5 ± 2 mU/mL × min); glucose AUC trended higher with alpelisib. Single-dose alpelisib was well tolerated and produced metabolic alterations consistent with acute induction of IR, validating its use for mechanistic study of insulin action in humans.

Muscle sn-1,2-diacylglycerol (DAG) and C18:0 ceramide accumulation in sarcolemmal and mitochondrial compartments have been proposed to regulate muscle insulin sensitivity. Here, we evaluated whether weight loss-induced improvements in insulin sensitivity were associated with changes in muscle sn-1,2-DAG and ceramide content in people with obesity and type 2 diabetes. We measured skeletal muscle insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled glucose tracer infusion, and skeletal muscle sn-1,2-DAG and ceramide contents by using liquid chromatography-tandem mass spectrometry after subcellular fractionation and DAG isomer separation in 14 adults with obesity and type 2 diabetes before and after marked (18.6 ± 2.1%) weight loss. Whole-body insulin sensitivity doubled after weight loss. Sarcolemmal sn-1,2-DAG and C18:0 ceramide contents after weight loss were not different from values before weight loss. In contrast, mitochondrial-endoplasmic reticulum (ER) C18:0 ceramide content decreased by ∼20% after weight loss (from 2.16 ± 0.08 to 1.71 ± 0.13 nmol/g, P < 0.005). These results suggest a decrease in muscle mitochondrial-ER C18:0 ceramide content could contribute to the beneficial effect of weight loss on skeletal muscle insulin sensitivity.

Melanocortin-4 receptor (Mc4r) is a G protein-coupled receptor that controls systemic energy balance by regulating food intake and energy expenditure. Although the detailed molecular mechanism remains unclear, the activation of cAMP signaling in Mc4r-expressing cells reportedly suppresses food intake and increases energy expenditure. CREBP-regulated transcriptional coactivator-1 (CRTC1) is selectively expressed in neuronal cells and participates in transcriptional control, thereby contributing to neuronal plasticity and energy homeostasis. Considering the cAMP-dependent regulation of CRTC1 activity, CRTC1 in Mc4r-expressing cells may contribute to energy balance regulation through the melanocortin pathway. In this context, we examined the physiological contribution of CRTC1 in Mc4r-expressing cells to energy metabolism. In this study, mice with CRTC1 deficiency in Mc4r-expressing cells exhibited 1) modest obesity, glucose intolerance, insulin resistance, hyperinsulinemia, and hyperlipidemia; 2) decreased systemic energy expenditure and thermogenesis; 3) suppression of melanocortin agonist-induced adaptation of energy expenditure and food intake; 4) impaired thermogenic programs and oxidative pathway in brown adipose tissue and skeletal muscle; and 5) enhanced lipogenic programs in the liver and white adipose tissue. These results provide novel insights into the molecular mechanisms underlying the regulation of energy balance by the melanocortin system.