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Michael Roden

Publications and source records attributed to Michael Roden.

At least 19 recordsLinked to original sources
PubMed2026

A narrative review of what cohorts have taught us and how they have laid the foundation for much of our understanding of type 2 diabetes.

This narrative review provides a historical perspective on how observational research on type 2 diabetes has been developed and consolidated over the last 50 years and how well-designed cohort studies will provide us with knowledge for research and practice in the future and aid guideline development. We have included data from a large number of cohorts from every continent that have been used to study the development and/or progression of type 2 diabetes, including cohorts that are general population-based, disease-based, intervention-based and registry-based. We have structured the results from the past 50 years based on the following themes: diagnosis and screening, complications, risk factors and pathophysiology. We also discuss the strengths and weaknesses of observational research when compared with other research designs. Finally, we discuss the emerging and future directions for type 2 diabetes research using cohorts, which include novel developments, such as artificial intelligence, precision health and the exposome. We conclude that cohort research has significantly advanced our understanding of type 2 diabetes and aided guideline development, and complements experimental work, such as human randomised controlled trials and animal studies. Both approaches are essential and complementary in our pursuit to provide a more comprehensive understanding of the development and progression of type 2 diabetes, and to change dogma, practice and policies for better outcomes.

Humans↗
PubMed2007

Hepatic autoregulation: response of glucose production and gluconeogenesis to increased glycogenolysis.

The effect of increased glycogenolysis, simulated by galactose's conversion to glucose, on the contribution of gluconeogenesis (GNG) to hepatic glucose production (GP) was determined. The conversion of galactose to glucose is by the same pathway as glycogen's conversion to glucose, i.e., glucose 1-phosphate --> glucose 6-phosphate --> glucose. Healthy men (n = 7) were fasted for 44 h. At 40 h, hepatic glycogen stores were depleted. GNG then contributed approximately 90% to a GP of approximately 8 micromol.kg(-1).min(-1). Galactose, 9 g/h, was infused over the next 4 h. The contribution of GNG to GP declined from approximately 90% to 65%, i.e., by approximately 2 micromol.kg(-1).min(-1). The rate of galactose conversion to blood glucose, measured by labeling the infused galactose with [1-(2)H]galactose (n = 4), was also approximately 2 micromol.kg(-1).min(-1). The 41st h GP rose by approximately 1.5 micromol.kg(-1).min(-1) and then returned to approximately 9 micromol.kg(-1).min(-1), while plasma glucose concentration increased from approximately 4.5 to 5.3 mM, accompanied by a rise in plasma insulin concentration. Over 50% of the galactose infused was accounted for in blood glucose and hepatic glycogen formation. Thus an increase in the rate of GP via the glycogenolytic pathway resulted in a concomitant decrease in the rate of GP via GNG. While the compensatory response to the galactose administration was not complete, since GP increased, hepatic autoregulation is operative in healthy humans during prolonged fasting.

Adult↗
PubMed2006

Free fatty acids normalize a rosiglitazone-induced visfatin release.

The detrimental effect of elevated free fatty acids (FFAs) on insulin sensitivity can be improved by thiazolidinediones (TZDs) in patients with type 2 diabetes mellitus. It is unknown whether this salutary action of TZD is associated with altered release of the insulin-mimetic adipocytokine visfatin. In this study, we investigated whether visfatin concentrations are altered by FFA and TZD treatment. In a randomized, double-blind, placebo-controlled, parallel-group study 16 healthy volunteers received an infusion of triglycerides/heparin to increase plasma FFA after 3 wk of treatment with rosiglitazone (8 mg/day, n = 8) or placebo (n = 8), and circulating plasma visfatin was measured. As a corollary, human adipocytes were incubated with synthetic fatty acids and rosiglitazone to assess visfatin release in vitro. The results were that rosiglitazone treatment increased systemic plasma visfatin concentrations from 0.6 +/- 0.1 to 1.7 +/- 0.2 ng/ml (P < 0.01). Lipid infusion caused a marked elevation of plasma FFA but had no effect on circulating visfatin in controls. In contrast, elevated visfatin concentrations in subjects receiving rosiglitazone were normalized by lipid infusion. In isolated adipocytes, visfatin was released into supernatant medium by acute addition and long-term treatment of rosiglitazone. This secretion was blocked by synthetic fatty acids and by inhibition of phosphatidylinositol 3-kinase or Akt. In conclusion, release of the insulin-mimetic visfatin may represent a major mechanism of metabolic TZD action. The presence of FFA antagonizes this action, which may have implications for visfatin bioactivity.

Adipocytes↗
PubMed2006

The role of endocrine counterregulation for estimating insulin sensitivity from intravenous glucose tolerance tests.

CONTEXT: During insulin-modified frequently sampled iv glucose tolerance tests (IM-FSIGT), which allow assessment of insulin action, plasma glucose can markedly decrease. OBJECTIVE: This study aimed to assess the counterregulatory impact of the insulin-induced fall of glucose on minimal model-derived indices of insulin sensitivity (S(I)) and glucose effectiveness. PARTICIPANTS: Thirteen nondiabetic volunteers (seven males, six females, aged 26 +/- 1 yr, body mass index 22.1 +/- 0.7 kg/m(2)) were studied. DESIGN: All participants were studied in random order during IM-FSIGT (0.3 g/kg glucose; 0.03 U/kg insulin at 20 min) and during identical conditions but with a variable glucose infusion preventing a decrease of plasma glucose concentration below euglycemia (IM-FSIGT-CLAMP). Five participants additionally underwent euglycemic-hyperinsulinemic (1 mU.kg(-1).min(-1)) clamp tests. RESULTS: Plasma glucose declined during IM-FSIGT to its nadir of 50 +/- 3 mg/dl at 60 min in parallel to a rise (P < 0.05 vs. basal) of plasma glucagon, cortisol, epinephrine, and GH. Glucose infusion rates of 4.6 +/- 0.5 mg.kg(-1).min(-1) between 30 and 180 min during IM-FSIGT-CLAMP prevented the decline of plasma glucose and the hypoglycemia counterregulatory hormone response. S(I) was approximately 68% lower during IM-FSIGT (3.40 +/- 0.36 vs. IM-FSIGT-CLAMP: 10.71 +/- 1.06 10(-4).min(-1) per microU/ml, P < 0.0001), whereas glucose effectiveness did not differ between both protocols (0.024 +/- 0.002 vs. 0.021 +/- 0.003 min(-1), P = NS). Compared with the euglycemic hyperinsulinemic clamp test, S(I) expressed in identical units from IM-FSIGT was approximately 66% (P < 0.001) lower but did not differ between the euglycemic hyperinsulinemic clamp test and the IM-FSIGT-CLAMP (P = NS). CONCLUSIONS: The transient fall of plasma glucose during IM-FSIGT results in lower estimates of S(I), which can be explained by hormonal response to hypoglycemia.

Adult↗
PubMed2006

[Diabetes mellitus].

Explore the source record for details and available documents.

Clinical Trials as Topic↗
PubMed2006

Mechanisms of Disease: hepatic steatosis in type 2 diabetes--pathogenesis and clinical relevance.

Hepatic steatosis is defined by an increased content of hepatocellular lipids (HCLs) and is frequently observed in insulin-resistant states including type 2 diabetes mellitus. A dietary excess of saturated fat contributes significantly to HCL accumulation. Elevated HCL levels mainly account for hepatic insulin resistance, which is probably mediated by partitioning of free fatty acids to the liver (fat overflow) and by an imbalance of adipocytokines (decreased adiponectin and/or increased proinflammatory cytokines). Both free fatty acids and adipocytokines activate inflammatory pathways that include protein kinase C, the transcription factor nuclear factor kappaB, and c-Jun N-terminal kinase 1 and can thereby accelerate the progression of hepatic steatosis to nonalcoholic steatohepatitis and cirrhosis. Proton magnetic resonance spectroscopy has made it possible to quantify HCL concentrations and to detect even small changes in these concentrations in clinical settings. Moderately hypocaloric, fat-reduced diets can decrease HCL levels by approximately 40-80% in parallel with loss of up to 8% of body weight. Treatment with thiazolidinediones (e.g. pioglitazone and rosiglitazone) reduces HCL levels by 30-50% by modulating insulin sensitivity and endocrine function of adipose tissue in type 2 diabetes. Metformin improves hepatic insulin action without affecting HCL levels, whereas insulin infusion for 67 h increases HCL levels by approximately 18%; furthermore, HCL levels positively correlate with the insulin dosage in insulin-treated type 2 diabetes. In conclusion, liver fat is a critical determinant of metabolic fluxes and inflammatory processes, thereby representing an important therapeutic target in insulin resistance and type 2 diabetes mellitus.

Diabetes Mellitus, Type 2↗
PubMed2006

C-peptide does not affect ocular blood flow in patients with type 1 diabetes.

OBJECTIVE: The aim of the present study was to investigate the effect of intravenous C-peptide infusion on ocular blood flow in patients with type 1 diabetes under euglycemic conditions. RESEARCH DESIGN AND METHODS: The study was performed in a randomized, placebo-controlled, double-masked, two-way, crossover design in 10 type 1 diabetic patients. C-peptide was intravenously administered at two different dosages (dosage 1: 25 pmol . kg(-1) . min(-1) bolus followed by 5 pmol . kg(-1) . min(-1) continuous infusion; dosage 2: six times higher than dosage 1), each for 60 min. Physiologic saline solution was used as a control for C-peptide on a different study day. On both study days, euglycemic clamps were performed. To assess retinal blood flow, laser Doppler velocimetry (blood flow velocities) and retinal vessel analyzer (vessels diameters) measurements were performed. Laser interferometric measurements of fundus pulsation were used to assess pulsatile choroidal blood flow. Blood velocities in the ophthalmic artery were measured using color Doppler imaging. RESULTS: Eight patients (two female and six male) completed the study according to the protocol and without adverse events. One patient developed an anaphylactic reaction to C-peptide, which resolved without sequelae. The following results originate from the remaining eight subjects. Systemic hemodynamic parameters remained stable during both study days. Infusion of C-peptide did not affect any ocular hemodynamic parameter. CONCLUSIONS: The data of the present study indicate that exogenous C-peptide exerts no effect on ocular hemodynamic parameters in type 1 diabetic patients under euglycemic conditions. The maximum detectable change in these parameters was <25%.

Adult↗
PubMed2006

Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle.

Insulin resistance correlates with intramyocellular lipid content (IMCL) and plasma free fatty acids (FFAs) and was recently linked to mitochondrial dysfunction. We examined the underlying relationships by measuring skeletal muscle ATP synthase flux, glucose transport/phosphorylation, and IMCL in response to different plasma insulin and plasma FFA concentrations. Healthy men were studied twice during hyperinsulinemic-euglycemic clamps with (LIP) or without (CON) lipid infusion (plasma FFA: CON approximately 36 vs. LIP approximately 1,034 micromol/l, P < 0.001). ATP synthase flux, glucose-6-phosphate (G6P), and IMCL were determined before and during the clamp in calf muscle using (31)P and (1)H magnetic resonance spectroscopy. Plasma lipid elevation resulted in approximately 46% reduced whole-body glucose metabolism (180-360 min; P < 0.0001 vs. CON) and a 70% lower rise of G6P (P < 0.05 vs. CON) without significant changes in IMCL (LIP 117 +/- 12% vs. CON 93 +/- 3% of basal, P = 0.073). During the clamp, ATP synthase flux increased by approximately 60% under control conditions (P = 0.02 vs. baseline) and was 24% lower during lipid infusion (LIP 11.0 +/- 0.9 vs. CON 14.6 +/- 1.2 micromol . g muscle(-1) . min(-1), P < 0.05). Physiologically increased plasma FFA concentrations reduce insulin-stimulated muscle ATP synthase flux in parallel with induction of insulin resistance.

Adenosine Triphosphate↗
PubMed2005

Muscle type-specific fatty acid metabolism in insulin resistance: an integrated in vivo study in Zucker diabetic fatty rats.

Intramyocellular lipid content (IMCL) serves as a good biomarker of skeletal muscle insulin resistance (IR). However, intracellular fatty acid metabolites [malonyl-CoA, long-chain acyl-CoA (LCACoA)] rather than IMCL are considered to be responsible for IR. This study aimed to investigate dynamics of IMCL and fatty acid metabolites during fed-to-starved-to-refed transition in lean and obese (IR) Zucker diabetic fatty rats in the following different muscle types: soleus (oxidative), extensor digitorum longus (EDL, intermediary), and white tibialis anterior (wTA, glycolytic). In the fed state, IMCL was significantly elevated in obese compared with lean rats in all three muscle types (soleus: 304%, EDL: 333%, wTA: 394%) in the presence of elevated serum triglycerides but similar levels of free fatty acids (FFA), malonyl-CoA, and total LCACoAs. During starvation, IMCL in soleus remained relatively constant, whereas in both rat groups IMCL increased significantly in wTA and EDL after comparable dynamics of starvation-induced FFA availability. The decreases of malonyl-CoA in wTA and EDL during starvation were more pronounced in lean than in obese rats, although there were no changes in soleus muscles for both groups. The concomitant increase in IMCL with the fall of malonyl-CoA support the concept that, as a reaction to starvation-induced FFA availability, muscle will activate lipid oxidation more the lower its oxidative capacity and then store the rest as IMCL.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2005

The role of intramyocellular lipids during hypoglycemia in patients with intensively treated type 1 diabetes.

CONTEXT: Endocrine defensive mechanisms provide for energy supply during hypoglycemia. Intramyocellular lipids (IMCL) were recently shown to contribute to energy supply during exercise. OBJECTIVE: The objective of this study was to assess the contribution of IMCL compared with lipolysis and endogenous glucose production (EGP) to insulin-mediated hypoglycemia counterregulation in patients with type 1 diabetes mellitus (T1DM). DESIGN AND SETTING: This was a prospective explorative study performed in a university research facility. PARTICIPANTS: Six well-controlled T1DM (age, 29 +/- 4 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 6.3 +/- 0.1%) and six nondiabetic humans (controls; age, 28 +/- 2 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 5.1 +/- 0.1%) were studied. INTERVENTIONS: We performed 240-min hypoglycemic (approximately 3 mM)-hyperinsulinemic (0.8 mU/kg x min) clamps on separate days to measure: 1) systemic lipolysis ([2H5]glycerol turnover), EGP ([6,6-(2)H2]glucose), and local lipolysis in abdominal s.c. adipose tissue and gastrocnemius muscle (microdialysis); and 2) IMCL (by 1H nuclear magnetic resonance spectroscopy) in soleus and tibialis anterior muscle. MAIN OUTCOME MEASURES: The main outcome measures were changes in IMCL during prolonged hypoglycemia. RESULTS: At baseline, EGP, glycerol turnover, and IMCL were not different between the groups. During hypoglycemia, hormonal counterregulation was blunted in T1DM (peak: glucagon, 68 +/- 4 vs. 170 +/- 37 pg/ml; cortisol, 16 +/- 2 vs. 24 +/- 2 microg/dl; epinephrine, 274 +/- 84 vs. 597 +/- 212 pg/ml; all P < 0.05 vs. control). T1DM had approximately 50% lower EGP (4.6 +/- 0.6 vs. 10.9 +/- 0.5 micromol/kg x min; P < 0.005), but approximately 40% higher glycerol turnover (374 +/- 21 vs. 272 +/- 19 micromol/kg x min; P < 0.01). Glycerol concentrations in muscle (T1DM, 302 +/- 22 control, 346 +/- 17 micromol/liter) and adipose tissue (264 +/- 25 vs. 318 +/- 25 micromol/liter) did not differ between groups. IMCL in soleus and tibialis anterior muscle did not change from baseline during hypoglycemia. CONCLUSIONS: In well-controlled T1DM, impaired hypoglycemia counterregulation is associated with decreased glucose production and augmented whole body lipolysis, which cannot be explained by either hydrolysis of muscle triglycerides or increased abdominal s.c. adipose tissue lipolysis.

Adipose Tissue↗
PubMed2005

Hepatic leptin signaling in obesity.

Obesity, a state of apparent "leptin resistance" is well known to be associated with insulin resistance. In diet-induced obesity (DIO), hepatic insulin signaling is impaired but the link between leptin and insulin signaling pathways is only incompletely defined. The aim of the present study was to evaluate the effects of DIO on leptin and insulin cross-signaling in the liver. Leptin receptor expression was measured by in situ hybridization with pan-leptin receptor probes and by immunoblotting. Furthermore, intracellular signaling was investigated in vivo under basal conditions and at 45 and 360 min after stimulation with a bolus of human recombinant leptin (hrec-leptin; 1 mg/kg body wt) or saline. At baseline, all forms of the leptin receptor were markedly to completely down-regulated in DIO rats. Hrec-leptin bolus injection stimulated leptin-dependent signaling with a fivefold increase in JAK-2pY in lean but not in DIO rats. Basal IRpY, IRS-1pY, IRS-1p85, IRS-2pY, IRSp85, and PKBpT308 levels were reduced (P<0.01) in DIO rats as compared with lean controls. Basal GSK-3beta serine phosphorylation (S9) was higher (P<0.01) in lean animals along with lower basal PEPCK activity compared with DIO rats consistent with the insulin and leptin resistance of the latter. Only in lean animals phosphorylation of PKB (T308) and GSK-3beta (S9) was acutely stimulated by leptin at 45 min followed by inhibition at 6 h after application. AMPKalpha protein levels as well as basal and leptin-stimulated total and alpha-specific AMPK activity were comparable in both groups. These data show that in a model of dietary-induced obesity 1) leptin receptors and subsequent signaling events are down-regulated, 2) basal insulin signaling is impaired, and 3) the cross-talk between leptin and insulin signaling is differentially regulated by the nutritional status, which is sensed by AMPK in rat liver. Thus, the liver seems to play a major role in the modulation of the leptin signal and insulin resistance in obesity.

AMP-Activated Protein Kinases↗
PubMed2005

Insulin glargine in combination with oral antidiabetic drugs as a cost-equivalent alternative to conventional insulin therapy in type 2 diabetes mellitus.

BACKGROUND AND RATIONALE: Recent data suggest that insulin glargine might be a cost-effective alternative to conventional insulin therapy in patients with type 2 diabetes mellitus (T2DM). The aim of this observational study was to evaluate the treatment costs of insulin glargine in combination with oral antidiabetic drugs (OADs) compared with conventional insulin therapy in T2DM in everyday clinical practice. PATIENTS AND METHODS: Data were obtained from a cohort of 678 patients with T2DM not adequately controlled by OADs alone (HbA1c mean 9.1 +/- 1.7%). Patients received either insulin glargine in addition to oral therapy or were switched to conventional insulin therapy. Treatment and dosing decisions were made at the physician's discretion, reflecting everyday practice. Patients were followed for 2-4 months. Primary outcome parameters were total treatment costs and clinical efficacy. RESULTS: The two therapeutic regimens were equally effective in decreasing HbA1c to 7.8% (p < 10(-9)). Patients in the insulin glargine plus OAD group controlled their blood glucose level at endpoint with a median of 60 test strips per month and those in the conventional insulin therapy group with a median of 80 strips per month (p = 0.000000739). Total daily costs of insulin, needles, glycemic control and OAD treatment per patient were similar in the two treatment groups (insulin glargine group 1.91 Euro vs conventional group 1.99 Euro). CONCLUSION: The two treatment regimens were equally effective in improving glycemic control. These results were achieved with significantly lower insulin doses and fewer blood glucose test strips in the insulin glargine group, which therefore led to cost equivalence when compared with conventional insulin therapy.

Administration, Oral↗
PubMed2005

Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability.

To examine the molecular mechanisms by which plasma amino acid elevation impairs insulin action, we studied seven healthy men twice in random order during infusion of an amino acid mixture or saline (total plasma amino acid approximately 6 vs. approximately 2 mmol/l). Somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia ( approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia ( approximately 430 pmol/l, 180-360 min). At low peripheral hyperinsulinemia, endogenous glucose production (EGP) did not change during amino acid infusion but decreased by approximately 70% during saline infusion (EGP(150-180 min) 11 +/- 1 vs. 3 +/- 1 mumol . kg(-1) . min(-1), P = 0.001). Prandial-like peripheral hyperinsulinemia completely suppressed EGP during both protocols, whereas whole-body rate of glucose disappearance (R(d)) was approximately 33% lower during amino acid infusion (R(d) (330-360 min) 50 +/- 4 vs. 75 +/- 6 mumol . kg(-1) . min(-1), P = 0.002) indicating insulin resistance. In skeletal muscle biopsies taken before and after prandial-like peripheral hyperinsulinemia, plasma amino acid elevation markedly increased the ability of insulin to activate S6 kinase 1 compared with saline infusion ( approximately 3.7- vs. approximately 1.9-fold over baseline). Furthermore, amino acid infusion increased the inhibitory insulin receptor substrate-1 phosphorylation at Ser312 and Ser636/639 and decreased insulin-induced phosphoinositide 3-kinase activity. However, plasma amino acid elevation failed to reduce insulin-induced Akt/protein kinase B and glycogen synthase kinase 3alpha phosphorylation. In conclusion, amino acids impair 1) insulin-mediated suppression of glucose production and 2) insulin-stimulated glucose disposal in skeletal muscle. Our results suggest that overactivation of the mammalian target of rapamycin/S6 kinase 1 pathway and inhibitory serine phosphorylation of insulin receptor substrate-1 underlie the impairment of insulin action in amino acid-infused humans.

Adult↗
PubMed2004

Relationship between serum lipoprotein ratios and insulin resistance in obesity.

BACKGROUND: The fasting serum lipid profile [triglycerides (TGs), total cholesterol (TC), and LDL- and HDL-cholesterol (LDL-C and HDL-C)] is used to calculate lipid ratios (TC/HDL-C, LDL-C/HDL-C, TG/HDL-C) that allow identification of individuals at increased risk for cardiovascular disease. Because these individuals are also frequently insulin resistant, this study analyzed the relationships between lipid ratios and insulin sensitivity. METHODS: In 132 obese [mean (SE) body mass index, 37.5 (0.6) kg/m(2)] outpatients without known diabetes mellitus, fasting serum lipid profiles and 75-g oral glucose tolerance tests were performed. Insulin sensitivity was assessed from surrogate estimates for fasting (QUICKI) and dynamic (OGIS) conditions. RESULTS: After exclusion of other endocrine diseases (n = 35), the remaining patients were classified as glucose tolerant (n = 56), glucose intolerant (n = 22), or as having type 2 diabetes (n = 19). QUICKI and OGIS indicated severe insulin resistance in all individuals with type 2 diabetes and impaired glucose tolerance compared with glucose-tolerant individuals: QUICKI, glucose tolerant, 0.302 (0.002); glucose intolerant, 0.290 (0.002); type 2 diabetes, 0.281 (0.005); P <0.001; OGIS (mL . m(-2) . min(-1)), glucose tolerant, 343 (7), glucose intolerant, 293 (9); type 2 diabetes, 256 (12); P <0.001. Serum TG (P <0.005) and TG/HDL-C ratios (P <0.05) were increased in individuals with impaired glucose tolerance. TG/HDL-C ratios negatively correlated with QUICKI (r = -0.370; P < 0.001) and OGIS (r = -0.333; P < 0.005) in nondiabetic individuals (glucose tolerant plus glucose intolerant), but not in patients with type 2 diabetes (not significant). CONCLUSIONS: This study demonstrates that the TG/HDL-C ratio positively correlates with insulin resistance in severely obese nondiabetic individuals.

Adult↗
PubMed2004

Fenofibrate impairs rat mitochondrial function by inhibition of respiratory complex I.

Fibrates are used for the treatment of dyslipidemia and known to affect mitochondrial function in vitro. To better understand the mechanisms underlying their mitochondrial effects, fibrate actions on complex I of the respiratory chain and cell respiration were studied in vitro. In homogenates of rat skeletal muscle, fenofibrate, and to a lesser extent clofibrate, reduced the activity of complex I (10, 30, and 100 microM fenofibrate: -41 +/- 7%, -70 +/- 2%, and -78 +/- 4%; 100 microM clofibrate: -27 +/- 7%; p < 0.005 each). Inhibition of complex I by fenofibrate (100 microM) was confirmed by reduced state 3 respiration of isolated mitochondria consuming glutamate + malate as substrates for complex I (-33 +/- 4%; p < 0.0005), but not of such consuming succinate as substrate for complex II (-8 +/- 4%; NS). In isolated rat muscle, 24-h fenofibrate exposure (25, 50, and 100 microM) decreased CO(2) production from palmitate (-15 +/- 7%, -23 +/- 8%, and -22 +/- 7%; p < 0.05 each) and increased lactate release (+15 +/- 5%, +14 +/- 5%, and + 17 +/- 6%; p < 0.02 each) indicating impaired cell respiration. Ciprofibrate and gemfibrocil (but not bezafibrate) impaired cell respiration without any inhibition of complex I. Our findings support the notion that individual fibrates induce mitochondrial dysfunction via different molecular mechanisms and show that fenofibrate predominantly acts by inhibition of complex I of the respiratory chain.

Animals↗
PubMed2004

[Future targets in the treatment of type 2 diabetes].

Prevention and treatment of type 2 diabetes mellitus (T2DM) and the metabolic syndrome represent a major clinical challenge, because effective strategies such as fat restriction and exercise are difficult to implement into diabetes treatment. Based on the increasing knowledge on the pathogenesis of T2DM, new therapeutic approaches are currently under investigation. Potential targets of new therapeutic approaches include: (i) Inhibition of hepatic glucose production, (ii) stimulation of glucose-dependent insulin secretion, (iii) enhancement of insulin signal transduction, and (iv) reduction of body fat mass. Agonists of glucagon-like-peptide 1 (GLP-1) and antagonists of dipeptidylpeptidase IV, which inactivates GLP-1, stimulate glucose-dependent insulin secretion, improve hyperglycemia and are already tested in clinical trials. In humans, glucagon antagonists and an amylin analogue reduce glucagon-dependent glucose production. The glucose-lowering effect of current modulators of lipid oxidation is not pronounced and their use could be limited by side effects. In addition to clinically approved thiazolidendiones, new agonists of the peroxisome proliferator activator receptor gamma (PPAR gamma) as well as combined PPAR alpha/gamma agonists are developed at present. The direct modulation of insulin signal transduction is still limited to experimental studies.

Animals↗