Roles of insulin resistance and obesity in regulation of plasma insulin concentrations

Jones, Clare; Carantoni, M.; Polonsky, Kenneth S.; Reaven, Gerald M.

doi:10.1152/ajpendo.2000.278.3.e501

Cited by 101 publications

(86 citation statements)

References 19 publications

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“…Fasting plasma concentrations of fatty acids, triglyceride, and cholesterol were similar in both groups; this observation may reflect increased flux of lipids from adipose tissue to liver and other oxidative tissues. HFD-induced or obesity-related insulin resistance is usually accompanied by impaired insulin clearance (35)(36)(37), and weight loss enhances insulin clearance (35,38). Consistent with these findings, we observed lower plasma insulin concentrations in Acc2 Ϫ/Ϫ mice during the hyperinsulinemic-euglycemic clamp.…”

Section: Discussionsupporting

confidence: 89%

Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

Choi¹,

Savage²,

Abu-Elheiga

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

283

232

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Acetyl-CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact of ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total energy expenditure in Acc2 ؊/؊ and WT control mice fed either regular or high-fat diets. To determine insulin action in vivo, we also measured whole-body insulinstimulated liver and muscle glucose metabolism during a hyperinsulinemic-euglycemic clamp in Acc2 ؊/؊ and WT control mice fed a high-fat diet. Contrary to previous studies that have suggested that increased fat oxidation might result in lower glucose oxidation, both fat and carbohydrate oxidation were simultaneously increased in Acc2 ؊/؊ mice. This increase in both fat and carbohydrate oxidation resulted in an increase in total energy expenditure, reductions in fat and lean body mass and prevention from diet-induced obesity. Furthermore, Acc2 ؊/؊ mice were protected from fat-induced peripheral and hepatic insulin resistance. These improvements in insulin-stimulated glucose metabolism were associated with reduced diacylglycerol content in muscle and liver, decreased PKC activity in muscle and PKC activity in liver, and increased insulin-stimulated Akt2 activity in these tissues. Taken together with previous work demonstrating that Acc2 ؊/؊ mice have a normal lifespan, these data suggest that Acc2 inhibition is a viable therapeutic option for the treatment of obesity and type 2 diabetes. diet-induced obesity prevention ͉ intracellular diacylglycerol ͉ increased fat oxidation ͉ insulin resistance prevention

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Section: Discussionsupporting

confidence: 89%

Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

Choi¹,

Savage²,

Abu-Elheiga

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

283

232

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“…In both early-and late-onset patients, general (BMI) and central (waist circumference) obesity clustered with cardiovascular risk factors and hyperinsulinemia. These findings were consistent with the important role of obesity in insulin-resistant and hyperinsulinemic states (43,44). The high rate of having a parental history of diabetes and obesity with its associated cardiovascular and complication risks in the early-onset patients prompts further search for other MODY-or obesity-associated genes.…”

Section: Resultssupporting

confidence: 82%

Familial Early-Onset Type 2 Diabetes in Chinese Patients

Lee

et al. 2001

Diabetes Care

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OBJECTIVE -We examined the prevalence of different forms of diabetes in Hong KongChinese patients with familial early-onset type 2 diabetes and compared their clinical features with patients with familial late-onset type 2 diabetes. RESEARCH DESIGN AND METHODS-A total of 145 young patients with earlyonset diabetes (age and age at diagnosis Յ40 years) and a family history of diabetes were studied. They were screened for mutations in the genes encoding glucokinase, hepatocyte nuclear factor (HNF)-4␣, and HNF-1␣. The mitochondrial DNA A3 G at nucleotide 3243 (mt3243) and amylin S20G mutations were studied, and antibodies to GAD (anti-GADs) were also examined.RESULTS -The prevalence of putative diabetogenic gene mutations and autoimmune markers were 4% for glucokinase, 0% for HNF-4␣, 5% for HNF-1␣, 3% for mt3243, 2% for amylin S20G, and 4% for anti-GAD. Compared with late-onset patients, the patients with early-onset diabetes had a higher prevalence of a parental history of diabetes and were generally more obese. When classified by obesity indexes (BMI and waist circumference), the obese patients, especially those with early-onset diabetes, had a clustering of cardiovascular risk factors and increased rates of retinopathy and albuminuria.CONCLUSIONS -Genetic factors (up to 14%) and obesity (55%) play more significant roles than autoimmunity (4%) in familial type 2 diabetes in young Chinese patients. The significance of obesity-related genes and other gene-gene and gene-environment interactions in these young patients remains to be determined.

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“…The liver removes ;80% of endogenous insulin, and the remainder is cleared by the kidneys and muscles (23). However, clearance rates for insulin decrease in glucose intolerance (24), obesity, abdominal obesity in particular (25), hypertension (26), hepatic cirrhosis, and nonalcoholic fatty liver disease (27), implicating a possible link between insulin resistance and reduced insulin clearance (28). Reduced insulin clearance has important implications in the pathophysiology of T2DM and IGR.…”

Section: Discussionmentioning

confidence: 99%

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

et al. 2015

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OBJECTIVEA gene mutation of the Wnt/b-catenin signaling cascade is present in rare patients with the insulin resistance syndrome. Sclerostin is a circulating peptide inhibiting Wnt/b-catenin signaling. Our aims were to evaluate serum sclerostin in subjects with prediabetes and to analyze its relationship with insulin resistance and b-cell function. RESEARCH DESIGN AND METHODSWe performed a cross-sectional study including 43 healthy normal glucose-tolerant (NGT) individuals and 79 individuals with impaired glucose regulation (IGR), which included subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG-IGT, undergoing oral glucose tolerance test (OGTT) and dual-energy X-ray absorptiometry. A subgroup of 18 with NGT and 30 with IGR also underwent a euglycemic-hyperinsulinemic clamp with tracer. RESULTSSclerostin levels were higher in IGR compared with NGT (50.8 6 2.4 vs. 38.7 6 2.3 pmol/L; P = 0.01), positively correlated with HOMA-insulin resistance (IR) (r = 0.62; P < 0.001), and negatively correlated with insulin-mediated total body glucose disposal (r = 20.40; P < 0.001). Fasting endogenous glucose production (EGP) and hepatic and adipose tissue insulin resistance indexes were positively correlated with sclerostin levels (r = 0.48, r = 0.62, and r = 0.61, respectively; P < 0.001). Fasting and OGTT insulin clearance were inversely correlated with sclerostin serum levels (r = 20.52 and r = 20.44, respectively; both P < 0.001). Sclerostin levels were not correlated with b-cell function parameters. In multiple linear regression analysis, the addition of sclerostin levels to the traditional risk factors for insulin resistance improved the r 2 associated with HOMA-IR (r 2 change: 0.055; F change: 28.893; P = 0.001) and insulin-mediated total body glucose disposal (r 2 change: 0.059; F change: 4.938; P = 0.033). CONCLUSIONSSclerostin levels are increased in individuals with prediabetes and correlated with insulin resistance in skeletal muscle, liver, and adipose tissue. The correlation between sclerostin and insulin clearance at fasting state and during OGTT is novel; thus, studies are needed to explore the potential causal relationship.

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Roles of insulin resistance and obesity in regulation of plasma insulin concentrations

Cited by 101 publications

References 19 publications

Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

Familial Early-Onset Type 2 Diabetes in Chinese Patients

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

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