Cardio-protective role of Humanin in myocardial ischemia-reperfusion.

Mitochondria-derived peptides (MDPs) are bioactive peptides encoded by and secreted from the mitochondria. To date, a few MDPs including humanin, MOTS-c and SHLP1-6, and their diverse biological functions have been identified. The first and most studied MDP is humanin, a 24-amino-acid poly peptide. It was first identified in 2001 in the surviving neurons of patient with Alzheimer's disease, and since then has been well characterized for its neuro-protective effect through inhibition of apoptosis. Over the past two decades, humanin has been reported to play critical roles in aging as well as multiple diseases including metabolic disorders, cardiovascular diseases, and autoimmune disease. Humanin has been shown to modulate multiple biological processes including autophagy, ER stress, cellular metabolism, oxidative stress, and inflammation. A role for humanin has been shown in a wide range of cardiovascular diseases, such as coronary heart disease, atherosclerosis, and myocardial fibrosis. In this minireview, we will summarize the literature demonstrating a role for humanin in cardio-protection following myocardial ischemia-reperfusion induced injury and the potential mechanisms that mediate it.

Implications of the School Day on Health Behaviors for Children With Type 1 Diabetes: A Survey of Parent Perspectives During the COVID-19 Pandemic.

PURPOSE: The purpose of this study is to survey parents of youth with type 1 diabetes during the COVID-19 pandemic with school closures to better understand the implications of the school day on health care behaviors. METHODS: A cross-sectional, online survey was distributed to parents of youth with type 1 diabetes ≤19 years of age in a large, academic diabetes center. Questions encompassed perceived changes in management behaviors and plans for return to school. Subgroup analysis compared parent responses by child's age, reported stressors, and socioeconomic markers. RESULTS: Parents reported a worsening in their child's diabetes health behaviors during school closures compared to what they perceived during a regular school day before the pandemic. More than half of parents reported feeling that their child was unable to maintain a normal routine, with particular implications for snacking between meals, daily physical activity, and sleep habits. Families with adolescents or those experiencing multiple pandemic-related stressors reported greater challenges. In open-ended responses, families highlighted difficulty in balancing school, work, and diabetes care and expressed concerns about the mental health repercussions of school closures for their children. Nearly half of parents reported being at least moderately worried about return to school, whereas only a minority reported seeking guidance from their diabetes provider. CONCLUSIONS: Parent-reported disruptions of school-day routines frequently had adverse consequences for diabetes management in this population. These findings highlight the importance of a school-day routine for children with type 1 diabetes; during closures, families may benefit from mitigating strategies to maintain effective habits.

Sleep in Parental Caregivers and Children With Type 1 Diabetes.

The purpose of this cross-sectional, descriptive, pilot study was to examine the correlations in sleep between caregivers (≥18 years) and young (6-12 years) children with type 1 diabetes. Sleep was measured in both parent and child over 7 days using actigraphy and a sleep diary. Parents completed questionnaires on sleep, stress, depressive symptoms, and demographics. Children completed pediatric anxiety and fatigue questionnaires, and A1C (Hemoglobin A1c) was documented at clinic. Descriptive statistics and Pearson correlations were used to analyze data. Parents (N = 18, mean age: 39.3 ± 5.4 years, 100% Caucasian, 83% mothers) and children (N = 18, mean age: 9.6 ± 2.4 years, diagnosed for mean 3.0 ± 2.4 years, 66% female, mean A1C: 7.5 ± 0.8%) were recruited. Strong to moderate correlations were found for several measures including sleep measures based on actigraphy: mean sleep duration (hours; 7.6 ± 0.7 for parents and 8.8 ± 0.8 for children; r = .638, p = .004), mean sleep efficiency (r = .823, p < .001), and mean daily wake after sleep onset (minutes; r = .530, p = .024).

Efficacy of a Novel Mitochondrial-Derived Peptide in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.

With the complexities that surround myocardial ischemia/reperfusion (MI/R) injury, therapies adjunctive to reperfusion that elicit beneficial pleiotropic effects and do not overlap with standard of care are necessary. This study found that the mitochondrial-derived peptide S14G-humanin (HNG) (2 mg/kg), an analogue of humanin, reduced infarct size in a large animal model of MI/R. However, when ischemic time was increased, the infarct-sparing effects were abolished with the same dose of HNG. Thus, although the 60-min MI/R study showed that HNG cardioprotection translates beyond small animal models, further studies are needed to optimize HNG therapy for longer, more patient-relevant periods of cardiac ischemia.

Adiposity and Asthma in a Nationwide Study of Children and Adults in the United States.

RATIONALE: Although obesity has been associated with asthma, body mass index is suboptimal to fully characterize adiposity. OBJECTIVES: We examined the relation between adiposity and asthma in a large sample of the U.S. population, using indices defined by dual-energy X-ray absorptiometry. METHODS: We analyzed data from 8,886 children (aged 8-19 yr) and 12,795 adults (aged 20-69 yr) from the 2001 to 2006 National Health and Nutrition Examination Survey. In addition to body mass index, percent body fat, waist circumference, and waist-to-height ratio, dual-energy X-ray absorptiometry was used to calculate whole-body and local adiposity indices: fat mass index; total, trunk, and legs percent fat; and trunk-to-total fat mass ratio, legs-to-total fat mass ratio, and trunk-to-legs fat mass ratios. Logistic regression was used for the analysis of adiposity measures and asthma. RESULTS: Among children, general adiposity was significantly associated with asthma, with no major differences by sex. Results were driven by nonatopic children, in whom trunk-predominant (central) adiposity (assessed by waist circumference, waist-to-height ratio, trunk-to-total fat mass ratio, and trunk-to-legs fat mass ratio) was also associated with asthma. There were no significant associations among atopic children. Among adults, all adiposity indices were associated with asthma, with central adiposity significant only among women. The results in adults were driven by atopy, especially in women. CONCLUSIONS: Adiposity measured by dual-energy X-ray absorptiometry provides similar information to that obtained by using anthropometric indices among children of both sexes and among adult men. However, dual-energy X-ray absorptiometry provides additional information in adult women, in whom dual-energy X-ray absorptiometry-measured central adiposity is significantly associated with asthma, particularly atopic asthma.

Metabolic pathways at the crossroads of diabetes and inborn errors.

Research over the past two decades has led to advances in our understanding of the genetic and metabolic factors that underlie the pathogenesis of type 2 diabetes mellitus (T2DM). While T2DM is defined by its hallmark metabolic symptoms, the genetic risk factors for T2DM are more immune-related than metabolism-related, and the observed metabolic disease may be secondary to chronic inflammation. Regardless, these metabolic changes are not benign, as the accumulation of some metabolic intermediates serves to further drive the inflammation and cell stress, eventually leading to insulin resistance and ultimately to T2DM. Because many of the biochemical changes observed in the pre-diabetic state (i.e., ectopic lipid storage, increased acylcarnitines, increased branched-chain amino acids) are also observed in patients with rare inborn errors of fatty acid and amino acid metabolism, an interesting question is raised regarding whether isolated metabolic gene defects can confer an increased risk for T2DM. In this review, we attempt to address this question by summarizing the literature regarding the metabolic pathways at the crossroads of diabetes and inborn errors of metabolism. Studies using cell culture and animal models have revealed that, within a given pathway, disrupting some genes can lead to insulin resistance while for others there may be no effect or even improved insulin sensitivity. This differential response to ablating a single metabolic gene appears to be dependent upon the specific metabolic intermediates that accumulate and whether these intermediates subsequently activate inflammatory pathways. This highlights the need for future studies to determine whether certain inborn errors may confer increased risk for diabetes as the patients age.

Corrigendum to "Pancreatic Function, Type 2 Diabetes, and Metabolism in Aging".

[This corrects the article DOI: 10.1155/2012/320482.].

Central effects of humanin on hepatic triglyceride secretion.

Humanin (HN) is an endogenous mitochondria-associated peptide that has been shown to protect against various Alzheimer's disease-associated insults, myocardial ischemia-reperfusion injury, and reactive oxygen species-induced cell death. We have shown previously that HN improves whole body glucose homeostasis by improving insulin sensitivity and increasing glucose-stimulated insulin secretion (GSIS) from the ß-cells. Here, we report that intraperitoneal treatment with one of HN analogs, HNG, decreases body weight gain, visceral fat, and hepatic triglyceride (TG) accumulation in high-fat diet-fed mice. The decrease in hepatic TG accumulation is due to increased activity of hepatic microsomal triglyceride transfer protein (MTTP) and increased hepatic TG secretion. Both intravenous (iv) and intracerebroventricular (icv) infusion of HNG acutely increase TG secretion from the liver. Vagotomy blocks the effect on both iv and icv HNG on TG secretion, suggesting that the effects of HNG on hepatic TG flux are centrally mediated. Our data suggest that HN is a new player in central regulation of peripheral lipid metabolism.

Insulin resistance, metabolic syndrome, and lung function in US adolescents with and without asthma.

BACKGROUND: Obesity increases both the risk of asthma and asthma severity and is a well-known risk factor for insulin resistance and the metabolic syndrome (MS) in children and adolescents. OBJECTIVE: We aimed to examine the association among obesity, insulin sensitivity, MS, and lung function in US adolescents with and without asthma. METHODS: We performed a cross-sectional study of 1429 adolescents aged 12 to 17 years in the 2007-2010 National Health and Nutrition Examination Survey. Adjusted regression was used to assess the relationships among obesity, insulin sensitivity/resistance, MS, and lung function in children with and without asthma. RESULTS: Insulin resistance was negatively associated with FEV1 and forced vital capacity (FVC) in adolescents with and without asthma, whereas MS was associated with lower FEV1/FVC ratios, with a more pronounced decrease found among asthmatic patients; these associations were driven by overweight/obese adolescents. Higher body mass index was associated with a decrease in FEV1/FVC ratios among adolescents with insulin resistance. Compared with healthy participants, adolescents with MS had an approximately 2% decrease in FEV1/FVC ratios, adolescents with asthma had an approximately 6% decrease, and those with MS and asthma had approximately 10% decreased FEV1/FVC ratios (P < .05). CONCLUSION: Insulin resistance and MS are associated with worsened lung function in overweight/obese adolescents. Asthma and MS synergistically decrease lung function, as do obesity and insulin resistance. These factors might contribute to the pathogenesis of asthma severity in obese patients and warrant further investigation.

Mangiferin stimulates carbohydrate oxidation and protects against metabolic disorders induced by high-fat diets.

Excessive dietary fat intake causes systemic metabolic toxicity, manifested in weight gain, hyperglycemia, and insulin resistance. In addition, carbohydrate utilization as a fuel is substantially inhibited. Correction or reversal of these effects during high-fat diet (HFD) intake is of exceptional interest in light of widespread occurrence of diet-associated metabolic disorders in global human populations. Here we report that mangiferin (MGF), a natural compound (the predominant constituent of Mangifera indica extract from the plant that produces mango), protected against HFD-induced weight gain, increased aerobic mitochondrial capacity and thermogenesis, and improved glucose and insulin profiles. To obtain mechanistic insight into the basis for these effects, we determined that mice exposed to an HFD combined with MGF exhibited a substantial shift in respiratory quotient from fatty acid toward carbohydrate utilization. MGF treatment significantly increased glucose oxidation in muscle of HFD-fed mice without changing fatty acid oxidation. These results indicate that MGF redirects fuel utilization toward carbohydrates. In cultured C2C12 myotubes, MGF increased glucose and pyruvate oxidation and ATP production without affecting fatty acid oxidation, confirming in vivo and ex vivo effects. Furthermore, MGF inhibited anaerobic metabolism of pyruvate to lactate but enhanced pyruvate oxidation. A key target of MGF appears to be pyruvate dehydrogenase, determined to be activated by MGF in a variety of assays. These findings underscore the therapeutic potential of activation of carbohydrate utilization in correction of metabolic syndrome and highlight the potential of MGF to serve as a model compound that can elicit fuel-switching effects.

Reductions in serum IGF-1 during aging impair health span.

In lower or simple species, such as worms and flies, disruption of the insulin-like growth factor (IGF)-1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF-1 levels in serum and tissues and can modulate lifespan via/or independent of IGF-1. Rodent models, where the GH/IGF-1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF-1 levels are high throughout life, in humans, serum IGF-1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/IGF-1 axis are unable to clearly distinguish between developmental and age-related effects of GH/IGF-1 on health. To overcome this caveat, we developed an inducible liver IGF-1-deficient (iLID) mouse that allows temporal control of serum IGF-1. Deletion of liver Igf-1 gene at one year of age reduced serum IGF-1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF-1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF-1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology.

Obesity, hyperglycemia and endothelial function in inner city Bronx adolescents: a cross-sectional study.

BACKGROUND: Along with the rise in obesity, cardiovascular disease (CVD) has become the major cause of death in developed countries. Although overt coronary heart disease rarely manifests during childhood, atherosclerosis can begin by the second decade of life. Therefore, identifying reliable risk markers of early vascular disease in childhood could be important. Alteration in endothelial function (EF) is an early preclinical marker of the atherosclerotic process and can be assessed non-invasively using reactive hyperemia peripheral arterial tonometry (RH-PAT). The purpose of this study was to investigate if obesity in children is associated with lower EF as measured with RH-PAT, and if obese children with impaired glucose regulation have further impairment in RH-PAT measured EF compared to obese children with normal glucose tolerance. METHODS: Cardiovascular risk factors, adipocytokines and EF using RH-PAT were evaluated in lean (n = 14) and obese (n = 37) adolescents (age 12-18 years). Based on an oral glucose tolerance test, the obese group was subdivided into: obese with normal (NGT, n = 22) and obese with impaired glucose regulation (IGR, n = 15). RESULTS: RH-PAT score was lower in obese subjects compared to lean controls (1.70 ± 0.02 vs. 1.98 ± 0.09, P = 0.02), indicating worse EF. This difference remained significant when adjusted for age, sex and ethnicity (P = 0.02). We observed a pattern of worsening EF with increasing metabolic burden, with RH-PAT scores of 1.98 ± 0.09,1.73 ± 0.08 and 1.65 ± 0.12 in the lean, obese-NGT and obese-IGR groups, respectively, ptrend = 0.03. Obese subjects were more insulin resistant [higher HOMA] (p = 0.03), and had higher levels of leptin (p = 0.004), hsCRP (p = 0.0004), and TNF-α (p = 0.03) compared to lean subjects. Adjusting for insulin resistance and adipocytokines substantially attenuated the obesity association with RH-PAT, suggesting that insulin resistance and inflammation may mediate the association of EF with obesity. CONCLUSIONS: Risk factors for adult cardiovascular disease, including impaired EF, insulin resistance and inflammation, are evident in obese adolescents. Whether early detection of these cardiovascular risk factors will be useful for informing interventions to prevent disease progression needs further study. TRIAL REGISTRATION: Clinical Trials Identifier: NCT01879033.

Epigenetic genome-wide association methylation in aging and longevity.

The aging phenotype is the result of a complex interaction between genetic, epigenetic and environmental factors. Evidence suggests that epigenetic changes (i.e., a set of reversible, heritable changes in gene function or other cell phenotype that occurs without a change in DNA sequence) may affect the aging process and may be one of the central mechanisms by which aging predisposes to many age-related diseases. The total number of altered methylation sites increases with increasing age, such that they could serve as marker for chronological age. This article systematically highlights the advances made in the field of epigenomics and their contribution to the understanding of the complex physiology of aging, lifespan and age-associated diseases.

Pancreatic function, type 2 diabetes, and metabolism in aging.

Aging is a risk factor for impaired glucose tolerance and diabetes. Of the reported 25.8 million Americans estimated to have diabetes, 26.9% are over the age of 65. In certain ethnic groups, the proportion is even higher; almost 1 in 3 older Hispanics and African Americans and 3 out of 4 Pima Indian elders have diabetes. As per the NHANES III (Third National Health and Nutrition Examination) survey, the percentage of physician-diagnosed diabetes increased from 3.9% in middle-aged adults (40-49 years) to 13.2% in elderly adults (≥75 years). The higher incidence of diabetes is especially alarming considering that diabetes in itself increases the risk for multiple other age-related diseases such as cancer, stroke, cardiovascular diseases, Parkinson's disease, and Alzheimer's disease (AD). In this review, we summarize the current evidence on how aging affects pancreatic ß cell function, ß cell mass, insulin secretion and insulin sensitivity. We also review the effects of aging on the relationship between insulin sensitivity and insulin secretion. Understanding the mechanisms that lead to impaired glucose homeostasis and T2D in the elderly will lead to development of novel treatments that will prevent or delay diabetes, substantially improve quality of life and ultimately increase overall life span.

The critical role of metabolic pathways in aging.

Aging is characterized by a deterioration in the maintenance of homeostatic processes over time, leading to functional decline and increased risk for disease and death. The aging process is characterized metabolically by insulin resistance, changes in body composition, and physiological declines in growth hormone (GH), insulin-like growth factor-1 (IGF-1), and sex steroids. Some interventions designed to address features of aging, such as caloric restriction or visceral fat depletion, have succeeded in improving insulin action and life span in rodents. Meanwhile, pharmacologic interventions and hormonal perturbations have increased the life span of several mammalian species without necessarily addressing features of age-related metabolic decline. These interventions include inhibition of the mammalian target of rapamycin and lifetime deficiency in GH/IGF-1 signaling. However, strategies to treat aging in humans, such as hormone replacement, have mostly failed to achieve their desired response. We will briefly discuss recent advances in our understanding of the complex role of metabolic pathways in the aging process and highlight important paradoxes that have emerged from these discoveries. Although life span has been the major outcome of interest in the laboratory, a special focus is made in this study on healthspan, as improved quality of life is the goal when translated to humans.

Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice.

OBJECTIVE: Humanin (HN), an endogenous antiapoptotic peptide, has previously been shown to protect against Alzheimer's disease and a variety of cellular insults. We evaluated the effects of a potent analog of HN (HNG) in an in vivo murine model of myocardial ischemia and reperfusion. METHODS AND RESULTS: Male C57BL6/J mice (8 to 10 week old) were subjected to 45 minutes of left coronary artery occlusion followed by a 24-hour reperfusion. HNG or vehicle was administered IP 1 hour prior or at the time of reperfusion. The extent of myocardial infarction per area-at-risk was evaluated at 24 hours using Evans Blue dye and 2-3-5-triphenyl tetrazolium chloride staining. Left ventricular function was evaluated at 1 week after ischemia using high-resolution, 2D echocardiography (VisualSonics Vevo 770). Myocardial cell signaling pathways and apoptotic markers were assessed at various time points (0 to 24 hours) following reperfusion. Cardiomyocyte survival and apoptosis in response to HNG were assessed in vitro. HNG reduced infarct size relative to the area-at-risk in a dose-dependent fashion, with a maximal reduction at the dose of 2 mg/kg. HNG therapy enhanced left ventricular ejection fraction and preserved postischemic left ventricular dimensions (end-diastolic and end-systolic), resulting in improved cardiac function. Treatment with HNG significantly increased phosphorylation of AMPK and phosphorylation of endothelial nitric oxide synthase in the heart and attenuated Bcl-2-associated X protein and B-cell lymphoma-2 levels following myocardial ischemia and reperfusion. HNG improved cardiomyocyte survival and decreased apoptosis in response to daunorubicin in vitro. CONCLUSIONS: These data show that HNG provides cardioprotection in a mouse model of myocardial ischemia and reperfusion potentially through activation of AMPK-endothelial nitric oxide synthase-mediated signaling and regulation of apoptotic factors. HNG may represent a novel agent for the treatment of acute myocardial infarction.

Aging per se increases the susceptibility to free fatty acid-induced insulin resistance.

Elevations in systemic free fatty acids (FFA) contribute to insulin resistance. To determine the effects of an acute elevation in FFA on insulin action with aging, we infused saline or intralipid (IL) during a hyperinsulinemic-euglycemic clamp in three groups of rats: young ad libitum-fed (YAL), old ad libitum-fed (OAL), and old on lifelong calorie restriction (OCR). The OCR group was included to distinguish between aging per se and age-related changes in body fat distribution. IL induced marked insulin resistance in both YAL and OCR, but the onset of insulin resistance was approximately two to three times more rapid in OCR as compared with YAL. In response to IL infusion, plasminogen-activating inhibitor-1 (PAI-1) expression was increased in subcutaneous fat from OAL animals. In visceral fat, a marked increase in PAI-1 and interleukin-6 expression was observed in OAL and OCR rats, but not YAL, in response to IL treatment. Thus, aging per se increases the inflammatory response to excess nutrients and vulnerability to FFA-induced insulin resistance with aging.

Comparison between surrogate indexes of insulin sensitivity/resistance and hyperinsulinemic euglycemic clamp estimates in rats.

Assessing insulin resistance in rodent models gives insight into mechanisms that cause type 2 diabetes and the metabolic syndrome. The hyperinsulinemic euglycemic glucose clamp, the reference standard for measuring insulin sensitivity in humans and animals, is labor intensive and technically demanding. A number of simple surrogate indexes of insulin sensitivity/resistance have been developed and validated primarily for use in large human studies. These same surrogates are also frequently used in rodent studies. However, in general, these indexes have not been rigorously evaluated in animals. In a recent validation study in mice, we demonstrated that surrogates have a weaker correlation with glucose clamp estimates of insulin sensitivity/resistance than in humans. This may be due to increased technical difficulties in mice and/or intrinsic differences between human and rodent physiology. To help distinguish among these possibilities, in the present study, using data from rats substantially larger than mice, we compared the clamp glucose infusion rate (GIR) with surrogate indexes, including QUICKI, HOMA, 1/HOMA, log (HOMA), and 1/fasting insulin. All surrogates were modestly correlated with GIR (r = 0.34-0.40). Calibration analyses of surrogates adjusted for body weight demonstrated similar predictive accuracy for GIR among all surrogates. We conclude that linear correlations of surrogate indexes with clamp estimates and predictive accuracy of surrogate indexes in rats are similar to those in mice (but not as substantial as in humans). This additional rat study (taken with the previous mouse study) suggests that application of surrogate insulin sensitivity indexes developed for humans may not be appropriate for determining primary outcomes in rodent studies due to intrinsic differences in metabolic physiology. However, use of surrogates may be appropriate in rodents, where feasibility of clamps is an obstacle and measurement of insulin sensitivity is a secondary outcome.

Humanin: a novel central regulator of peripheral insulin action.

BACKGROUND: Decline in insulin action is a metabolic feature of aging and is involved in the development of age-related diseases including Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD). A novel mitochondria-associated peptide, Humanin (HN), has a neuroprotective role against AD-related neurotoxicity. Considering the association between insulin resistance and AD, we investigated if HN influences insulin sensitivity. METHODS AND FINDINGS: Using state of the art clamp technology, we examined the role of central and peripheral HN on insulin action. Continuous infusion of HN intra-cerebro-ventricularly significantly improved overall insulin sensitivity. The central effects of HN on insulin action were associated with activation of hypothalamic STAT-3 signaling; effects that were negated by co-inhibition of hypothalamic STAT-3. Peripheral intravenous infusions of novel and potent HN derivatives reproduced the insulin-sensitizing effects of central HN. Inhibition of hypothalamic STAT-3 completely negated the effects of IV HN analog on liver, suggesting that the hepatic actions of HN are centrally mediated. This is consistent with the lack of a direct effect of HN on primary hepatocytes. Furthermore, single treatment with a highly-potent HN analog significantly lowered blood glucose in Zucker diabetic fatty rats. Based upon the link of HN with two age-related diseases, we examined if there were age associated changes in HN levels. Indeed, the amount of detectable HN in hypothalamus, skeletal muscle, and cortex was decreased with age in rodents, and circulating levels of HN were decreased with age in humans and mice. CONCLUSIONS: We conclude that the decline in HN with age could play a role in the pathogenesis of age-related diseases including AD and T2DM. HN represents a novel link between T2DM and neurodegeneration and along with its analogues offers a potential therapeutic tool to improve insulin action and treat T2DM.