Glycoprotein 130 (gp130) is a critical signal transducer in the interleukin-6 (IL-6) receptor family, regulates immune response, inflammation, and metabolic processes. In obesity, elevated levels of proinflammatory cytokines like IL-6 can lead to chronic activation of gp130, disrupting normal signaling in tissues such as skeletal muscle. The aim of the study was to investigate the expression of IL-6–related and JAK/STAT pathway genes in human skeletal muscle and to explore their association with insulin sensitivity, as well as to evaluate the role of serum soluble gp130 (sgp130) in the development of overweight and obesity. The study included 57 participants, 25 with normal body weight (control group), 17 with overweight and 15 with obesity. Hyperinsulinemic-euglycemic clamp and muscle biopsy were conducted. Muscle mRNA expression was analysed by qPCR. Individuals with overweight exhibited significantly lower IL6R expression in skeletal muscle, while those with obesity showed reduced IL6ST expression. The expression levels of IL6R (r = 0.28, p = 0.036), IL6ST (r = 0.46, p < 0.001), JAK2 (r = 0.32, p = 0.015), and STAT3 (r = 0.44, p < 0.001) and PRKAA2 (r = 0.26, p = 0.049) in skeletal muscle were positively correlated with insulin sensitivity. Additionally, individuals with overweight and obesity had significantly higher serum sgp130 levels. Serum sgp130 was positively correlated with BMI (r = 0.43, P < 0.01) and inversely associated with insulin sensitivity (r = -0.44, P < 0.01). Gp130 is associated with insulin sensitivity in skeletal muscle in obesity, revealing a novel mechanism linking gp130 to metabolic regulation.

Background: Taurine (2-aminoethanesulfonic acid) is a conditionally essential, sulfur-containing amino acid that has attracted growing interest for its multifaceted role in metabolic regulation. Unlike proteinogenic amino acids, taurine exerts diverse physiological functions including bile acid conjugation, osmoregulation, antioxidant defense, and mitochondrial support. Emerging evidence indicates that taurine modulates key metabolic processes implicated in obesity, type 2 diabetes, metabolic dysfunction-associated liver disease, and metabolic syndrome. Mechanistically, taurine influences insulin signaling, lipid oxidation, inflammatory cascades (e.g., nuclear factor-kappa B), and energy metabolism via pathways involving AMP-activated protein kinase, peroxisome proliferator-activated receptor alpha, and mitochondrial function. Preclinical models demonstrate improvements in insulin sensitivity, and inflammatory profiles with taurine administration. Human trials, though limited in scale and heterogenous in design, suggest potential benefits in glycemic control and lipid metabolism. However, inconsistencies in dosage, duration, and subject stratification limit the generalizability of findings. Summary: This review synthesizes current data on taurine biological activity and its relevance to metabolic pathophysiology. Key message: Taurine shows promise as a multifunctional metabolic regulator capable of influencing insulin sensitivity, lipid metabolism, and inflammation.

Retinoid X receptors (RXRs) are nuclear hormone receptors (NRs) functioning as transcription factors. There are three RXR isoforms: RXRA (NR2B1), RXRB (NR2B2), and RXRG (NR2B3). RXRs serve as master regulators of gene networks governing cell growth, differentiation, survival, and death. RXRs might affect insulin action, but very little data currently supports this relationship. The aim of the study was to analyze the relationship between the expression of RXRs in skeletal muscles and insulin sensitivity in young, normal-weight, overweight and obese people. The research group consisted of 45 volunteers, 20 had normal body weight, 13 were overweight, and 12 were obese. Insulin sensitivity was measured with hyperinsulinemic-euglycemic clamp. Vastus lateralis muscle biopsies were taken before each clamp, and RXRs mRNA expression was analyzed. RXRA expression was lower in overweight, obese subjects in comparison with normal-weight volunteers (P = 0.003, P = 0.002, respectively). RXRB and RXRG expression did not differ between the groups. RXRA expression in muscle was positively correlated with insulin sensitivity (r = 0.49, P = 0.001). The relationship between muscle tissue RXRA and insulin sensitivity was independent of BMI (β = 0.35, P = 0.02). Our results indicate that RXRA expression in skeletal muscle is linked to insulin sensitivity. The data suggest that muscle-associated RXRs may play a role in modulating insulin action.

Background and Aims Adipose tissue (AT) serves as a vital energy storage site and plays a pivotal role in metabolic regulation, exhibiting a high response to insulin. Impairment in this response may closely associate with obesity, and NFAT (nuclear factor of activated T cells) family genes may be involved in the process. However, human data linking NFAT and AT remains elusive. The aim of this study was to assess the expression of NFAT family genes and markers of adipogenesis in subcutaneous adipose tissue (SAT) among normal-weight and overweight/obese individuals before and after weight loss, in relation to insulin sensitivity. Methods and Results The study included 45 participants, 15 normal-weight (control group) and 30 overweight or obese, who underwent a 12-week dietary intervention (DI) program. Before and after the program hyperinsulinemic-euglycemic clamp and SAT biopsy were conducted. Before DI, a positive correlations was observed in the expression of NFATc1, NFATc4, and NFAT5 with insulin sensitivity. The expression of NFAT family genes and markers of adipogenesis in SAT was lower in individuals with overweight or obesity compared to normal-weight. Additionally, a positive correlation was noted between NFAT family genes and adipogenesis markers both before and after weight loss. Following the DI program, there was an increase in the expression of NFATc3, NFATc4, and NFAT5 in SAT. Conclusion Decreased SAT expression of NFAT genes in obesity is partly reversed in response to weight loss. NFAT genes in SAT are associated with insulin sensitivity and adipogenesis.Registration number for clinical trial: NCT01393210.

Insulin resistance, i.e., decreased biological response to insulin, is a risk factor for many diseases, such as obesity, type 2 diabetes (T2DM), cardiovascular disease, polycystic ovary syndrome, some forms of cancer and neurodegenerative diseases. One of its main causes is chronic low-grade inflammation, mediated by the proinflammatory pathways, such as the c-Jun N-terminal kinase (JNK) pathway and the nuclear factor kappa B (NFκB) pathway. Interleukin (IL)-38 (IL-38) is a newly discovered cytokine that belongs to the IL-1 family. There are three hypothetical pathways through which IL-38 may bind to the specific receptors and inhibit their proinflammatory activity. Those pathways are associated with IL-36 receptor (IL-36R), IL-1 receptor accessory protein-like 1 (IL1RAPL1) and IL-1 receptor 1 (IL1R1). There are studies linking IL-38 to improve insulin sensitivity through the difference in serum IL-38 in patients with insulin resistance or the correlation of IL-38 concentrations with insulin resistance indexes. However, many questions still remain regarding the biological activity of IL-38 itself and its role in the pathogenesis of insulin resistance. The goal of this study is to showcase IL-38, its biological activity, hypothesized signaling pathways, connection with insulin resistance and future perspectives of research on IL-38. We present that IL-38 associated signaling can be a potential target for the treatment of insulin resistance and associated diseases.

Patients and methods Study groupThe study group comprised 59 young (age, 18-35 years) individuals, 30 with normal weight (body mass index [BMI] <25 kg/m 2 ; 19 men and 11 wom en) and 29 with overweight or obesity (BMI, 25-40 kg/m 2 ; 20 men and 9 women).All partici pants were nonsmokers, led a sedentary lifestyle, had no serious diseases, morbid obesity, or clinical

Background: Ghrelin is an orexigenic peptide secreted mainly by the stomach. Serum ghrelin concentrations are suppressed after a meal, probably due to insulin release. Individuals with obesity are characterized by a lower fasting serum ghrelin and a lower ghrelin decrease after a meal. The effect of weight loss on the ability of insulin to suppress serum ghrelin concentration remains unknown. Objective: The aim of the present study was to analyze the effect of weight -reducing dietary intervention on the ability of hyperinsulinemia to suppress serum ghrelin concentration in young individuals with uncomplicated obesity. Methods: We examined 38 individuals with marked overweight or obesity, who underwent a 12 -wk dietary intervention program. Serum ghrelin concentration was measured before and after a 2-h hyperinsulinemic - euglycemic clamp, both pre- and post -intervention. Twenty normal -weight individuals served as a control group and were examined at baseline only. Results: Individuals with overweight/obesity were characterized by a lower fasting serum ghrelin concentration than normal -weight individuals ( P = 0.006). Insulin decreased serum ghrelin concentration in both groups ( P < 0.001); however, this decrease was markedly lower in individuals with overweight/obesity than in normal -weight individuals (99.70 +/- 136.37 vs. 215.45 +/- 250.28 pg/mL; P = 0.026). Fasting serum ghrelin concentration increased after the intervention. After weight -reducing dietary intervention, the decrease in serum ghrelin concentration after the clamp was significantly greater than the pre -intervention value (99.70 +/- 136.37 vs. 221.82 +/- 228.75 pg/mL; P = 0.002). Conclusions: Weight -reducing dietary intervention restores the ability of hyperinsulinemia to suppress serum ghrelin concentration. It may suggest an enhanced feeling of satiety after moderate weight loss in individuals with overweight/obesity.

Background & aims We have recently demonstrated that subcutaneous adipose tissue (SAT) expression of genes associated with thyroid hormone (TH) action is altered in obesity and insulin resistance. The aim of the present study was to examine the effect of diet-induced weight-loss on SAT expression of genes associated with TH action. Methods The study group comprised 38 individuals with overweight/obesity, which completed 12-week dietary intervention program. Hyperinsulinemic-euglycemic clamp and SAT biopsy were performed before and after the program. Fifteen normal-weight individuals were examined at baseline only. Results Overweight/obese individuals had lower free thyroxine (fT4) and higher free triiodothyronine (fT3)/fT4 ratio, lower SAT TH receptor isoforms (TRα and TRβ, encoded by THRA and THRB, respectively) and peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A) mRNA expression and higher SAT type II and type III iodothyronine deiodinase (encoded by DIO2 and DIO3, respectively) and nuclear receptor corepressor (NCOR1) mRNA expression in comparison with normal-weight individuals. Diet-induced weight loss resulted in a decrease in fT3 and fT3/fT4 ratio and an increase in SAT THRA, THRB and PPARGC1A. SAT NCOR1 and forkhead box protein O1 (FOXO1) decreased only in individuals, who lost at least 10 kg (n = 20). Higher increase in insulin sensitivity after weight loss was associated with a lower decrease in fT3/fT4 ratio. Conclusions Diet-induced weight loss partly reverses alterations in SAT expression of genes associated with TH action. Responses of circulating TH and SAT expression of genes associated with TH action to diet-induced weight loss are related to body weight and insulin sensitivity.

Background: Appropriate adipogenesis leads to the "healthy" expansion of adipose tissue and is a crucial component in maintaining metabolic homeostasis. The Hippo signaling network may balance adipocyte proliferation/differentiation regulating adipogenic footpath.Objectives: Our study aimed to assess subcutaneous adipose tissue (SAT) expression of genes involved in Hippo signaling network in subjects with marked overweight or obesity after dietary intervention (DI) in relation to obesity and insulin sensitivity. Methods: Forty overweight or obese subjects (O/O) [mean +/- SD age 33 +/- 7 y, 45% men, BMI (in kg/m2) 32.9 +/- 3.1] completed DI [low -calorie diet (20 kcal/kg of proper body weight) for 12 wks]. The control group comprising 20 normal-weight subjects (mean +/- SD age: 24 +/- 2 y, 40% men, BMI: 22.4 +/- 2.3 ) was examined at baseline only. Hyperinsulinemic-euglycemic clamp and SAT biopsy with gene expression analysis were performed. Student's t-test for unpaired and paired samples and Pearson correlation analysis were applied. This is an exploratory analysis of the DI program.Results: SAT mRNA expression of mammalian sterile 20-like kinase 2 (MST2) encoded by serine/threonine kinase 3 gene (STK3)->, large tumor suppressor kinase 2 (LATS2), and salvador family WW domain containing protein 1 (SAV1), the upstream members of the Hippo pathway, were decreased (21%, 40%, and 36%, respectively) in O/O in comparison with weight subjects individuals before DI (all P < 0.05). At baseline, positive correlations between SAT SAV1, LATS2 expression and adiponectin (ADIPOQ) (r = 0.50, P < 0.001; r = 0.53, P = 0.004, respectively) and solute carrier family 2 member 4 (SLC2A4) (r = 0.35, P = 0.007; r = 0.28, P = 0.03, respectively) expression were observed in the entire study group. Body weight of the O/O group decreased during DI (11.2 +/- 3.8 kg, P < 0.001), and there was an increase in insulin sensitivity (by 27%) and SAT expression of STK3, LATS2 (both by 19%), and SAV1 (by 26%) (all P < 0.05). After DI, SAT SLC2A4 expression was correlated with STK3 (r = 0.47, P = 0.003), LATS2 (r = 0.56, P < 0.001), and yes-associated protein (r = 0.50, P = 0.001) expression.Conclusions: Obesity is associated with altered mRNA expression of upstream effectors of the Hippo pathway in SAT in young adults. DI may improve adipogenic capacity.

OBJECTIVE:The circadian rhythms are controlled by the central clock in the hypothalamic suprachiasmatic nuclei and by the peripheral clocks in tissues, including adipose tissue. The adipose tissue circadian clock may be associated with the regulation of insulin action; however, human data are limited. The aim of this study was to analyze the expression of subcutaneous adipose tissue circadian genes as they relate to obesity and insulin sensitivity before and after diet-induced weight loss. METHODS:The study group comprised 38 individuals who were overweight or obese. The individuals completed a 12-wk dietary intervention program. Hyperinsulinemic-euglycemic clamp and subcutaneous adipose tissue biopsy were performed before and after the program. Sixteen normal weight individuals were examined at baseline and served as a control group. RESULTS:At baseline, individuals who were overweight/obese had lower adipose tissue expression of NR1D1, NR1D2, DBP, PER1, and PER2 than normal weight individuals. The expression of ARNTL, CLOCK, and CRY did not differ between the groups. A weight-reducing dietary intervention resulted in an increase in the expression of adipose tissue NR1D2 and DBP, which was positively related to insulin sensitivity both before (in the entire study group and in the subgroup of overweight/obese individuals) and after the dietary intervention. CONCLUSIONS:Adipose tissue circadian gene expression is decreased in obesity and this decrease may be partially reversed by dietary intervention. Among circadian genes, NR1D2 and DBP seem to be specifically associated with insulin action.

baseline C. The effect of weight-reducing dietary intervention on SAT HSD11B1, HSD11B2 and GRα expression in overweight/obese individuals in study group 2 (n=38) * P<0.05 vs baseline Data are presented as geometric mean (geometric SD factor)

The remodeling of skeletal muscle extracellular matrix (ECM) components is related to the degree of insulin resistance (IR). Membrane receptors such as integrins provide two-way signaling ("inside-out" and "outside-in" signaling) between ECM components of skeletal muscle (e.g., collagen, laminin, fibronectin) and intracellular signaling pathways. The aim of the study was to analyze the relationship between the expression of integrins in skeletal muscle and insulin sensitivity (IS) in young, healthy, non-obese volunteers. We studied 36 healthy non-obese male participants. Subjects were divided into three subgroups on the basis of the hyperinsulinemic-euglycemic clamp: upper IS tertile, medium IS tertile, and lower IS tertile. Vastus lateralis muscle biopsies were performed before each clamp. Next, analysis of integrin mRNA expression was performed. Waist circumference, percent body fat, fasting serum insulin, total cholesterol, triglycerides and LDL-cholesterol were higher in the lower IS tertile subgroup compared to the other two subgroups (p < 0.05). The lower IS tertile showed increased expression of ITGA5, ITGA6, ITGA7, SPARC (p < 0.05) in comparison with the upper IS tertile and ITGA6 (p < 0.05) compared to the medium IS tertile. ITGA2, ITGA3, ITGA5, ITGA6, ITGA7, SPARC correlated inversely with IS (p < 0.05). Skeletal muscle integrin are associated with low IS in healthy nonobese men. Our data suggest that factors associated with ECM in muscle may be involved in modulation of insulin action even at the early stages of the development of IR.

Skeletal muscle is the tissue directly involved in insulin-stimulated glucose uptake. Glucose is the primary energy substrate for contracting muscles, and proper metabolism of glucose is essential for health. Contractile activity and the associated Ca2+signaling regulate functional capacity and muscle mass. A high concentration of Ca2+and the presence of calmodulin (CaM) leads to the activation of calcineurin (CaN), a protein with serine-threonine phosphatase activity. The signaling pathway linked with CaN and transcription factors like the nuclear factor of activated T cells (NFAT) is essential for skeletal muscle development and reprogramming of fast-twitch to slow-twitch fibers. CaN activation may promote metabolic adaptations in muscle cells, resulting in better insulin-stimulated glucose transport. The molecular mechanisms underlying the altered insulin response remain unclear. The role of the CaN/NFAT pathway in regulating skeletal muscle hypertrophy is better described than its involvement in the pathogenesis of insulin resistance. Thus, there are opportunities for future research in that field. This review presents the role of CaN/NFAT signaling and suggests the relationship with insulin-resistant muscles.

Skeletal muscle is the main metabolic tissue responsible for glucose homeostasis in the body. It is surrounded by the extracellular matrix (ECM) consisting of three layers: epimysium, perimysium, and endomysium. ECM plays an important role in the muscle, as it provides integrity and scaffolding cells. The observed disturbances in this structure are related to the abnormal remodeling of the ECM (through an increase in the concentration of its components). ECM rearrangement may impair insulin action by increasing the physical barrier to insulin transport and reducing insulin transport into muscle cells as well as by directly inhibiting insulin action through integrin signaling. Thus, improper ECM remodeling may contribute to the development of insulin resistance (IR) and related comorbidities. In turn, IR-associated conditions may further aggravate disturbances of ECM in skeletal muscle. This review describes the major components of the ECM that are necessary for its proper function. Particular attention was also paid to receptors (integrins) involved in the signaling of metabolic pathways. Finally, changes in ECM components in the context of clinical and animal studies are discussed. This article will help the reader to systematize knowledge related to the ECM and to better understand the relationship between ECM remodeling and IR, and its role in the pathogenesis of T2DM. The information in this article presents the concept of the role of ECM and its remodeling in the pathogenesis of IR, which may contribute to developing new therapeutic solutions.

Recent studies suggest that FK506 binding protein 51 (FKBP51), a negative regulator of glucocorticoid response, encoded by FKBP5, may influence insulin action. The aim of the present study was to assess the relationship between subcutaneous adipose tissue (AT) and skeletal muscle FKBP5 expression in relation to insulin sensitivity in healthy individuals and to study its regulation by insulin and circulating free fatty acid (FFA) elevation. The study group comprised 96 male subjects, 49 normal-weight and 47 overweight/obese. Hyperinsulinemic clamp, subcutaneous AT and skeletal muscle biopsies were performed. In a subgroup of 20 subjects, two 6 h clamps were performed, with and without Intralipid/heparin infusion, and tissue biopsies were obtained before and after each clamp. AT FKBP5 expression was lower in overweight/obese individuals in comparison with normal-weight individuals (p = 0.004). Muscle FKBP5 expression did not differ between the groups, however, it was inversely related to insulin sensitivity (r = −0.32, p = 0.002). FKBP5 expression decreased in AT (p = 0.003) and increased in muscle (p < 0.0001) after insulin infusion. Intralipid/heparin diminished insulin-induced increase in muscle FKBP5. Our data show that lower AT FKBP5 expression is related to obesity, whereas muscle FKBP5 expression is associated with insulin resistance. AT and muscle FKBP5 expression is differentially regulated by insulin.

2022 Guidelines on the management of patients with diabetes A position of Diabetes Poland Rules for diagnosing carbohydrate metabolism disordersKey recommendations• Blood sugar tests for early detection of prediabetes/type 2 diabetes should be performed for people over 45, as well as for younger overweight or obese people if there is at least one additional risk factor of diabetes.[B]• Women not previously diagnosed with diabetes should undergo an oral glucose tolerance test between 24 th and 28 th week of pregnancy to diagnose gestational diabetes.[A]• Diagnosing diabetes in children during the first 9 weeks after birth requires genetic tests for neonatal diabetes.[a]• Patients with cystic fibrosis aged 10 and above should undergo an oral glucose tolerance test each year to diagnose diabetes.[a]Diabetes is a group of metabolic diseases characterised by hyperglycaemia resulting from a defect in insulin secretion and/or activity.Chronic hyperglycaemia is associated with damage, dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels. I. Symptoms indicative of potentialdiabetes with significant hyperglycaemia:• increased diuresis (polyuria);• increased thirst;• loss of weight not explained by intentional dieting;• other, less typical symptoms: weakness and increased sleepiness, purulent skin lesions and inflammation of genitourinary organs. II. Rules for diagnosing carbohydrate metabolism disorders:• if symptoms of diabetes occur, a random blood sugar test should be performed, with result ≥ 200 mg/dl (≥ 11.1 mmol/l) constituting grounds for diagnosing diabetes;2022 Guidelines on the management of patients with diabetes A position of Diabetes Poland Prevention and delay of diabetes Key recommendations• Patients with pre-diabetes should be given recommendations on a healthy lifestyle (physical activity at least 150 min/week; in case of overweight and obese patients, weight reduction of at least 7% and weight maintenance) and information on the effectiveness of such measures in preventing the development of diabetes.[a]• Apart from the modification of lifestyle, pharmacological prevention of diabetes in the form of metformin should be considered in pre-diabetic patients, especially patients with concomitant IFG and IGT and/or a body mass index (BMI) ≥ 35 kg/m 2 and/or patients under 60 years of age, as well as in women with a history of gestational diabetes mellitus.[a]• Screening should be performed using fasting glucose, oral glucose.[c] Type 1 diabetesCurrently, there is no effective method of preventing type 1 diabetes either in the general population or at-risk people.Type 2 diabetes 1. Screening should be performed using fasting glucose or oral glucose tolerance test.2. Risk factors of type 2 diabetes (see chapter 1). Review of recommendations for preventing or delaying the development of diabetes:2022 Guidelines on the management of patients with diabetes A position of Diabetes Poland Monitoring of glucose Key recommendations• Most people on insulin therapy using the method of multiple daily injections should self-monitor blood glucose (SMBG) both before and after meals, at bedtime, before planned physical activity, when low blood glucose is suspected, and before activities where hypoglycaemia is particularly dangerous (e.g.driving).[B] 2022 Guidelines on the management of patients with diabetes A position of Diabetes Poland Setting objectives for diabetes managementKey recommendations• In individuals with diabetes, the overall target for glycaemic control expressed by the HbA 1c level is no more than 7.0% (53 mmol/mol).[a]• LDL fraction cholesterol less than 55 mg/dl (less than 1.4mmol/l) and a reduction of at least 50% from baseline in individuals with very high cardiovascular risk diabetes.[B]• LDL-C concentration less than 70 mg/dl (1.8 mmol/l) and a reduction of at least 50% from baseline in individuals with high cardiovascular risk diabetes.[a]• LDL-C levels less than 100 mg/dl (2.6 mmol/l) in individuals at moderate cardiovascular risk (young people under 35 yrs.with type 1 diabetes without chronic complications and other cardiovascular risk factors or with type 2 diabetes below 50 yrs.with a diabetes duration of less than 10 years, without other risk factors).[a]• Recommended arterial blood pressure: less than 130/80 mm Hg. [a]

BACKGROUND:Insulin resistance is a risk factor for cardiovascular disease. Recently, we have developed a novel index, FLAIS (Fasting Laboratory Assessment of Insulin Sensitivity), which accurately reflects insulin sensitivity, measured with hyperinsulinemic-euglycemic clamp, in different groups of subjects. The aim of the present study was to assess the relationship of FLAIS with cardiovascular risk factors in a population-based study.METHODS:The study group comprised 339 individuals from the ongoing Białystok Plus study, without previously known diabetes. Clinical examination, oral glucose tolerance test and the measurement of blood laboratory parameters were performed.RESULTS:Prediabetes (impaired fasting glucose and/or impaired glucose tolerance) was diagnosed in 165 individuals whereas type 2 diabetes was diagnosed in 19 subjects. FLAIS was lower in individuals with prediabetes and diabetes in comparison with individuals with normal glucose tolerance. FLAIS was significantly related to waist circumference, systolic and diastolic blood pressure, triglycerides, HDL-cholesterol and LDL-cholesterol in the entire study group and in the subgroups with normal glucose tolerance and with prediabetes/diabetes. HOMA-IR, QUICKI and Matsuda index were not related to blood pressure and LDL-cholesterol in individuals with normal glucose tolerance. Majority of the adjusted models with FLAIS were characterized by better fit with the data in comparison with other indices for all cardiovascular risk factors except waist circumference.CONCLUSIONS:FLAIS represents useful index to assess the cluster of insulin resistance-associated cardiovascular risk factors in general population.