High-Fat Diet During Mouse Pregnancy and Lactation Targets GIP-Regulated Metabolic Pathways in Adult Male Offspring.

Maternal obesity is a worldwide problem associated with increased risk of metabolic diseases in the offspring. Genetic deletion of the gastric inhibitory polypeptide (GIP) receptor (GIPR) prevents high-fat diet (HFD)-induced obesity in mice due to specific changes in energy and fat cell metabolism. We investigated whether GIP-associated pathways may be targeted by fetal programming and mimicked the situation by exposing pregnant mice to control or HFD during pregnancy (intrauterine [IU]) and lactation (L). Male wild-type (WT) and Gipr(-/-) offspring received control chow until 25 weeks of age followed by 20 weeks of HFD. Gipr(-/-) offspring of mice exposed to HFD during IU/L became insulin resistant and obese and exhibited increased adipose tissue inflammation and decreased peripheral tissue substrate utilization after being reintroduced to HFD, similar to WT mice on regular chow during IU/L. They showed decreased hypothalamic insulin sensitivity compared with Gipr(-/-) mice on control diet during IU/L. DNA methylation analysis revealed increased methylation of CpG dinucleotides and differential transcription factor binding of promoter regions of genes involved in lipid oxidation in the muscle of Gipr(-/-) offspring on HFD during IU/L, which were inversely correlated with gene expression levels. Our data identify GIP-regulated metabolic pathways that are targeted by fetal programming.

Nutritional strategy to prevent fatty liver and insulin resistance independent of obesity by reducing glucose-dependent insulinotropic polypeptide responses in mice.

AIMS/HYPOTHESIS: High intake of carbohydrates, particularly sucrose, in western societies is associated with the development of non-alcoholic fatty liver (NAFL) and diabetes mellitus. It is unclear whether this is related primarily to the carbohydrate quantity or to the hormonal responses, particularly glucose-dependent insulinotropic polypeptide (GIP), which is released in the proximal intestine. Therefore, we investigated the role of GIP by comparing two glucose-fructose dimers, sucrose and Palatinose (isomaltulose), resorbed proximally or distally. METHODS: The glycaemic and incretin responses to sucrose and Palatinose were studied by oral gavage and meal tests. We then analysed phenotypic and metabolic diet-induced changes in C57Bl/6J mice exposed to isoenergetic diets differing in carbohydrate type. Studies were repeated in GIP receptor knockout (Gipr(-/-)) mice and their wild-type littermates. RESULTS: Compared with sucrose, Palatinose intake resulted in slower glucose absorption and reduced postprandial insulin and GIP levels. After 22 weeks, Palatinose feeding prevented hepatic steatosis (48.5%) compared with sucrose and improved glucose tolerance, without differences in body composition and food intake. Ablation of GIP signalling in Gipr(-/-) mice completely prevented the deleterious metabolic effects of sucrose feeding. Furthermore, our microarray analysis indicated that sucrose increased 2.3-fold the hepatic expression of Socs2, which is involved in the growth hormone signalling pathway and participates in the development of NAFL. CONCLUSIONS/INTERPRETATION: Our results suggest that the site of glucose absorption and the GIP response determine liver fat accumulation and insulin resistance. GIP may play a role in sucrose induced fatty liver by regulating the expression of Socs2.

Hepatic insulin clearance is closely related to metabolic syndrome components.

OBJECTIVE: Insulin clearance is decreased in type 2 diabetes mellitus (T2DM) for unknown reasons. Subjects with metabolic syndrome are hyperinsulinemic and have an increased risk of T2DM. We aimed to investigate the relationship between hepatic insulin clearance (HIC) and different components of metabolic syndrome and tested the hypothesis that HIC may predict the risk of metabolic syndrome. RESEARCH DESIGN AND METHODS: Individuals without diabetes from the Metabolic Syndrome Berlin Brandenburg (MeSyBePo) study (800 subjects with the baseline examination and 189 subjects from the MeSyBePo recall study) underwent an oral glucose tolerance test (OGTT) with assessment of insulin secretion (insulin secretion rate [ISR]) and insulin sensitivity. Two indices of HIC were calculated. RESULTS: Both HIC indices showed lower values in subjects with metabolic syndrome (P < 0.001) at baseline. HIC indices correlate inversely with waist circumference, diastolic blood pressure, fasting glucose, triglycerides, and OGTT-derived insulin secretion index. During a mean follow-up of 5.1 ± 0.9 years, 47 individuals developed metabolic syndrome and 33 subjects progressed to impaired glucose metabolism. Both indices of HIC showed a trend of an association with increased risk of metabolic syndrome (HICC-peptide odds ratio 1.13 [95% CI 0.97-1.31], P = 0.12, and HICISR 1.38 [0.88-2.17], P = 0.16) and impaired glucose metabolism (HICC-peptide 1.12 [0.92-1.36], P = 0.26, and HICISR 1.31 [0.74-2.33] P = 0.36), although point estimates reached no statistical significance. CONCLUSIONS: HIC was associated with different components of metabolic syndrome and markers of insulin secretion and insulin sensitivity. Decreased HIC may represent a novel pathophysiological mechanism of the metabolic syndrome, which may be used additionally for early identification of high-risk subjects.

Glucose-dependent insulinotropic polypeptide reduces fat-specific expression and activity of 11ß-hydroxysteroid dehydrogenase type 1 and inhibits release of free fatty acids.

Glucose-dependent insulinotropic polypeptide (GIP) has been suggested to have direct effects on nonislet tissues. GIP also reportedly increased glucose uptake and inhibition of lipolysis in adipocytes after inhibition of the intracellular cortisone-cortisol shuttle 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). We here analyzed whether GIP modifies lipid metabolism and further elucidated the relation between GIP, 11ß-HSD1, and fatty acid metabolism. GIP reduced activity of 11ß-HSD1 promoter constructs and the expression and activity of 11ß-HSD1 in differentiated 3T3-L1 adipocytes in a time- and dose-dependent fashion. This was paralleled by a reduction of free fatty acid (FFA) release and a reduced expression of key enzymes regulating lipolysis in adipose tissue. Preinhibition of 11ß-HSD1 completely abolished GIP-induced effects on FFA release. To investigate the acute effects of GIP in humans, a randomized clinical trial was performed. GIP lowered circulating FFAs compared with saline control and reduced expression and ex vivo activity of 11ß-HSD1 and adipose triglyceride lipase expression in subcutaneous fat biopsies. Our data suggest that GIP reduces FFA release from adipose tissue by inhibition of lipolysis or by increased reesterification. This process appears to depend on a modification of 11ß-HSD1 activity. In general, the presented data support that GIP has direct and insulin-independent effects on adipose tissue.

Effects of supplemented isoenergetic diets differing in cereal fiber and protein content on insulin sensitivity in overweight humans.

BACKGROUND: Despite their beneficial effects on weight loss and blood lipids, high-protein (HP) diets have been shown to increase insulin resistance and diabetes risk, whereas high-cereal-fiber (HCF) diets have shown the opposite effects on these outcomes. OBJECTIVE: We compared the effects of isoenergetic HP and HCF diets and a diet with moderate increases in both cereal fibers and dietary protein (Mix diet) on insulin sensitivity, as measured by using euglycemic-hyperinsulinemic clamps with infusion of [6,6-(2)H(2)]glucose. DESIGN: We randomly assigned 111 overweight adults with features of the metabolic syndrome to 1 of 4 two-phased, 18-wk isoenergetic diets by group-matching. Per 3-d food protocols, the percentages of energy derived from protein and carbohydrates and the intake of cereal fiber per day, respectively, were as follows-after 6 wk: 17%, 52%, and 14 g (control); 17%, 52%, and 43 g (HCF); 28%, 43%, and 13 g (HP); 23%, 44%, and 26 g (Mix); after 18 wk: 17%, 51%, and 15 g (control); 17%, 51%, and 41 g (HCF); 26%, 45%, and 14 g (HP); and 22%, 46%, and 26 g (Mix). Eighty-four participants completed the study successfully and were included in the final analyses. Adherence was supported by the provision of tailored dietary supplements twice daily in all groups. RESULTS: Insulin sensitivity expressed as an M value was 25% higher after 6 wk of the HCF diet than after 6 wk of the HP diet (subgroup analysis: 4.61 ± 0.38 compared with 3.71 ± 0.36 mg · kg(-1) · min(-1), P = 0.008; treatment × time interaction: P = 0.005). Effects were attenuated after 18 wk (treatment × time interaction: P = 0.054), which was likely explained by lower adherence to the HP diet. HP intake was associated with a tendency to increased protein expression in adipose tissue of the translation initiation factor serine-kinase-6-1, which is known to mediate amino acid-induced insulin resistance. Biomarkers of protein intake indicated interference of cereal fibers with dietary protein absorption. CONCLUSION: Greater changes in insulin sensitivity after intake of an isoenergetic HCF than after intake of an HP diet might help to explain the diverse effects of these diets on diabetes risk. This trial is registered at clinicaltrials.gov as NCT00579657.

Androgen receptor CAG repeat length polymorphism modifies the impact of testosterone on insulin sensitivity in men.

OBJECTIVE: Low circulating testosterone concentrations have been associated with insulin resistance (IR). Androgen action is mediated by the androgen receptor (AR) whose activity is modulated by a polymorphic CAG repeat sequence within exon 1. An interaction between testosterone and CAG repeat length (CAG length) with respect to IR has been described in women. OBJECTIVE: We investigated such a putative interaction between testosterone and the CAG length with respect to IR in men with normal glucose tolerance. DESIGN: Cross-sectional study. METHODS: In 113 non-diabetic men calculated free testosterone, the CAG length, and a multiplicative interaction term were investigated by multiple linear regression analysis for an association with IR, as indicated by homeostasis model assessment (HOMA %S). RESULTS: In a multivariate regression analysis adjusted for age and body mass index, free testosterone, CAG length, and a multiplicative interaction term were significantly associated with IR (P=0.001, P=0.001, P=0.01 respectively). The model explained 36.6% of the variation of IR and predicted that in carriers with a CAG length of 23, changes in testosterone would only minimally affect IR. For CAG lengths longer than 23, however, an increase in testosterone would improve IR, namely the longer the CAG length, the greater the effect. In contrast, in the case of CAG lengths shorter than 23, the effect of increasing testosterone would be the opposite. CONCLUSIONS: In men, testosterone and the AR CAG repeat length polymorphism interacted with respect to IR. The interpretation of the association between testosterone and IR seems to require consideration of the AR CAG repeat polymorphism.

Activation of mitochondrial energy metabolism protects against cardiac failure.

Cardiac failure is the most prevalent cause of death at higher age, and is commonly associated with impaired energy homeostasis in the heart. Mitochondrial metabolism appears critical to sustain cardiac function to counteract aging. In this study, we generated mice transgenically over-expressing the mitochondrial protein frataxin, which promotes mitochondrial energy conversion by controlling iron-sulfur-cluster biogenesis and hereby mitochondrial electron flux. Hearts of transgenic mice displayed increased mitochondrial energy metabolism and induced stress defense mechanisms, while overall oxidative stress was decreased. Following standardized exposure to doxorubicin to induce experimental cardiomyopathy, cardiac function and survival was significantly improved in the transgenic mice. The insulin/IGF-1 signaling cascade is an important pathway that regulates survival following cytotoxic stress through the downstream targets protein kinase B, Akt, and glycogen synthase kinase 3. Activation of this cascade is markedly inhibited in the hearts of wild-type mice following induction of cardiomyopathy. By contrast, transgenic overexpression of frataxin rescues impaired insulin/IGF-1 signaling and provides a mechanism to explain enhanced cardiac stress resistance in transgenic mice. Taken together, these findings suggest that increased mitochondrial metabolism elicits an adaptive response due to mildly increased oxidative stress as a consequence of increased oxidative energy conversion, previously named mitohormesis. This in turn activates protective mechanisms which counteract cardiotoxic stress and promote survival in states of experimental cardiomyopathy. Thus, induction of mitochondrial metabolism may be considered part of a generally protective mechanism to prevent cardiomyopathy and cardiac failure.

Role of the gut Peptide glucose-induced insulinomimetic Peptide in energy balance.

Glucose-induced insulinomimetic peptide (GIP) is a gut hormone produced by enteroendocrine K-cells in the intestinal mucosa in response to fat, glucose, and also protein. GIP releases insulin from the ß cells of the pancreatic islets of Langerhans and therefore is an incretin hormone. GIP acts on a G-protein-coupled receptor that is widely distributed in the body including adipose tissue, stomach, brain, and others. Deletion of the GIP receptor (GIPR) renders mice resistant to weight gain induced by a high fat diet.We observed that weight gain induced by ovarectomy in female mice is prevented by GIPR deletion that is linked to reduced food intake and reduced hypothalamic expression of orectic neurotransmitters. Moreover, old male GIPR(-/-) mice placed on a high glycemic index diet maintained a high insulin sensitivity and were much more active than controls, which was not seen in young animals. Thus, GIP elicits central effects in response to nutrients that protect against obesity and insulin resistance. We then investigated the acute responses of humans to treatment with GIP over 4h in a dose mimicking postprandial plasma levels of about 100pmol/L. At basal glucose, GIP does not elicit insulin release. Fat biopsies taken before and after 4h of GIP treatment were analyzed for transcriptomic responses using Agilent whole human genome assays. There was a highly significant upregulation of an inflammatory expression pattern in a pathway analysis.

A high normal TSH is associated with the metabolic syndrome.

OBJECTIVE: Obesity and insulin resistance are key features of the metabolic syndrome. In euthyroidism, the relationships between TSH and insulin resistance or the metabolic syndrome are less clear. We investigated the associations between TSH and the features and prevalence of the metabolic syndrome in euthyroid German subjects. METHODS: In a cross-sectional study, glucose metabolism was defined by an oral glucose tolerance test (oGTT) (except for those with evident diabetes) in 1333 subjects with TSH values between 0.3 and 4.5 mU/l who did not take any thyroid medication. Lipid parameters were measured, blood pressure and anthromopmetric parameters were taken, and insulin resistance was quantified as HOMA%S. RESULTS: TSH was weakly correlated with BMI (R = 0.061, P = 0.025). This association remained significant after adjustment for sex, age, and impaired glucose metabolism (P = 0.002). Subjects with a TSH in the upper normal range (2.5-4.5 mU/l, n = 119) had a significantly higher BMI (30.47 +/- 0.57 vs. 28.74 +/- 0.18 kg/m(2), P = 0.001) and higher fasting triglycerides (1.583 +/- 0.082 vs. 1.422 +/- 0.024 mmol/l, P = 0.023), and their likeliness for fulfilling the ATP III criteria of the metabolic syndrome was 1.7-fold increased (95% CI: 1.11- 2.60). CONCLUSION: In euthyroidism, subjects with a TSH in the upper normal range (2.5-4.5 mU/l) were more obese, had higher triglycerides, and had an increased likeliness for the metabolic syndrome. Therefore, a TSH below 2.5 mU/l is associated with a favourable metabolic profile. Whether lowering TSH to levels below 2.5 mU/l improves metabolism needs to be investigated in intervention trials.

Circulating vaspin is unrelated to insulin sensitivity in a cohort of nondiabetic humans.

OBJECTIVE: To study the association of vaspin with glucose metabolism. DESIGN: Cross-sectional and intervention study. SUBJECTS AND METHODS: The association of serum vaspin with metabolic and anthropometric characteristics was investigated in 108 volunteers. Euglycemic-hyperinsulinemic clamps (EHC) were performed in 83 of the participants. Changes of circulating vaspin levels were additionally studied in a crossover study using 300 min EHC with lipid versus saline infusion (n=10). RESULTS: Neither glucose tolerance status nor insulin sensitivity, both as measured using EHCs and using homeostasis model assessment for insulin resistance (HOMA-IR), was significantly associated with serum vaspin in the cross-sectional study. Furthermore, there was no effect of short-term lipid-induced insulin resistance due to a 300 min intravenous lipid challenge on circulating vaspin. However, circulating vaspin levels were significantly elevated in women using oral contraceptives (OC), both compared to women without OC intake (1.17+/-0.26 vs 0.52+/-0.09 ng/ml, P=0.02) and males (1.17+/-0.26 vs 0.29+/-0.04 ng/ml, P=0.01). After exclusion of OC using females and stratification according to body mass index (BMI), a significant sexual dimorphism in subjects with a BMI <25 kg/m(2) was observed (males 0.21+/-0.04 ng/ml versus females 0.70+/-0.16 ng/ml, P=0.009). CONCLUSION: Our results support the existence of a sexual dimorphism regarding circulating vaspin. The lack of an association of serum vaspin with HOMA-IR and M value indicates, however, no major role for vaspin concerning insulin sensitivity in nondiabetic humans.

Effects of long-term soluble vs. insoluble dietary fiber intake on high-fat diet-induced obesity in C57BL/6J mice.

Although most of the proposed beneficial effects of fiber consumption have been attributed to viscous and gel-forming properties of soluble fiber, it is mainly insoluble cereal fiber and whole grains that are strongly associated with reduced diabetes risk in prospective cohort studies, indicating that other unknown mechanisms are likely to be involved. We performed a long-term study investigating potential protective effects of adding soluble guar fiber (10% w/w) vs. insoluble cereal fiber (10% w/w) to an isoenergetic and macronutrient matched high-fat diet in obesity-prone C57BL/6J mice. After 45 weeks, mice fed soluble vs. insoluble fiber showed both significantly increased body weight (41.8+/-3.0 vs. 33.6+/-1.5 g, P=.03) and elevated markers of insulin resistance. In mice fed soluble fiber, energy loss via the feces was significantly lower and colonic fermentation with production of short chain fatty acids (SCFA) was markedly increased. Gene expression analysis in white adipose tissue showed significantly increased levels of the fatty acid target G-protein coupled receptor-40 in soluble fiber-fed mice. Liver gene expression in the insoluble fiber group showed a pattern consistent with increased fatty acid oxidation. The present results show that soluble vs insoluble dietary fiber added to a high-fat, Western-style diet differently affected body weight and estimates of insulin sensitivity in obesity-prone mice. Soluble fiber intake with increased SCFA production significantly contributed to digested energy, thereby potentially outweighing the well known short-term beneficial effects of soluble fiber consumption.

Increased interleukin-10 but unchanged insulin sensitivity after 4 weeks of (1, 3)(1, 6)-beta-glycan consumption in overweight humans.

Obesity-induced insulin resistance has been suggested to be a systemic inflammatory condition with activation of the innate immune system. Animal studies indicate that certain dietary fibers such as (1,3)(1,6)-beta-D-glycans (BDG) have potent effects on immune activity such as increasing the antiinflammatory cytokine interleukin-10 (IL-10) and reducing the secretion of inflammatory factors. Therefore, we hypothesized that BDG consumption improves inflammatory markers and insulin sensitivity in overweight and obese subjects with moderately increased levels of C-reactive protein, indicating subclinical inflammation. We screened 180 overweight and obese subjects for moderately increased C-reactive protein levels on 2 or more occasions, in the absence of any signs of acute infection. Twelve of the subjects met all inclusion criteria and were investigated in a randomized, double-blind, placebo-controlled, crossover design for 2 x 4 weeks (washout > or =4 weeks). Subjects ingested capsules containing 3 x 0.5 g of highly purified BDG or 3 x 0.5 g of placebo (waxy maize starch) daily. Maintenance of the normal diet of the participants and the correct intake of the capsules were monitored, using 6 x 3-day food recording and counting of the provided capsules. Predefined outcome measures were BDG-induced changes in pro and antiinflammatory markers in circulating blood and gene expression in adipose tissue and peripheral insulin sensitivity expressed as M value. The BDG consumption for 4 weeks significantly increased both circulating levels and adipose tissue messenger RNA (mRNA) expression of the antiinflammatory cytokine IL-10 in overweight and obese humans. Insulin sensitivity as well as circulating levels and mRNA expression of proinflammatory cytokines were unaffected by BDG treatment. Increased IL-10 after BDG consumption might be a contributing factor to the known beneficial effects of dietary fiber intake.

Deficiency of glucose-dependent insulinotropic polypeptide receptor prevents ovariectomy-induced obesity in mice.

Menopause and premature gonadal steroid deficiency are associated with increases in fat mass and body weight. Ovariectomized (OVX) mice also show reduced locomotor activity. Glucose-dependent-insulinotropic-polypeptide (GIP) is known to play an important role both in fat metabolism and locomotor activity. Therefore, we hypothesized that the effects of estrogen on the regulation of body weight, fat mass, and spontaneous physical activity could be mediated in part by GIP signaling. To test this hypothesis, C57BL/6 mice and GIP-receptor knockout mice (Gipr(-/-)) were exposed to OVX or sham operation (n = 10 per group). The effects on body composition, markers of insulin resistance, energy expenditure, locomotor activity, and expression of hypothalamic anorexigenic and orexigenic factors were investigated over 26 wk in all four groups of mice. OVX wild-type mice developed obesity, increased fat mass, and elevated markers of insulin resistance as expected. This was completely prevented in OVX Gipr(-/-) animals, even though their energy expenditure and spontaneous locomotor activity levels did not significantly differ from those of OVX wild-type mice. Cumulative food intake in OVX Gipr(-/-) animals was significantly reduced and associated with significantly lower hypothalamic mRNA expression of the orexigenic neuropeptide Y (NPY) but not of cocaine-amphetamine-related transcript (CART), melanocortin receptors (MCR-3 and MCR-4), or thyrotropin-releasing hormone (TRH). GIP receptors thus interact with estrogens in the hypothalamic regulation of food intake in mice, and their blockade may carry promising potential for the prevention of obesity in gonadal steroid deficiency.

Identification of a functional protein kinase Cbeta promoter polymorphism in humans related to insulin resistance.

Protein kinase Cbeta (PKCbeta) is known to inhibit insulin production in beta-cells and to support insulin action in skeletal muscle. We therefore searched for functional polymorphisms among already known genetic variants in the PKCbeta promoter and investigated their relation to glucose metabolism in humans. We found that the gene variant in the PKCbeta promoter at position -546 significantly reduced promoter activity in functional assays (P<0.05). Human subjects carrying this variant had a 3.5-fold decrease in PKCbeta2-protein expression in their thrombocytes (P=0.006). Additionally, we tested whether this variant affects parameters of glucose metabolism using 1012 humans included into the MeSyBePo study (Metabolic Syndrome Berlin Potsdam). The -546 variant was highly significant associated with increased homeostasis model assessment for insulin resistance (HOMA-IR, P=0.009) in the cohort. This association was accompanied by significantly increased fasting insulin concentrations in carriers of the homozygous polymorphism (P=0.021). Our results suggest that the -546 polymorphism in the PKCbeta promoter reduces promoter activity, which leads to a decreased expression of PKCbeta2 and subsequently is associated with decreased peripheral insulin-dependent glucose uptake.

A Thr94Ala mutation in human liver fatty acid-binding protein contributes to reduced hepatic glycogenolysis and blunted elevation of plasma glucose levels in lipid-exposed subjects.

Liver fatty acid-binding protein (L-FABP) is a highly conserved key factor in lipid metabolism. Amino acid replacements in L-FABP might alter its function and thereby affect glucose metabolism in lipid-exposed subjects, as indicated by studies in L-FABP knockout mice. Amino acid replacements in L-FABP were investigated in a cohort of 1,453 Caucasian subjects. Endogenous glucose production (EGP), gluconeogenesis, and glycogenolysis were measured in healthy carriers of the only common Thr(94)-to-Ala amino acid replacement (Ala/Ala(94)) vs. age-, sex-, and BMI-matched wild-type (Thr/Thr(94)) controls at baseline and after 320-min lipid/heparin-somatostatin-insulin-glucagon clamps (n = 18). Whole body glucose disposal was further investigated (subset; n = 13) using euglycemic-hyperinsulinemic clamps without and with lipid/heparin infusion. In the entire cohort, the only common Ala/Ala(94) mutation was significantly associated with reduced body weight, which is in agreement with a previous report. In lipid-exposed, individually matched subjects there was a genotype vs. lipid-treatment interaction for EGP (P = 0.009) driven mainly by reduced glycogenolysis in Ala/Ala(94) carriers (0.46 +/- 0.05 vs. 0.59 +/- 0.05 mgxkg(-1)xmin(-1), P = 0.013). The lipid-induced elevation of plasma glucose levels was smaller in Ala/Ala(94) carriers compared with wild types (P < 0.0001). Whole body glucose disposal was not different between lipid-exposed L-FABP genotypes. In summary, the Ala/Ala(94)-mutation contributed significantly to reduced glycogenolysis and less severe hyperglycemia in lipid-exposed humans and was further associated with reduced body weight in a large cohort. Data clearly show that investigation of L-FABP phenotypes in the basal overnight-fasted state yielded incomplete information, and a challenge test was essential to detect phenotypical differences in glucose metabolism between L-FABP genotypes.

Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice.

We have disrupted expression of the mitochondrial Friedreich ataxia protein frataxin specifically in murine hepatocytes to generate mice with impaired mitochondrial function and decreased oxidative phosphorylation. These animals have a reduced life span and develop multiple hepatic tumors. Livers also show increased oxidative stress, impaired respiration and reduced ATP levels paralleled by reduced activity of iron-sulfur cluster (Fe/S) containing proteins (ISP), which all leads to increased hepatocyte turnover by promoting both apoptosis and proliferation. Accordingly, phosphorylation of the stress-inducible p38 MAP kinase was found to be specifically impaired following disruption of frataxin. Taken together, these findings indicate that frataxin may act as a mitochondrial tumor suppressor protein in mammals.

Frataxin deficiency in pancreatic islets causes diabetes due to loss of beta cell mass.

Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. We have disrupted expression of the mitochondrial protein frataxin selectively in pancreatic beta cells. Mice were born healthy but subsequently developed impaired glucose tolerance progressing to overt diabetes mellitus. These observations were explained by impairment of insulin secretion due to a loss of beta cell mass in knockout animals. This phenotype was preceded by elevated levels of reactive oxygen species in knockout islets, an increased frequency of apoptosis, and a decreased number of proliferating beta cells. Hence, disruption of the frataxin gene in pancreatic beta cells causes diabetes following cellular growth arrest and apoptosis, paralleled by an increase in reactive oxygen species in islets. These observations might provide insight into the deterioration of beta cell function observed in different subtypes of diabetes in humans.