Miikka-Juhani Honka

Effects of Insulin on Brain Glucose Metabolism in Impaired Glucose Tolerance

OBJECTIVE Insulin stimulates brain glucose metabolism, but this effect of insulin is already maximal at fasting concentrations in healthy subjects. It is not known whether insulin is able to stimulate glucose metabolism above fasting concentrations in patients with impaired glucose tolerance. RESEARCH DESIGN AND METHODS We studied the effects of insulin on brain glucose metabolism and cerebral blood flow in 13 patients with impaired glucose tolerance and nine healthy subjects using positron emission tomography (PET). All subjects underwent PET with both [18F]fluorodeoxyglucose (for brain glucose metabolism) and [15O]H2O (for cerebral blood flow) in two separate conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp). Arterial blood samples were acquired during the PET scans to allow fully quantitative modeling. RESULTS The hyperinsulinemic clamp increased brain glucose metabolism only in patients with impaired glucose tolerance (whole brain: +18%, P = 0.001) but not in healthy subjects (whole brain: +3.9%, P = 0.373). The hyperinsulinemic clamp did not alter cerebral blood flow in either group. CONCLUSIONS We found that insulin stimulates brain glucose metabolism at physiological postprandial levels in patients with impaired glucose tolerance but not in healthy subjects. These results suggest that insulin stimulation of brain glucose metabolism is maximal at fasting concentrations in healthy subjects but not in patients with impaired glucose tolerance.

Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids

Aims/hypothesisWe examined whether analysis of lipids by ultra-performance liquid chromatography (UPLC) coupled to MS allows the development of a laboratory test for non-alcoholic fatty-liver disease (NAFLD), and how a lipid-profile biomarker compares with the prediction of NAFLD and liver-fat content based on routinely available clinical and laboratory data.MethodsWe analysed the concentrations of molecular lipids by UPLC-MS in blood samples of 679 well-characterised individuals in whom liver-fat content was measured using proton magnetic resonance spectroscopy (1H-MRS) or liver biopsy. The participants were divided into biomarker-discovery (n = 287) and validation (n = 392) groups to build and validate the diagnostic models, respectively.ResultsIndividuals with NAFLD had increased triacylglycerols with low carbon number and double-bond content while lysophosphatidylcholines and ether phospholipids were diminished in those with NAFLD. A serum-lipid signature comprising three molecular lipids (‘lipid triplet’) was developed to estimate the percentage of liver fat. It had a sensitivity of 69.1% and specificity of 73.8% when applied for diagnosis of NAFLD in the validation series. The usefulness of the lipid triplet was demonstrated in a weight-loss intervention study.Conclusions/interpretationThe liver-fat-biomarker signature based on molecular lipids may provide a non-invasive tool to diagnose NAFLD, in addition to highlighting lipid molecular pathways involved in the disease.

Circulating Triacylglycerol Signatures in Nonalcoholic Fatty Liver Disease Associated With the I148M Variant in PNPLA3 and With Obesity

We examined whether relative concentrations of circulating triacylglycerols (TAGs) between carriers compared with noncarriers of PNPLA3I148M gene variant display deficiency of TAGs, which accumulate in the liver because of defective lipase activity. We also analyzed the effects of obesity-associated nonalcoholic fatty liver disease (NAFLD) independent of genotype, and of NAFLD due to either PNPLA3I148M gene variant or obesity on circulating TAGs. A total of 372 subjects were divided into groups based on PNPLA3 genotype or obesity. Absolute and relative deficiency of distinct circulating TAGs was observed in the PNPLA3148MM/148MI compared with the PNPLA3148II group. Obese and ‘nonobese’ groups had similar PNPLA3 genotypes, but the obese subjects were insulin-resistant. Liver fat was similarly increased in obese and PNPLA3148MM/148MI groups. Relative concentrations of TAGs in the obese subjects versus nonobese displayed multiple changes. These closely resembled those between obese subjects with NAFLD but without PNPLA3I148M versus those with the I148M variant and NAFLD. The etiology of NAFLD influences circulating TAG profiles. ‘PNPLA3 NAFLD’ is associated with a relative deficiency of TAGs, supporting the idea that the I148M variant impedes intrahepatocellular lipolysis rather than stimulates TAG synthesis. ‘Obese NAFLD’ is associated with multiple changes in TAGs, which can be attributed to obesity/insulin resistance rather than increased liver fat content per se.

Effect of Bariatric Surgery on Adipose Tissue Glucose Metabolism in Different Depots in Patients With or Without Type 2 Diabetes

OBJECTIVE We investigated fat distribution and tissue-specific insulin-stimulated glucose uptake (GU) in seven fat compartments (visceral and subcutaneous) and skeletal muscle in morbidly obese patients with (T2D) and without (ND) type 2 diabetes before and 6 months after bariatric surgery. RESEARCH DESIGN AND METHODS A total of 23 obese patients (BMI 43.0 ± 3.6 kg/m2; 9 T2D and 14 ND) were recruited from a larger, randomized multicenter SLEEVEPASS study. MRI (for fat distribution) and [18F]-fluorodeoxyglucose PET (for GU) studies were performed for the obese patients before and 6 months postsurgery; 10 lean subjects served as control subjects and were studied once. RESULTS At baseline, visceral fat GU was 30 ± 7% of muscle GU in control subjects and 57 ± 5% in obese patients. Visceral and deep subcutaneous fat were more abundant (despite same total fat mass) and less insulin sensitive in T2D than ND; in both, GU was impaired compared with control subjects. Postsurgery, visceral fat mass decreased (∼40%) more than subcutaneous fat (7%). Tissue-specific GU was improved, but not normalized, at all sites in T2D and ND alike. The contribution of visceral fat to whole-body GU was greater in T2D than ND but decreased similarly with surgery. Subcutaneous fat made a fourfold greater contribution to whole-body GU in obese versus lean subjects (15% vs. 4%) both before and after surgery. CONCLUSIONS Bariatric surgery leads to sustained weight loss and improves tissue-specific glucose metabolism in morbidly obese patients. We conclude that 1) enhanced visceral fat accumulation is a feature of T2D, 2) severe obesity compromises muscle insulin sensitivity more than fat insulin sensitivity, and 3) fat mass expansion is a sink for plasma glucose.

Systemic metabolic markers and myocardial glucose uptake in type 2 diabetic and coronary artery disease patients treated for 16 weeks with rosiglitazone, a PPARγ agonist

Abstract Introduction. Treatment with rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, in type 2 diabetic mellitus (T2DM) patients is under scrutiny because it affects adversely cardiovascular outcomes. In T2DM patients, with existing coronary heart disease, short-term treatment with rosiglitazone increases myocardial glucose uptake (MGU). Serum metabolic and lipoprotein subclass changes, which may be associated with this rosiglitazone-induced improvement, are unknown. Methods. Patients with both T2DM and coronary heart disease were separated into placebo (n = 26) and treatment (rosiglitazone 4–8 mg; n = 25) groups. After 16 weeks of treatment, serum NMR metabolomics was used to measure circulating low-molecular-weight metabolites and lipoprotein subclasses and lipids that are associated with T2DM before and after the treatment. Significant metabolic measure changes after rosiglitazone treatment were correlated to MGU values assessed with [18F]fluorodeoxyglucose positron emission tomography. Results. Compared to placebo, the treatment significantly increased circulating glutamine and decreased lactate concentrations. Circulating lactate concentrations showed a significant inverse association with MGU after rosiglitazone treatment. Conclusion. In T2DM patients with existing coronary heart disease, short-term rosiglitazone treatment caused minor improvements in metabolism: serum lactate and glutamine concentrations changed, reflecting improvements in insulin sensitivity, and circulating lactate concentrations inversely correlated to increases in myocardial glucose uptake.

The interaction of blood flow, insulin, and bradykinin in regulating glucose uptake in lower-body adipose tissue in lean and obese subjects.

CONTEXT Impaired adipose tissue (AT) blood flow has been implicated in the pathogenesis of insulin resistance in obesity. Insulin and bradykinin are meal-stimulated promoters of AT blood flow and glucose metabolism. OBJECTIVE We tested whether blood flow regulates glucose metabolism in AT, insulin and bradykinin exert additive effects on AT blood flow and metabolism, and any of these actions explains the insulin resistance observed in obese individuals. DESIGN Perfusion and glucose metabolism in the AT of the thighs were studied by positron emission tomography and H(2)(15)O (flow tracer) and (18)F-2-fluoro-2-deoxyglucose. Study I included five subjects in whom positron emission tomography imaging was performed in the fasting state during intraarterial infusion of bradykinin in the left leg; the right leg served as a control. Study II included seven lean and eight obese subjects in whom the imaging protocol was performed during euglycemic hyperinsulinemia. RESULTS Bradykinin alone doubled fasting AT blood flow without modifying glucose uptake. Hyperinsulinemia increased AT blood flow (P ≤ 0.05) similarly in lean and obese individuals. In the lean group, bradykinin increased insulin-mediated AT glucose uptake from 8.6 ± 1.6 to 12.3 ± 2.4 μmol/min · kg (P = 0.038). In the obese group, AT glucose uptake was impaired (5.0 ± 1.0 μmol/min · kg, P = 0.05 vs. the lean group), and bradykinin did not exert any metabolic action (6.0 ± 0.8 μmol/min · kg, P = 0.01 vs. the lean group). CONCLUSION AT blood flow is not an independent regulator of AT glucose metabolism. Insulin is a potent stimulator of AT blood flow, and bradykinin potentiates the hemodynamic and metabolic actions of insulin in lean but not in obese individuals.

The Pro12Ala polymorphism of the PPARγ2 gene is associated with hepatic glucose uptake during hyperinsulinemia in subjects with type 2 diabetes mellitus

The Ala12 allele of the peroxisome proliferator-activated receptor gamma gene (PPARG2) has been associated with reduced risk of type 2 diabetes mellitus (T2DM) and increased whole-body and skeletal muscle insulin sensitivity in nondiabetic subjects. The effect of the Pro12Ala polymorphism on tissue specific insulin sensitivity in subjects with T2DM has not been previously investigated. We studied the effect of the Pro12Ala polymorphism on the rates of whole-body, skeletal muscle, and subcutaneous adipose tissue glucose uptake (GU) in T2DM subjects, and the rates of hepatic GU in nondiabetic and T2DM subjects during hyperinsulinemia. Our study included 105 T2DM subjects whose whole-body, skeletal muscle, subcutaneous adipose tissue, and hepatic GUs were measured using (18)F-fluorodeoxyglucose and positron emission tomography during the hyperinsulinemic euglycemic clamp. Hepatic GU was also measured in 68 nondiabetic subjects. In obese (body mass index >or=27 kg/m(2)) subjects with T2DM, the rate of hepatic GU was 28% lower in subjects with the Pro12Pro genotype than in carriers of the Ala12 allele (P = .001); and a similar trend was observed in nondiabetic obese subjects (P = .137). No effect of the Pro12Ala polymorphism on the rates of whole-body, skeletal muscle, or subcutaneous adipose tissue GU was observed in T2DM subjects. We conclude that the Ala12 allele of PPARG2 is associated with higher hepatic GU in obese subjects with T2DM.

Adipose Tissue Oxygenation in Obesity: A Matter of Cardiovascular Risk?

Obesity, a chronic low-grade inflammation disorder characterized by an expansion in adipose tissue mass, is rapidly expanding worldwide leading to an increase in the incidence of comorbidities such as insulin resistance, type 2 diabetes and cardiovascular diseases. This has led to a renewed interest in the adipose tissue function, historically considered as a passive fat storage. It is now well established that adipose tissue is an organ with an active role in production and release of a variety of molecules called adipocytokines. Dysregulated production of adipocytokines seems to be responsible for the pathogenesis of insulin resistance and type 2 diabetes; however, the mechanisms are still unclear. Hypoxia, that occurs when adipocytes expand in obesity, has been proposed as a possible cause of adipose tissue inflammation. On the other hand, recent studies have shown that adipose tissue oxygen tension was actually higher (hyperoxia) than normal and associated with insulin resistance in obesity, despite a reduction in blood flow. This might be explained by the role of mitochondrial oxygen consumption. Hence, further studies are needed to understand the role of adipose tissue oxygenation and perfusion in obesity to assess pathophysiology and novel opportunities for treating the diseases.

Insulin-stimulated glucose uptake in skeletal muscle, adipose tissue and liver: a positron emission tomography study

Objective Insulin resistance is reflected by the rates of reduced glucose uptake (GU) into the key insulin-sensitive tissues, skeletal muscle, liver and adipose tissue. It is unclear whether insulin resistance occurs simultaneously in all these tissues or whether insulin resistance is tissue specific. Design and methods We measured GU in skeletal muscle, adipose tissue and liver and endogenous glucose production (EGP), in a single session using 18F-fluorodeoxyglucose with positron emission tomography (PET) and euglycemic–hyperinsulinemic clamp. The study population consisted of 326 subjects without diabetes from the CMgene study cohort. Results Skeletal muscle GU less than 33 µmol/kg tissue/min and subcutaneous adipose tissue GU less than 11.5 µmol/kg tissue/min characterized insulin-resistant individuals. Men had considerably worse insulin suppression of EGP compared to women. By using principal component analysis (PCA), BMI inversely and skeletal muscle, adipose tissue and liver GU positively loaded on same principal component explaining one-third of the variation in these measures. The results were largely similar when liver GU was replaced by EGP in PCA. Liver GU and EGP were positively associated with aging. Conclusions We have provided threshold values, which can be used to identify tissue-specific insulin resistance. In addition, we found that insulin resistance measured by GU was only partially similar across all insulin-sensitive tissues studied, skeletal muscle, adipose tissue and liver and was affected by obesity, aging and gender.

Brain glucose uptake is associated with endogenous glucose production in obese patients before and after bariatric surgery and predicts metabolic outcome at follow-up

To investigate further the finding that insulin enhances brain glucose uptake (BGU) in obese but not in lean people by combining BGU with measures of endogenous glucose production (EGP), and to explore the associations between insulin‐stimulated BGU and peripheral markers, such as metabolites and inflammatory markers.