Long-term effects of high-fat or high-carbohydrate diets on glucose tolerance in mice with heterozygous carnitine palmitoyltransferase-1a deficiency

Background: Abnormal fatty acid metabolism is an important feature in the mechanisms of insulin resistance and β-cell dysfunction. Carnitine palmitoyltransferase-1a (CPT-1a, liver isoform) has a pivotal role in the regulation of mitochondrial fatty acid oxidation. We investigated the role of CPT-1a in the development of impaired glucose tolerance using a mouse model for CPT-1a deficiency when challenged by either a high-carbohydrate (HCD) or a high-fat diet (HFD) for a total duration of up to 46 weeks

β-Cells with Relative Low HIMP1 Overexpression Levels in a Transgenic Mouse Line Enhance Basal Insulin Production and Hypoxia/Hypoglycemia Tolerance

Rodent pancreatic β-cells that naturally lack hypoglycemia/hypoxia inducible mitochondrial protein 1 (HIMP1) are susceptible to hypoglycemia and hypoxia influences. A linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 is suggested in a recent study using transformed β-cells lines. To further illuminate this linkage, we applied mouse insulin 1 gene promoter (MIP) to control HIMP1-a isoform cDNA and have generated three lines (L1 to L3) of heterozygous HIMP1 transgenic (Tg) mice by breeding of three founders with C57BL/6J mice. In HIMP1-Tg mice/islets, we performed quantitative polymerase chain reaction (PCR), immunoblot, histology, and physiology studies to investigate HIMP1 overexpression and its link to β-cell function/survival and body glucose homeostasis. We found that the HIMP1 level increased steadily in β-cells of L1 to L3 heterozygous HIMP1-Tg mice. HIMP1 overexpression at relatively lower levels in L1 heterozygotes results in a negligible decline in blood glucose concentrations and an insignificant elevation in blood insulin levels, while HIMP1 overexpression at higher levels are toxic, causing hyperglycemia in L2/3 heterozygotes. Follow-up studies in 5–30-week-old L1 heterozygous mice/islets found that HIMP1 overexpression at relatively lower levels in β-cells has enhanced basal insulin biosynthesis, basal insulin secretion, and tolerances to low oxygen/glucose influences. The findings enforced the linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 in β-cells, and show a potential value of HIMP1 overexpression at relatively lower levels in modulating β-cell function and survival

Isosteviol Has Beneficial Effects on Palmitate-Induced α-Cell Dysfunction and Gene Expression

BACKGROUND: Long-term exposure to high levels of fatty acids impairs insulin secretion and exaggerates glucagon secretion. The aim of this study was to explore if the antihyperglycemic agent, Isosteviol (ISV), is able to counteract palmitate-induced α-cell dysfunction and to influence α-cell gene expression. METHODOLOGY/PRINCIPAL FINDINGS: Long-term incubation studies with clonal α-TC1-6 cells were performed in the presence of 0.5 mM palmitate with or without ISV. We investigated effects on glucagon secretion, glucagon content, cellular triglyceride (TG) content, cell proliferation, and expression of genes involved in controlling glucagon synthesis, fatty acid metabolism, and insulin signal transduction. Furthermore, we studied effects of ISV on palmitate-induced glucagon secretion from isolated mouse islets. Culturing α-cells for 72-h with 0.5 mM palmitate in the presence of 18 mM glucose resulted in a 56% (p<0.01) increase in glucagon secretion. Concomitantly, the TG content of α-cells increased by 78% (p<0.01) and cell proliferation decreased by 19% (p<0.05). At 18 mM glucose, ISV (10(-8) and 10(-6) M) reduced palmitate-stimulated glucagon release by 27% (p<0.05) and 27% (p<0.05), respectively. ISV (10(-6) M) also counteracted the palmitate-induced hypersecretion of glucagon in mouse islets. ISV (10(-6) M) reduced α-TC1-6 cell proliferation rate by 25% (p<0.05), but ISV (10(-8) and 10(-6) M) had no effect on TG content in the presence of palmitate. Palmitate (0.5 mM) increased Pcsk2 (p<0.001), Irs2 (p<0.001), Fasn (p<0.001), Srebf2 (p<0.001), Acaca (p<0.01), Pax6 (p<0.05) and Gcg mRNA expression (p<0.05). ISV significantly (p<0.05) up-regulated Insr, Irs1, Irs2, Pik3r1 and Akt1 gene expression in the presence of palmitate. CONCLUSIONS/SIGNIFICANCE: ISV counteracts α-cell hypersecretion and apparently contributes to changes in expression of key genes resulting from long-term exposure to palmitate. ISV apparently acts as a glucagonostatic drug with potential as a new anti-diabetic drug for the treatment of type 2 diabetes

Sarcopenic obesity and complex interventions with nutrition and exercise in community-dwelling older persons &ndash; a narrative review

Sabine Goisser,1 Wolfgang Kemmler,2 Simone Porzel,3 Dorothee Volkert,1 Cornel Christian Sieber,1,4 Leo Cornelius Bollheimer,1,4 Ellen Freiberger1 1Institute for Biomedicine of Aging (IBA), Friedrich-Alexander-Universit&auml;t (FAU) Erlangen-N&uuml;rnberg, Nuremberg, 2Institute of Medical Physics (IMP), Friedrich-Alexander-Universit&auml;t (FAU) Erlangen-N&uuml;rnberg, 3Nutricia GmbH, Danone Medical Nutrition, Erlangen, 4Department of Internal Medicine and Geriatrics, St John of God Hospital (Barmherzige Br&uuml;der), Regensburg, Germany Abstract: One of the many threats to independent life is the age-related loss of muscle mass and muscle function commonly referred to as sarcopenia. Another important health risk in old age leading to functional decline is obesity. Obesity prevalence in older persons is increasing, and like sarcopenia, severe obesity has been consistently associated with several negative health outcomes, disabilities, falls, and mobility limitations. Both sarcopenia and obesity pose a health risk for older persons per se, but in combination, they synergistically increase the risk for negative health outcomes and an earlier onset of disability. This combination of sarcopenia and obesity is commonly referred to as sarcopenic obesity. The present narrative review reports the current knowledge on the effects of complex interventions containing nutrition and exercise interventions in community-dwelling older persons with sarcopenic obesity. To date, several complex interventions with different outcomes have been conducted and have shown promise in counteracting either sarcopenia or obesity, but only a few studies have addressed the complex syndrome of sarcopenic obesity. Strong evidence exists on exercise interventions in sarcopenia, especially on strength training, and for obese older persons, strength exercise in combination with a dietary weight loss intervention demonstrated positive effects on muscle function and body fat. The differences in study protocols and target populations make it impossible at the moment to extract data for a meta-analysis or give state-of-the-art recommendations based on reliable evidence. A conclusion that can be drawn from this narrative review is that more exercise programs containing strength and aerobic exercise in combination with dietary interventions including a supervised weight loss program and/or protein supplements should be conducted in order to investigate possible positive effects on sarcopenic obesity. Keywords: sarcopenia, obesity, mobility, nutrition, weight loss diets, exercise, review, function&nbsp

Prevalence of sarcopenia in Germany and the corresponding effect of osteoarthritis in females 70 years and older living in the community: results of the FORMoSA study

Wolfgang Kemmler,1 Marc Teschler,1 Sabine Goisser,2 Michael Bebenek,1 Simon von Stengel,1 Leo Cornelius Bollheimer,2,3 Cornel C Sieber,2,3 Ellen Freiberger2 1Institute of Medical Physics, University of Erlangen-N&uuml;rnberg, Erlangen, Germany; 2Institute for Biomedicine of Aging, University Erlangen-N&uuml;rnberg, N&uuml;rnberg, Germany; 3Department of General Internal Medicine and Geriatrics, St&nbsp;John of God Hospital, Regensburg, GermanyBackground: Although sarcopenia represents a challenging burden for health care systems around the world, its prevalence in the elderly population varies widely. The primary aim of the study was to determine the prevalence of sarcopenia in community-dwelling (CD) German women aged 70 years and older; the secondary aim was to assess the effect of osteoarthritis (OA) on sarcopenia prevalence in this cohort.Methods: A total of 689 Caucasian females 18&ndash;35 years old and 1,325 CD females 70 years+ living in Northern Bavaria, Germany, were assessed during the initial phase of the FORMoSA research project. Anthropometry, total and regional muscle mass, were assessed by segmental multifrequency Bioelectrical Impedance Analysis. Further 10 m walking speed and handgrip strength were evaluated to apply the European Working Group on Sarcopenia in Older People definition of sarcopenia. Covariates were determined by questionnaires and interviews.Results: Applying the algorithm of the European Working Group on Sarcopenia in Older People of two standard deviations below the mean value for appendicular skeletal muscle mass of a reference cohort of the young cohort (5.66 kg/m2), low gait speed (&le;0.8 m/s), and low grip strength (&lt;20 kg), the prevalence of sarcopenia in CD German females 70 years and older was 4.5% (70&ndash;79 years: 2.8% vs &ge;80 years: 9.9%; P&lt;0.001). Participants with OA at the hip and lower limbs (n=252) exhibited significantly higher rates of sarcopenia (OA: 9.1 vs non-OA: 3.5%). Of importance, anthropometric, demographic, health, and lifestyle parameters (except exercise participation) of our cohorts corresponded with Bavarian or German data for CD women 70 years+.Conclusion: The prevalence of sarcopenia in CD German females 70 years+ is relatively low. However, participants with OA at the hip or lower limbs were at increased risk for sarcopenia.Keywords: sarcopenia, prevalence, osteoarthritis, German

The balance between proinsulin biosynthesis and insulin secretion: where can imbalance lead?

Insulin is stored in pancreatic beta-cells in beta-granules. Whenever insulin is secreted in response to a nutrient secretagogue, there is a complementary increase in proinsulin biosynthesis to replenish intracellular insulin stores. This specific nutrient regulation of proinsulin biosynthesis is predominately regulated at the translational level. Recently, a highly conserved cis-element in the 5'-untranslated region (UTR) of preproinsulin mRNA, named ppIGE, has been identified that is required for specific translational regulation of proinsulin biosynthesis. This ppIGE is also found in the 5'-UTR of certain other translationally regulated beta-granule protein mRNAs, including the proinsulin processing endopeptidases, PC1/3 and PC2. This provides a mechanism whereby proinsulin processing is adaptable to changes in proinsulin biosynthesis. However, relatively few b-granules undergo secretion, with most remaining in the storage pool for similar to 5 days. Aged b-granules are retired by intracellular degradation mechanisms, either via crinophagy and/or autophagy, as another long-term means of maintaining beta-granule stores at optimal levels. When a disconnection between insulin production and secretion arises, as may occur in type 2 diabetes, autophagy further increases to maintain beta-granule numbers. However, if this increased autophagy becomes chronic, autophagia-mediated cell death occurs that could then contribute to beta-cell loss in type 2 diabetes