Multi-organ Insulin Resistance Research Articles

Modern Management of Cardiometabolic Continuum: From Overweight/Obesity to Prediabetes/Type2 Diabetes Mellitus. Recommendations from the Eastern and Southern Europe Diabetes and Obesity Expert Group.

The increasing global incidence of obesity and type2 diabetes mellitus (T2D) underscores the urgency of addressing these interconnected health challenges. Obesity enhances genetic and environmental influences on T2D, being not only a primary risk factor but also exacerbating its severity. The complex mechanisms linking obesity and T2D involve adiposity-driven changes in β-cell function, adipose tissue functioning, and multi-organ insulin resistance (IR). Early detection and tailored treatment of T2D and obesity are crucial to mitigate future complications. Moreover, personalized and early intensified therapy considering the presence of comorbidities can delay disease progression and diminish the risk of cardiorenal complications. Employing combination therapies and embracing a disease-modifying strategy are paramount. Clinical trials provide evidence confirming the efficacy and safety of glucagon-like peptide1 receptor agonists (GLP-1 RAs). Their use is associated with substantial and durable body weight reduction, exceeding 15%, and improved glucose control which further translate into T2D prevention, possible disease remission, and improvement of cardiometabolic risk factors and associated complications. Therefore, on the basis of clinical experience and current evidence, the Eastern and Southern Europe Diabetes and Obesity Expert Group recommends a personalized, polymodal approach (comprising GLP-1 RAs) tailored to individual patient's disease phenotype to optimize diabetes and obesity therapy. We also expect that the increasing availability of dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists will significantly contribute to the modern management of the cardiometabolic continuum.

Obesity to Type 2 Diabetes Mellitus: Importance of Longitudinal Characterization of the Progressive Phases as Identified in Rhesus Monkeys Maintained Under Constant Diet and Environmental Conditions

The complex physiological mechanisms that underlie the links between obesity and T2DM involve “adiposity-induced” alterations in beta cell function —not yet mechanistically understood. Clearly the changes in beta cell function are greatly increased during the progression of obesity, --not reduced!! AND multiorgan insulin resistance whose mechanisms are unknown (although likely reduced by weight loss). Rhesus monkeys have shown these and have provided an amazing look at the Phases that lead to T2DM. We have previously summarized, in a table of 49 variables, the many ways that the nonhuman primate rhesus monkey offers exciting opportunities for insight into these extraordinary conditions compared to the human with T2DM. The Importance of longitudinal characterization, with a number of measurements that are regularly and periodically carried out to assess longitudinally some of the pathophysiological processes that develop spontaneously and naturally in these monkeys as they progress from normal, lean, young animals to obese animals with or without various physiological disturbances undergo the aging process. Usually these disturbances develop at varying rates in different monkeys and include hypertension, hyperlipidemia, hyperinsulinemia, hyperglycemia, impaired glucose tolerance, insulin resistance, peripheral neuropathy, impaired renal clearance, and cardiovascular disease—in short, the entire syndrome that becomes manifest in aged and diabetic humans. The longitudinal studies depend specifically on regular assessment of each animal and determination of the rate at which that animal is or is not progressing in the development of pathophysiological disturbances. Identification of phases allows one to estimate where a given monkey is in regard to the progression to overt diabetes. Application to humans will greatly increase our predictive ability to understand the mechanisms underlying both obesity and T2DM. NIA NO1AG3 1012. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Removal of Epididymal Visceral Adipose Tissue Prevents Obesity-Induced Multi-organ Insulin Resistance in Male Mice.

Obesity is associated with insulin resistance, an important risk factor of type 2 diabetes, atherogenic dyslipidemia, and nonalcoholic fatty liver disease. The major purpose of this study was to test hypothesize that prophylactic removal of epididymal visceral adipose tissue (VAT) prevents obesity-induced multi-organ (liver, skeletal muscle, adipose tissue) insulin resistance. Accordingly, we surgically removed epididymal VAT pads from adult C57BL/6J mice and evaluated in vivo and cellular metabolic pathways involved in glucose and lipid metabolism following chronic high-fat diet (HFD) feeding. We found that VAT removal decreases HFD-induced body weight gain while increasing subcutaneous adipose tissue (SAT) mass. Strikingly, VAT removal prevents obesity-induced insulin resistance and hyperinsulinemia and markedly enhances insulin-stimulated AKT-phosphorylation at serine-473 (Ser473) and threonine-308 (Thr308) sites in SAT, liver, and skeletal muscle. VAT removal leads to decreases in plasma lipid concentrations and hepatic triglyceride (TG) content. In addition, VAT removal increases circulating adiponectin, a key insulin-sensitizing adipokine, whereas it decreases circulating interleukin 6, a pro-inflammatory adipokine. Consistent with these findings, VAT removal increases adenosine monophosphate–activated protein kinase C phosphorylation, a major downstream target of adiponectin signaling. Data obtained from RNA sequencing suggest that VAT removal prevents obesity-induced oxidative stress and inflammation in liver and SAT, respectively. Taken together, these findings highlight the metabolic benefits and possible action mechanisms of prophylactic VAT removal on obesity-induced insulin resistance and hepatosteatosis. Our results also provide important insight into understanding the extraordinary capability of adipose tissue to influence whole-body glucose and lipid metabolism as an active endocrine organ.

OR17-01 Leptin Decreases De Novo Lipogenesis in Lipodystrophic Patients

De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). In rodent models of both health and lipodystrophy (LD), leptin decreases DNL. In human patients with LD, reduced adipose tissue results in adipokine deficiencies, including lower plasma leptin, which contributes to insulin resistance, dyslipidemia and ectopic accumulation of triglycerides (TG). The mechanisms by which leptin regulates serum and hepatic-TG are not well elucidated. Studying patients with LD before and after leptin therapy provides an important clinical model for understanding leptin’s effect on DNL. We hypothesized that leptin treatment in lipodystrophic patients would decrease DNL by decreasing insulin resistance and glycemia, resulting in reduced circulating and hepatic-TG.Leptin-naïve patients with LD (n=11) were treated with recombinant leptin (metreleptin) for 6 months. All measurements were performed after an 8–12 hr fast. The % of TG in TG-rich lipoproteins (TRLP-TG) derived from DNL (% DNL) was measured using body water labeling (oral D2O) of TG and mass spectrometry analysis. Absolute DNL was calculated as the product of TRLP-TG and % DNL. HbA1c and serum-TG were measured biochemically, hepatic-TG by MRI, and total body and hepatic insulin sensitivity measured during a hyperinsulinemic-euglycemic clamp.DNL decreased after metreleptin: % DNL from 22.8±6.8 to 9.1±5.1% (p=0.0008) and absolute DNL from 54.2±32.1 to 8.6±6.5 mg/dl (p=0.003). TRLP-TG decreased from (median [interquartile range]) 160 [107, 280] to 98 [66, 147] mg/dl (p=0.01). Total body and hepatic insulin sensitivity increased from 3.7 [3.0, 7.3] to 8.4 [5.1,10.6] mg/kgFFM/min (p=0.03) and from 61.0 [48.5, 69.3] to 84.7 [75.2, 107.6] % (p =0.01), respectively. HbA1c decreased from 8.6±1.8 to 7.1±1.4% (p=0.04), hepatic-TG decreased from 17.6±11.9 to 10.3±9.1% (p=0.02), and serum-TG from 386 [216, 686] to 223 [118, 497] mg/dl (p=0.06). DNL correlated negatively with insulin sensitivity both before (r=-0.73, p=0.03) and after (r=-0.85, p=0.004) metreleptin. DNL correlated positively with hepatic-TG before (r=0.70 p=0.03) and tended to correlate after metreleptin (r=0.65, p=0.06). The change in DNL correlated with change in serum-TG (r=0.77, p=0.04) but not the change in hepatic-TG (p=0.80).We show here for the first time that 6 months of metreleptin treatment in humans with LD decreased DNL by 84% and was associated with reductions in glycemia and improved peripheral and hepatic insulin sensitivity. These data indicate a strong link between metreleptin’s effects to increase clearance of blood glucose by peripheral tissues and reduce hepatic carbohydrate flux, resulting in DNL reductions. This led to lowered hepatic steatosis and dyslipidemia and suggests treatments that target multi-organ insulin resistance may lead to decreased NAFLD and cardiovascular risk.

Adipose Tissue CTGF Expression is Associated with Adiposity and Insulin Resistance in Humans.

Connective tissue growth factor (CTGF) is an important regulator of fibrogenesis in many organs. This study evaluated the interrelationship among adipose tissue CTGF expression, fat mass, and insulin resistance in humans. This study examined (1) CTGF gene expression in human subcutaneous preadipocytes before and after inducing adipogenesis; (2) relationships among abdominal subcutaneous adipose tissue CTGF gene expression, body fat mass, and indices of insulin sensitivity, including the hepatic insulin sensitivity index and the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotope glucose tracer infusion, in 72 people who had marked differences in adiposity and insulin sensitivity; (3) localization of CTGF protein in subcutaneous adipose tissue; and (4) effect of progressive (5%, 11%, and 16%) weight loss on adipose tissue CTGF gene expression. CTGF was highly expressed in preadipocytes, not adipocytes. Adipose tissue CTGF expression was strongly correlated with body fat mass and both skeletal muscle and liver insulin sensitivity, and CTGF-positive cells were predominantly found in areas of fibrosis. Progressive weight loss caused a stepwise decrease in adipose tissue CTGF expression. It was concluded that increased CTGF expression is associated with adipose tissue expansion, adipose tissue fibrosis, and multi-organ insulin resistance in people with obesity.

Short-Term Interval and Continuous Training Improves Pancreatic ß-Cell Function Adjusted for Skeletal Muscle Insulin Resistance in Adults with Prediabetes

Exercise improves pancreatic function in an energy dose-dependent manner. We previously showed that when calories are matched, an acute exercise bout changes glucose-stimulated insulin secretion (GSIS) relative to multi-organ insulin resistance (IR) in an intensity-based manner during the immediate post-exercise period in people with prediabetes. However, the impact of short-term training intensity on ß-cell function is unknown. Thus, we examined the impact of high-intensity interval and moderate-continuous training on GSIS relative to multi-organ IR in adults with prediabetes. Thirty-one adults (Age: 61±8y; BMI: 33±6 kg/m2) with prediabetes according to ADA 75g OGTT and/or HbA1c criteria were randomized to energy-matched interval (INT: 60-min/d alternating 3-min at 90 and 50% HRpeak) or continuous training (CONT: 60-min/d 70% HRpeak) for 2 weeks. Fitness (VO2peak) and body mass were measured before and after, and a 120-min 75g OGTT with blood samples for glucose, insulin, C-peptide and FFA were determined every 30-min. GSIS (C-pep/Glc tAUC0-120min) and ß-cell function (Disposition Index [DI: GSIS/IR]) relative to skeletal muscle (InsulintAUC x GlctAUC), hepatic (HOMA-IR) and adipose (Adipose-IRfasting) IR were calculated. Training increased VO2peak (+1.1±2.1 mL/kg/min), and reduced body mass (-0.6±1.1 kg) and IR (-11±31%), independent of intensity (P<0.05). INT and CONT also decreased GSIS to a similar extent (Interaction: P=0.88). Short-term training improved skeletal muscle DI by ∼24% (P<0.05), but there was no effect on hepatic or adipose DI. Collectively, short-term INT and CONT training improves ß-cell function relative to skeletal muscle, but not hepatic or adipose, IR. These data suggest unique mechanisms regulate glucose metabolism following single vs. habitual physical activity in adults with prediabetes. Disclosure M.E. Francois: None. N. Eichner: None. N.M. Gilbertson: None. E.M. Heiston: None. E. Barrett: None. S.K. Malin: None.

Stable isotope-based flux studies in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with the worldwide epidemics of obesity, diabetes and cardiovascular diseases. NAFLD ranges from benign fat accumulation in the liver (steatosis) to non-alcoholic steatohepatitis (NASH), and cirrhosis which can progress to hepatocellular carcinoma and liver failure. Mass spectrometry and magnetic resonance spectroscopy-coupled stable isotope-based flux studies provide new insights into the understanding of NAFLD pathogenesis and the disease progression. This review focuses mainly on the utilization of mass spectrometry-based methods for the understanding of metabolic abnormalities in the different stages of NAFLD. For example, stable isotope-based flux studies demonstrated multi-organ insulin resistance, dysregulated glucose, lipids and lipoprotein metabolism in patients with NAFLD. We also review recent developments in the stable isotope-based technologies for the study of mitochondrial dysfunction, oxidative stress and fibrogenesis in NAFLD. We highlight the limitations of current methodologies, discuss the emerging areas of research in this field, and future directions for the applications of stable isotopes to study NAFLD and its complications.

Enhancing Exercise Responsiveness across Prediabetes Phenotypes by Targeting Insulin Sensitivity with Nutrition.

Exercise is a cornerstone therapy for chronic diseases related to multiorgan insulin resistance. However, not all individuals show the anticipated improvement in insulin sensitivity following exercise and these individuals are considered exercise resistant. Caloric restriction is an approach to enhance the effect of exercise on increasing peripheral and hepatic insulin sensitivity, as replenishing expended calories blunts these benefits. Alternatively, restricting carbohydrate intake, independent of energy balance, following exercise provides an additive effect on peripheral insulin sensitivity when compared to refeeding carbohydrate. Although carbohydrate composition modulates insulin sensitivity, few have studied effects of low glycemic index or whole-grain diets following exercise across prediabetes phenotypes on insulin sensitivity. Herein, we propose the novel hypothesis that the combination of individualized nutrition therapy and exercise should be based on the clinical pathology of prediabetes to overcome exercise resistance and improve responsiveness in people at risk for type 2 diabetes and cardiovascular disease.

NAMPT-Mediated NAD+ Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD(+) biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle and adipose tissue dysfunction, manifested by increased plasma free fatty acid concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. These deleterious alterations were normalized by administering rosiglitazone or a key NAD(+) intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance.

Is the β-cell the key for remission of diabetes after bariatric surgery?

Type 2 diabetes (T2D) is a major complication of obesity and an important global health problem, because of its high prevalence, causal relationship with serious medical complications, adverse effects on quality-of-life and economic impact due to increased health care costs and loss of productivity. The pathogenesis of T2D involves multi-organ insulin resistance, particularly insulin-resistant glucose metabolism in skeletal muscle (impaired insulin-mediated stimulation of glucose uptake) and the liver (impaired insulin-mediated suppression of glucose production), in conjunction with inadequate insulin secretion from pancreatic β-cells. Even though a large number of effective medications are available to treat T2D, approximately half of patients fail to achieve adequate glycaemic control, defined by the American Diabetes Association as HbA1c < 7%.

Beyond the Protein-Coding Sequence: Noncoding RNAs in the Pathogenesis of Type 2 Diabetes

Diabetes mellitus results from a deficiency or failure to maintain normal glucose homeostasis. The most common form of the disease is type 2 diabetes (T2D), a progressive metabolic disorder characterized by elevated glucose levels that develops in response to either multi-organ insulin resistance or insufficient insulin secretion from pancreatic β-cells. Although the etiology of T2D is complex, many factors are known to contribute to defects of glucose homeostasis, including obesity, unhealthy lifestyle choices, genetic susceptibility, and environmental exposures. In addition to these factors, noncoding RNAs (ncRNAs) have been recently implicated in the pathogenesis of T2D, playing roles in several of the pathophysiological mechanisms underlying the disease, particularly in insulin-sensitive tissues such as pancreatic β-cells, liver, muscle, and adipose tissue. A growing number of publications demonstrate that polymorphisms in ncRNAs or their target genes may represent a new class of genetic variation contributing to the development of T2D. This review summarizes both the current state of knowledge of ncRNAs, specifically microRNAs (miRNAs), involved in the regulation of β-cell function, insulin sensitivity, and insulin action in peripheral organs. The role of genetic variation in miRNAs or miRNA binding sites in the pathogenesis of T2D is also discussed. While far less is known about the impact of long ncRNAs (lncRNAs) in the development of T2D, emerging evidence suggests that these molecules may be able to contribute to β-cell dysfunction in response to hyperglycemia. This article provides an overview of the studies conducted to date in this field, focusing on lncRNAs that are dysregulated in human pancreatic islets.

Relationship between Adipose Tissue Lipolytic Activity and Skeletal Muscle Insulin Resistance in Nondiabetic Women

Increased adipose tissue lipolytic activity is considered an important factor in the pathogenesis of skeletal muscle insulin resistance associated with obesity. The objective of the study was to evaluate the relationship between the rate of release of free fatty acids (FFA) into plasma and skeletal muscle insulin sensitivity in human subjects. We determined the palmitate rate of appearance (Ra) per kilogram fat-free mass (an index of FFA availability to lean tissues) during basal conditions and during insulin infusion (to simulate postprandial insulin concentrations) and skeletal muscle insulin sensitivity, defined as the percent increase in the glucose rate of disappearance, in 110 nondiabetic women (body mass index 20.6-46.4 kg/m(2)) by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotope tracer methods. Basal (r(s) = -0.379, P < 0.001) and insulin-suppressed (r(s) = -0.631, P < 0.001) palmitate Ra correlated negatively with skeletal muscle insulin sensitivity. However, the strength of the correlation was greater for palmitate Ra during insulin infusion than palmitate Ra during basal conditions (P = 0.0007) when lipolytic rates and FFA availability were reduced to less than 20% of basal values. The relative suppression of palmitate Ra correlated directly with the relative stimulation of glucose rate of disappearance during insulin infusion (r(s) = 0.530, P < 0.001). These data suggest that the correlation between FFA kinetics and muscle glucose metabolism is due to multiorgan insulin resistance rather than a direct effect of FFA itself on skeletal muscle insulin action and challenge the view that increased adipose tissue lipolytic rate is an important cause of insulin resistance.

Diet and Exercise in the Treatment of Fatty Liver

Diet and Exercise in the Treatment of Fatty Liver

Reproducibility of glucose, fatty acid and VLDL kinetics and multi-organ insulin sensitivity in obese subjects with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is associated with abnormalities in basal glucose and free fatty acid (FFA) metabolism, multi-organ insulin resistance and alterations in lipoprotein kinetics. These metabolic outcomes can be evaluated in vivo by using stable isotopically labeled tracer methods. An understanding of the reproducibility of these measures is necessary to ensure adequate statistical power in studies designed to evaluate metabolic function in subjects with NAFLD. We determined the degree of intra-individual variability of skeletal muscle, adipose tissue, and hepatic insulin sensitivity and basal plasma glucose, FFA, and very-low-density lipoprotein triglyceride and apolipoprotein B-100 (apoB-100) kinetics in eight obese subjects with NAFLD (age: 44 ± 3 years; body mass index: 38.2 ± 1.7 kg m(-2); intrahepatic triglyceride content: 24.5 ± 3.9%), by using the hyperinsulinemic-euglycemic clamp technique and stable isotope-labeled tracer methods and mathematical modeling on two separate occasions ∼2 months apart. The intra-individual variability (coefficient of variation) ranged from 6% for basal glucose production to 21% for insulin-stimulated glucose disposal (percentage increase from basal). We estimated that a 25% difference in any outcome measure can be detected with a sample size of ≤ 8 subjects for paired studies and ≤ 15 subjects per group for unpaired studies, assuming an α value of 0.05 and a β value of 0.20 (that is, 80% power). These results demonstrate that only a small number of subjects are needed to detect clinically relevant effects in insulin sensitivity and hepatic lipoprotein metabolism in obese subjects with NAFLD, and will be useful to determine appropriate sample size for future metabolic studies.

Pathogenesis and Pathophysiology of the Cardiometabolic Syndrome

The cardiometabolic syndrome represents a cluster of metabolic abnormalities that are risk factors for cardiovascular disease. The mechanism(s) responsible for developing the cardiometabolic syndrome is not known, but it is likely that multi-organ insulin resistance, which is a common feature of the cardiometabolic syndrome, is involved. Insulin resistance is an important risk factor for type 2 diabetes and can cause vasoconstriction and renal sodium reabsorption, leading to increased blood pressure. Alterations in adipose tissue fatty acid and adipokine metabolism are involved in the pathogenesis of insulin resistance. Excessive rates of fatty acid release into the bloodstream can impair the ability of insulin to stimulate muscle glucose uptake and suppress hepatic glucose production. Noninfectious systemic inflammation associated with adipocyte and adipose tissue macrophage cytokine production can also cause insulin resistance. In addition, increased free fatty acid delivery to the liver can stimulate hepatic very low-density lipoprotein triglyceride production, leading to dyslipidemia.

Alterations in liver, muscle, and adipose tissue insulin sensitivity in men with HIV infection and dyslipidemia

Dyslipidemia is common in patients with HIV infection. In this study, a two-stage euglycemic hyperinsulinemic clamp, with infusion of stable isotopically labeled tracers, was used to evaluate insulin action in skeletal muscle, liver, and adipose tissue in HIV-infected men with dyslipidemia (HIV-DL; plasma triglyceride >250 mg/dl and HDL <45 mg/dl; n=12), HIV-infected men without dyslipidemia (HIV w/o DL; n=12), and healthy men (n=6). Basal rates of glucose production (glucose R(a)), glucose disposal (glucose R(d)), and lipolysis (palmitate R(a)) were similar between groups. The relative suppression of glucose R(a) (63+/- 4, 77+/- 2, and 78+/- 3%, P=0.008) and palmitate R(a) (49+/-4, 63+/-3, and 68+/-3%, P=0.005) during ow-dose insulin infusion (plasma insulin approximately 30 microU/ml), and the relative stimulation of glucose R(d) (214+/-21, 390+/-25, and 393+/-46%, P=0.001) during high-dose insulin infusion (plasma insulin approximately 75 microU/ml) were lower in HIV-DL than in HIV w/o DL and healthy volunteers, respectively. Suppression of basal glucose R(a) correlated with plasma adiponectin (r=0.44, P=0.02) and inversely with plasma IL-6 (r=-0.49, P<0.001). Stimulation of glucose R(d) correlated directly with adiponectin (r=0.48, P<0.01) and inversely with IL-6 (r=-0.49, P=0.02). We conclude that dyslipidemia in HIV-infected men is indicative of multiorgan insulin resistance, and circulating adipokines may be important in the pathogenesis of impaired insulin action.