Hypothesis: Role of Reduced Hepatic Insulin Clearance in the Pathogenesis of Type 2 Diabetes

Bergman, Richard N.; Kabir, Morvarid; Kolka, Cathryn M.; Ader, Marilyn

doi:10.2337/db19-0098

Cited by 69 publications

(63 citation statements)

References 53 publications

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“…Some data support the hypothesis that decreased insulin clearance is primarily observed in healthy individuals and might elicit insulin resistance, suggesting that reduced insulin clearance could be a upstream risk factor for the onset of type 2 diabetes. Our group showed impaired insulin clearance even in apparently healthy non‐obese men, and this is associated with modestly lower insulin sensitivity in muscle.…”

Section: Introductionsupporting

confidence: 85%

“…Recent data suggest that decreased insulin clearance might elicit insulin resistance and thus increase the risk of type 2 diabetes. Individuals with a monophasic curve are at higher risk for future type 2 diabetes, but the association between GRC type and insulin clearance has not been addressed.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, reduced insulin clearance might be genetically determined, at least partially. Modest visceral fat accumulation might also contribute to reduced insulin clearance, but it is also possible that resulting hyperinsulinemia as a result of reduced insulin clearance might simultaneously induce visceral fat accumulation and insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

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Shape of the glucose response curve during an oral glucose tolerance test is associated with insulin clearance and muscle insulin sensitivity in healthy non‐obese men

Tamura

Takeno

Kakehi

et al. 2020

J of Diabetes Invest

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Individuals with a monophasic glucose response curve (GRC) during a 75-g oral glucose tolerance test have a higher risk for type 2 diabetes than those with a biphasic GRC. However, no studies have addressed the association between GRC type and insulin clearance. Thus, we studied 49 healthy non-obese Japanese men. We divided study participants into the monophasic or biphasic group based on the shape of their GRC. We evaluated tissue-specific insulin sensitivity and insulin clearance using a two-step hyperinsulinemic-euglycemic clamp. The monophasic group had more visceral fat, lower insulin clearance and lower muscle insulin sensitivity than the biphasic group, whereas liver and adipose tissue insulin sensitivity, and insulin secretion were comparable. In conclusion, healthy non-obese men with a monophasic GRC have lower insulin clearance and muscle insulin sensitivity.

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Section: Introductionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Shape of the glucose response curve during an oral glucose tolerance test is associated with insulin clearance and muscle insulin sensitivity in healthy non‐obese men

Tamura

Takeno

Kakehi

et al. 2020

J of Diabetes Invest

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“…This study comprises a comprehensive investigation of insulin clearance and its relationships with hepatic fat and insulin sensitivity in paradigm, which proposes that impairments in insulin clearance are the primary aetiological mechanism of glucose intolerance in this ethnic group. 35,36 In this study, the response to intravenous glucose in BA men was characterized by a pronounced hyperinsulinaemia compared with that of WE men (Figure 1). While this is well documented in the literature, it has previously been described as a compensatory response by the beta cell to increased insulin resistance and/or a consequence of 'upregulated' beta-cell function.…”

Section: Discussionmentioning

confidence: 56%

“…In Americans, which reported lower IDE activity in African Americans. 51 While reduced insulin clearance is widely regarded as an early response to insulin resistance, 52,53 it is also possible that changes in insulin clearance are not only a compensatory mechanism but also a primary determinant of peripheral insulin levels 36,54 in BA populations.…”

Section: Discussionmentioning

confidence: 99%

Insulin clearance as the major player in the hyperinsulinaemia of black African men without diabetes

Ladwa

Bello

Hakim

et al. 2020

Diabetes Obesity Metabolism

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Aim To investigate relationships between insulin clearance, insulin secretion, hepatic fat accumulation and insulin sensitivity in black African (BA) and white European (WE) men. Methods Twenty‐three BA and twenty‐three WE men with normal glucose tolerance, matched for age and body mass index, underwent a hyperglycaemic clamp to measure insulin secretion and clearance, hyperinsulinaemic‐euglycaemic clamp with stable glucose isotope infusion to measure whole‐body and hepatic‐specific insulin sensitivity, and magnetic resonance imaging to quantify intrahepatic lipid (IHL). Results BA men had higher glucose‐stimulated peripheral insulin levels (48.1 [35.5, 65.2] × 103 vs. 29.9 [23.3, 38.4] × 103 pmol L−1 × min, P = .017) and lower endogeneous insulin clearance (771.6 [227.8] vs. 1381 [534.3] mL m−2 body surface area min −1, P < .001) compared with WE men. There were no ethnic differences in beta‐cell insulin secretion or beta‐cell responsivity to glucose, even after adjustment for prevailing insulin sensitivity. In WE men, endogenous insulin clearance was correlated with whole‐body insulin sensitivity (r = 0.691, P = .001) and inversely correlated with IHL (r = −0.674, P = .001). These associations were not found in BA men. Conclusions While normally glucose‐tolerant BA men have similar insulin secretory responses to their WE counterparts, they have markedly lower insulin clearance, which does not appear to be explained by either insulin resistance or hepatic fat accumulation. Low insulin clearance may be the primary mechanism of hyperinsulinaemia in populations of African origin.

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Loss of Hepatic Carcinoembryonic Antigen‐Related Cell Adhesion Molecule 1 Links Nonalcoholic Steatohepatitis to Atherosclerosis

et al. 2020

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Patients with nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) commonly develop atherosclerosis through a mechanism that is not well delineated. These diseases are associated with steatosis, inflammation, oxidative stress, and fibrosis. The role of insulin resistance in their pathogenesis remains controversial. Albumin ( Alb ) Cre + Cc1 flox ( fl ) /fl mice with the liver‐specific null deletion of the carcinoembryonic antigen‐related cell adhesion molecule 1 ( Ceacam1 ; alias Cc1 ) gene display hyperinsulinemia resulting from impaired insulin clearance followed by hepatic insulin resistance, elevated de novo lipogenesis, and ultimately visceral obesity and systemic insulin resistance. We therefore tested whether this mutation causes NAFLD/NASH and atherosclerosis. To this end, mice were propagated on a low‐density lipoprotein receptor ( Ldlr ) −/− background and at 4 months of age were fed a high‐cholesterol diet for 2 months. We then assessed the biochemical and histopathologic changes in liver and aortae. Ldlr −/− AlbCre + Cc1 fl/fl mice developed chronic hyperinsulinemia with proatherogenic hypercholesterolemia, a robust proinflammatory state associated with visceral obesity, elevated oxidative stress (reduced NO production), and an increase in plasma and tissue endothelin‐1 levels. In parallel, they developed NASH (steatohepatitis, apoptosis, and fibrosis) and atherosclerotic plaque lesions. Mechanistically, hyperinsulinemia caused down‐regulation of the insulin receptor followed by inactivation of the insulin receptor substrate 1–protein kinase B–endothelial NO synthase pathway in aortae, lowering the NO level. This also limited CEACAM1 phosphorylation and its sequestration of Shc‐transforming protein (Shc), activating the Shc–mitogen‐activated protein kinase–nuclear factor kappa B pathway and stimulating endothelin‐1 production. Thus, in the presence of proatherogenic dyslipidemia, hyperinsulinemia and hepatic insulin resistance driven by liver‐specific deletion of Ceacam1 caused metabolic and vascular alterations reminiscent of NASH and atherosclerosis. Conclusion: Altered CEACAM1‐dependent hepatic insulin clearance pathways constitute a molecular link between NASH and atherosclerosis.

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Hypothesis: Role of Reduced Hepatic Insulin Clearance in the Pathogenesis of Type 2 Diabetes

Abstract: Barbara Corkey suggested, in a highly influential publication (18), that hypersecretion of insulin and the resulting

Cited by 69 publications

References 53 publications

Shape of the glucose response curve during an oral glucose tolerance test is associated with insulin clearance and muscle insulin sensitivity in healthy non‐obese men

Shape of the glucose response curve during an oral glucose tolerance test is associated with insulin clearance and muscle insulin sensitivity in healthy non‐obese men

Insulin clearance as the major player in the hyperinsulinaemia of black African men without diabetes

Loss of Hepatic Carcinoembryonic Antigen‐Related Cell Adhesion Molecule 1 Links Nonalcoholic Steatohepatitis to Atherosclerosis

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