Impaired Insulin Clearance as the Initial Regulator of Obesity-Associated Hyperinsulinemia: Novel Insight Into the Underlying Mechanism Based on Serum Bile Acid Profiles

Abstract

To investigate the roles of insulin clearance and insulin secretion in the development of hyperinsulinemia in obese subjects and to reveal the association between insulin clearance and bile acids (BAs). RESEARCH DESIGN AND METHODSIn cohort 1, insulin secretion, sensitivity, and endogenous insulin clearance were evaluated with an oral glucose tolerance test in 460 recruited participants. In cohort 2, 81 participants underwent an intravenous glucose tolerance test and a hyperinsulinemic-euglycemic clamp to assess insulin secretion, endogenous and exogenous insulin clearance, and insulin sensitivity. Based on insulin resistance levels ranging from mild to severe, obese participants without diabetes were further divided into 10 quantiles in cohort 1 and into tertiles in cohort 2. Forty serum BAs were measured incohort2toexaminetheassociationbetweenBAsandinsulinclearance. RESULTSAll obese participants had impaired insulin clearance, and it worsened with additional insulin resistance in obese subjects without diabetes. However, insulin secretion was unchanged from quantile 1 to 3 in cohort 1, and no difference was found in cohort 2. After adjustments for all confounding factors, serum-conjugated BAs, especially glycodeoxycholic acid (GDCA; b 5 20.335, P 5 0.004) and taurodeoxycholic acid (TDCA; b 5 20.333, P 5 0.003), were negatively correlated with insulin clearance. The ratio of unconjugated to conjugated BAs (b 5 0.335, P 5 0.002) was positively correlated with insulin clearance. CONCLUSIONSHyperinsulinemia in obese subjects might be primarily induced by decreased insulin clearance rather than increased insulin secretion. Changes in circulating conjugated BAs, especially GDCA and TDCA, might play an important role in regulating insulin clearance.Hyperinsulinemia has been well demonstrated as a common phenomenon associated with obesity and could occur before the development of dysglycemia (1).

Metabolism Score for Visceral Fat (METS-VF): A New Predictive Surrogate for CKD Risk

“… 17–19 In addition, if excessive accumulation of visceral fat leads to the impairment of insulin clearance and transmission of signaling pathways in pancreatic islets, it affects the energy supply of the kidneys which, eventually, leads to kidney damage. 20–22 In our study, levels of TG, FPG, and HOMA-IR were increased in the CKD group, and the differences were significant. In the HOMA-IR subgroup, the CKD risk increased by 2.43-times for each SD increase in METS-VF.…”

“…Impairment of insulin clearance in obese individuals, and the accompanying insulin resistance and disorders of glucose metabolism in tissues and organs, promote morbidly obesity. 20 , 27 Increased circulating levels of TGs, decreased clearance of LDL-C, and long-term maintenance of lower levels of HDL-C are involved in obesity development. 28 , 29 METS-VF integrates the above parameters stated above to assess the metabolic status of visceral fat, which can reflect the risk of human disease to a certain extent.…”

“…Due to the unfavorable changes in diets, the prevalence of obesity and metabolic abnormalities has increased year-by-year in China, 34 and the prevalence of metabolic abnormalities-related kidney diseases has also increased gradually. Studies have shown that increasing age, 23 overnutrition, 24 sex differences in the number of lipid glucocorticoid receptors and estrogen secretion, 25 , 26 abnormal lipid levels, 28 , 29 and insulin resistance 20 , 27 are involved in the development of morbid obesity. We attempted to predict CKD risk using the anthropometric indicators BMI, WHtR, 35 , 36 visceral fat index, 37 and insulin resistance.…”

Long‐Term High‐Fat Diet Decreases Renal Insulin‐Degrading Enzyme Expression and Function by Inhibiting the PPARγ Pathway

“…Impaired insulin clearance is an important factor causing increased serum insulin levels, which can be a cause of insulin resistance. [14,30,31] Therefore, we investigated the insulin clearance in HFD-induced obese and control mice. After an insulin challenge for the indicated times (15, 30, and 60 min), insulin levels were significantly greater in HFD-fed obese than chow diet-fed mice (Figure 1G).…”

“…[ 13 ] A recent study found that hyperinsulinemia in obese subjects may be caused primarily by impaired insulin clearance rather than by increased insulin secretion. [ 14 ] Thus, the current evidence suggests that impaired insulin clearance is not only a consequence but also a major and independent cause of insulin resistance. [ 15 ] Moreover, previous studies have also shown that HFD and cafeteria diet, which more closely resemble Western diet, lead to impaired insulin clearance in mice.…”